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Research Publications

Browse scientific publications from the NIH-funded RDCRN network and its 19 consortia or research teams to find information about rare disease research and read rare disease publications. Publications are sorted by consortium and year.

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Beslow LA, Kim H, Hetts SW, Ratjen F, Clancy MS, Gossage JR, Faughnan ME. Brain and lung arteriovenous malformation rescreening practices for children and adults with hereditary hemorrhagic telangiectasia. Orphanet J Rare Dis. 2024 Nov 9;19(1):421. doi: 10.1186/s13023-024-03402-8. PMID: 39522006; PMCID: PMC11549847.

Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder of the blood vessels that can cause excessive bleeding. Patients with HHT are at risk for organ vascular malformations, including arteriovenous malformations (AVMs) in the brain and lungs. Although HHT guidelines recommend initial screening in children and adults, rescreening is not consistently addressed.

In this study, researchers determined current rescreening practices for brain and lung AVMs in children and adults with HHT. The team surveyed 30 North American HHT Centers of Excellence on rescreening practices for new brain and lung AVMs in patients with initial negative screening.

Results show that most HHT Centers of Excellence routinely rescreen children for brain and lung AVMs and adults for lung AVMs when initial screening is negative. However, adults are infrequently rescreened for brain AVMs. Authors note that long-term data regarding risk for new brain and lung AVMs are required to establish practice guidelines for rescreening.

Juhász C, Behen ME, Gjolaj N, Luat AF, Xuan Y, Jeong JW. Feasibility and Potential Diagnostic Value of Noncontrast Brain MRI in Nonsedated Children With Sturge-Weber Syndrome and Healthy Siblings. J Child Neurol. 2024 Aug;39(9-10):343-353. doi: 10.1177/08830738241272064. Epub 2024 Aug 23.

Beslow LA, Krings T, Kim H, Hetts SW, Lawton MT, Ratjen F, Whitehead KJ, Gossage JR, McCulloch CE, Clancy M, Bagheri N, Faughnan ME. De Novo Brain Vascular Malformations in Hereditary Hemorrhagic Telangiectasia. Pediatr Neurol. 2024 Jun;155:120-125. doi: 10.1016/j.pediatrneurol.2024.03.013. Epub 2024 Mar 22. PMID: 38631080; PMCID: PMC11102835.

Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder of the blood vessels that can cause excessive bleeding. About 10% of individuals with HHT have brain vascular malformations, which occur when the blood vessels in the brain develop abnormally. Children with HHT are screened for brain vascular malformations upon initial diagnosis, and many North American centers rescreen children for brain vascular malformations at interval throughout childhood. However, not much is known about whether people with HHT can develop new brain vascular malformations over time.

In this study, researchers investigated the formation of new brain vascular malformations in patients with HHT. The team analyzed data from 1,909 patients enrolled in the Brain Vascular Malformation Consortium natural history study, searching for brain vascular malformations that were new since previous imaging was performed.

Results showed that 409 patients had brain vascular malformations, with three showing new malformations confirmed by neuroimaging review. These findings demonstrate that patients with HHT can form new brain vascular malformations over time, though this is probably a rare occurrence. Authors note that more information about the frequency of new brain vascular malformation formation is needed.

Frias-Anaya E, Gallego-Gutierrez H, Gongol B, Weinsheimer S, Lai CC, Orecchioni M, Sriram A, Bui CM, Nelsen B, Hale P, Pham A, Shenkar R, DeBiasse D, Lightle R, Girard R, Li Y, Srinath A, Daneman R, Nudleman E, Sun H, Guma M, Dubrac A, Mesarwi OA, Ley K, Kim H, Awad IA, Ginsberg MH, Lopez-Ramirez MA. Mild Hypoxia Accelerates Cerebral Cavernous Malformation Disease Through CX3CR1-CX3CL1 Signaling. Arterioscler Thromb Vasc Biol. 2024 Jun;44(6):1246-1264. doi: 10.1161/ATVBAHA.123.320367. Epub 2024 Apr 25.

Beslow LA, Vossough A, Kim H, Nelson J, Lawton MT, Pollak J, Lin DDM, Ratjen F, Hammill AM, Hetts SW, Gossage JR, Whitehead KJ, Faughnan ME, Krings T; Brain Vascular Malformation Consortium HHT Investigator Group. Brain AVM compactness score in children with hereditary hemorrhagic telangiectasia. Childs Nerv Syst. 2024 Mar 22. doi: 10.1007/s00381-024-06366-z. Online ahead of print.

Jeong JW, Lee MH, Luat AF, Xuan Y, Haacke EM, Juhász C. Quantification of enlarged deep medullary vein volumes in Sturge-Weber syndrome. Quant Imaging Med Surg. 2024 Feb 1;14(2):1916-1929. doi: 10.21037/qims-23-1271. Epub 2024 Jan 23. PMID: 38415136; PMCID: PMC10895099.

Sturge-Weber syndrome (SWS) is a condition resulting in abnormal blood vessel formation in the brain, eyes, and skin at birth. In patients with SWS, enlarged deep medullary veins—mostly located in the white matter in the brain—may form early and can expand during the first years of life to provide compensatory collateral venous drainage of brain regions affected by leptomeningeal venous malformations localized on the brain surface.

The extent of enlarged deep veins during the early SWS disease course could be an imaging marker of this deep venous remodeling in an attempt to compensate for impaired brain surface venous blood flow. In this prospective imaging study, researchers used brain magnetic resonance imaging (MRI) to develop and optimize a quantitative approach to measure deep vein volumes in the affected brain of young patients with SWS and compare the findings to those of their healthy siblings. 

By combining two types of MRI (susceptibility-weighted imaging and volumetric T1 images), the authors were able to measure the volumes of deep veins, which were 10-12 fold higher than venous volumes in their healthy siblings. Greater deep vein volumes were associated with lower cortical surface area of the affected hemisphere, a measure of cortical atrophy. This new analytic approach of brain MRI can provide an objective way to assess the extent of deep venous remodeling in SWS and other disorders affecting the medullary veins of the brain.

Cheng HC, Faughnan ME, terBrugge KG, Liu HM, Krings T; Brain Vascular Malformation Consortium Hereditary Hemorrhagic Telangiectasia Investigator Group. Prevalence and Characteristics of Intracranial Aneurysms in Hereditary Hemorrhagic Telangiectasia. AJNR Am J Neuroradiol. 2023 Dec 11;44(12):1367-1372. doi: 10.3174/ajnr.A8058. PMID: 38050014; PMCID: PMC10714847.

Kim SJW, Lupo JM, Chen Y, Pampaloni MH, VanBrocklin HF, Narvid J, Kim H, Seo Y. A feasibility study for quantitative assessment of cerebrovascular malformations using flutriciclamide ([(18)F]GE-180) PET/MRI. Front Med (Lausanne). 2023 Apr 5;10:1091463. doi: 10.3389/fmed.2023.1091463. eCollection 2023.

Kilian A, Latino GA, White AJ, Ratjen F, McDonald J, Whitehead KJ, Gossage JR, Krings T, Lawton MT, Kim H, Faughnan ME, The Brain Vascular Malformation Consortium Hht Investigator Group. Comparing Characteristics and Treatment of Brain Vascular Malformations in Children and Adults with HHT. J Clin Med. 2023 Apr 4;12(7):2704. doi: 10.3390/jcm12072704.

Cannavicci A, Zhang Q, Kutryk MJB. The Potential Role of MiRs-139-5p and -454-3p in Endoglin-Knockdown-Induced Angiogenic Dysfunction in HUVECs. Int J Mol Sci. 2023 Mar 3;24(5):4916. doi: 10.3390/ijms24054916.

Weinsheimer S, Nelson J, Abla AA, Ko NU, Tsang C, Okoye O, Zabramski JM, Akers A, Zafar A, Mabray MC, Hart BL, Morrison L, McCulloch CE, Kim H; Brain Vascular Malformation Consortium Cerebral Cavernous Malformation Investigator Group. Intracranial Hemorrhage Rate and Lesion Burden in Patients With Familial Cerebral Cavernous Malformation. J Am Heart Assoc. 2023 Feb 7;12(3):e027572. doi: 10.1161/JAHA.122.027572. Epub 2023 Jan 25. PMID: 36695309; PMCID: PMC9973654.

Familial cerebral cavernous malformation (CCM) is an inherited disease characterized by abnormally enlarged spaces in the brain where blood collects near irregularly shaped, enlarged capillaries (tiny blood vessels) which have abnormally thin walls prone to leaking. CCM can cause intracranial hemorrhage (ICH), which can lead to death or long-term neurological damage. However, few studies have focused on ICH rates and risk factors in familial CCM.

In this study, researchers report ICH rates and assess whether CCM lesion burden—a disease severity marker—is associated with risk of symptomatic ICH in familial CCM. The team studied 386 patients with familial CCM with follow‐up data enrolled in the Brain Vascular Malformation Consortium CCM Project.

Results show that patients with familial CCM with a prior history of an ICH event are at higher risk for rehemorrhage during follow‐up. In addition, CCM lesion burden is significantly associated with an increased risk of subsequent symptomatic ICH. Authors note that these findings demonstrate the importance of lesion burden as a predictor of patient outcomes, which can also help to assess patient risk.

Juhász C, Luat AF, Behen ME, Gjolaj N, Jeong JW, Chugani HT, Kumar A. Deep Venous Remodeling in Unilateral Sturge-Weber Syndrome: Robust Hemispheric Differences and Clinical Correlates. Pediatr Neurol. 2023 Feb;139:49-58. doi: 10.1016/j.pediatrneurol.2022.11.011. Epub 2022 Nov 25. PMID: 36521316; PMCID: PMC9840672.

Sturge-Weber syndrome (SWS) is a condition resulting in abnormal blood vessel development in the brain, eyes, and skin at birth. In patients with SWS, enlarged deep medullary veins (EDMVs)—located in the white matter in the brain—could allow for drainage of brain regions affected by leptomeningeal venous malformations (LVM), a type of vascular malformation of the brain. In this study, researchers evaluated the prevalence, extent, hemispheric differences, and clinical correlates of EDMVs in SWS. Fifty children with SWS underwent brain magnetic resonance imaging that included susceptibility weighted imaging, as well as neurocognitive evaluations. The team then assessed the extent of EDMVs, comparing between patients with right and left hemispheric SWS. Results show that EDMVs are common in SWS. For patients with right hemispheric SWS, extensive EDMVs appear to develop more commonly and earlier than in left hemispheric SWS. Authors note that deep venous remodeling may contribute to better clinical outcomes in some patients with SWS.

Yeom S, Comi AM. Updates on Sturge-Weber Syndrome. Stroke. 2022 Dec;53(12):3769-3779. doi: 10.1161/STROKEAHA.122.038585. Epub 2022 Oct 20.

Galeffi F, Snellings DA, Wetzel-Strong SE, Kastelic N, Bullock J, Gallione CJ, North PE, Marchuk DA. A novel somatic mutation in GNAQ in a capillary malformation provides insight into molecular pathogenesis. Angiogenesis. 2022 May 30. doi: 10.1007/s10456-022-09841-w. Epub ahead of print. PMID: 35635655.

Sturge-Weber syndrome (SWS) is a condition resulting in abnormal blood vessel development in the brain, eyes, and skin at birth. A hallmark feature is capillary malformation, also known as a port-wine birthmark (a red, pink, or purple facial birthmark). SWS and capillary malformations are both caused by mutations in the GNAQ gene. In this study, researchers sequenced skin biopsies of capillary malformations from nine patients. They identified the same type of GNAQ mutation (R183Q) in nearly all samples. However, one sample exhibited a new type of GNAQ mutation (Q209R). To explore its effects, the team compared this new mutation with other GNAQ mutations. The authors found that although the different mutations varied in signaling strength, they all had the same effects in cells. Since some of these same mutations are also found in cancer, pharmaceutical companies are working on inhibiting the effects of this gene. Thus, drugs that may work for certain cancers with GNAQ mutations may also work for SWS.

Ananiadis T, Faughnan ME, Clark D, Prabhudesai V, Kim H, Lawton MT, Vozoris NT; Brain Vascular Malformation Consortium HHT Investigator Group. Neurovascular Complications and Pulmonary Arteriovenous Malformation Feeding Artery Size. Ann Am Thorac Soc. 2022 Apr 20. doi: 10.1513/AnnalsATS.202202-130RL. Online ahead of print.

Winkler E, Wu D, Gil E, McCoy D, Narsinh K, Sun Z, Mueller K, Ross J, Kim H, Weinsheimer S, Berger M, Nowakowski T, Lim D, Abla A, Cooke D. Endoluminal Biopsy for Molecular Profiling of Human Brain Vascular Malformations. Neurology. 2022 Apr 19;98(16):e1637-e1647. doi: 10.1212/WNL.0000000000200109. Epub 2022 Feb 10.

Cannavicci A, Zhang Q, Faughnan ME, Kutryk MJB. MicroRNA-132-3p, Downregulated in Myeloid Angiogenic Cells from Hereditary Hemorrhagic Telangiectasia Patients, Is Enriched in the TGFβ and PI3K/AKT Signalling Pathways. Genes (Basel). 2022 Apr 9;13(4):665. doi: 10.3390/genes13040665.

Winkler EA, Kim CN, Ross JM, Garcia JH, Gil E, Oh I, Chen LQ, Wu D, Catapano JS, Raygor K, Narsinh K, Kim H, Weinsheimer S, Cooke DL, Walcott BP, Lawton MT, Gupta N, Zlokovic BV, Chang EF, Abla AA, Lim DA, Nowakowski TJ. A single-cell atlas of the normal and malformed human brain vasculature. Science. 2022 Mar 4;375(6584):eabi7377. doi: 10.1126/science.abi7377. Epub 2022 Mar 4.

Sheth KN, Anderson CD, Biffi A, Dlamini N, Falcone GJ, Fox CK, Fullerton HJ, Greenberg SM, Hemphill JC, Kim A, Kim H, Ko NU, Roland JL, Sansing LH, van Veluw SJ, Rosand J. Maximizing Brain Health After Hemorrhagic Stroke: Bugher Foundation Centers of Excellence. Stroke. 2022 Mar;53(3):1020-1029. doi: 10.1161/STROKEAHA.121.036197. Epub 2022 Feb 3.

Cardinell JL, Ramjist JM, Chen C, Shi W, Nguyen NQ, Yeretsian T, Choi M, Chen D, Clark DS, Curtis A, Kim H, Faughnan ME, Yang VXD; Brain Vascular Malformation Consortium HHT Investigator Group. Quantification metrics for telangiectasia using optical coherence tomography. Sci Rep. 2022 Feb 2;12(1):1805. doi: 10.1038/s41598-022-05272-1.

Narsinh KH, Paez R, Mueller K, Caton MT, Baker A, Higashida RT, Halbach VV, Dowd CF, Amans MR, Hetts SW, Norbash AM, Cooke DL. Robotics for neuroendovascular intervention: Background and primer. Neuroradiol J. 2022 Feb;35(1):25-35. doi: 10.1177/19714009211034829. Epub 2021 Aug 16.

Gill RE, Tang B, Smegal L, Adamek JH, McAuliffe D, Lakshmanan BM, Srivastava S, Quain AM, Sebold AJ, Lin DDM, Kossoff EH, Caffo B, Comi AM, Ewen JB. Quantitative EEG improves prediction of Sturge-Weber syndrome in infants with port-wine birthmark. Clin Neurophysiol. 2021 Oct;132(10):2440-2446. doi: 10.1016/j.clinph.2021.06.030. Epub 2021 Aug 5.

Thompson KP, Nelson J, Kim H, Weinsheimer SM, Marchuk DA, Lawton MT, Krings T, Faughnan ME; Brain Vascular Malformation Consortium HHT Investigator Group. Utility of modified Rankin Scale for brain vascular malformations in hereditary hemorrhagic telangiectasia. Orphanet J Rare Dis. 2021 Sep 19;16(1):390. doi: 10.1186/s13023-021-02012-y.

Choksi F, Weinsheimer S, Nelson J, Pawlikowska L, Fox CK, Zafar A, Mabray MC, Zabramski J, Akers A, Hart BL, Morrison L, McCulloch CE, Kim H. Assessing the association of common genetic variants in EPHB4 and RASA1 with phenotype severity in familial cerebral cavernous malformation. Mol Genet Genomic Med. 2021 Sep 7:e1794. doi: 10.1002/mgg3.1794. Online ahead of print.

Cerebral cavernous malformations (CCMs) are collections of small blood vessels in the brain that are enlarged and irregular in structure, leading to altered blood flow. While approximately 25 percent of individuals with CCMs never experience any related medical problems, other people with CCMs may experience serious symptoms such as headaches, seizures, paralysis, hearing or vision deficiencies, and cerebral hemorrhage. In addition to lesions in the brain, familial cases have lesions present on the skin. Interestingly, similar appearing skin lesions have been reported in another inherited vascular disease called capillary malformation-arteriovenous malformation (CM-AVM), which is caused by mutations in RASA1 and EPHB4. In this study, researchers investigated whether common variants in the EPHB4 and RASA1 genes are associated with familial CCM disease severity, including intracranial hemorrhage (ICH), total lesions, and large lesion counts. They found that EPHB4 variants were not associated with CCM severity, but a common RASA1 variant may be associated with ICH and large lesion count. These findings could improve understanding of the natural history of CCM, leading to better predictions of disease course and new medical therapies for treatment.

Wetzel-Strong SE, Weinsheimer S, Nelson J, Pawlikowska L, Clark D, Starr MD, Liu Y, Kim H, Faughnan ME, Nixon AB, Marchuk DA. Pilot investigation of circulating angiogenic and inflammatory biomarkers associated with vascular malformations. Orphanet J Rare Dis. 2021 Sep 3;16(1):372. doi: 10.1186/s13023-021-02009-7.

Vascular malformations are growths composed of blood vessels involving arteries, veins, capillaries, and lymphatics. Patients with vascular malformations in the central nervous system may experience a range of debilitating or life-threatening symptoms including seizures, headaches, and increased risk of cerebral hemorrhage. Due to their inaccessible location, these malformations are difficult to monitor and treat. Therefore, biomarkers from a non-invasive tissue source, such as blood, may aid in predicting disease severity and outcomes. In this study, researchers compared circulating biomarker levels in plasma from patients with sporadic brain arteriovenous malformation (BAVM), familial cerebral cavernous malformations (CCM), and hereditary hemorrhagic telangiectasia (HHT). They found that biomarkers may be unique to each type of vascular malformation, indicating potential usefulness in assessing phenotypic traits of vascular malformations.

Fox CK, Nelson J, McCulloch CE, Weinsheimer S, Pawlikowska L, Hart B, Mabray M, Zafar A, Morrison L, Zabramski JM, Akers A, Kim H. Seizure Incidence Rates in Children and Adults With Familial Cerebral Cavernous Malformations. Neurology. 2021 Aug 13;97(12):e1210-6. doi: 10.1212/WNL.0000000000012569. Online ahead of print.

Sabeti S, Ball KL, Bhattacharya SK, Bitrian E, Blieden LS, Brandt JD, Burkhart C, Chugani HT, Falchek SJ, Jain BG, Juhasz C, Loeb JA, Luat A, Pinto A, Segal E, Salvin J, Kelly KM. Consensus Statement for the Management and Treatment of Sturge-Weber Syndrome: Neurology, Neuroimaging, and Ophthalmology Recommendations. Pediatr Neurol. 2021 Aug;121:59-66. doi: 10.1016/j.pediatrneurol.2021.04.013. Epub 2021 May 6.

Keränen S, Suutarinen S, Mallick R, Laakkonen JP, Guo D, Pawlikowska L, Jahromi BR, Rauramaa T, Ylä-Herttuala S, Marchuk D, Krings T, Koivisto T, Lawton M, Radovanovic I, Kim H, Faughnan ME, Frösen J. Cyclo-oxygenase 2, a putative mediator of vessel remodeling, is expressed in the brain AVM vessels and associates with inflammation. Acta Neurochir (Wien). 2021 Sep;163(9):2503-2514. doi: 10.1007/s00701-021-04895-z. Epub 2021 Jun 29.

Brain ateriovenous malformations (bAVM) are rare vascular anomalies that may bleed causing epilepsy, neurological deficits, or death. Cyclo-oxygenase-2 (COX2) is an enzyme that plays a key role in promoting inflammation. Researchers examined tissue samples from surgery of 139 patients with bAVMs and compared them to 21 normal samples. They were seeking to determine if COX2 is expressed in bAVMs and whether it associates with inflammation and hemorrhage in these lesions. They concluded that COX2 is induced in bAVMs, and possibly participates in the regulation of vessel wall remodeling and ongoing inflammation. Authors suggest that COX2 may be a target for drug therapy stabilizing bAVMs.  

Mirza MH, Schwertner A, Kohlbrenner R, Dowd CF, Narsinh KH. Intracranial hemorrhage due to central venous occlusion from hemodialysis access: A case report. Interdiscip Neurosurg. 2021 Jun;24:101081. doi: 10.1016/j.inat.2020.101081. Epub 2021 Jan 4.

Narsinh KH, Caton MT, Mahmood NF, Higashida RT, Halbach VV, Hetts SW, Amans MR, Dowd CF, Cooke DL. Intrasaccular flow disruption (WEB) of a large wide-necked basilar apex aneurysm using PulseRider-assistance. Interdiscip Neurosurg. 2021 Jun;24:101072. doi: 10.1016/j.inat.2020.101072. Epub 2020 Dec 29.

Smegal LF, Sebold AJ, Hammill AM, Juhász C, Lo WD, Miles DK, Wilfong AA, Levin AV, Fisher B, Ball KL, Pinto AL, Comi AM; National Institutes of Health Sponsor: Rare Disease Clinical Research Consortium (RDCRN) Brain Vascular Malformation Consortium (BVMC) SWS Investigator Group. Multicenter Research Data of Epilepsy Management in Patients With Sturge-Weber Syndrome. Pediatr Neurol. 2021 Jun;119:3-10. doi: 10.1016/j.pediatrneurol.2021.02.006. Epub 2021 Mar 5.

Zhang Q, Wang C, Cannavicci A, Faughnan ME, Kutryk MJB. Endoglin deficiency impairs VEGFR2 but not FGFR1 or TIE2 activation and alters VEGF-mediated cellular responses in human primary endothelial cells. Transl Res. 2021 Sep;235:129-143. doi: 10.1016/j.trsl.2021.04.005. Epub 2021 Apr 22.

Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder of the blood vessels that can cause excessive bleeding. People with HHT can develop abnormal blood vessels called arteriovenous malformations (AVMs) in several areas of the body, including the skin, brain, lungs, liver, or intestines. Endoglin (ENG) is one of the genes commonly mutated in this autosomal dominant disease. In this study, researchers sought to investigate the interplay of the ENG gene with several other genes in endothelial cells. They found that ENG deficiency alters the vascular endothelial growth factor (VEGF)/VEGFR2 pathway, which may play a role in the development of HHT.

Narsinh KH, Kilbride BF, Mueller K, Murph D, Copelan A, Massachi J, Vitt J, Sun CH, Bhat H, Amans MR, Dowd CF, Halbach VV, Higashida RT, Moore T, Wilson MW, Cooke DL, Hetts SW. Combined Use of X-ray Angiography and Intraprocedural MRI Enables Tissue-based Decision Making Regarding Revascularization during Acute Ischemic Stroke Intervention. Radiology. 2021 Apr;299(1):167-176. doi: 10.1148/radiol.2021202750. Epub 2021 Feb 9.

Thorpe J, Frelin LP, McCann M, Pardo CA, Cohen BA, Comi AM, Pevsner J. Identification of a Mosaic Activating Mutation in GNA11 in Atypical Sturge-Weber Syndrome. J Invest Dermatol. 2021 Mar;141(3):685-688. doi: 10.1016/j.jid.2020.03.978. Epub 2020 Aug 7.

Sebold AJ, Day AM, Ewen J, Adamek J, Byars A, Cohen B, Kossoff EH, Mizuno T, Ryan M, Sievers J, Smegal L, Suskauer SJ, Thomas C, Vinks A, Zabel TA, Hammill AM, Comi AM. Sirolimus Treatment in Sturge-Weber Syndrome. Pediatr Neurol. 2021 Feb;115:29-40. doi: 10.1016/j.pediatrneurol.2020.10.013. Epub 2020 Nov 2.

Hart BL, Mabray MC, Morrison L, Whitehead KJ, Kim H. Systemic and CNS manifestations of inherited cerebrovascular malformations. Clin Imaging. 2021 Jul;75:55-66. doi: 10.1016/j.clinimag.2021.01.020. Epub 2021 Jan 20.

Review paper examines imaging and clinical features of cerebrovascular malformations with a genetic basis, summarizing the current state of knowledge of these conditions, salient features regarding mechanisms of development, and treatment prospects.

Thompson KP, Nelson J, Kim H, Pawlikowska L, Marchuk DA, Lawton MT, Faughnan ME; Brain Vascular Malformation Consortium HHT Investigator Group. Predictors of mortality in patients with hereditary hemorrhagic telangiectasia. Orphanet J Rare Dis. 2021 Jan 6;16(1):12. doi: 10.1186/s13023-020-01579-2.

Ross JM, Kim C, Allen D, Crouch EE, Narsinh K, Cooke DL, Abla AA, Nowakowski TJ, Winkler EA. The Expanding Cell Diversity of the Brain Vasculature. Front Physiol. 2020 Dec 3;11:600767. doi: 10.3389/fphys.2020.600767. eCollection 2020.

Narsinh KH, Mueller K, Nelson J, Massachi J, Murph DC, Copelan AZ, Hetts SW, Halbach VV, Higashida RT, Abla AA, Amans MR, Dowd CF, Kim H, Cooke DL. Interrater Reliability in the Measurement of Flow Characteristics on Color-Coded Quantitative DSA of Brain AVMs. AJNR Am J Neuroradiol. 2020 Dec;41(12):2303-2310. doi: 10.3174/ajnr.A6846. Epub 2020 Oct 29.

Copelan AZ, Smith ER, Drocton GT, Narsinh KH, Murph D, Khangura RS, Hartley ZJ, Abla AA, Dillon WP, Dowd CF, Higashida RT, Halbach VV, Hetts SW, Cooke DL, Keenan K, Nelson J, Mccoy D, Ciano M, Amans MR. Recent Administration of Iodinated Contrast Renders Core Infarct Estimation Inaccurate Using RAPID Software. AJNR Am J Neuroradiol. 2020 Dec;41(12):2235-2242. doi: 10.3174/ajnr.A6908. Epub 2020 Nov 19.

Isikbay M, Narsinh KH, Arroyo S, Smith WS, Cooke DL, Higashida RT, Amans MR. Computed tomography perfusion abnormalities after carotid endarterectomy help in the diagnosis of reversible cerebral vasoconstriction syndrome. J Vasc Surg Cases Innov Tech. 2020 Oct 27;7(1):171-175. doi: 10.1016/j.jvscit.2020.10.010. eCollection 2021 Mar.

Cannavicci A, Zhang Q, Kutryk MJB. Non-Coding RNAs and Hereditary Hemorrhagic Telangiectasia. J Clin Med. 2020 Oct 17;9(10):3333. doi: 10.3390/jcm9103333.

Copelan A, Drocton G, Caton MT, Smith ER, Cooke DL, Nelson J, Abla AA, Fox C, Amans MR, Dowd CF, Halbach VV, Higashida RT, Lawton MT, Kim H, Fullerton HJ, Gupta N, Hetts SW; UCSF Center For Cerebrovascular Research and UCSF Pediatric Brain Center. Brain Arteriovenous Malformation Recurrence After Apparent Microsurgical Cure: Increased Risk in Children Who Present With Arteriovenous Malformation Rupture. Stroke. 2020 Oct;51(10):2990-2996. doi: 10.1161/STROKEAHA.120.030135. Epub 2020 Sep 11.

Morshed RA, Abla AA, Murph D, Dao JM, Winkler EA, Burkhardt JK, Colao K, Hetts SW, Fullerton HJ, Lawton MT, Gupta N, Fox CK. Clinical outcomes after revascularization for pediatric moyamoya disease and syndrome: A single-center series. J Clin Neurosci. 2020 Sep;79:137-143. doi: 10.1016/j.jocn.2020.07.016. Epub 2020 Aug 19.

Kilian A, Latino GA, White AJ, Clark D, Chakinala MM, Ratjen F, McDonald J, Whitehead K, Gossage JR, Lin D, Henderson K, Pollak J, McWilliams JP, Kim H, Lawton MT, Faughnan ME; the Brain Vascular Malformation Consortium HHT Investigator Group. Genotype-Phenotype Correlations in Children with HHT. J Clin Med. 2020 Aug 22;9(9):2714. doi: 10.3390/jcm9092714.

Mabray MC, Caprihan A, Nelson J, McCulloch CE, Zafar A, Kim H, Hart BL, Morrison L. Effect of Simvastatin on Permeability in Cerebral Cavernous Malformation Type 1 Patients: Results from a Pilot Small Randomized Controlled Clinical Trial. Transl Stroke Res. 2020 Jun;11(3):319-321. doi: 10.1007/s12975-019-00737-4. Epub 2019 Oct 23.

Mabray MC, Starcevich J, Hallstrom J, Robinson M, Bartlett M, Nelson J, Zafar A, Kim H, Morrison L, Hart BL. High Prevalence of Spinal Cord Cavernous Malformations in the Familial Cerebral Cavernous Malformations Type 1 Cohort. AJNR Am J Neuroradiol. 2020 Jun;41(6):1126-1130. doi: 10.3174/ajnr.A6584. Epub 2020 May 28.

Polster SP, Sharma A, Tanes C, Tang AT, Mericko P, Cao Y, Carrión-Penagos J, Girard R, Koskimäki J, Zhang D, Stadnik A, Romanos SG, Lyne SB, Shenkar R, Yan K, Lee C, Akers A, Morrison L, Robinson M, Zafar A, Bittinger K, Kim H, Gilbert JA, Kahn ML, Shen L, Awad IA. Permissive microbiome characterizes human subjects with a neurovascular disease cavernous angioma. Nat Commun. 2020 May 27;11(1):2659. doi: 10.1038/s41467-020-16436-w.

Manole AK, Forrester VJ, Zlotoff BJ, Hart BL, Morrison LA. Cutaneous findings of familial cerebral cavernous malformation syndrome due to the common Hispanic mutation. Am J Med Genet A. 2020 May;182(5):1066-1072. doi: 10.1002/ajmg.a.61519. Epub 2020 Feb 26.

Campbell R, Petranovich CL, Cheek S, Morrison L, Hart B. Subjective Cognitive Concerns and Attitudes toward Genetic Testing Are Associated with Depressive Symptoms and Quality of Life after Genetic Testing for the Cerebral Cavernous Malformation Common Hispanic Mutation (CCM1). J Behav Brain Sci. 2020 Feb;10(2):118-127. doi: 10.4236/jbbs.2020.102007. Epub 2020 Feb 25.

Tandberg SR, Bocklage T, Bartlett MR, Morrison LA, Nelson J, Hart BL. Vertebral Intraosseous Vascular Malformations in a Familial Cerebral Cavernous Malformation Population: Prevalence, Histologic Features, and Associations With CNS Disease. AJR Am J Roentgenol. 2020 Feb;214(2):428-436. doi: 10.2214/AJR.19.21492. Epub 2019 Dec 11.

Choquet H, Kim H. Genome-wide Genotyping of Cerebral Cavernous Malformation Type 1 Individuals to Identify Genetic Modifiers of Disease Severity. Methods Mol Biol. 2020;2152:77-84. doi: 10.1007/978-1-0716-0640-7_6.

Shirali AS, Lluri G, Guihard PJ, Conrad MB, Kim H, Pawlikowska L, Boström KI, Iruela-Arispe ML, Aboulhosn JA. Angiopoietin-2 predicts morbidity in adults with Fontan physiology. Sci Rep. 2019 Dec 4;9(1):18328. doi: 10.1038/s41598-019-54776-w.

Harmon KA, Day AM, Hammill AM, Pinto AL, McCulloch CE, Comi AM; National Institutes of Health Rare Disease Clinical Research Consortium (RDCRN) Brain and Vascular Malformation Consortium (BVMC) SWS Investigator Group. Quality of Life in Children With Sturge-Weber Syndrome. Pediatr Neurol. 2019 Dec;101:26-32. doi: 10.1016/j.pediatrneurol.2019.04.004. Epub 2019 Apr 24.

Cho S, Maharathi B, Ball KL, Loeb JA, Pevsner J. Sturge-Weber Syndrome Patient Registry: Delayed Diagnosis and Poor Seizure Control. J Pediatr. 2019 Dec;215:158-163.e6. doi: 10.1016/j.jpeds.2019.08.025. Epub 2019 Oct 3.

Tang AT, Sullivan KR, Hong CC, Goddard LM, Mahadevan A, Ren A, Pardo H, Peiper A, Griffin E, Tanes C, Mattei LM, Yang J, Li L, Mericko-Ishizuka P, Shen L, Hobson N, Girard R, Lightle R, Moore T, Shenkar R, Polster SP, Roedel CJ, Li N, Zhu Q, Whitehead KJ, Zheng X, Akers A, Morrison L, Kim H, Bittinger K, Lengner CJ, Schwaninger M, Velcich A, Augenlicht L, Abdelilah-Seyfried S, Min W, Marchuk DA, Awad IA, Kahn ML. Distinct cellular roles for PDCD10 define a gut-brain axis in cerebral cavernous malformation. Sci Transl Med. 2019 Nov 27;11(520):eaaw3521. doi: 10.1126/scitranslmed.aaw3521.

Day AM, McCulloch CE, Hammill AM, Juhász C, Lo WD, Pinto AL, Miles DK, Fisher BJ, Ball KL, Wilfong AA, Levin AV, Thau AJ, Comi AM; National Institute of Health Sponsor: Rare Disease Clinical Research Consortium (RDCRN) Brain and Vascular Malformation Consortium (BVMC) SWS Investigator Group, Koenig JI, Lawton MT, Marchuk DA, Moses MA, Freedman SF, Pevsner J. Physical and Family History Variables Associated With Neurological and Cognitive Development in Sturge-Weber Syndrome. Pediatr Neurol. 2019 Jul;96:30-36. doi: 10.1016/j.pediatrneurol.2018.12.002. Epub 2018 Dec 20.

Cannavicci A, Zhang Q, Dai SC, Faughnan ME, Kutryk MJB. Decreased levels of miR-28-5p and miR-361-3p and increased levels of insulin-like growth factor 1 mRNA in mononuclear cells from patients with hereditary hemorrhagic telangiectasia (1). Can J Physiol Pharmacol. 2019 Jun;97(6):562-569. doi: 10.1139/cjpp-2018-0508. Epub 2018 Dec 4.

Zafar A, Quadri SA, Farooqui M, Ikram A, Robinson M, Hart BL, Mabray MC, Vigil C, Tang AT, Kahn ML, Yonas H, Lawton MT, Kim H, Morrison L. Familial Cerebral Cavernous Malformations. Stroke. 2019 May;50(5):1294-1301. doi: 10.1161/STROKEAHA.118.022314.

Wellman RJ, Cho SB, Singh P, Tune M, Pardo CA, Comi AM; BVMC Sturge–Weber syndrome Project Workgroup. Gαq and hyper-phosphorylated ERK expression in Sturge-Weber syndrome leptomeningeal blood vessel endothelial cells. Vasc Med. 2019 Feb;24(1):72-75. doi: 10.1177/1358863X18786068. Epub 2018 Aug 16.

Klostranec JM, Chen L, Mathur S, McDonald J, Faughnan ME, Ratjen F, Krings T. A theory for polymicrogyria and brain arteriovenous malformations in HHT. Neurology. 2019 Jan 1;92(1):34-42. doi: 10.1212/WNL.0000000000006686.

Day AM, Hammill AM, Juhász C, Pinto AL, Roach ES, McCulloch CE, Comi AM; National Institutes of Health Sponsor: Rare Diseases Clinical Research Network (RDCRN) Brain and Vascular Malformation Consortium (BVMC) SWS Investigator Group. Hypothesis: Presymptomatic treatment of Sturge-Weber Syndrome With Aspirin and Antiepileptic Drugs May Delay Seizure Onset. Pediatr Neurol. 2019 Jan;90:8-12. doi: 10.1016/j.pediatrneurol.2018.04.009. Epub 2018 Nov 24.

Morrison MA, Payabvash S, Chen Y, Avadiappan S, Shah M, Zou X, Hess CP, Lupo JM. A user-guided tool for semi-automated cerebral microbleed detection and volume segmentation: Evaluating vascular injury and data labelling for machine learning. Neuroimage Clin. 2018 Aug 4;20:498-505. doi: 10.1016/j.nicl.2018.08.002. eCollection 2018.

De la Torre AJ, Luat AF, Juhász C, Ho ML, Argersinger DP, Cavuoto KM, Enriquez-Algeciras M, Tikkanen S, North P, Burkhart CN, Chugani HT, Ball KL, Pinto AL, Loeb JA. A Multidisciplinary Consensus for Clinical Care and Research Needs for Sturge-Weber Syndrome. Pediatr Neurol. 2018 Jul;84:11-20. doi: 10.1016/j.pediatrneurol.2018.04.005. Epub 2018 Apr 18.

Pawlikowska L, Nelson J, Guo DE, McCulloch CE, Lawton MT, Kim H, Faughnan ME; Brain Vascular Malformation Consortium HHT Investigator Group. Association of common candidate variants with vascular malformations and intracranial hemorrhage in hereditary hemorrhagic telangiectasia. Mol Genet Genomic Med. 2018 May;6(3):350-356. doi: 10.1002/mgg3.377. Epub 2018 Mar 6.

Walcott BP, Winkler EA, Zhou S, Birk H, Guo D, Koch MJ, Stapleton CJ, Spiegelman D, Dionne-Laporte A, Dion PA, Kahle KT, Rouleau GA, Lawton MT. Identification of a rare BMP pathway mutation in a non-syndromic human brain arteriovenous malformation via exome sequencing. Hum Genome Var. 2018 Mar 8;5:18001. doi: 10.1038/hgv.2018.1. eCollection 2018.

Meybodi AT, Kim H, Nelson J, Hetts SW, Krings T, terBrugge KG, Faughnan ME, Lawton MT; Brain Vascular Malformation Consortium HHT Investigator Group. Surgical Treatment vs Nonsurgical Treatment for Brain Arteriovenous Malformations in Patients with Hereditary Hemorrhagic Telangiectasia: A Retrospective Multicenter Consortium Study. Neurosurgery. 2018 Jan 1;82(1):35-47. doi: 10.1093/neuros/nyx168.

Offermann EA, Sreenivasan A, DeJong MR, Lin DDM, McCulloch CE, Chung MG, Comi AM; National Institute of Health Sponsor; Rare Disease Clinical Research Consortium (RDCRN); Brain and Vascular Malformation Consortium (BVMC); National Sturge-Weber Syndrome Workgroup. Reliability and Clinical Correlation of Transcranial Doppler Ultrasound in Sturge-Weber Syndrome. Pediatr Neurol. 2017 Sep;74:15-23.e5. doi: 10.1016/j.pediatrneurol.2017.04.026. Epub 2017 May 8.

Dymerska M, Kirkorian AY, Offermann EA, Lin DD, Comi AM, Cohen BA. Size of Facial Port-Wine Birthmark May Predict Neurologic Outcome in Sturge-Weber Syndrome. J Pediatr. 2017 Sep;188:205-209.e1. doi: 10.1016/j.jpeds.2017.05.053. Epub 2017 Jul 12.

Strickland CD, Eberhardt SC, Bartlett MR, Nelson J, Kim H, Morrison LA, Hart BL. Familial Cerebral Cavernous Malformations Are Associated with Adrenal Calcifications on CT Scans: An Imaging Biomarker for a Hereditary Cerebrovascular Condition. Radiology. 2017 Aug;284(2):443-450. doi: 10.1148/radiol.2017161127. Epub 2017 Mar 20.

Zou X, Hart BL, Mabray M, Bartlett MR, Bian W, Nelson J, Morrison LA, McCulloch CE, Hess CP, Lupo JM, Kim H. Automated algorithm for counting microbleeds in patients with familial cerebral cavernous malformations. Neuroradiology. 2017 Jul;59(7):685-690. doi: 10.1007/s00234-017-1845-8. Epub 2017 May 22.

Kasthuri RS, Montifar M, Nelson J, Kim H, Lawton MT, Faughnan ME; Brain Vascular Malformation Consortium HHT Investigator Group. Prevalence and predictors of anemia in hereditary hemorrhagic telangiectasia. Am J Hematol. 2017 Jun 22:10.1002/ajh.24832. doi: 10.1002/ajh.24832. Online ahead of print.

Tang AT, Choi JP, Kotzin JJ, Yang Y, Hong CC, Hobson N, Girard R, Zeineddine HA, Lightle R, Moore T, Cao Y, Shenkar R, Chen M, Mericko P, Yang J, Li L, Tanes C, Kobuley D, Võsa U, Whitehead KJ, Li DY, Franke L, Hart B, Schwaninger M, Henao-Mejia J, Morrison L, Kim H, Awad IA, Zheng X, Kahn ML. Endothelial TLR4 and the microbiome drive cerebral cavernous malformations. Nature. 2017 May 18;545(7654):305-310. doi: 10.1038/nature22075. Epub 2017 May 10.

Lo WD, Kumar R. Arterial Ischemic Stroke in Children and Young Adults. Continuum (Minneap Minn). 2017 Feb;23(1, Cerebrovascular Disease):158-180. doi: 10.1212/CON.0000000000000438.

Pilli VK, Chugani HT, Juhász C. Enlargement of deep medullary veins during the early clinical course of Sturge-Weber syndrome. Neurology. 2017 Jan 3;88(1):103-105. doi: 10.1212/WNL.0000000000003455. Epub 2016 Nov 18.

Walcott BP, Choudhri O, Lawton MT. Brainstem cavernous malformations: Natural history versus surgical management. J Clin Neurosci. 2016 Oct;32:164-5. doi: 10.1016/j.jocn.2016.03.021. Epub 2016 Jun 16.

Walcott BP, Winkler EA, Rouleau GA, Lawton MT. Molecular, Cellular, and Genetic Determinants of Sporadic Brain Arteriovenous Malformations. Neurosurgery. 2016 Aug;63 Suppl 1(Suppl 1 CLINICAL NEUROSURGERY):37-42. doi: 10.1227/NEU.0000000000001300.

Walcott BP, Reinshagen C, Stapleton CJ, Choudhri O, Rayz V, Saloner D, Lawton MT. Predictive modeling and in vivo assessment of cerebral blood flow in the management of complex cerebral aneurysms. J Cereb Blood Flow Metab. 2016 Jun;36(6):998-1003. doi: 10.1177/0271678X16641125. Epub 2016 Mar 23.

Merkel PA, Manion M, Gopal-Srivastava R, Groft S, Jinnah HA, Robertson D, Krischer JP; Rare Diseases Clinical Research Network. The partnership of patient advocacy groups and clinical investigators in the rare diseases clinical research network. Orphanet J Rare Dis. 2016 May 18;11(1):66. doi: 10.1186/s13023-016-0445-8.

Kaplan EH, Kossoff EH, Bachur CD, Gholston M, Hahn J, Widlus M, Comi AM. Anticonvulsant Efficacy in Sturge-Weber Syndrome. Pediatr Neurol. 2016 May;58:31-6. doi: 10.1016/j.pediatrneurol.2015.10.015. Epub 2016 Jan 11.

Comi AM, Sahin M, Hammill A, Kaplan EH, Juhász C, North P, Ball KL, Levin AV, Cohen B, Morris J, Lo W, Roach ES; 2015 Sturge-Weber Syndrome Research Workshop. Leveraging a Sturge-Weber Gene Discovery: An Agenda for Future Research. Pediatr Neurol. 2016 May;58:12-24. doi: 10.1016/j.pediatrneurol.2015.11.009. Epub 2016 Mar 16.

Choquet H, Trapani E, Goitre L, Trabalzini L, Akers A, Fontanella M, Hart BL, Morrison LA, Pawlikowska L, Kim H, Retta SF. Cytochrome P450 and matrix metalloproteinase genetic modifiers of disease severity in Cerebral Cavernous Malformation type 1. Free Radic Biol Med. 2016 Mar;92:100-109. doi: 10.1016/j.freeradbiomed.2016.01.008. Epub 2016 Jan 19.

Kavanaugh B, Sreenivasan A, Bachur C, Papazoglou A, Comi A, Zabel TA. [Formula: see text]Intellectual and adaptive functioning in Sturge-Weber Syndrome. Child Neuropsychol. 2016;22(6):635-48. doi: 10.1080/09297049.2015.1028349. Epub 2015 May 8.

Comi A. Current Therapeutic Options in Sturge-Weber Syndrome. Semin Pediatr Neurol. 2015 Dec;22(4):295-301. doi: 10.1016/j.spen.2015.10.005. Epub 2015 Nov 11.

Choquet H, Pawlikowska L, Lawton MT, Kim H. Genetics of cerebral cavernous malformations: current status and future prospects. J Neurosurg Sci. 2015 Sep;59(3):211-20. Epub 2015 Apr 22.

Hart BL, Ketai L. Armies of pestilence: CNS infections as potential weapons of mass destruction. AJNR Am J Neuroradiol. 2015 Jun;36(6):1018-25. doi: 10.3174/ajnr.A4177. Epub 2014 Dec 4.

Pawlikowska L, Nelson J, Guo DE, McCulloch CE, Lawton MT, Young WL, Kim H, Faughnan ME; Brain Vascular Malformation Consortium HHT Investigator Group. The ACVRL1 c.314-35A>G polymorphism is associated with organ vascular malformations in hereditary hemorrhagic telangiectasia patients with ENG mutations, but not in patients with ACVRL1 mutations. Am J Med Genet A. 2015 Jun;167(6):1262-7. doi: 10.1002/ajmg.a.36936. Epub 2015 Apr 2.

Kim H, Nelson J, Krings T, terBrugge KG, McCulloch CE, Lawton MT, Young WL, Faughnan ME; Brain Vascular Malformation Consortium HHT Investigator Group. Hemorrhage rates from brain arteriovenous malformation in patients with hereditary hemorrhagic telangiectasia. Stroke. 2015 May;46(5):1362-4. doi: 10.1161/STROKEAHA.114.007367. Epub 2015 Apr 9.

Golden MJ, Morrison LA, Kim H, Hart BL. Increased number of white matter lesions in patients with familial cerebral cavernous malformations. AJNR Am J Neuroradiol. 2015 May;36(5):899-903. doi: 10.3174/ajnr.A4200. Epub 2015 Jan 2.

Krings T, Kim H, Power S, Nelson J, Faughnan ME, Young WL, terBrugge KG; Brain Vascular Malformation Consortium HHT Investigator Group. Neurovascular manifestations in hereditary hemorrhagic telangiectasia: imaging features and genotype-phenotype correlations. AJNR Am J Neuroradiol. 2015 May;36(5):863-70. doi: 10.3174/ajnr.A4210. Epub 2015 Jan 8.

Golden M, Saeidi S, Liem B, Marchand E, Morrison L, Hart B. Sensitivity of patients with familial cerebral cavernous malformations to therapeutic radiation. J Med Imaging Radiat Oncol. 2015 Feb;59(1):134-6. doi: 10.1111/1754-9485.12269. Epub 2015 Jan 7.

Comi AM. Sturge-Weber syndrome. Handb Clin Neurol. 2015;132:157-68. doi: 10.1016/B978-0-444-62702-5.00011-1.

Latino GA, Kim H, Nelson J, Pawlikowska L, Young W, Faughnan ME; Brain Vascular Malformation Consortium HHT Investigator Group. Severity score for hereditary hemorrhagic telangiectasia. Orphanet J Rare Dis. 2014 Dec 29;9:188. doi: 10.1186/s13023-014-0188-3.

Reidy TG, Suskauer SJ, Bachur CD, McCulloch CE, Comi AM. Preliminary reliability and validity of a battery for assessing functional skills in children with Sturge-Weber syndrome. Childs Nerv Syst. 2014 Dec;30(12):2027-36. doi: 10.1007/s00381-014-2573-6. Epub 2014 Oct 26.

Lance EI, Lanier KE, Zabel TA, Comi AM. Stimulant use in patients with sturge-weber syndrome: safety and efficacy. Pediatr Neurol. 2014 Nov;51(5):675-80. doi: 10.1016/j.pediatrneurol.2013.11.009. Epub 2013 Nov 21.

Cheng KH, Mariampillai A, Lee KK, Vuong B, Luk TW, Ramjist J, Curtis A, Jakubovic H, Kertes P, Letarte M, Faughnan ME; Brain Vascular Malformation Consortium HHT Investigator Group, Yang VX. Histogram flow mapping with optical coherence tomography for in vivo skin angiography of hereditary hemorrhagic telangiectasia. J Biomed Opt. 2014 Aug;19(8):086015. doi: 10.1117/1.JBO.19.8.086015.

Choquet H, Nelson J, Pawlikowska L, McCulloch CE, Akers A, Baca B, Khan Y, Hart B, Morrison L, Kim H. Association of cardiovascular risk factors with disease severity in cerebral cavernous malformation type 1 subjects with the common Hispanic mutation. Cerebrovasc Dis. 2014;37(1):57-63. doi: 10.1159/000356839. Epub 2013 Dec 21.

Choquet H, Pawlikowska L, Nelson J, McCulloch CE, Akers A, Baca B, Khan Y, Hart B, Morrison L, Kim H; Brain Vascular Malformation Consortium (BVMC) Study. Polymorphisms in inflammatory and immune response genes associated with cerebral cavernous malformation type 1 severity. Cerebrovasc Dis. 2014;38(6):433-40. doi: 10.1159/000369200. Epub 2014 Dec 3.

Hart BL, Taheri S, Rosenberg GA, Morrison LA. Dynamic contrast-enhanced MRI evaluation of cerebral cavernous malformations. Transl Stroke Res. 2013 Oct;4(5):500-6. doi: 10.1007/s12975-013-0285-y. Epub 2013 Sep 21.

Bachur CD, Comi AM. Sturge-weber syndrome. Curr Treat Options Neurol. 2013 Oct;15(5):607-17. doi: 10.1007/s11940-013-0253-6.

Arora KS, Quigley HA, Comi AM, Miller RB, Jampel HD. Increased choroidal thickness in patients with Sturge-Weber syndrome. JAMA Ophthalmol. 2013 Sep;131(9):1216-9. doi: 10.1001/jamaophthalmol.2013.4044.

Sreenivasan AK, Bachur CD, Lanier KE, Curatolo AS, Connors SM, Moses MA, Comi AM. Urine vascular biomarkers in Sturge-Weber syndrome. Vasc Med. 2013 Jun;18(3):122-8. doi: 10.1177/1358863X13486312.

Shirley MD, Tang H, Gallione CJ, Baugher JD, Frelin LP, Cohen B, North PE, Marchuk DA, Comi AM, Pevsner J. Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N Engl J Med. 2013 May 23;368(21):1971-9. doi: 10.1056/NEJMoa1213507. Epub 2013 May 8.

Lopez J, Yeom KW, Comi A, Van Haren K. Case report of subdural hematoma in a patient with Sturge-Weber syndrome and literature review: questions and implications for therapy. J Child Neurol. 2013 May;28(5):672-5. doi: 10.1177/0883073812449514. Epub 2012 Jul 17.

Akers AL, Ball KL, Clancy M, Comi AM, Faughnan ME, Gopal-Srivastava R, Jacobs TP, Kim H, Krischer J, Marchuk DA, McCulloch CE, Morrison L, Moses M, Moy CS, Pawlikowska L, Young WL. Brain Vascular Malformation Consortium: Overview, Progress and Future Directions. J Rare Disord. 2013 Apr 1;1(1):5.

Lance EI, Sreenivasan AK, Zabel TA, Kossoff EH, Comi AM. Aspirin use in Sturge-Weber syndrome: side effects and clinical outcomes. J Child Neurol. 2013 Feb;28(2):213-8. doi: 10.1177/0883073812463607. Epub 2012 Oct 30.

Siddique L, Sreenivasan A, Comi AM, Germain-Lee EL. Importance of utilizing a sensitive free thyroxine assay in Sturge-Weber syndrome. J Child Neurol. 2013 Feb;28(2):269-74. doi: 10.1177/0883073812463606. Epub 2012 Oct 30.

Nishida T, Faughnan ME, Krings T, Chakinala M, Gossage JR, Young WL, Kim H, Pourmohamad T, Henderson KJ, Schrum SD, James M, Quinnine N, Bharatha A, Terbrugge KG, White RI Jr. Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: gene-phenotype correlations. Am J Med Genet A. 2012 Nov;158A(11):2829-34. doi: 10.1002/ajmg.a.35622. Epub 2012 Sep 18.

Lo W, Marchuk DA, Ball KL, Juhász C, Jordan LC, Ewen JB, Comi A; Brain Vascular Malformation Consortium National Sturge-Weber Syndrome Workgroup. Updates and future horizons on the understanding, diagnosis, and treatment of Sturge-Weber syndrome brain involvement. Dev Med Child Neurol. 2012 Mar;54(3):214-23. doi: 10.1111/j.1469-8749.2011.04169.x. Epub 2011 Dec 23.

Bharatha A, Faughnan ME, Kim H, Pourmohamad T, Krings T, Bayrak-Toydemir P, Pawlikowska L, McCulloch CE, Lawton MT, Dowd CF, Young WL, Terbrugge KG. Brain arteriovenous malformation multiplicity predicts the diagnosis of hereditary hemorrhagic telangiectasia: quantitative assessment. Stroke. 2012 Jan;43(1):72-8. doi: 10.1161/STROKEAHA.111.629865. Epub 2011 Oct 27.

Comi AM. Presentation, diagnosis, pathophysiology, and treatment of the neurological features of Sturge-Weber syndrome. Neurologist. 2011 Jul;17(4):179-84. doi: 10.1097/NRL.0b013e318220c5b6.

Petersen TA, Morrison LA, Schrader RM, Hart BL. Familial versus sporadic cavernous malformations: differences in developmental venous anomaly association and lesion phenotype. AJNR Am J Neuroradiol. 2010 Feb;31(2):377-82. doi: 10.3174/ajnr.A1822. Epub 2009 Oct 15.

Nicol LE, Baines H, Koike S, Liu W. Cross-sectional and longitudinal analysis of bone age maturation during peri-pubertal growth in children with type I, III and IV osteogenesis imperfecta. Bone. 2024 Oct;187:117192. doi: 10.1016/j.bone.2024.117192. Epub 2024 Jul 4. PMID: 38969279; PMCID: PMC11324408.

Osteogenesis imperfecta (OI) is a group of inherited connective tissue disorders associated with a wide range of symptoms, including fragile bones that break easily. In typically developing children, radiographic images can reveal predictable patterns of changes in the size, shape, and mineralization of the hand and wrist bones. Known as the bone age, this metric can be used to assess time remaining for growth as well as the onset and duration of puberty, helping to determine the timing of surgeries or reveal deviations in a child’s growth pattern.

In this study, researchers explored bone age maturation during adolescent growth in patients with OI. The team compared radiographs of the hand and wrist in 159 children with OI ages 8 to 17 with healthy controls. Bone ages were repeated around two years later and analyzed by both an endocrinologist and automated program called BoneXpert.  

Results showed that in children with mild-to-moderate OI (types I and IV), skeletal maturation is comparable to healthy controls. For those with more severe forms of OI (type III), results showed a delayed pattern of skeletal maturation of less than a year at baseline and a delayed rate of maturation over the two-year follow-up. However, authors note that these differences may not be clinically significant, concluding that bone age can be used in the OI population in a way that is similar to the general pediatric population.

Marulanda J, Retrouvey JM, Lee B, Sutton VR; Members of the BBDC; Rauch F, Briner M. Cranio-cervical abnormalities in moderate-to-severe osteogenesis imperfecta - Genotypic and phenotypic determinants. Orthod Craniofac Res. 2024 Apr;27(2):237-243. doi: 10.1111/ocr.12707. Epub 2023 Aug 29.

Marom R, Song IW, Busse EC, Washington ME, Berrier AS, Rossi VC, Ortinau L, Jeong Y, Jiang MM, Dawson BC, Adeyeye M, Leynes C, Lietman CD, Stroup BM, Batkovskyte D, Jain M, Chen Y, Cela R, Castellon A, Tran AA, Lorenzo I, Meyers DN, Huang S, Turner A, Shenava V, Wallace M, Orwoll E, Park D, Ambrose CG, Nagamani SC, Heaney JD, Lee BH. The IFITM5 mutation in osteogenesis imperfecta type V is associated with an ERK/SOX9-dependent osteoprogenitor differentiation defect. J Clin Invest. 2024 Jun 17;134(15):e170369. doi: 10.1172/JCI170369.

Cho HE, Shepherd WS, Colombo GM, Wiese AD, Rork WC, Kostick KM, Nguyen D; Members of the BBDC; Murali CN, Robinson ME, Schneider SC, Qian JH, Lee B, Sutton VR, Storch EA. Resilience and coping: a qualitative analysis of cognitive and behavioral factors in adults with osteogenesis Imperfecta. Disabil Rehabil. 2024 Jun 6:1-10. doi: 10.1080/09638288.2024.2358903. Online ahead of print.

Hald JD, Langdahl B, Folkestad L, Wekre LL, Johnson R, Nagamani SCS, Raggio C, Ralston SH, Semler O, Tosi L, Orwoll E. Osteogenesis Imperfecta: Skeletal and Non-skeletal Challenges in Adulthood. Calcif Tissue Int. 2024 Jun 5. doi: 10.1007/s00223-024-01236-x. Online ahead of print.

Busse E, Lee B, Nagamani SCS. Genetic Evaluation for Monogenic Disorders of Low Bone Mass and Increased Bone Fragility: What Clinicians Need to Know. Curr Osteoporos Rep. 2024 Apr 11. doi: 10.1007/s11914-024-00870-6. Epub ahead of print. PMID: 38600318.

Monogenic disorders of osteoporosis are characterized by low bone mass, increased bone fragility, and increased risk of fractures. There are currently over 50 different known types of these disorders, which are each caused by variations in a single gene. Widespread availability of clinical genetic testing offers an opportunity to correctly diagnose individuals with these disorders.

In this review paper, researchers discuss genetic testing for patients with suspected monogenic forms of osteoporosis. The team outlines the principles of clinical genetic testing and provides practical guidance for clinicians to navigate the process.

Authors note that clinicians should be aware of how to incorporate genetic testing into their practices, as these techniques could help identify the appropriate diagnosis for patients with low bone mass, multiple or unusual fractures, and severe or early-onset osteoporosis.

Liu W, Nicol L, Orwoll E. Current and Developing Pharmacologic Agents for Improving Skeletal Health in Adults with Osteogenesis Imperfecta. Calcif Tissue Int. 2024 Mar 12. doi: 10.1007/s00223-024-01188-2. Epub ahead of print. PMID: 38472351.

Osteogenesis imperfecta (OI) is a group of inherited connective tissue disorders associated with a wide range of symptoms, including fragile bones that break easily. Drugs to improve skeletal health—including those initially developed to treat osteoporosis as well as new bone-protective agents—are in various phases of clinical trials for adults with OI.

In this review article, researchers summarize current and developing pharmacologic agents for improving skeletal health in adults with OI. The team performed online database searches to review published studies and clinical trials.

Results include ongoing clinical trials for several therapeutics, including those that may be useful in improving bone mineral density. Authors note that clinical trials involving gene editing may be possible in the coming decade.

Rork WC, Hertz AG, Wiese AD, Kostick KM, Nguyen D, Schneider SC, Shepherd WS, Cho H; Members of the BBDC; Murali CN, Lee B, Sutton VR, Storch EA. A qualitative exploration of patient perspectives on psychosocial burdens and positive factors in adults with osteogenesis imperfecta. Am J Med Genet A. 2023 Sep;191(9):2267-2275. doi: 10.1002/ajmg.a.63323. Epub 2023 Jun 15. PMID: 37317786

Osteogenesis imperfecta (OI) is a group of inherited connective tissue disorders associated with a wide range of symptoms, including fragile bones that break easily. Although progress has been made in understanding the spectrum of physical symptoms, less is known about the impact of OI on psychosocial well-being, as well as factors that can help lessen negative outcomes.

In this study, researchers developed a qualitative approach to assess perspectives from individuals with OI on psychosocial burdens and positive factors related to OI. Among 15 adults with varying disease status, the team conducted semi-structured interviews and identified themes from responses.

Participants reported negative psychosocial outcomes related to bone fractures and recovery, uncertainty of future fractures, and self-image. Participants also described positive traits related to OI and their lived experience with a chronic disease. Authors note that these insights highlight a need for continued research on the relationship between OI disease status and psychosocial outcomes, as well as the development of psychological interventions designed for individuals with OI.

Liu W, Lee B, Nagamani SCS, Nicol L, Rauch F, Rush ET, Sutton VR, Orwoll E. Approach to the Patient: Pharmacological therapies for fracture risk reduction in adults with osteogenesis imperfecta. J Clin Endocrinol Metab. 2023 Jan 20:dgad035. doi: 10.1210/clinem/dgad035. Epub ahead of print. PMID: 36658750.

Osteogenesis imperfecta (OI) is a group of 21 rare, inherited disorders caused by 19 gene mutations resulting in fragile bones that break easily. The effectiveness of medications used for fracture reduction in adults with OI, as well as practice recommendations, are not well established.

In this review paper, researchers summarize current knowledge on pharmacologic treatment options for reducing fracture risk in adults with OI. In addition to manual searches of reference lists, the team performed a PubMed online database search of all study types published in the English language using the terms “osteogenesis imperfecta,” “OI,” and “brittle bone disease.”

Findings show that despite limited clinical trial data, bisphosphonate and teriparatide therapies may help improve bone mineral density in adults with OI. Authors state that further research is needed to develop medications for adults with OI that will lead to definite fracture rate reduction.

Marulanda J, Ludwig K, Glorieux F, Lee B, Sutton VR; Members of the BBD Consortium; Retrouvey JM, Rauch F. Craniofacial and dental phenotype of two girls with osteogenesis imperfecta due to mutations in CRTAP. Bone. 2022 Nov;164:116516. doi: 10.1016/j.bone.2022.116516. Epub 2022 Aug 12.

Rodriguez Celin M, Kruger KM, Caudill A, Murali CN, Nagamani SCS, Members Of The Brittle Bone Disorders Consortium Bbdc, Smith PA, Harris GF. A multicenter study to evaluate pain characteristics in osteogenesis imperfecta. Am J Med Genet A. 2023 Jan;191(1):160-172. doi: 10.1002/ajmg.a.63009. Epub 2022 Oct 22. PMID: 36271817; PMCID: PMC10399129.

Osteogenesis imperfecta (OI) is a group of rare, inherited disorders caused by gene mutations resulting in fragile bones that break easily. Symptoms include skeletal and joint deformities, hearing loss, a bluish tint to the sclerae (whites of the eyes), dental problems, respiratory problems, and chronic pain. In this study, researchers aimed to describe pain characteristics and treatments used in individuals with varying severity of OI, as well as investigate variables associated with pain. Using data from a natural history study of OI conducted by the Brittle Bone Disorders Consortium (BBDC), the team analyzed the prevalence, characteristics, treatments, and predictors of chronic pain. Among 861 individuals with OI, results showed that 41.8% had chronic pain, which was most frequently located in the back. Predictors of chronic pain for all OI types included age, use of a wheelchair, and number of fractures per year. Compared to participants without chronic pain, participants with chronic pain missed more days from school or work per year and performed worse in all mobility metrics. The most common treatments were nonsteroidal anti-inflammatory drugs and bisphosphonates. These results show that chronic pain is prevalent in OI across all types, affects mobility, and interferes with participation.

Song IW, Nagamani SC, Nguyen D, Grafe I, Sutton VR, Gannon FH, Munivez E, Jiang MM, Tran A, Wallace M, Esposito P, Musaad S, Strudthoff E, McGuire S, Thornton M, Shenava V, Rosenfeld S, Huang S, Shypailo R, Orwoll E, Lee B. Targeting TGF-β for treatment of osteogenesis imperfecta. J Clin Invest. 2022 Apr 1;132(7):e152571. doi: 10.1172/JCI152571.

Marom R, Burrage LC, Venditti R, Clément A, Blanco-Sánchez B, Jain M, Scott DA, Rosenfeld JA, Sutton VR, Shinawi M, Mirzaa G, DeVile C, Roberts R, Calder AD, Allgrove J, Grafe I, Lanza DG, Li X, Joeng KS, Lee YC, Song IW, Sliepka JM, Batkovskyte D, Washington M, Dawson BC, Jin Z, Jiang MM, Chen S, Chen Y, Tran AA, Emrick LT, Murdock DR, Hanchard NA, Zapata GE, Mehta NR, Weis MA, Scott AA, Tremp BA, Phillips JB, Wegner J, Taylor-Miller T, Gibbs RA, Muzny DM, Jhangiani SN, Hicks J, Stottmann RW, Dickinson ME, Seavitt JR, Heaney JD, Eyre DR; Undiagnosed Diseases Network, Westerfield M, De Matteis MA, Lee B. COPB2 loss of function causes a coatopathy with osteoporosis and developmental delay. Am J Hum Genet. 2021 Sep 2;108(9):1710-1724. doi: 10.1016/j.ajhg.2021.08.002. Epub 2021 Aug 26.

Vesicle coat proteins help cells sort and transport or “traffic” proteins and lipids. Pathogenic variants (mutations) in genes that encode subunits of coat complexes called coatomers are believed to contribute to a number of genetic disorders called coatopathies that can affect the skeletal and central nervous systems. In this study, researchers examined loss-of-function variants in the gene COPB2, which encodes for a protein in the coatomer complex, in six individuals from five unrelated families who have osteoporosis or osteopenia (brittle bones that may fracture easily) and variable degree of developmental delay. Researchers also used zebrafish and mouse models to further study the effect of COPB2 deficiency on collagen trafficking because of the critical role of collagen secretion in bone development. The authors conclude that COPB2 haploinsufficiency (meaning only 50% of the normal active form of a particular protein is expressed) is a cause of this form of coatopathy. They also tested ascorbic acid supplementation as a potential treatment and found that it had a beneficial effect on animal models.

Taqi D, Moussa H, Schwinghamer T, Vieira AR, Dagdeviren D, Retrouvey JM, Rauch F, Tamimi F; Members of the BBDC. Missing and unerupted teeth in osteogenesis imperfecta. Bone. 2021 Sep;150:116011. doi: 10.1016/j.bone.2021.116011. Epub 2021 May 18.

Osteogenesis imperfecta (OI) is a genetic disorder characterized by bone fragility and craniofacial and dental abnormalities. It is believed that OI patients have missing or unerupted teeth at a rate twice the general population. To better understand the factors influencing missing and unerupted teeth, researchers studied 144 OI patients. They examined clinical phenotype (OI type), the genetic variant type, the tooth type and the onset of biophosphonate treatment, which slows bone loss. They found that the presence of missing and unerupted teeth varied according to the nature of the collagen variants and OI type. These findings highlight the role of collagen in tooth development and eruption.

Rao R, Cuthbertson D, Nagamani SCS, Sutton VR, Lee BH, Krischer J, Krakow D. Pregnancy in women with osteogenesis imperfecta: pregnancy characteristics, maternal, and neonatal outcomes. Am J Obstet Gynecol MFM. 2021 Jul;3(4):100362. doi: 10.1016/j.ajogmf.2021.100362. Epub 2021 Mar 26.

Women with rare diseases considering pregnancy often lack data regarding outcomes, specific risks, and management strategies. The Brittle Bone Disorders Consortium established an Osteogenesis Imperfecta Pregnancy Registry to collect data on pregnancy, maternal, and neonatal outcomes in women with osteogenesis imperfecta (OI), or brittle bone disease. A total of 132 participants with OI completed a cross-sectional, survey-based study. Of respondents, 34% had moderate to severe OI. Researchers compared self-reported information on pregnancy and maternal and neonatal outcomes of women with OI with data on the general population, referenced by literature-based standards. Results indicated that women with OI had higher rates than the general population of diabetes in pregnancy, cesarean delivery, need for blood transfusion, and fractures before or after delivery. Individuals with moderate or severe OI reported higher maternal hospitalization and delivery rates than those with mild OI. Babies born to women with OI had higher rates of neonatal intensive care unit admissions and higher neonatal mortality, regardless of neonatal OI status. Study authors say that patients and providers should be aware of these findings, particularly the need for blood products (hemorrhage) and the increased rate of fractures, low birthweight infants, and neonatal mortality. They suggest that survey results can support both preconception counseling and proactive measures to reduce harm and recognize modifiable risk factors related to pregnancy.

Murali CN, Slater B, Musaad S, Cuthbertson D, Nguyen D, Turner A, Azamian M, Tosi L, Rauch F, Sutton VR, Lee B; Members of the BBD Consortium, Nagamani SCS. Health-related quality of life in adults with osteogenesis imperfecta. Clin Genet. 2021 Jun;99(6):772-779. doi: 10.1111/cge.13939. Epub 2021 Feb 22.

Taqi D, Moussa H, Schwinghamer T, Ducret M, Dagdeviren D, Retrouvey JM, Rauch F, Tamimi F; Members of the BBDC. Osteogenesis imperfecta tooth level phenotype analysis: Cross-sectional study. Bone. 2021 Jun;147:115917. doi: 10.1016/j.bone.2021.115917. Epub 2021 Mar 16.

Nicol LE, Coghlan RF, Cuthbertson D, Nagamani SCS, Lee B, Olney RC, Horton W; Members of the Brittle Bone Disease Consortium, Orwoll E. Alterations of a serum marker of collagen X in growing children with osteogenesis imperfecta. Bone. 2021 Aug;149:115990. doi: 10.1016/j.bone.2021.115990. Epub 2021 Apr 28.

Osteogenesis imperfecta is a genetic disorder characterized by bone fragility, abnormal bone growth, and short stature. In this study, researchers sought to better understand the mechanisms by which abnormalities in collagen contribute to growth plate dysfunction. Growth plates are the areas of new bone growth in children and teens, which are made up of cartilage. Researchers examined the presence of Type X collagen (CXM), which has been found to be a reliable marker for new bone formation in cartilage, in blood samples of 187 subjects ages 8 months to 40 years with OI compared with control subjects. All subjects had higher levels of CXM early in life and during puberty, but there was greater variability for the OI cohort and a weaker relationship with growth velocity. The ratio of CXM level to growth velocity was elevated in children with type III/IV OI compared to controls. Results suggest that the relationship between growth plate and the end point of skeletal growth is disrupted in OI. 

Rauch D, Robinson ME, Seiltgens C, Sutton VR, Lee B, Glorieux F, Rauch F. Assessment of longitudinal bone growth in osteogenesis imperfecta using metacarpophalangeal pattern profiles. Bone. 2020 Nov;140:115547. doi: 10.1016/j.bone.2020.115547. Epub 2020 Jul 27.

Rodriguez Celin M, Kruger KM, Caudill A, Nagamani SCS; Brittle Bone Disorders Consortium (BBDC); Linked Clinical Research Centers (LCRC), Harris GF, Smith PA. A Multicenter Study of Intramedullary Rodding in Osteogenesis Imperfecta. JB JS Open Access. 2020 Sep 11;5(3):e20.00031. doi: 10.2106/JBJS.OA.20.00031. eCollection 2020 Jul-Sep.

Najirad M, Madathil SA, Rauch F, Sutton VR, Lee B, Retrouvey JM; Members of the Brittle Bone Diseases Consortium, Esfandiari S. Malocclusion traits and oral health-related quality of life in children with osteogenesis imperfecta: A cross-sectional study. J Am Dent Assoc. 2020 Jul;151(7):480-490.e2. doi: 10.1016/j.adaj.2020.03.040.

Machol K, Hadley TD, Schmidt J, Cuthbertson D, Traboulsi H, Silva RC, Citron C, Khan S, Citron K, Carter E, Brookler K, Shapiro JR, Steiner RD, Byers PH, Glorieux FH, Durigova M, Smith P, Bober MB, Sutton VR, Lee BH; Members of the BBD Consortium, Nagamani SCS, Raggio C. Hearing loss in individuals with osteogenesis imperfecta in North America: Results from a multicenter study. Am J Med Genet A. 2020 Apr;182(4):697-704. doi: 10.1002/ajmg.a.61464. Epub 2019 Dec 26.

Murali CN, Cuthbertson D, Slater B, Nguyen D, Turner A, Harris G, Sutton VR, Lee B; Members of the BBD Consortium, Nagamani SCS. Pediatric Outcomes Data Collection Instrument is a Useful Patient-Reported Outcome Measure for Physical Function in Children with Osteogenesis Imperfecta. Genet Med. 2020 Mar;22(3):581-589. doi: 10.1038/s41436-019-0688-6. Epub 2019 Nov 27.

Ortinau LC, Wang H, Lei K, Deveza L, Jeong Y, Hara Y, Grafe I, Rosenfeld SB, Lee D, Lee B, Scadden DT, Park D. Identification of Functionally Distinct Mx1+αSMA+ Periosteal Skeletal Stem Cells. Cell Stem Cell. 2019 Dec 5;25(6):784-796.e5. doi: 10.1016/j.stem.2019.11.003.

Retrouvey JM, Taqi D, Tamimi F, Dagdeviren D, Glorieux FH, Lee B, Hazboun R, Krakow D, Sutton VR; Members of the BBD Consortium. Oro-dental and cranio-facial characteristics of osteogenesis imperfecta type V. Eur J Med Genet. 2019 Dec;62(12):103606. doi: 10.1016/j.ejmg.2018.12.011. Epub 2018 Dec 26.

Rossi V, Lee B, Marom R. Osteogenesis imperfecta: advancements in genetics and treatment. Curr Opin Pediatr. 2019 Dec;31(6):708-715. doi: 10.1097/MOP.0000000000000813.

Dagdeviren D, Tamimi F, Lee B, Sutton R, Rauch F, Retrouvey JM. Dental and craniofacial characteristics caused by the p.Ser40Leu mutation in IFITM5. Am J Med Genet A. 2018 Oct 5. doi: 10.1002/ajmg.a.40383. PMID: 30289614.

Jain M, Tam A, Shapiro JR, Steiner RD, Smith PA, Bober MB, Hart T, Cuthbertson D, Krischer J, Mullins M, Bellur S, Byers PH, Pepin M, Durigova M, Glorieux FH, Rauch F, Lee B, Sutton VR; , Members of the Brittle Bone Disorders Consortium*, Nagamani SCS. Growth characteristics in individuals with osteogenesis imperfecta in North America: results from a multicenter study. Genet Med. 2018 Jul 4. doi: 10.1038/s41436-018-0045-1. PMID: 29970925.

Bains JS, Carter EM, Citron KP, Boskey AL, Shapiro JR, Steiner RD, Smith PA, Bober MB, Hart T, Cuthbertson D, Krischer J, Byers PH, Pepin M, Durigova M, Glorieux FH, Rauch F, Sliepka JM, Sutton VR, Lee B; Members of the BBD Consortium, Nagamani SC, Raggio CL. A Multicenter Observational Cohort Study to Evaluate the Effects of Bisphosphonate Exposure on Bone Mineral Density and Other Health Outcomes in Osteogenesis Imperfecta. JBMR Plus. 2019 Jan 7;3(5):e10118. doi: 10.1002/jbm4.10118. eCollection 2019 May.

Kruger KM, Caudill A, Rodriguez Celin M, Nagamani SCS, Shapiro JR, Steiner RD, Bober MB, Hart T, Cuthbertson D, Krischer J, Byers PH, Durigova M, Glorieux FH, Rauch F, Sutton VR, Lee B, Rush ET, Smith PA, Harris GF. Mobility in Osteogenesis Imperfecta: A Multicenter North American Study. Genet Med. 2019 Mar 28. doi: 10.1038/s41436-019-0491-4. PMID: 30918359.

Ma MS, Najirad M, Taqi D, Retrouvey JM, Tamimi F, Dagdeviren D, Glorieux FH, Lee B, Sutton VR, Rauch F, Esfandiari S. Caries Prevalence and Experience in Individuals with Osteogenesis Imperfecta. Spec Care Dentist. 2019 Mar;39(2):214-219. Epub 2019 Feb 13. https://doi.org/10.1101/418806. PMID: 30758072.

Swezey T, Reeve BB, Hart TS, Floor MK, Dollar CM, Gillies AP, Tosi LL. Incorporating the patient perspective in the study of rare bone disease: insights from the osteogenesis imperfecta community. Osteoporos Int. 2019 Feb;30(2):507-511. doi: 10.1007/s00198-018-4690-7. Epub 2018 Sep 6. PMID:30191258.

Tosi LL, Floor MK, Dollar CM, Gillies AP; Members of the Brittle Bone Disease Consortium, Hart TS, Cuthbertson DD, Sutton VR, Krischer JP. Assessing Disease Experience across the Life Span for Individuals with Osteogenesis Imperfecta: Challenges and Opportunities for Patient-Reported Outcomes (PROs) Measurement. Orphanet J Rare Dis. 2019 Jan 29;14(1):23. doi: 10.1186/s13023-019-1004-x. PMID: 30696467; PMCID: PMC6350324.

Alhamdi S, Lee YC, Chowdhury S, Byers PH, Gottschalk M, Taft RJ, Joeng KS, Lee BH, Bird LM. Heterozygous WNT1 variant causing a variable bone phenotype. Am J Med Genet A. 2018 Nov;176(11):2419-2424. doi: 10.1002/ajmg.a.40347. Epub 2018 Sep 24.

Najirad M, Ma MS, Rauch F, Sutton VR, Lee B, Retrouvey JM; Members of the BBD, Esfandiari S. Oral Health-Related Quality of Life in Children and Adolescents with Osteogenesis Imperfecta: cross- sectional study. Orphanet J Rare Dis. 2018 Oct 25;13(1):187. doi: https://doi.org/10.1101/424812. PMID: 30359278.

Tam A, Chen S, Schauer E, Grafe I, Bandi V, Shapiro JR, Steiner RD, Smith PA, Bober MB, Hart T, Cuthbertson D, Krischer J, Mullins M, Byers PH, Sandhaus RA, Durigova M, Glorieux FH, Rauch F, Reid Sutton V, Lee B; Members of the Brittle Bone Disorders Consortium, Rush ET, Nagamani SCS. A Multicenter Study to Evaluate Pulmonary Function in Osteogenesis Imperfecta. Clin Genet. 2018 Dec;94(6):502-511. doi: 10.1111/cge.13440. Epub 2018 Sep 24. PMID: 30152014.

Rousseau M, Retrouvey JM; Members of the Brittle Bone Disease Consortium. Osteogenesis imperfecta: potential therapeutic approaches. PeerJ. 2018 Aug 17;6:e5464. doi: 10.7717/peerj.5464. eCollection 2018. PMID: 30128210.

Reznikov N, Dagdeviren D, Tamimi F, Glorieux F, Rauch F, Retrouvey JM. Cone‐Beam Computed Tomography of Osteogenesis Imperfecta Types III and IV: Three‐Dimensional Evaluation of Craniofacial Features and Upper Airways. JBMR Plus. 2019 Feb 7;3(6):e10124. doi: 10.1002/jbm4.10124. PMID: 31346560; PMCID: PMC6636768.

Lim J, Grafe I, Alexander S, Lee B. Genetic causes and mechanisms of Osteogenesis Imperfecta. Bone. 2017 Sep;102:40-49. doi: 10.1016/j.bone.2017.02.004. Epub 2017 Feb 15.

Abdelkarim A, Jerrold L. Orthodontic chart documentation. Am J Orthod Dentofacial Orthop. 2017 Jul;152(1):126-130. doi: 10.1016/j.ajodo.2017.03.018.

Lietman CD, Lim J, Grafe I, Chen Y, Ding H, Bi X, Ambrose CG, Fratzl-Zelman N, Roschger P, Klaushofer K, Wagermaier W, Schmidt I, Fratzl P, Rai J, Weis M, Eyre D, Keene DR, Krakow D, Lee BH. Fkbp10 Deletion in Osteoblasts Leads to Qualitative Defects in Bone. J Bone Miner Res. 2017 Jun;32(6):1354-1367. doi: 10.1002/jbmr.3108. Epub 2017 Mar 20.

Bi X, Grafe I, Ding H, Flores R, Munivez E, Jiang MM, Dawson B, Lee B, Ambrose CG. Correlations Between Bone Mechanical Properties and Bone Composition Parameters in Mouse Models of Dominant and Recessive Osteogenesis Imperfecta and the Response to Anti-TGF-β Treatment. J Bone Miner Res. 2017 Feb;32(2):347-359. doi: 10.1002/jbmr.2997. Epub 2016 Oct 20.

Bellur S, Jain M, Cuthbertson D, Krakow D, Shapiro JR, Steiner RD, Smith PA, Bober MB, Hart T, Krischer J, Mullins M, Byers PH, Pepin M, Durigova M, Glorieux FH, Rauch F, Sutton VR, Lee B; Members of the BBD Consortium, Nagamani SC. Cesarean delivery is not associated with decreased at-birth fracture rates in osteogenesis imperfecta. Genet Med. 2016 Jun;18(6):570-6. doi: 10.1038/gim.2015.131. Epub 2015 Oct 1. PMID: 26426884.

Grafe I, Alexander S, Yang T, Lietman C, Homan EP, Munivez E, Chen Y, Jiang MM, Bertin T, Dawson B, Asuncion F, Ke HZ, Ominsky MS, Lee B. Sclerostin Antibody Treatment Improves the Bone Phenotype of Crtap(-/-) Mice, a Model of Recessive Osteogenesis Imperfecta. J Bone Miner Res. 2016 May;31(5):1030-40. doi: 10.1002/jbmr.2776. Epub 2016 Feb 12.

Lietman CD, Marom R, Munivez E, Bertin TK, Jiang MM, Chen Y, Dawson B, Weis MA, Eyre D, Lee B. A transgenic mouse model of OI type V supports a neomorphic mechanism of the IFITM5 mutation. J Bone Miner Res. 2015 Mar;30(3):489-98. doi: 10.1002/jbmr.2363.

Demaegd KC, Kernan A, Cooper-Knock J, van Vugt JJFA, Harvey C, Moll T, O'Brien D, Gornall S, Drury L, Farhan SMK, Dion PA, Rouleau GA, Western A, Parsons PJ, Mclean B, Benatar M, van den Berg LH, Van Damme P, Willem Dankbaar J, Hendrikse J, Koole W, de Bie C, Hobson E, Veldink JH, van de Warrenburg B, Pasterkamp RJ, van Rheenen W, Kirby J, Shaw PJ, van Es MA. An observational study of pleiotropy and penetrance of amyotrophic lateral sclerosis associated with CAG-repeat expansion of ATXN2. Eur J Hum Genet. 2025 Feb 16. doi: 10.1038/s41431-025-01811-2. Online ahead of print.

Deecke L, Ohlei O, Goldeck D, Homann J, Toepfer S, Demuth I, Bertram L, Pawelec G, Lill CM. Peripheral Immune Profiles in Individuals at Genetic Risk of Amyotrophic Lateral Sclerosis and Alzheimer's Disease. Cells. 2025 Feb 10;14(4):250. doi: 10.3390/cells14040250.

Benatar M, Robertson J, Andersen PM. Amyotrophic lateral sclerosis caused by SOD1 variants: from genetic discovery to disease prevention. Lancet Neurol. 2025 Jan;24(1):77-86. doi: 10.1016/S1474-4422(24)00479-4.

Laansma MA, Zhao Y, van Heese EM, Bright JK, Owens-Walton C, Al-Bachari S, Anderson TJ, Assogna F, van Balkom TD, Berendse HW, Cendes F, Dalrymple-Alford JC, Debove I, Dirkx MF, Druzgal J, Emsley HCA, Fouche JP, Garraux G, Guimarães RP, Helmich RC, Hu M, van den Heuvel OA, Isaev D, Kim HB, Klein JC, Lochner C, McMillan CT, Melzer TR, Newman B, Parkes LM, Pellicano C, Piras F, Pitcher TL, Poston KL, Rango M, Ribeiro LF, Rocha CS, Rummel C, Santos LSR, Schmidt R, Schwingenschuh P, Squarcina L, Stein DJ, Vecchio D, Vriend C, Wang J, Weintraub D, Wiest R, Yasuda CL, Jahanshad N, Thompson PM, van der Werf YD, Gutman BA. A worldwide study of subcortical shape as a marker for clinical staging in Parkinson's disease. NPJ Parkinsons Dis. 2024 Nov 19;10(1):223. doi: 10.1038/s41531-024-00825-9.

Lee I, Garret MA, Wuu J, Harrington EA, Berry JD, Miller TM, Harms M, Benatar M, Shneider N. Body mass index is lower in asymptomatic C9orf72 expansion carriers but not in SOD1 pathogenic variant carriers compared to gene negatives. Amyotroph Lateral Scler Frontotemporal Degener. 2024 Nov;25(7-8):672-679. doi: 10.1080/21678421.2024.2396831. Epub 2024 Aug 27.

Koch JC, Leha A, Bidner H, Cordts I, Dorst J, Günther R, Zeller D, Braun N, Metelmann M, Corcia P, De La Cruz E, Weydt P, Meyer T, Großkreutz J, Soriani MH, Attarian S, Weishaupt JH, Weyen U, Kuttler J, Zurek G, Rogers ML, Feneberg E, Deschauer M, Neuwirth C, Wuu J, Ludolph AC, Schmidt J, Remane Y, Camu W, Friede T, Benatar M, Weber M, Lingor P; ROCK-ALS Study group. Safety, tolerability, and efficacy of fasudil in amyotrophic lateral sclerosis (ROCK-ALS): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2024 Nov;23(11):1133-1146. doi: 10.1016/S1474-4422(24)00373-9.

Benatar M, Macklin EA, Malaspina A, Rogers ML, Hornstein E, Lombardi V, Renfrey D, Shepheard S, Magen I, Cohen Y, Granit V, Statland JM, Heckmann JM, Rademakers R, McHutchison CA, Petrucelli L, McMillan CT, Wuu J; CReATe Consortium PGB1 Study Investigators. Prognostic clinical and biological markers for amyotrophic lateral sclerosis disease progression: validation and implications for clinical trial design and analysis. EBioMedicine. 2024 Sep 12;108:105323. doi: 10.1016/j.ebiom.2024.105323. Online ahead of print.

Crayle JI, Rampersaud E, Myers JR, Wuu J, Taylor JP, Wu G, Benatar M, Bedlack RS. Genetic Associations With an Amyotrophic Lateral Sclerosis Reversal Phenotype. Neurology. 2024 Aug 27;103(4):e209696. doi: 10.1212/WNL.0000000000209696. Epub 2024 Jul 30.

Piecuch CE, Webber-Davis IF, Teener SJ, Feldman EL, Zhao L, Goutman SA. Peripheral Immune Profiles Predict ALS Progression in an Age- and Sex-Dependent Manner. Neurol Neuroimmunol Neuroinflamm. 2024 May;11(3):e200241. doi: 10.1212/NXI.0000000000200241. Epub 2024 Apr 16. PMID: 38626361; PMCID: PMC11087030.

Benatar M, Wuu J, Huey ED, McMillan CT, Petersen RC, Postuma R, McHutchison C, Dratch L, Arias JJ, Crawley A, Houlden H, McDermott MP, Cai X, Thakur N, Boxer A, Rosen H, Boeve BF, Dacks P, Cosentino S, Abrahams S, Shneider N, Lingor P, Shefner J, Andersen PM, Al-Chalabi A, Turner MR; Attendees of the Second International Pre-Symptomatic ALS Workshop. The Miami Framework for ALS and related neurodegenerative disorders: an integrated view of phenotype and biology. Nat Rev Neurol. 2024 Jun;20(6):364-376. doi: 10.1038/s41582-024-00961-z. Epub 2024 May 20.

Kerestes R, Laansma MA, Owens-Walton C, Perry A, van Heese EM, Al-Bachari S, Anderson TJ, Assogna F, Aventurato ÍK, van Balkom TD, Berendse HW, van den Berg KRE, Betts R, Brioschi R, Carr J, Cendes F, Clark LR, Dalrymple-Alford JC, Dirkx MF, Druzgal J, Durrant H, Emsley HCA, Garraux G, Haroon HA, Helmich RC, van den Heuvel OA, João RB, Johansson ME, Khachatryan SG, Lochner C, McMillan CT, Melzer TR, Mosley PE, Newman B, Opriessnig P, Parkes LM, Pellicano C, Piras F, Pitcher TL, Poston KL, Rango M, Roos A, Rummel C, Schmidt R, Schwingenschuh P, Silva LS, Smith V, Squarcina L, Stein DJ, Tavadyan Z, Tsai CC, Vecchio D, Vriend C, Wang JJ, Wiest R, Yasuda CL, Young CB, Jahanshad N, Thompson PM, van der Werf YD, Harding IH; ENIGMA-Parkinson's Study. Cerebellar Volume and Disease Staging in Parkinson's Disease: An ENIGMA-PD Study. Mov Disord. 2023 Dec;38(12):2269-2281. doi: 10.1002/mds.29611. Epub 2023 Nov 14.

Monnakgotla NR, Mahungu AC, Heckmann JM, Botha G, Mulder NJ, Wu G, Rampersaud E, Myers J, Van Blitterswijk M, Rademakers R, Taylor JP, Wuu J, Benatar M, Nel M. Analysis of Structural Variants Previously Associated With ALS in Europeans Highlights Genomic Architectural Differences in Africans. Neurol Genet. 2023 Jun 16;9(4):e200077. doi: 10.1212/NXG.0000000000200077. eCollection 2023 Aug.

Jin HA, McMillan CT, Yannatos I, Fisher L, Rhodes E, Jacoby SF, Irwin DJ, Massimo L. Racial Differences in Clinical Presentation in Individuals Diagnosed With Frontotemporal Dementia. JAMA Neurol. 2023 Sep 11:e233093. doi: 10.1001/jamaneurol.2023.3093. Online ahead of print.

McHutchison CA, Wuu J, McMillan CT, Rademakers R, Statland J, Wu G, Rampersaud E, Myers J, Hernandez JP, Abrahams S, Benatar M; CReATe Consortium. Temporal course of cognitive and behavioural changes in motor neuron diseases. J Neurol Neurosurg Psychiatry. 2023 Oct 12:jnnp-2023-331697. doi: 10.1136/jnnp-2023-331697.

While people with motor neuron disease (MND) experience cognitive and behavioral dysfunction, the onset and progression of these symptoms, relative to motor manifestations, remains unclear. In this study, CReATe Consortium researchers explored changes in these deficits over time, and whether demographic, clinical, or genetic factors affected these symptoms.

A total of 237 participants were recruited through the consortium’s Phenotype-Genotype-Biomarker study. The Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis Screen was administered every three to six months to assess ALS-specific cognitive issues, such as executive function, verbal fluency, and language; and ALS non-specific memory and visuospatial functions. Behavioral symptoms like apathy, disinhibition, loss of sympathy and perseveration and hyperorality, were reported through semi-structured interviews.

In this large observational study, cognitive impairment at initial assessment was infrequent, but when present, most often involved language and executive functions. These impairments were associated with lower educational levels, but not with the C9ORF72 repeat expansion. We also found that cognition remained stable over time for most patients. However, a small subset showed decline on all cognitive domains, which was not entirely explained by the presence of a C9ORF72 repeat expansion. Behavioral symptoms in these MND participants were uncommon.

Our findings raise questions about the timing of cognitive impairment in MND, and whether it arises during early clinically manifest disease or even prior to motor manifestations. This highlights the need for future research to identify when these cognitive symptoms begin and what other factors are associated with decline over time.

Varma A, Weinstein J, Seabury J, Rosero S, Zizzi C, Alexandrou D, Wagner E, Dilek N, Heatwole J, Wuu J, Caress J, Bedlack R, Granit V, Statland J, Mehta P, Benatar M, Kaat A, Heatwole C. The amyotrophic lateral sclerosis-health index (ALS-HI): development and evaluation of a novel outcome measure. Amyotroph Lateral Scler Frontotemporal Degener. 2023 Aug;24(5-6):514-522. doi: 10.1080/21678421.2023.2204871. Epub 2023 May 15. PMID: 37190795

Amyotrophic lateral sclerosis (ALS) patients experience a wide variety of physical, mental, emotional, and social symptoms of the disease. Tools to track a patient’s subtle but important changes over time are important for managing the disease burden as well as assessing promising new therapeutic agents. Therefore, highly reliable, sensitive, and valid disease-specific outcome measures for ALS are vital for clinicians and researchers, as well as patients and family members.

In this study, the authors report the development of the Amyotrophic Lateral Sclerosis-Health Index (ALS-HI), which was created and validated in accordance with FDA guidance. This is a multifactorial, disease-specific patient-reported outcome measure capable of measuring meaningful changes in how an ALS patient feels and functions.

To develop the ALS-HI, the authors surveyed a national cross section of 497 individuals with ALS. After identifying the most important symptoms of ALS, they performed factor analysis, qualitative patient interviews, test-retest reliability assessment, and known groups analysis to evaluate and validate the ALS-HI. Fifteen participants took part in a beta test and found the ALS-HI to be clear, easy to use, and relevant. 

The study supports use of the ALS-HI as a valid, sensitive, and reliable instrument to assess the disease burden of individual patients with ALS. The ALS-HI could also serve as an effective mechanism to track disease progression and treatment efficacy during therapeutic trials.

Mahungu AC, Steyn E, Floudiotis N, Wilson LA, Vandrovcova J, Reilly MM, Record CJ, Benatar M, Wu G, Raga S, Wilmshurst JM, Naidu K, Hanna M, Nel M, Heckmann JM. The mutational profile in a South African cohort with inherited neuropathies and spastic paraplegia. Front Neurol. 2023 Aug 29;14:1239725. doi: 10.3389/fneur.2023.1239725. eCollection 2023.

Zizzi C, Seabury J, Rosero S, Alexandrou D, Wagner E, Weinstein JS, Varma A, Dilek N, Heatwole J, Wuu J, Caress J, Bedlack R, Granit V, Statland JM, Mehta P, Benatar M, Heatwole C. Patient reported impact of symptoms in amyotrophic lateral sclerosis (PRISM-ALS): A national, cross-sectional study. EClinicalMedicine. 2022 Dec 13;55:101768. doi: 10.1016/j.eclinm.2022.101768. PMID: 36531982; PMCID: PMC9755057.

Kessler C, Ruschil C, Abdelhak A, Wilke C, Maleska A, Kuhle J, Krumbholz M, Kowarik MC, Schüle R. Serum. Neurofilament Light Chain and Glial Fibrillary Acidic Protein as Biomarkers in Primary Progressive Multiple Sclerosis and Hereditary Spastic Paraplegia Type 4. Int J Mol Sci. 2022 Nov 3;23(21):13466. doi: 10.3390/ijms232113466. PMID: 36362248; PMCID: PMC9657281.

Primary progressive multiple sclerosis (PPMS) and hereditary spastic paraplegia (HSP) are inherited disorders affecting nerves that send messages to the muscles. Because patients with both disorders can present with slowly progressive spastic paraparesis (weakness in the legs), accurate diagnoses are often challenging. In this study, researchers investigated the use of serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) as biomarkers to support diagnosis. The team assessed sNfl and sGFAP levels in 25 patients with PPMS, 25 patients with spastic paraplegia type 4 (SPG4, the most common type of HSP), and 60 control subjects. Results showed that sNfl levels were significantly higher in patients with PPMS compared to patients with SPG4. Researchers also observed a trend toward relatively higher sGFAP levels in patients with PPMS. However, because both groups of patients showed overlapping biomarker values, the team did not find sNfL and sGFAP to be useful biomarkers. As findings indicate that sNfL and sGFAP are most significantly elevated in the early disease stages of PPMS, authors note that further investigation is warranted.

Albertyn CH, Hardy A, Bakker LA, Hlangani M, Van Der Walt K, Zeilinga B, Thomas KGF, Heckmann JM. Adaptation and norming of the Edinburgh Cognitive and behavioural amyotrophic lateral sclerosis screen (ECAS) for three language groups in South Africa. Amyotroph Lateral Scler Frontotemporal Degener. 2022 Nov;23(7-8):532-541. doi: 10.1080/21678421.2022.2030361. Epub 2022 Feb 4.

Benatar M, Wuu J, Turner MR. Neurofilament light chain in drug development for amyotrophic lateral sclerosis: a critical appraisal. Brain. 2022 Oct 31:awac394. doi: 10.1093/brain/awac394. Epub ahead of print. PMID: 36310538.

Interest in amyotrophic lateral sclerosis (ALS) biomarkers has grown exponentially over the course of the last 25 years, with great hope that they might serve as tools to facilitate the development of meaningful therapies for this otherwise progressive and fatal disease. Effective use of biomarkers, however, requires an understanding of what it means for them to be “fit-for-purpose,” as well as an appreciation of the nuances of the clinical contexts in which they will be applied. Neurofilament light chain (NfL) has emerged as a leading candidate with enormous potential to aid ALS therapy development. However, Nfl is also profoundly misunderstood. Within the conceptual framework of the BEST (Biomarkers, EndpointS, and other Tools) Resource developed by the National Institutes of Health and the Food & Drug Administration in the United States, authors consider the evidence supporting the use of NfL for a variety of purposes in different clinical contexts. Authors conclude that NfL may serve as a susceptibility/risk biomarker in populations at elevated risk for ALS, and that NfL has value as a prognostic biomarker when measured early in the course of established disease. Authors also conclude that NfL may serve as a pharmacodynamic biomarker, as a reduction in NfL in response to an experimental therapeutic might aid go/no-go decisions in phase 2 clinical trials. A reduction in NfL may also be a reasonably likely surrogate endpoint for experimental therapeutics administered early in the course of disease.

Benatar M, Granit V, Andersen PM, Grignon AL, McHutchison C, Cosentino S, Malaspina A, Wuu J. Mild motor impairment as prodromal state in amyotrophic lateral sclerosis: a new diagnostic entity. Brain. 2022 May 20:awac185. doi: 10.1093/brain/awac185. Epub ahead of print. PMID: 35594156.

Amyotrophic lateral sclerosis (ALS) is traditionally regarded as a clinical syndrome. Emerging biomarker evidence of disease prior to clinical manifestations of disease, however, have fostered the view that ALS should be considered a biological entity with pre-symptomatic and clinically manifest stages of disease. New data from Pre-fALS, a natural history and biomarker study of people at genetic risk for ALS, now indicate that pre-symptomatic should not necessarily be taken to mean “clinically silent.” Systematic clinical characterization of 20 phenoconverters–pre-symptomatic gene mutation carriers who have been followed from the pre-symptomatic to the clinically manifest stages of disease–reveals evidence of a prodromal state of mild motor impairment (MMI). MMI is characterized by symptoms, signs, or electromyographic findings that represent a departure from normal, but which are insufficiently severe or widespread to clearly indicate ALS. The duration of prodromal MMI varies among carriers of different genetic mutations. Based on these findings, the authors conclude that in three of the most common genetic forms of ALS, MMI is an observable state that is prodromal to clinically manifest disease. The authors hypothesize that this may also be true for all genetic ALS and non-genetic forms of ALS as well. Importantly, MMI is considered both an intermediate (transitional) and an indeterminate state, as not everyone with MMI will progress to develop ALS. As a new diagnostic label, MMI should generate fresh urgency for developing diagnostic biomarkers that might permit earlier therapeutic intervention.

Chen W, Wang S, Tithi SS, Ellison DW, Schaid DJ, Wu G. A rare variant analysis framework using public genotype summary counts to prioritize disease-predisposition genes. Nat Commun. 2022 May 11;13(1):2592. doi: 10.1038/s41467-022-30248-0.

Wang TW, Wuu J, Cooley A, Yeh TS, Benatar M, Weisskopf M. Occupational lead exposure and survival with amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2022 Apr 9;1-8. doi: 10.1080/21678421.2022.2059379. Online ahead of print.

Environmental risk factors are thought to play a role in ALS risk but may also impact the rate of disease progression and survival. Lead, given its known neurotoxicity, is one such exposure. Prior studies that have relied on biomarkers of lead exposure have yielded conflicting results. In this study, researchers evaluated the relationship between occupational lead exposure prior to onset of ALS on the one hand, and disease progression and survival following onset of ALS on the other hand. Lead exposure was determined using a job-exposure matrix based on occupations held prior to onset of ALS. This approach avoids the potential for reverse causation bias that may result from reliance on lead biomarkers after disease onset. The impact on disease progression was quantified through both survival analysis and estimation of the rate of functional decline. Results suggest that lead exposure before onset of ALS is associated with more rapid functional decline and shorter survival following onset of ALS, even after adjusting for other factors known to influence disease progression.

McMillan CT, Wuu J, Rascovsky K, Cosentino S, Grossman M, Elman L, Quinn C, Rosario L, Stark JH, Granit V, Briemberg H, Chenji S, Dionne A, Genge A, Johnston W, Korngut L, Shoesmith C, Zinman L; Canadian ALS Neuroimaging Consortium (CALSNIC), Kalra S, Benatar M. Defining cognitive impairment in amyotrophic lateral sclerosis: an evaluation of empirical approaches. Amyotroph Lateral Scler Frontotemporal Degener. 2022 Mar 7:1-10. doi: 10.1080/21678421.2022.2039713. Online ahead of print.

Kessler C, Serna-Higuita LM, Wilke C, Rattay TW, Hengel H, Reichbauer J, Stransky E, Leyva-Gutiérrez A, Mengel D, Synofzik M, Schöls L, Martus P, Schüle R. Characteristics of serum neurofilament light chain as a biomarker in hereditary spastic paraplegia type 4. Ann Clin Transl Neurol.. 2022 Mar;9(3):326-338. doi: 10.1002/acn3.51518. Epub 2022 Feb 16. PMID: 35171517; PMCID: PMC8935322.

Hereditary spastic paraplegia (HSP) is a group of inherited neurological disorders characterized by muscle weakness and tightness (spasticity) in the legs. Easily accessible fluid biomarkers are lacking in spastic paraplegia type 4 (SPG4), the most prevalent form of HSP. In this study, researchers investigated serum neurofilament light chain (sNfL) as a potential therapy response, diagnostic, monitoring, and prognostic biomarker in SPG4. The team assessed sNfL levels in 93 patients with SPG4 and 60 healthy controls. They found that sNfL levels are not suitable to monitor disease progression in SPG4, but may be valuable as a therapy response biomarker. Authors note that because sNfL levels appear to be most dynamic around the onset of SPG4, the ability to detect a therapy response is especially promising in younger patients, matching the need to initiate treatment in early disease stages.

Benatar M, Wuu J, McHutchison C, Postuma RB, Boeve BF, Petersen R, Ross CA, Rosen H, Arias JJ, Fradette S, McDermott MP, Shefner J, Stanislaw C, Abrahams S, Cosentino S, Andersen PM, Finkel RS, Granit V, Grignon AL, Rohrer JD, McMillan CT, Grossman M, Al-Chalabi A, Turner MR; First International Pre-Symptomatic ALS Workshop. Preventing amyotrophic lateral sclerosis: insights from pre-symptomatic neurodegenerative diseases. Brain. 2022 Mar 29;145(1):27-44. doi: 10.1093/brain/awab404. PMID: 34677606; PMCID: PMC8967095.

Significant progress has been made in understanding the pre-symptomatic phase of amyotrophic lateral sclerosis (ALS). Much is still unknown, however, and advances in other neurodegenerative diseases—including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), spinal muscular atrophy (SMA), and frontotemporal dementia (FTD)—highlight opportunities for discovery in ALS. This article builds on discussions at the First International Pre-Symptomatic ALS Workshop (January 2020, Miami, Florida). Lessons from AD illustrate the importance of conceptualizing neurodegenerative diseases as biological entities. PD and HD, respectively, highlight the value of prodromal clinical markers and the value of tools to predict age of onset. FTD elucidates nuanced differences in pre-symptomatic disease based on genotype, and SMA underscores the value of early therapeutic intervention. The authors discuss a conceptual framework for pre-symptomatic ALS that includes clinically silent and prodromal stages of disease. They also provide recommendations for the study of motor, cognitive, and behavioral manifestations of early ALS; emphasize the critical importance of biomarkers; discuss the challenges of genetic and biomarker counseling as well as a range of ethical, legal, and social issues relevant to pre-symptomatic disease. Last, but not least, they present ideas about the design of early intervention and disease prevention clinical trials. Ultimately, the authors present a road map to early intervention—and perhaps even disease prevention—for all forms of ALS.

Phillips JS, Nitchie FJ 4th, Da Re F, Olm CA, Cook PA, McMillan CT, Irwin DJ, Gee JC, Dubroff JG, Grossman M, Nasrallah IM; Alzheimer's Disease Neuroimaging Initiative. Rates of longitudinal change in (18) F-flortaucipir PET vary by brain region, cognitive impairment, and age in atypical Alzheimer's disease. Alzheimers Dement. 2022 Jun;18(6):1235-1247. doi: 10.1002/alz.12456. Epub 2021 Sep 13.

Nel M, Mahungu AC, Monnakgotla N, Botha GR, Mulder NJ, Wu G, Rampersaud E, van Blitterswijk M, Wuu J, Cooley A, Myers J, Rademakers R, Taylor JP, Benatar M, Heckmann JM. Revealing the Mutational Spectrum in Southern Africans with Amyotrophic Lateral Sclerosis. Neurol Genet. 2022 Jan 12;8(1):e654. doi: 10.1212/NXG.0000000000000654. PMID: 35047667; PMCID: PMC8756565.

Melina Ramic, Nadja S Andrade, Matthew J Rybin, Rustam Esanov, Claes Wahlestedt, Michael Benatar, Zane Zeier. Epigenetic small moleculars rescue nucleocytoplasmic transport and DNA damage phenotypes in C9ORF72 ALS/FTD. . 2021 Nov 20;11(11):1543. doi: 10.3390/brainsci11111543. PMID: 34827542.

Ramic M, Andrade NS, Rybin MJ, Esanov R, Wahlestedt C, Benatar M, Zeier Z. Epigenetic Small Molecules Rescue Nucleocytoplasmic Transport and DNA Damage Phenotypes in C9ORF72 ALS/FTD. Brain Sci. 2021 Nov 20;11(11):1543. doi: 10.3390/brainsci11111543.

Puentes F, Lombardi V, Lu CH, Yildiz O, Fratta P, Isaacs A, Bobeva Y, Wuu J; ALS Biomarker Consortium; CReATe Consortium, Benatar M, Malaspina A. Humoral response to neurofilaments and dipeptide repeats in ALS progression. Ann Clin Transl Neurol. 2021 Sep;8(9):1831-1844. doi: 10.1002/acn3.51428. Epub 2021 Jul 27.

Neurofilaments, both light chain (NfL) and phosphorylated neurofilament heavy (pNfH), are structural components of axons. Both NfL and pNfH are known to increase during the pre-symptomatic and early symptomatic phases of disease and then to reach a stable but elevated plateau despite continued progression of disease. Although these proteins, most notably NfL, have emerged as the most promising prognostic and potential pharmacodynamic biomarkers, it remains unclear why neurofilament levels do not change as disease progresses. The current study focused on the immune response to neurofilaments (and dipeptide repeat proteins in patients with the C9orf72 genetic form of ALS), quantifying levels of antibodies and immune complexes that represent the humeral response to the release of these proteins. The investigators observed a trend towards increasing concentrations of NfL antibodies and immune complexes over the course of longitudinal follow among patients with faster progressing disease, raising the possibility that the immune response is partially responsible for clearing NfL and stabilizing plasma levels of this protein despite increased production as neurodegeneration progresses.

Lingor P, Koch JC, Statland JM, Hussain S, Hennecke C, Wuu J, Langbein T, Ahmed R, Günther R, Ilse B, Kassubek J, Kollewe K, Kuttler J, Leha A, Lengenfeld T, Meyer T, Neuwirth C, Tostmann R, Benatar M. Challenges and opportunities for Multi-National Investigator-Initiated clinical trials for ALS: European and United States collaborations. Amyotroph Lateral Scler Frontotemporal Degener. 2021 Aug;22(5-6):419-425. doi: 10.1080/21678421.2021.1879866. Epub 2021 Feb 3.

Si Y, Kazamel M, Benatar M, Wuu J, Kwon Y, Kwan T, Jiang N, Kentrup D, Faul C, Alesce L, King PH. FGF23, a novel muscle biomarker detected in the early stages of ALS. Sci Rep. 2021 Jun 8;11(1):12062. doi: 10.1038/s41598-021-91496-6.

Murdock BJ, Famie JP, Piecuch CE, Raue KD, Mendelson FE, Pieroni CH, Iniguez SD, Zhao L, Goutman SA, Feldman EL. NK cells associate with ALS in a sex- and age-dependent manner. JCI Insight. 2021 Jun 8;6(11):e147129. doi: 10.1172/jci.insight.147129.

DeJesus-Hernandez M, Aleff RA, Jackson JL, Finch NA, Baker MC, Gendron TF, Murray ME, McLaughlin IJ, Harting JR, Graff-Radford NR, Oskarsson B, Knopman DS, Josephs KA, Boeve BF, Petersen RC, Fryer JD, Petrucelli L, Dickson DW, Rademakers R, Ebbert MTW, Wieben ED, van Blitterswijk M.. Long-read targeted sequencing ucnovers clinicopathological associations for Cr0rf72-linked diseases. . 2021 May 7;144(4):1082-1088. doi: 10.1093/brain/awab006. PMID: 33889947.

Kessler C, Serna-Higuita LM, Rattay TW, Maetzler W, Wurster I, Hayer S, Wilke C, Hengel H, Reichbauer J, Armbruster M, Schöls L, Martus P, Schüle R. Neurofilament light chain is a cerebrospinal fluid biomarker in hereditary spastic paraplegia. Ann Clin Transl Neurol. 2021 May;8(5):1122-1131. doi: 10.1002/acn3.51358. Epub 2021 Apr 5.

Murdock BJ, Goutman SA, Boss J, Kim S, Feldman EL. Amyotrophic Lateral Sclerosis Survival Associates With Neutrophils in a Sex-specific Manner. Neurol Neuroimmunol Neuroinflamm. 2021 Feb 2;8(2):e953. doi: 10.1212/NXI.0000000000000953. Print 2021 Mar.

Granit V, Grignon AL, Wuu J, Katz J, Walk D, Hussain S, Hernandez J, Jackson C, Caress J, Yosick T, Smider N, Benatar M. Harnessing the power of the electronic health record for ALS research and quality improvement: CReATe CAPTURE-ALS and the ALS Toolkit. Muscle Nerve. 2022 Feb;65(2):154-161. doi: 10.1002/mus.27454. Epub 2021 Nov 16. PMID: 34730240; PMCID: PMC8752483.

Effective use of electronic health record (EHR) data for research purposes has been a long-standing goal of physicians caring for patients with amyotrophic lateral sclerosis (ALS). Several barriers, however, have impeded progress toward this goal, including the limited quality and completeness of clinical documentation, as well as the burden of duplicative entry of clinical data into a research database. To address these barriers, researchers developed the ALS Toolkit, a set of interactive digital forms integrated into the EHR. Used routinely during clinic visits, the ALS Toolkit enables seamless, structured and consistent collection of data elements relevant to ALS patient care, with the expectation that these will also be suitable for research purposes. Since it incorporates AAN quality measures for the care of ALS patients, the ALS Toolkit may also be used to facilitate quality improvement initiatives. CReATe’s Clinical Procedures to Support Research in ALS (CAPTURE-ALS) study utilizes the ALS Toolkit to facilitate multi-center aggregation of data collected at the point of clinical care, empowering research and driving quality improvement. With the goal of collecting data from all patients receiving care through multidisciplinary clinics, CAPTURE-ALS will yield data that reflects the true diversity of populations affected by ALS, rather than the restricted subset of patients currently participating in dedicated research studies.

Placek K, Benatar M, Wuu J, Rampersaud E, Hennessy L, Van Deerlin VM, Grossman M, Irwin DJ, Elman L, McCluskey L, Quinn C, Granit V, Statland JM, Burns TM, Ravits J, Swenson A, Katz J, Pioro EP, Jackson C, Caress J, So Y, Maiser S, Walk D, Lee EB, Trojanowski JQ, Cook P, Gee J, Sha J, Naj AC, Rademakers R; CReATe Consortium, Chen W, Wu G, Paul Taylor J, McMillan CT. Machine learning suggests polygenic risk for cognitive dysfunction in amyotrophic lateral sclerosis. EMBO Mol Med. 2021 Jan 11;13(1):e12595. doi: 10.15252/emmm.202012595. Epub 2020 Dec 3. PMID: 33270986; PMCID: PMC7799365.

Nel M, Mavundla T, Gultig K, Botha G, Mulder N, Benatar M, Wuu J, Cooley A, Myers J, Rampersaud E, Wu G, Heckmann JM. Repeats expansions in ATXN2, NOP56, NIPA1 and ATXN1 are not associated with ALS in Africans. IBRO Neurosci Rep. 2021 Feb 10;10:130-135. doi: 10.1016/j.ibneur.2021.02.002. eCollection 2021 Jun.

Shepheard SR, Karnaros V, Benyamin B, Schultz DW, Dubowsky M, Wuu J, Chataway T, Malaspina A, Benatar M, Rogers ML. Urinary neopterin: A novel biomarker of disease progression in amyotrophic lateral sclerosis. Eur J Neurol. 2021 Dec 29. doi: 10.1111/ene.15237. Epub ahead of print. PMID: 34967083.

Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease that leads to progressive muscle weakness. There are currently no meaningfully effective treatments for ALS, which is invariably fatal. Biomarkers that are suitably fit-for-purpose have great potential to enhance therapy development efforts. A research team led by Dr. Mary Louise-Rogers at Flinders University in Australia has found that urinary neopterin, a marker of an underlying pro-inflammatory state, is elevated in ALS compared to age-matched controls, and progressively increases as the disease advances. In addition to its potential utility as a biomarker of disease progression, neopterin might also have potential as a predictive biomarker, identifying a subset of patients who may stand to benefit from therapeutics that target inflammatory pathways.

Bereman MS, Kirkwood KI, Sabaretnam T, Furlong S, Rowe DB, Guillemin GJ, Mellinger AL, Muddiman DC. Metabolite Profiling Reveals Predictive Biomarkers and the Absence of β-Methyl Amino-l-alanine in Plasma from Individuals Diagnosed with Amyotrophic Lateral Sclerosis. J Proteome Res. 2020 Aug 7;19(8):3276-328. PMID: 32418425.

Habes M, Grothe MJ, Tunc B, McMillan C, Wolk DA, Davatzikos C. Disentangling Heterogeneity in Alzheimer's Disease and Related Dementias Using Data-Driven Methods. Biol Psychiatry. 2020 Jul 1;88(1):70-82. doi: 10.1016/j.biopsych.2020.01.016. Epub 2020 Jan 31.

Andrade N, Ramic M, Esanov R, et al. Dipeptide repeat proteins inhibit homology-directed DNA double strand break repair in C9ORF72 ALS/FTD. Mol Neurodegener. 2020 Feb 24;15(1):13. doi: 10.1186/s13024-020-00365-9. PMID: 32093728; PMCID: PMC7041170.

Figueroa-Romero C,1, Guo K,2, Murdock BJ, et al. Temporal evolution of the microbiome, immune system and epigenome with disease progression in ALS mice. Dis Model Mech. 2020 Feb 1; 13(2). PMCID: PMC6906635, PMID: 31597644.

Lombardi V, Carassiti D, Giovannoni G, Lu CH, Adiutori R, Malaspina A. The potential of neurofilaments analysis using dry-blood and plasma spots. Sci Rep. 2020 Jan 9;10(1):97. PMID: 31919375, PMCID: PMC6952412.

Benatar M, Zhang L, Wang L, Granit V, Statland J, Barohn R, Swenson A, Ravits J, Jackson C, Burns TM, Trivedi J, Pioro EP, Caress J, Katz J, McCauley JL, Rademakers R, Malaspina A, Ostrow LW, Wuu J; CReATe Consortium. Validation of serum neurofilaments as prognostic and potential pharmacodynamic biomarkers for ALS. Neurology. 2020 Jul 7;95(1):e59-e69. PMID: 32385188, PMCID: PMC7371380.

Farhan SMK, Howrigan DP, Abbott LE, Klim JR, Topp SD, Byrnes AE, Churchhouse C, Phatnani H, Smith BN, Rampersaud E, Wu G, Wuu J, Shatunov A, Iacoangeli A, Al Khleifat A, Mordes DA, Ghosh S; ALSGENS Consortium; FALS Consortium; Project MinE Consortium; CReATe Consortium, Eggan K, Rademakers R, McCauley JL, Schüle R, Züchner S, Benatar M, Taylor JP, Nalls M, Gotkine M, Shaw PJ, Morrison KE, Al-Chalabi A, Traynor B, Shaw CE, Goldstein DB, Harms MB, Daly MJ, Neale BM. Exome sequencing in amyotrophic lateral sclerosis implicates a novel gene, DNAJC7, encoding a heat-shock protein. Nat Neurosci. 2019 Dec; 22(12): 1966–1974. PMCID: PMC6919277, PMID: 31768050.

Edmonson MN, Patel AN, Hedges DJ, Wang Z, Rampersaud E, Kesserwan CA, Zhou X, Liu Y, Newman S, Rusch MC, McLeod CL, Wilkinson MR, Rice SV, Soussi T, Taylor JP, Benatar M, Becksfort JB, Nichols KE, Robison LL, Downing JR, Zhang J.. Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE): a cloud-based platform for curating and classifying germline variants. Genome Res. 2019 Sep;29(9):1555-1565. doi: 10.1101/gr.250357.119. Epub 2019 Aug 22. PMID: 31439692.

Aladesuyi Arogundade O, Stauffer JE, Saberi S, Diaz-Garcia S, Malik S, Basilim H, Rodriguez MJ, Ohkubo T, Ravits J. Antisense RNA foci are associated with nucleoli and TDP-43 mislocalization in C9orf72-ALS/FTD: a quantitative study. Acta Neuropathol. 2019 Mar;137(3):527-530. doi: 10.1007/s00401-018-01955-0. Epub 2019 Jan 21. PMID: 30666413; PMCID: PMC6397670.

Placek K, Baer GM, Elman L, McCluskey L, Hennessy L, Ferraro PM, Lee EB, Lee VMY, Trojanowski JQ, Van Deerlin VM, Grossman M, Irwin DJ, McMillan CT. UNC13A polymorphism contributes to frontotemporal disease in sporadic amyotrophic lateral sclerosis. Neurobiol Aging. 2019; 73:190-199. PMID:30368160, PMCID: PMC6251755.

Eidhof I, Baets J, Kamsteeg EJ, Deconinck T, van Ninhuijs L, Martin JJ, Schüle R, Züchner S, De Jonghe P, Schenck A, van de Warrenburg BP. GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia. Brain. 2018 Sep 1;141(9):2592-2604. doi: 10.1093/brain/awy198.

Pottier C, Rampersaud E, Baker M, Wu G, Wuu J, McCauley JL, Zuchner S, Schule R, Bermudez C, Hussain S, Cooley A, Wallace M, Zhang J, Taylor JP, Benatar M, Rademakers R. Identification of compound heterozygous variants in OPTN in an ALS-FTD patient from the CReATe consortium: a case report. Amyotroph Lateral Scler Frontotemporal Degener. 2018 Aug;19(5-6):469-471. doi: 10.1080/21678421.2018.1452947. Epub 2018 Mar 20. PMID: 29558868; PMCID: PMC6116528.

Chen J, Kostenko V, Pioro EP, Trapp BD. MR Imaging-based Estimation of Upper Motor Neuron Density in Patients with Amyotrophic Lateral Sclerosis: A Feasibility Study. Radiology. 2018 Jun;287(3):955-964. doi: 10.1148/radiol.2018162967. Epub 2018 Jan 23. PMID: 29361242; PMCID: PMC5978454.

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Lassuthova P, Rebelo AP, Ravenscroft G, Lamont PJ, Davis MR, Manganelli F, Feely SM, Bacon C, Brožková DŠ, Haberlova J, Mazanec R, Tao F, Saghira C, Abreu L, Courel S, Powell E, Buglo E, Bis DM, Baxter MF, Ong RW, Marns L, Lee YC, Bai Y, Isom DG, Barro-Soria R, Chung KW, Scherer SS, Larsson HP, Laing NG, Choi BO, Seeman P, Shy ME, Santoro L, Zuchner S. Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2. Am J Hum Genet. 2018 Mar 1;102(3):505-514. doi: 10.1016/j.ajhg.2018.01.023. PMID: 29499166; PMCID: PMC5985288.

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Wilke C, Rattay TW, Hengel H, Zimmermann M, Brockmann K, Schöls L, Kuhle J, Schüle R, Synofzik M. Serum neurofilament light chain is increased in hereditary spastic paraplegias. Ann Clin Transl Neurol. 2018;5(7):876-882. PMID:30009206, PMCID: PMC6043776.

Karanevich AG, Weisbrod LJ, Jawdat O, Barohn RJ, Gajewski BJ, He J, Statland JM. Using automated electronic medical record data extraction to model ALS survival and progression. BMC Neurol. 2018;18(1):205. PMID:30547800, PMCID: PMC6295028.

Murdock BJ, Zhou T, Kashlan SR, Little RJ, Goutman SA, Feldman EL. Correlation of Peripheral Immunity With Rapid Amyotrophic Lateral Sclerosis Progression. JAMA neurology. 2017 Dec 1;74(12):1446-1454. doi: 10.1001/jamaneurol.2017.2255. PMID: 28973548; PMCID: PMC5822195.

Schöls L, Rattay TW, Martus P, Meisner C, Baets J, Fischer I, Jägle C, Fraidakis MJ, Martinuzzi A, Saute JA, Scarlato M, Antenora A, Stendel C, Höflinger P, Lourenco CM, Abreu L, Smets K, Paucar M, Deconinck T, Bis DM, Wiethoff S, Bauer P, Arnoldi A, Marques W, Jardim LB, Hauser S, Criscuolo C, Filla A, Züchner S, Bassi MT, Klopstock T, De Jonghe P, Björkhem I, Schüle R. Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial. Brain. 2017 Dec 1;140(12):3112-3127. doi: 10.1093/brain/awx273. PMID: 29126212; PMCID: PMC5841036.

DeJesus-Hernandez M, Finch NA, Wang X, Gendron TF, Bieniek KF, Heckman MG, Vasilevich A, Murray ME, Rousseau L, Weesner R, Lucido A, Parsons M, Chew J, Josephs KA, Parisi JE, Knopman DS, Petersen RC, Boeve BF, Graff-Radford NR, de Boer J, Asmann YW, Petrucelli L, Boylan KB, Dickson DW, van Blitterswijk M, Rademakers R. In-depth clinico-pathological examination of RNA foci in a large cohort of C9ORF72 expansion carriers. Acta Neuropathol. 2017 Aug;134(2):255-269. doi: 10.1007/s00401-017-1725-7. Epub 2017 May 15. PMID: 28508101; PMCID: PMC5508036.

Jacquier A, Delorme C, Belotti E, Juntas-Morales R, Solé G, Dubourg O, Giroux M, Maurage CA, Castellani V, Rebelo A, Abrams A, Züchner S, Stojkovic T, Schaeffer L, Latour P. Cryptic amyloidogenic elements in mutant NEFH causing Charcot-Marie-Tooth 2 trigger aggresome formation and neuronal death. Acta Neuropathol Commun. 2017 Jul 14;5(1):55. doi: 10.1186/s40478-017-0457-1. PMID: 28709447; PMCID: PMC5513089.

Esanov R, Cabrera GT, Andrade NS, Gendron TF, Brown RH Jr, Benatar M, Wahlestedt C, Mueller C, Zeier Z. A C9ORF72 BAC mouse model recapitulates key epigenetic perturbations of ALS/FTD. Mol Neurodegener. 2017 Jun 12;12(1):46. doi: 10.1186/s13024-017-0185-9. PMID: 28606110; PMCID: PMC5468954.

Finch NA, Wang X, Baker MC, Heckman MG, Gendron TF, Bieniek KF, Wuu J, DeJesus-Hernandez M, Brown PH, Chew J, Jansen-West KR, Daughrity LM, Nicholson AM, Murray ME, Josephs KA, Parisi JE, Knopman DS, Petersen RC, Petrucelli L, Boeve BF, Graff-Radford NR, Asmann YW, Dickson DW, Benatar M, Bowser R, Boylan KB, Rademakers R, van Blitterswijk M. Abnormal expression of homeobox genes and transthyretin in C9ORF72 expansion carriers. Neurol Genet. 2017 Jun 7;3(4):e161. doi: 10.1212/NXG.0000000000000161. PMID: 28660252; PMCID: PMC5479438.

Strong MJ, Abrahams S, Goldstein LH, Woolley S, Mclaughlin P, Snowden J, Mioshi E, Roberts-South A, Benatar M, HortobáGyi T, Rosenfeld J, Silani V, Ince PG, Turner MR. Amyotrophic lateral sclerosis - frontotemporal spectrum disorder (ALS-FTSD): Revised diagnostic criteria. Amyotroph Lateral Scler Frontotemporal Degener. 2017 May;18(3-4):153-174. doi: 10.1080/21678421.2016.1267768. Epub 2017 Jan 5. PMID: 28054827; PMCID: PMC7409990.

Gendron TF; C9ORF72 Neurofilament Study Group, Daughrity LM, Heckman MG, Diehl NN, Wuu J, Miller TM, Pastor P, Trojanowski JQ, Grossman M, Berry JD, Hu WT, Ratti A, Benatar M, Silani V, Glass JD, Floeter MK, Jeromin A, Boylan KB, Petrucelli L. Phosphorylated neurofilament heavy chain: A biomarker of survival for C9ORF72-associated amyotrophic lateral sclerosis. Ann Neurol. 2017 Jul;82(1):139-146. doi: 10.1002/ana.24980. PMID: 28628244; PMCID: PMC5676468.

Gendron TF, Chew J, Stankowski JN, Hayes LR, Zhang YJ, Prudencio M, Carlomagno Y, Daughrity LM, Jansen-West K, Perkerson EA, O'Raw A, Cook C, Pregent L, Belzil V, van Blitterswijk M, Tabassian LJ, Lee CW, Yue M, Tong J, Song Y, Castanedes-Casey M, Rousseau L, Phillips V, Dickson DW, Rademakers R, Fryer JD, Rush BK, Pedraza O, Caputo AM, Desaro P, Palmucci C, Robertson A, Heckman MG, Diehl NN, Wiggs E, Tierney M, Braun L, Farren J, Lacomis D, Ladha S, Fournier CN, McCluskey LF, Elman LB, Toledo JB, McBride JD, Tiloca C, Morelli C, Poletti B, Solca F, Prelle A, Wuu J, Jockel-Balsarotti J, Rigo F, Ambrose C, Datta A, Yang W, Raitcheva D, Antognetti G, McCampbell A, Van Swieten JC, Miller BL, Boxer AL, Brown RH, Bowser R, Miller TM, Trojanowski JQ, Grossman M, Berry JD, Hu WT, Ratti A, Traynor BJ, Disney MD, Benatar M, Silani V, Glass JD, Floeter MK, Rothstein JD, Boylan KB, Petrucelli L. Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis. Sci Transl Med. 2017;9(383). PMID: 28356511, PMCID: PMC5576451.

Prudencio M, Gonzales PK, Cook CN, Gendron TF, Daughrity LM, Song Y, Ebbert MTW, van Blitterswijk M, Zhang YJ, Jansen-West K, Baker MC, DeTure M, Rademakers R, Boylan KB, Dickson DW, Petrucelli L, Link CD. Repetitive element transcripts are elevated in the brain of C9orf72 ALS/FTLD patients. Hum Mol Genet. 2017;26(17):3421-3431. PMID: 28637276.

Michael Benatar, Jonathan Katz, David Walk CReATe Consortium ALS Association Muscular Dystrophy Association (MDA). Research Toolkit: Capturing clinical data to advance ALS research. EpicCare Ambulatory. https://galaxy.epic.com/Redirect.aspx?DocumentID=3701881&Version=Epic 2017, EpicCare Ambulatory, 2017.

Mackenzie IR, Nicholson AM, Sarkar M, Messing J, Purice MD, Pottier C, Annu K, Baker M, Perkerson RB, Kurti A, Matchett BJ, Mittag T, Temirov J, Hsiung GR, Krieger C, Murray ME, Kato M, Fryer JD, Petrucelli L, Zinman L, Weintraub S, Mesulam M, Keith J, Zivkovic SA, Hirsch-Reinshagen V, Roos RP, Züchner S, Graff-Radford NR, Petersen RC, Caselli RJ, Wszolek ZK, Finger E, Lippa C, Lacomis D, Stewart H, Dickson DW, Kim HJ, Rogaeva E, Bigio E, Boylan KB, Taylor JP, Rademakers R. TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics. Neuron. 2017;95(4):808-816.e809. PMID: 28817800, PMCID: PMC5576574.

Shepheard SR, Wuu J, Cardoso M, Wiklendt L, Dinning PG, Chataway T, Schultz D, Benatar M, Rogers ML. Urinary p75(ECD): A prognostic, disease progression, and pharmacodynamic biomarker in ALS. Neurology. 2017;88(12):1137-1143. PMID: 28228570, PMCID: PMC5373786.

Murdock BJ, Bender DE, Kashlan SR, et al. Increased ratio of circulating neutrophils to monocytes in amyotrophic lateral sclerosis. Neurology(R) neuroimmunology & neuroinflammation. 2016 Jun 1;3(4):e242. doi: 10.1212/NXI.0000000000000242. PMID: 27308304; PMCID: PMC4897983.

Liu Y, Pattamatta A, Zu T, et al. C9orf72 BAC Mouse Model with Motor Deficits and Neurodegenerative Features of ALS/FTD. Neuron. 2016 May 4;90(3):521-34. doi: 10.1016/j.neuron.2016.04.005. Epub 2016 Apr 21. PMID: 27112499.

Rebelo AP, Abrams AJ, Cottenie E, Horga A, Gonzalez M, Bis DM, Sanchez-Mejias A, Pinto M, Buglo E, Markel K, Prince J, Laura M, Houlden H, Blake J, Woodward C, Sweeney MG, Holton JL, Hanna M, Dallman JE, Auer-Grumbach M, Reilly MM, Zuchner S. Cryptic Amyloidogenic Elements in the 3' UTRs of Neurofilament Genes Trigger Axonal Neuropathy. Am J Hum Genet. 2016 Apr 7;98(4):597-614. doi: 10.1016/j.ajhg.2016.02.022. Epub 2016 Mar 31. PMID: 27040688; PMCID: PMC4833435.

Esanov R, Belle KC, van Blitterswijk M, Belzil VV, Rademakers R, Dickson DW, Petrucelli L, Boylan KB, Dykxhoorn DM, Wuu J, Benatar M, Wahlestedt C, Zeier Z. C9orf72 promoter hypermethylation is reduced while hydroxymethylation is acquired during reprogramming of ALS patient cells. Exp Neurol. Mar 2016;277:171-177. PMID: 26746986, PMCID: PMC4761318.

Benatar M, Boylan K, Jeromin A, Rutkove SB, Berry J, Atassi N, Bruijn L. ALS biomarkers for therapy development: State of the field and future directions. Muscle Nerve. Feb 2016;53(2):169-182. PMID: 26574709, PMCID: PMC4718795.

Benatar M, Stanislaw C, Reyes E, Hussain S, Cooley A, Fernandez MC, Dauphin DD, Michon SC, Andersen PM, Wuu J.. Presymptomatic ALS genetic counseling and testing: Experience and recommendations. Neurology. 2016 Jun 14;86(24):2295-302. doi: 10.1212/WNL.0000000000002773. Epub 2016 May 18.

van Blitterswijk M, Rademakers R. Neurodegenerative disease: C9orf72 repeats compromise nucleocytoplasmic transport. Nat Rev Neurol. 2015 Dec;11(12):670-2. doi: 10.1038/nrneurol.2015.219. Epub 2015 Nov 3. PMID: 26526532.

van Blitterswijk M, Gendron TF, Baker MC, DeJesus-Hernandez M, Finch NA, Brown PH, Daughrity LM, Murray ME, Heckman MG, Jiang J, Lagier-Tourenne C, Edbauer D, Cleveland DW, Josephs KA, Parisi JE, Knopman DS, Petersen RC, Petrucelli L, Boeve BF, Graff-Radford NR, Boylan KB, Dickson DW, Rademakers R. Novel clinical associations with specific C9ORF72 transcripts in patients with repeat expansions in C9ORF72. Acta Neuropathol. Oct 5 2015. PMID: 26437865, PMCID: PMC4655160.

Gendron TF, van Blitterswijk M, Bieniek KF, Daughrity LM, Jiang J, Rush BK, Pedraza O, Lucas JA, Murray ME, Desaro P, Robertson A, Overstreet K, Thomas CS, Crook JE, Castanedes-Casey M, Rousseau L, Josephs KA, Parisi JE, Knopman DS, Petersen RC, Boeve BF, Graff-Radford NR, Rademakers R, Lagier-Tourenne C, Edbauer D, Cleveland DW, Dickson DW, Petrucelli L, Boylan KB. Cerebellar c9RAN proteins associate with clinical and neuropathological characteristics of C9ORF72 repeat expansion carriers. Acta Neuropathol. Oct 2015;130(4):559-573. PMID: 26350237, PMCID: PMC4575385.

Rossor AM, Oates EC, Salter HK, Liu Y, Murphy SM, Schule R, Gonzalez MA, Scoto M, Phadke R, Sewry CA, Houlden H, Jordanova A, Tournev I, Chamova T, Litvinenko I, Zuchner S, Herrmann DN, Blake J, Sowden JE, Acsadi G, Rodriguez ML, Menezes MP, Clarke NF, Auer Grumbach M, Bullock SL, Muntoni F, Reilly MM, North KN. Phenotypic and molecular insights into spinal muscular atrophy due to mutations in BICD2. Brain. 2015 Feb;138(Pt 2):293-310. doi: 10.1093/brain/awu356. Epub 2014 Dec 14. PMID: 25497877; PMCID: PMC4306822.

Turner MR, Benatar M. Ensuring continued progress in biomarkers for amyotrophic lateral sclerosis. Muscle Nerve. Jan 2015;51(1):14-18. PMID: 25288265, PMCID: PMC4270289.

Rollman TB, Berkebile ZW, Hicks DM, Hatfield JS, Chauhan P, Pravetoni M, Schleiss MR, Milligan GN, Morgan TK, Bierle CJ. CD4+ but not CD8+ T cells are required for protection against severe guinea pig cytomegalovirus infections. PLoS Pathog. 2024 Nov 4;20(11):e1012515. doi: 10.1371/journal.ppat.1012515. eCollection 2024 Nov.

Liu BM, Hayes AW. Mechanisms and Assessment of Genotoxicity of Metallic Engineered Nanomaterials in the Human Environment. Biomedicines. 2024 Oct 20;12(10):2401. doi: 10.3390/biomedicines12102401.

Seasely AR, Blanchard CT, Arora N, Battarbee AN, Casey BM, Dionne-Odom J, Leal SM Jr, Moates DB, Sinkey RG, Szychowski JM, Tita AT, Subramaniam A; CWRH's COVID-19 Working Group;. Maternal and Perinatal Outcomes Associated With the Omicron Variant of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection. Obstet Gyneco. 2022 Aug 1;140(2):262-265. doi: 10.1097/AOG.0000000000004849. Epub 2022 May 18. PMID: 35852277.

Seasely AR, Blanchard CT, Arora N, Battarbee AN, Casey BM, Dionne-Odom J, Leal SM Jr, Moates DB, Sinkey RG, Szychowski JM, Tita AT, Subramaniam A; CWRH COVID-19 Working Group. Maternal and Perinatal Outcomes Associated With the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Delta (B.1.617.2) Variant. Obstet Gynecol. 2021 Dec 1;138(6):842-844. doi: 10.1097/AOG.0000000000004607. PMID: 34592747.

Kim S, Ben-Baruch Morgenstern N, Osonoi K, Aceves SS, Arva NC, Chehade M, Collins MH, Dellon ES, Falk GW, Furuta GT, Gonsalves NP, Gupta SK, Hirano I, Hiremath G, Katzka DA, Khoury P, Leung J, Pesek R, Peterson KA, Pletneva MA, Spergel JM, Wechsler JB, Yang GY, Rothenberg ME, Shoda T. Nonepithelial Gene Expression Correlates With Symptom Severity in Adults With Eosinophilic Esophagitis. J Allergy Clin Immunol Pract. 2024 Dec;12(12):3346-3355.e1. doi: 10.1016/j.jaip.2024.05.015. Epub 2024 May 18. PMID: 38768900; PMCID: PMC11570700.

Eosinophilic esophagitis (EoE) is a disorder in which eosinophils (white blood cells of the immune system) build up in the esophagus, causing tissue damage. Symptoms can include difficulty swallowing, food getting stuck in the throat, vomiting, reflux, malnourishment, and poor appetite. Not much is known about the underlying causes of variation in EoE symptoms.

In this study, researchers explored the underlying causes of symptom severity in EoE. First, the team compared a validated patient-reported outcome metric with a set of transcripts expressed in the esophagus of 146 patients with EoE. Next, the team used single-cell RNA sequencing data to identify the cellular source of EoE genes and further analyzed patients with mild and severe symptoms.

Results reveal that EoE symptoms are correlated with nonepithelial esophageal gene expression. Authors note that these findings provide evidence that nonepithelial cells likely contribute to symptom severity.

Su BB, Blackmon W, Xu C, Holt C, Boateng N, Wang D, Szafron V, Anagnostou A, Anvari S, Davis CM. Diagnosis and management of shrimp allergy. Front Allergy. 2024 Oct 18;5:1456999. doi: 10.3389/falgy.2024.1456999. eCollection 2024.

Fulkerson PC, Lussier SJ, Bendixsen CG, Castina SM, Gebretsadik T, Marlin JS, Russell PB, Seibold MA, Everman JL, Moore CM, Snyder BM, Thompson K, Tregoning GS, Wellford S, Arbes SJ, Bacharier LB, Calatroni A, Camargo CA Jr, Dupont WD, Furuta GT, Gruchalla RS, Gupta RS, Hershey GK, Jackson DJ, Johnson CC, Kattan M, Liu AH, Murrison L, O'Connor GT, Phipatanakul W, Rivera-Spoljaric K, Rothenberg ME, Seroogy CM, Teach SJ, Zoratti EM, Togias A, Hartert TV, Heros Study Team OBOT. Human Epidemiology and Response to SARS-CoV-2 (HEROS): objectives, design, and enrollment results of a 12-city remote observational surveillance study of households with children, using direct-to-participant methods. Am J Epidemiol. 2024 Oct 7;193(10):1329-1338. doi: 10.1093/aje/kwae077.

Abonia JP, Rudman Spergel AK, Hirano I, Shoda T, Zhang X, Martin LJ, Mukkada VA, Putnam PE, Blacklidge M, Neilson D, Collins MH, Yang GY, Capocelli KE, Foote H, Eby M, Dong S, Aceves SS, Rothenberg ME; Consortium of Eosinophilic Gastrointestinal Disease Researchers. Losartan Treatment Reduces Esophageal Eosinophilic Inflammation in a Subset of Eosinophilic Esophagitis. J Allergy Clin Immunol Pract. 2024 Sep;12(9):2427-2438.e3. doi: 10.1016/j.jaip.2024.07.011. Epub 2024 Jul 25.

Wright BL, Abonia JP, Abud EM, Aceves SS, Ackerman SJ, Braskett M, Chang JW, Chehade M, Constantine GM, Davis CM, Dellon ES, Doyle AD, Durban R, Hill DA, Jensen ET, Kewalramani A, Khoury P, Klion AD, Kottyan L, Kuang FL, McGowan EC, Ruffner MA, Spencer LA, Spergel JM, Uchida AM, Wechsler JB, Pesek RD. Advances and ongoing challenges in eosinophilic gastrointestinal disorders presented at the CEGIR/TIGERs Symposium at the 2024 American Academy of Allergy, Asthma & Immunology meeting. J Allergy Clin Immunol. 2024 Aug 5:S0091-6749(24)00779-6. doi: 10.1016/j.jaci.2024.07.022. Online ahead of print.

Martin LJ, Zhang X, Chehade M, Davis CM, Dellon ES, Falk GW, Gupta SK, Hirano I, Hiremath GS, Katzka DA, Khoury P, Leung J, Menard-Katcher P, Gonsalves N, Pesek RD, Spergel JM, Wechsler JB, Kliewer K, Arva NC, Collins MH, Pletneva M, Yang GY, Furuta GT, Rothenberg ME, Aceves SS. Long-term durability between parent and child patient-reported outcomes in eosinophilic esophagitis. J Allergy Clin Immunol. 2024 Jul 25:S0091-6749(24)00740-1. doi: 10.1016/j.jaci.2024.07.011. Online ahead of print.

Eosinophilic esophagitis (EoE) is a disorder in which eosinophils (white blood cells of the immune system) build up in the esophagus, causing tissue damage. Symptoms include difficulty swallowing, food getting stuck in the throat, vomiting, reflux, malnourishment, and poor appetite. Because young children are unable to report their own symptoms, parents must report on the child’s behalf. However, not much is known about the long-term alignment of symptoms reported by parents and child patients.

In this study, researchers compared parent and child patient-reported outcomes in EoE over time. A total of 292 parent-child respondents completed 723 questionnaires about symptoms over a 5-year period, which researchers used to track long-term changes and similarities in reported outcomes.

Results show that there is strong long-term alignment between parent and child patient-reported outcomes. Authors note that these findings provide evidence that parent-report by proxy is an accurate means to monitor symptoms, which provides a framework for monitoring pediatric patients in clinical trials. 

Furuta GT, Dellon ES, Straumann A, Gonsalves N, Rothenberg ME, Hirano I. Building and implementing a research infrastructure for eosinophilic gastrointestinal diseases. J Allergy Clin Immunol. 2024 Jun;153(6):1536-1539. doi: 10.1016/j.jaci.2024.04.014.

Burk CM, Shreffler WG. Triggers for eosinophilic esophagitis (EoE): The intersection of food allergy and EoE. J Allergy Clin Immunol. 2024 Jun;153(6):1500-1509. doi: 10.1016/j.jaci.2024.04.010.

Sato H, Dellon ES, Aceves SS, Arva NC, Chehade M, Collins MH, Davis CM, Falk GW, Furuta GT, Gonsalves NP, Gupta SK, Hirano I, Hiremath G, Katzka DA, Khoury P, Leung J, Menard-Katcher P, Pesek R, Peterson KA, Pletneva MA, Spergel JM, Wechsler JB, Yang GY, Rothenberg ME, Shoda T. Clinical and molecular correlates of the Index of Severity for Eosinophilic Esophagitis. J Allergy Clin Immunol. 2024 May 13:S0091-6749(24)00465-2. doi: 10.1016/j.jaci.2024.04.025. Online ahead of print.

Haugen EJ, Locke AK, Correa H, Baba JS, Mahadevan-Jansen A, Hiremath G. Characterization of lamina propria remodeling in pediatric eosinophilic esophagitis using second harmonic generation microscopy. Transl Med Commun. 2024;9(1):10. doi: 10.1186/s41231-024-00170-2. Epub 2024 Mar 22.

Greuter T, Katzka D. Endoscopic Features of Eosinophilic Gastrointestinal Diseases. Immunol Allergy Clin North Am. 2024 May;44(2):357-368. doi: 10.1016/j.iac.2024.01.007. Epub 2024 Feb 13.

Wilson BE, Sacta MA, Wright BL, Spergel J, Wolfset N. The Relationship Between Eosinophilic Esophagitis and Immunotherapy. Immunol Allergy Clin North Am. 2024 May;44(2):281-291. doi: 10.1016/j.iac.2024.01.001. Epub 2024 Feb 14.

Shoda T, Taylor RJ, Sakai N, Rothenberg ME. Common and disparate clinical presentations and mechanisms in different eosinophilic gastrointestinal diseases. J Allergy Clin Immunol. 2024 Jun;153(6):1472-1484. doi: 10.1016/j.jaci.2024.03.013. Epub 2024 Mar 28.

Dehbozorgi S, Ramsey N, Lee ASE, Coleman A, Varshney P, Davis CM. Addressing Health Equity in Food Allergy. J Allergy Clin Immunol Pract. 2024 Mar;12(3):570-577. doi: 10.1016/j.jaip.2024.01.026. Epub 2024 Jan 25.

Cohen-Mekelburg S, Jordan A, Kenney B, Burgess HJ, Chang JW, Hu HM, Tapper E, Langa KM, Levine DA, Waljee AK. Loneliness and Depressive Symptoms Are High Among Older Adults With Digestive Disease and Associated With Lower Perceived Health. Clin Gastroenterol Hepatol. 2024 Mar;22(3):621-629.e2. doi: 10.1016/j.cgh.2023.08.027. Epub 2023 Sep 9.

Macaluso M, Rothenberg ME, Ferkol T, Kuhnell P, Kaminski HJ, Kimberlin DW, Benatar M, Chehade M; Principal Investigators of the Rare Diseases Clinical Research Network – Cycle 4. Impact of the COVID-19 Pandemic on People Living With Rare Diseases and Their Families: Results of a National Survey. JMIR Public Health Surveill. 2024 Feb 14;10:e48430. doi: 10.2196/48430.

Greuter T, Straumann A, Fernandez-Marrero Y, Germic N, Hosseini A, Chanwangpong A, Yousefi S, Simon D, Collins MH, Bussmann C, Chehade M, Dellon ES, Furuta GT, Gonsalves N, Hirano I, Moawad FJ, Biedermann L, Safroneeva E, Schoepfer AM, Simon HU. A MULTICENTER LONG-TERM COHORT STUDY OF EOSINOPHILIC ESOPHAGITIS VARIANTS AND THEIR PROGRESSION TO EOE OVER TIME. Clin Transl Gastroenterol. 2024 Feb 6. doi: 10.14309/ctg.0000000000000664. Epub ahead of print. PMID: 38318864.

Eosinophilic esophagitis (EoE) is a disorder in which eosinophils (white blood cells of the immune system) build up in the esophagus (the tube that carries food from the mouth to the stomach), causing tissue damage. Recently, conditions with symptoms of esophageal dysfunction resembling EoE—but without high amounts of eosinophils in the esophagus—have been characterized as EoE variants. However, not much is known about the progression and severity of these variants.

In this study, researchers investigated the progression of EoE variants to EoE over time. The team assessed clinical, immuno-histological, and molecular features of 54 patients with EoE variants from six EoE centers. Findings were compared with features of EoE patients and healthy controls.

Results suggest a disease spectrum, based on transition from EoE variants to EoE. Authors note that genes associated with the progression to EoE may represent potential therapeutic targets early in the course of disease. 

Chehade M, McGowan EC, Wright BL, Muir AB, Klion AD, Furuta GT, Jensen ET, Bailey DD. Barriers to Timely Diagnosis of Eosinophilic Gastrointestinal Diseases. J Allergy Clin Immunol Pract. 2024 Feb;12(2):302-308. doi: 10.1016/j.jaip.2023.12.020. Epub 2023 Dec 17.

Hirano I, Dellon ES, Falk GW, Gonsalves NP, Furuta GT, Bredenoord AJ; ASCENT WORKING GROUP. Ascending to New Heights for Novel Therapeutics for Eosinophilic Esophagitis. Gastroenterology. 2024 Jan;166(1):1-10. doi: 10.1053/j.gastro.2023.09.004. Epub 2023 Sep 9.

Heil A, Kuehlewindt T, Godat A, Simon HU, Simon D, Schreiner P, Saner C, Vavricka SR, Biedermann L, Safroneeva E, Rossel JB, Limacher A, Straumann A, Schoepfer AM, Greuter T. Histological Phenotyping in Eosinophilic Esophagitis: Localized Proximal Disease Is Infrequent but Associated with Less Severe Disease and Better Disease Outcome. Int Arch Allergy Immunol. 2024;185(1):63-72. doi: 10.1159/000533815. Epub 2023 Oct 20.

Ruffner MA, Shoda T, Lal M, Mrozek Z, Muir AB, Spergel JM, Dellon ES, Rothenberg ME. Persistent esophageal changes after histologic remission in eosinophilic esophagitis. J Allergy Clin Immunol. 2024 Apr;153(4):1063-1072. doi: 10.1016/j.jaci.2023.12.012. Epub 2023 Dec 27.

Peterson K, Collins MH, Aceves SS, Chehade M, Gonsalves N. Concepts and Controversies in Eosinophilic Esophagitis: What's Coming Down the Pipe?. Gastroenterology. 2024 Mar;166(3):382-395. doi: 10.1053/j.gastro.2023.10.035. Epub 2023 Dec 3.

Mehta P, Pan Z, Zhou W, Kwan BM, Furuta GT. Medication Adherence Rates in Adolescents With Eosinophilic Esophagitis Are Low and Are Associated With Health Habits. J Pediatr Gastroenterol Nutr. 2023 Oct 1;77(4):532-535. doi: 10.1097/MPG.0000000000003885. Epub 2023 Sep 20.

Chehade M, Wright BL, Atkins D, Aceves SS, Ackerman SJ, Assa'ad AH, Bauer M, Collins MH, Commins SP, Davis CM, Dellon ES, Doerfler B, Gleich GJ, Gupta SK, Hill DA, Jensen ET, Katzka D, Kliewer K, Kodroff E, Kottyan LC, Kyle S, Muir AB, Pesek RD, Peterson K, Shreffler WG, Spergel JM, Strobel MJ, Wechsler J, Zimmermann N, Furuta GT, Rothenberg ME. Breakthroughs in understanding and treating eosinophilic gastrointestinal diseases presented at the CEGIR/TIGERs Symposium at the 2022 American Academy of Allergy, Asthma & Immunology Meeting. J Allergy Clin Immunol. 2023 Sep 1:S0091-6749(23)01103-X. doi: 10.1016/j.jaci.2023.08.021. Online ahead of print.

Eosinophilic gastrointestinal disorders (EGIDs) are a group of chronic immune system disorders in which a type of white blood cell (eosinophils) build up in the gastrointestinal tract, causing inflammation or injury. 

In February 2022, the American Academy of Allergy, Asthma, and Immunology hosted their annual meeting to discuss innovations in research. During the meeting, CEGIR and the International Gastrointestinal Eosinophil Researchers organized a day-long symposium focused on breakthrough discoveries in EGIDs.

The symposium featured a review of recent discoveries in the basic biology, pathogenesis, and clinical features of EGIDs. Topics included diagnostic and management approaches, as well as clinical trials of emerging therapies.

Kliewer KL, Murray-Petzold C, Collins MH, Abonia JP, Bolton SM, DiTommaso LA, Martin LJ, Zhang X, Mukkada VA, Putnam PE, Kellner ES, Devonshire AL, Schwartz JT, Kunnathur VA, Rosenberg CE, Lyles JL, Shoda T, Klion AD, Rothenberg ME. Benralizumab for eosinophilic gastritis: a single-site, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Gastroenterol Hepatol. 2023 Sep;8(9):803-815. doi: 10.1016/S2468-1253(23)00145-0. Epub 2023 Jun 16.

Mehta P, Pan Z, Zhou W, Burger C, Menard-Katcher C, Bailey DD, Furuta GT. Examining Disparities in Pediatric Eosinophilic Esophagitis. J Allergy Clin Immunol Pract. 2023 Sep;11(9):2855-2859. doi: 10.1016/j.jaip.2023.06.011. Epub 2023 Jun 14.

Gonsalves N, Doerfler B, Zalewski A, Yang GY, Martin LJ, Zhang X, Shoda T, Brusilovsky M, Aceves S, Thompson K, Rudman Spergel AK, Furuta G, Rothenberg ME, Hirano I. Prospective study of an amino acid-based elemental diet in an eosinophilic gastritis and gastroenteritis nutrition trial. J Allergy Clin Immunol. 2023 Sep;152(3):676-688. doi: 10.1016/j.jaci.2023.05.024. Epub 2023 Jul 18.

Uchida AM, Burk CM, Rothenberg ME, Furuta GT, Spergel JM. Recent Advances in the Treatment of Eosinophilic Esophagitis. J Allergy Clin Immunol Pract. 2023 Sep;11(9):2654-2663. doi: 10.1016/j.jaip.2023.06.035. Epub 2023 Jun 28.

Benitez AJ, McGar A, Kohser K, Gibbons T, Muir A, Mascarenhas M, Rossi C, Dogias F, Golden A, Kassam-Adams N, Marsac ML. The Cellie Coping Kit for children with Eosinophilic Esophagitis: Feasibility, acceptability, and preliminary outcomes. J Child Health Care. 2023 Sep;27(3):374-385. doi: 10.1177/13674935211064126. Epub 2022 Jan 3.

Rothenberg ME, Dellon ES, Collins MH, Hirano I, Chehade M, Bredenoord AJ, Lucendo AJ, Spergel JM, Sun X, Hamilton JD, Mortensen E, Laws E, Maloney J, Mannent LP, McCann E, Liu X, Glotfelty L, Shabbir A. Efficacy and safety of dupilumab up to 52 weeks in adults and adolescents with eosinophilic oesophagitis (LIBERTY EoE TREET study): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol. 2023 Aug 31:S2468-1253(23)00204-2. doi: 10.1016/S2468-1253(23)00204-2. Online ahead of print.

Rubenstein JH, Fontaine S, MacDonald PW, Burns JA, Evans RR, Arasim ME, Chang JW, Firsht EM, Hawley ST, Saini SD, Wallner LP, Zhu J, Waljee AK. Predicting Incident Adenocarcinoma of the Esophagus or Gastric Cardia Using Machine Learning of Electronic Health Records. Gastroenterology. 2023 Dec;165(6):1420-1429.e10. doi: 10.1053/j.gastro.2023.08.011. Epub 2023 Aug 18.

Chehade M, Furuta G, Klion A, Abonia JP, Aceves S, Bose P, Collins MH, Davis C, Dellon ES, Eickel G, Falk G, Gupta S, Hiremath G, Howard A, Jensen ET, Kesh S, Khoury P, Kocher K, Kodroff E, Kyle S, Mak N, McCoy D, Mehta P, Menard-Katcher P, Mukkada V, Paliana A, Rothenberg M, Sable K, Schmitt C, Scott M, Spergel J, Strobel MJ, Wechsler JB, Yang GY, Zicarelli A, Muir AB, Wright BL, Bailey DD. Enhancing diversity, equity, inclusion, and accessibility in eosinophilic gastrointestinal disease research: the consortium for eosinophilic gastrointestinal disease researchers' journey. Ther Adv Rare Dis. 2023 Aug 14;4:26330040231180895. doi: 10.1177/26330040231180895. PMID: 37588777; PMCID: PMC10426297

Eosinophilic gastrointestinal diseases (EGIDs) are a group of chronic immune system disorders in which inflammation causes difficulties in daily life and the buildup of a type of white blood cell (eosinophils) in the gastrointestinal tract, which can lead to tissue damage and dysfunction.

To address systemic bias in patient care and research in EGIDs, the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) recently formed a diversity committee. The CEGIR diversity committee has defined its purpose through mission and vision statements. The committee has also developed structured educational and research initiatives to enhance diversity, equity, inclusivity, and accessibility (DEIA) in all CEGIR activities.

In this review article, researchers share the process of forming the diversity committee, highlighting milestones achieved and summarizing future directions. Authors hope that this report will serve as a guide and an inspiration for other researchers to enhance DEIA in their fields.

Chang JW, Kliewer K, Haller E, Lynett A, Doerfler B, Katzka DA, Peterson KA, Dellon ES, Gonsalves N; Consortium of Eosinophilic Gastrointestinal Disease Researchers. Development of a Practical Guide to Implement and Monitor Diet Therapy for Eosinophilic Esophagitis. Clin Gastroenterol Hepatol. 2023 Jul;21(7):1690-1698. doi: 10.1016/j.cgh.2023.03.006. Epub 2023 Mar 16.

Ben-Baruch Morgenstern N, Shoda T, Rochman Y, Caldwell JM, Collins MH, Mukkada V, Putnam PE, Bolton SM, Felton JM, Rochman M, Murray-Petzold C, Kliewer KL, Rothenberg ME. Local type 2 immunity in eosinophilic gastritis. J Allergy Clin Immunol. 2023 Jul;152(1):136-144. doi: 10.1016/j.jaci.2023.01.021. Epub 2023 Feb 7.

Leiman DA, Kamal AN, Otaki F, Bredenoord AJ, Dellon ES, Falk GW, Fernandez-Becker NQ, Gonsalves N, Hirano I, Katzka DA, Peterson K, Yadlapati R, Kathpalia P. Quality Indicators for the Diagnosis and Management of Eosinophilic Esophagitis. Am J Gastroenterol. 2023 Jun 1;118(6):1091-1095. doi: 10.14309/ajg.0000000000002138. Epub 2022 Dec 23.

Masuda MY, LeSuer WE, Horsley-Silva JL, Putikova A, Buras MR, Gibson JB, Pyon GC, Simmons TD, Doyle AD, Wright BL. Food-Specific IgG4 Is Elevated Throughout the Upper Gastrointestinal Tract in Eosinophilic Esophagitis. Dig Dis Sci. 2023 Jun;68(6):2406-2413. doi: 10.1007/s10620-023-07924-2. Epub 2023 Mar 27.

Gautam Y, Caldwell J, Kottyan L, Chehade M, Dellon ES, Rothenberg ME, Mersha TB; Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) investigators. Genome-wide admixture and association analysis identifies African ancestry-specific risk loci of eosinophilic esophagitis in African Americans. J Allergy Clin Immunol. 2023 May;151(5):1337-1350. doi: 10.1016/j.jaci.2022.09.040. Epub 2022 Nov 15.

Kliewer KL, Gonsalves N, Dellon ES, Katzka DA, Abonia JP, Aceves SS, Arva NC, Besse JA, Bonis PA, Caldwell JM, Capocelli KE, Chehade M, Cianferoni A, Collins MH, Falk GW, Gupta SK, Hirano I, Krischer JP, Leung J, Martin LJ, Menard-Katcher P, Mukkada VA, Peterson KA, Shoda T, Rudman Spergel AK, Spergel JM, Yang GY, Zhang X, Furuta GT, Rothenberg ME. One-food versus six-food elimination diet therapy for the treatment of eosinophilic oesophagitis: a multicentre, randomised, open-label trial. Lancet Gastroenterol Hepatol. 2023 May;8(5):408-421. doi: 10.1016/S2468-1253(23)00012-2. Epub 2023 Feb 28.

Hirano I, Rothenberg ME, Zhang S, de Oliveira C, Charriez CM, Coyne KS, Bacci ED, Dellon ES. Dysphagia Days as an Assessment of Clinical Treatment Outcome in Eosinophilic Esophagitis. Am J Gastroenterol. 2023 Apr 1;118(4):744-747. doi: 10.14309/ajg.0000000000002094. Epub 2022 Dec 20.

Shoda T, Rochman M, Collins MH, Caldwell JM, Mack LE, Osswald GA, Mukkada VA, Putnam PE, Rothenberg ME. Molecular analysis of duodenal eosinophilia. J Allergy Clin Immunol. 2023 Apr;151(4):1027-1039. doi: 10.1016/j.jaci.2022.12.814. Epub 2022 Dec 30.

Salvador Nunes VS, Straumann A, Salvador Nunes L, Schoepfer AM, Greuter T. Eosinophilic Esophagitis beyond Eosinophils - an Emerging Phenomenon Overlapping with Eosinophilic Esophagitis: Collegium Internationale Allergologicum (CIA) Update 2023. Int Arch Allergy Immunol. 2023;184(5):411-420. doi: 10.1159/000529910. Epub 2023 Mar 27.

Hiremath G, Sun L, Collins MH, Bonis PA, Arva NC, Capocelli KE, Chehade M, Davis CM, Falk GW, Gonsalves N, Gupta SK, Hirano I, Leung J, Khoury P, Mukkada VA, Martin LJ, Spergel JM, Wechsler JB, Yang GY, Aceves SS, Furuta GT, Rothenberg ME, Koyama T, Dellon ES. Esophageal Epithelium and Lamina Propria Are Unevenly Involved in Eosinophilic Esophagitis. Clin Gastroenterol Hepatol. 2023 Mar 24:S1542-3565(23)00222-7. doi: 10.1016/j.cgh.2023.03.014. Online ahead of print.

Eosinophilic esophagitis (EoE) is a disorder in which eosinophils (white blood cells of the immune system) build up in the esophagus (the tube that carries food from the mouth to the stomach), causing tissue damage. The nature of the involvement of esophageal tissue has been unclear.

In this study, the investigators estimated the intrabiopsy site agreements of an established EoE histologic scoring system (EoEHSS) in the esophageal epithelial and lamina propria and examined if the disease activity status influenced the intrabiopsy site agreement. Comparisons were made between proximal:distal, proximal:middle, and middle:distal esophageal biopsy sites.

Results show that except for the extent of dilated intercellular spaces in inactive EoE, epithelial features and lamina propria were unevenly affected across esophageal biopsy sites, regardless of disease status. Authors note that these findings enhance our understanding of the effects of EoE on esophageal tissue pathology.

Applequist J, Burroughs C, Merkel PA, Rothenberg M, Trapnell B, Desnick R, Sahin M, Krischer J. Direct-to-Consumer Recruitment Methods via Traditional and Social Media to Aid in Research Accrual for Clinical Trials for Rare Diseases: Comparative Analysis Study. J Med Internet Res. 2023 Mar 14;25:e39262. doi: 10.2196/39262.

Furuta GT, Fillon SA, Williamson KM, Robertson CE, Stevens MJ, Aceves SS, Arva NC, Chehade M, Collins MH, Davis CM, Dellon ES, Falk GW, Gonsalves N, Gupta SK, Hirano I, Khoury P, Leung J, Martin LJ, Menard-Katcher P, Mukkada VA, Peterson K, Spergel JM, Wechsler JB, Yang GY, Rothenberg ME, Harris JK. Mucosal Microbiota Associated With Eosinophilic Esophagitis and Eosinophilic Gastritis. J Pediatr Gastroenterol Nutr. 2023 Mar 1;76(3):347-354. doi: 10.1097/MPG.0000000000003685. Epub 2022 Dec 16. PMID: 36525669.

Eosinophilic esophagitis (EoE) and eosinophilic gastritis (EoG) are disorders in which eosinophils (white blood cells) of the immune system build up as a reaction to foods or allergens, causing tissue damage. This immune response occurs in the esophagus in EoE and in the stomach in EoG. To better understand the association of gut microbiota (microorganisms in the digestive tract) with EoE and EoG, multicenter studies with large patient cohorts are needed.

In this study, researchers identified the mucosal microbiota associated with EoE and EoG in a geographically diverse cohort of patients. The team collected and analyzed clinical data, mucosal biopsies, and stool of pediatric and adult individuals with eosinophilic gastrointestinal disease (EGID) from 10 clinical sites within the Consortium of Eosinophilic Gastrointestinal Disease Researchers.

Not surprisingly, microbiome samples collected in the esophagus and stomach were not similar to those collected in the stool, thus emphasizing the importance of site-specific capture of data. Taxa associated with EGIDs varied highly among individuals. Authors note that further research is needed to determine if therapeutic interventions contribute to these differences.

Sindher SB, Barshow S, Tirumalasetty J, Arasi S, Atkins D, Bauer M, Bégin P, Collins MH, Deschildre A, Doyle AD, Fiocchi A, Furuta GT, Garcia-Lloret M, Mennini M, Rothenberg ME, Spergel JM, Wang J, Wood RA, Wright BL, Zuberbier T, Chin AR, Long A, Nadeau KC, Chinthrajah RS. The role of biologics in pediatric food allergy and eosinophilic gastrointestinal disorders. J Allergy Clin Immunol. 2023 Mar;151(3):595-606. doi: 10.1016/j.jaci.2023.01.007. PMID: 36872039; PMCID: PMC9993424.

Eosinophilic gastrointestinal disorders (EGIDs) are a group of chronic immune system disorders in which a type of white blood cell (eosinophils) build up in the gastrointestinal tract, causing inflammation or injury. EGIDs and food allergy (FA) share similar inflammatory mechanisms. Because of this, many of the same biologics (medications developed from biological sources) are being investigated to target these mechanisms in both EGIDs and FA.

In this review article, a team of researchers led by CEGIR scholars discuss the enormous potential of biologics for the treatment of EGIDs and FA in pediatric patients. Discussion includes past and current research into the use of biologics in FA and EGIDs, as well as their potential role in improving treatment options in the future. Authors also note the need for wider availability of biologics for clinical use.

Dellon ES, Spergel JM. Biologics in eosinophilic gastrointestinal diseases. Ann Allergy Asthma Immunol. 2023 Jan;130(1):21-27. doi: 10.1016/j.anai.2022.06.015. Epub 2022 Jun 20.

Underwood B, Troutman TD, Schwartz JT. Breaking down the complex pathophysiology of eosinophilic esophagitis. Ann Allergy Asthma Immunol. 2023 Jan;130(1):28-39. doi: 10.1016/j.anai.2022.10.026. Epub 2022 Nov 6.

Doyle AD, Masuda MY, Pyon GC, Luo H, Putikova A, LeSuer WE, Flashner S, Rank MA, Nakagawa H, Kita H, Wright BL. Detergent exposure induces epithelial barrier dysfunction and eosinophilic inflammation in the esophagus. Allergy. 2023 Jan;78(1):192-201. doi: 10.1111/all.15457. Epub 2022 Aug 8.

Chang JW, Kliewer K, Katzka DA, Peterson KA, Gonsalves N, Gupta SK, Furuta GT, Dellon ES. Provider Beliefs, Practices, and Perceived Barriers to Dietary Elimination Therapy in Eosinophilic Esophagitis. Am J Gastroenterol. 2022 Dec 1;117(12):2071-2074. doi: 10.14309/ajg.0000000000001988. Epub 2022 Sep 1. PMID: 36066475; PMCID: PMC9722505.

Eosinophilic esophagitis (EoE) is a disorder in which eosinophils (white blood cells of the immune system) build up in the esophagus (the tube that carries food from the mouth to the stomach), causing tissue damage. This immune response can occur as a reaction to certain foods. Although effective dietary treatments are often available, physicians tend to prefer medications. In this study, researchers assessed providers’ perceptions of EoE dietary therapy, including effectiveness, practice patterns, and barriers. The team collected this data through a web-based survey of providers. Results show that providers view diet as the least effective treatment for EoE. Barriers to treatment include the belief that patients are disinterested and unlikely to adhere. In addition, providers indicated that with less access to dietitians, nonacademic providers often manage diets without dietitian guidance. As patients are often highly accepting of diets and multiple treatment options for EoE, authors state that clinicians need evidence-based knowledge on EoE diets, access to dietitians, and awareness of patient preferences.

Arar AM, DeLay K, Leiman DA, Menard-Katcher P. Esophageal Manifestations of Dermatological Diseases, Diagnosis and Management. Curr Treat Options Gastroenterol. 2022 Dec;20(4):513-528. doi: 10.1007/s11938-022-00399-6. Epub 2022 Oct 18.

Robinson LB, Ruffner MA. Proton Pump Inhibitors in Allergy: Benefits and Risks. J Allergy Clin Immunol Pract. 2022 Dec;10(12):3117-3123. doi: 10.1016/j.jaip.2022.09.022. Epub 2022 Sep 23.

Rothenberg ME. Scientific journey to the first FDA-approved drug for eosinophilic esophagitis. J Allergy Clin Immunol. 2022 Dec;150(6):1325-1332. doi: 10.1016/j.jaci.2022.09.027. Epub 2022 Oct 6.

Masuda MY, Barshow SM, Garg S, Putikova A, LeSuer WE, Alexander JA, Katzka DA, Dellon ES, Kita H, Horsley-Silva JL, Doyle AD, Wright BL. Eosinophil Peroxidase Staining Enhances the Diagnostic Utility of the Cytosponge in Eosinophilic Esophagitis. Clin Transl Gastroenterol. 2022 Nov 1;13(11):e00534. doi: 10.14309/ctg.0000000000000534.

Namjou B, Lape M, Malolepsza E, DeVore SB, Weirauch MT, Dikilitas O, Jarvik GP, Kiryluk K, Kullo IJ, Liu C, Luo Y, Satterfield BA, Smoller JW, Walunas TL, Connolly J, Sleiman P, Mersha TB, Mentch FD, Hakonarson H, Prows CA, Biagini JM, Khurana Hershey GK, Martin LJ, Kottyan L; eMERGE Network. Multiancestral polygenic risk score for pediatric asthma. J Allergy Clin Immunol. 2022 Nov;150(5):1086-1096. doi: 10.1016/j.jaci.2022.03.035. Epub 2022 May 18.

Larey A, Aknin E, Daniel N, Osswald GA, Caldwell JM, Rochman M, Wasserman T, Collins MH, Arva NC, Yang GY, Rothenberg ME, Savir Y. Harnessing artificial intelligence to infer novel spatial biomarkers for the diagnosis of eosinophilic esophagitis. Front Med (Lausanne). 2022 Oct 21;9:950728. doi: 10.3389/fmed.2022.950728. eCollection 2022.

Ruffner MA, Cotton CC, Dellon ES. Posttreatment Gene Scores Support Histologic and Endoscopic Response Thresholds in Eosinophilic Esophagitis. Am J Gastroenterol. 2022 Sep 1;117(9):1519-1522. doi: 10.14309/ajg.0000000000001802. Epub 2022 Apr 26.

Wechsler JB, Bolton SM, Gray E, Kim KY, Kagalwalla AF. Defining the Patchy Landscape of Esophageal Eosinophilia in Children With Eosinophilic Esophagitis. Clin Gastroenterol Hepatol. 2022 Sep;20(9):1971-1976.e2. doi: 10.1016/j.cgh.2021.12.023. Epub 2021 Dec 23.

Wright BL. Should We Pretreat Before We Go Nuts? Antihistamines Modestly Reduce the Side Effects of Peanut Oral Immunotherapy. J Allergy Clin Immunol Pract. 2022 Sep;10(9):2395-2396. doi: 10.1016/j.jaip.2022.06.015.

Greuter T, Straumann A, Fernandez-Marrero Y, Germic N, Hosseini A, Yousefi S, Simon D, Collins MH, Bussmann C, Chehade M, Dellon ES, Furuta GT, Gonsalves N, Hirano I, Moawad FJ, Biedermann L, Safroneeva E, Schoepfer AM, Simon HU. Characterization of eosinophilic esophagitis variants by clinical, histological, and molecular analyses: A cross-sectional multi-center study. Allergy. 2022 Aug;77(8):2520-2533. doi: 10.1111/all.15233. Epub 2022 Feb 17. PMID: 35094416.

Eosinophilic esophagitis (EoE) is an allergic condition characterized by inflammation in the esophagus that causes a range of symptoms. Patients can have symptoms of esophageal dysfunction without meeting the classical diagnostic criteria. To characterize and classify the range of variants, an international team of researchers studied 69 patients with EoE variants. They identified and described three histological subtypes. Study authors concluded that EoE variants appear to be part of a disease spectrum, with classical EoE as the most common and apparent phenotype.

Wright BL, Schwartz JT, Ruffner MA, Furuta GT, Gonsalves N, Dellon ES, Aceves SS. Eosinophilic gastrointestinal diseases make a name for themselves: A new consensus statement with updated nomenclature. J Allergy Clin Immunol. 2022 Aug;150(2):291-293. doi: 10.1016/j.jaci.2022.05.012. Epub 2022 May 29. PMID: 35649464; PMCID: PMC9378528.

Eosinophilic gastrointestinal diseases (EGIDs) are a group of chronic immune system disorders in which a type of white blood cell (eosinophils) build up in the gastrointestinal tract, causing inflammation or injury. Consensus recommendations have been developed for diagnosis of eosinophilic esophagitis (EoE), the most common EGID. However, there are currently no consensus guidelines for diagnosis of non-EoE EGIDs. Standardization of EGID terminology is one of the first priorities for developing these guidelines. In this study, a large group of researchers and clinicians aimed to reach international consensus for EGID nomenclature. The team used multiple rounds of surveys to develop a new tiered framework for EGID terms. Authors note that this revision of terms could advance both clinical care and research in EGIDs. Next steps include selection of specific disease markers and thresholds, definition of symptoms, exclusion of alternative diagnoses, and duration of disease.

Seibold MA, Moore CM, Everman JL, Williams BJM, Nolin JD, Fairbanks-Mahnke A, Plender EG, Patel BB, Arbes SJ, Bacharier LB, Bendixsen CG, Calatroni A, Camargo CA Jr, Dupont WD, Furuta GT, Gebretsadik T, Gruchalla RS, Gupta RS, Khurana Hershey GK, Murrison LB, Jackson DJ, Johnson CC, Kattan M, Liu AH, Lussier SJ, O'Connor GT, Rivera-Spoljaric K, Phipatanakul W, Rothenberg ME, Seroogy CM, Teach SJ, Zoratti EM, Togias A, Fulkerson PC, Hartert TV; HEROS study team. Risk factors for SARS-CoV-2 infection and transmission in households with children with asthma and allergy: A prospective surveillance study. J Allergy Clin Immunol. 2022 Aug;150(2):302-311. doi: 10.1016/j.jaci.2022.05.014. Epub 2022 Jun 1. PMID: 35660376; PMCID: PMC9155183.

Children and people with asthma or other allergic diseases are typically known as high-risk groups for many respiratory viruses. However, it is currently unknown whether these groups are at increased risk for severe acute respiratory syndrome virus 2 (SARS-CoV-2) infection. In this study, researchers aimed to determine the incidence of SARS-CoV-2 infection in households with children, as well as whether self-reported asthma or other allergic diseases are associated with infection and household transmission. Participants included allergic disease patients from the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR), which provided an accessible cohort for the study. For six months, the team collected biweekly nasal swabs and weekly surveys to calculate the probabilities of infection and transmission. Researchers then used regression analyses to determine associated risk factors. Results suggest that asthma does not increase the risk of SARS-CoV-2 infection. Food allergy was associated with lower infection risk, while body mass index was associated with increased infection risk. Authors note that understanding how these factors modify infection risk may offer new avenues for preventing infection.

Fulkerson PC, Lussier SJ, Bendixsen CG, Castina SM, Gebretsadik T, Marlin JS, Russell PB, Seibold MA, Everman JL, Moore CM, Snyder BM, Thompson K, Tregoning GS, Wellford S, Arbes SJ, Bacharier LB, Calatroni A, Camargo CA, Dupont WD, Furuta GT, Gruchalla RS, Gupta RS, Hershey GK, Jackson DJ, Johnson CC, Kattan M, Liu AH, Murrison L, Oâ Connor GT, Phipatanakul W, Rivera-Spoljaric K, Rothenberg ME, Seroogy CM, Teach SJ, Zoratti EM, Togias A, Hartert TV. Human Epidemiology and RespOnse to SARS-CoV-2 (HEROS): Objectives, Design and Enrollment Results of a 12-City Remote Observational Surveillance Study of Households with Children using Direct-to-Participant Methods. medRxiv. 2022 Jul 10:2022.07.09.22277457. doi: 10.1101/2022.07.09.22277457. Preprint.

Strauss AL, Falk GW. Refractory eosinophilic esophagitis: what to do when the patient has not responded to proton pump inhibitors, steroids and diet. Curr Opin Gastroenterol. 2022 Jul 1;38(4):395-401. doi: 10.1097/MOG.0000000000000842.

Dellon ES, Khoury P, Muir AB, Liacouras CA, Safroneeva E, Atkins D, Collins MH, Gonsalves N, Falk GW, Spergel JM, Hirano I, Chehade M, Schoepfer AM, Menard-Katcher C, Katzka DA, Bonis PA, Bredenoord AJ, Geng B, Jensen ET, Pesek RD, Feuerstadt P, Gupta SK, Lucendo AJ, Genta RM, Hiremath G, McGowan EC, Moawad FJ, Peterson KA, Rothenberg ME, Straumann A, Furuta GT, Aceves SS. A Clinical Severity Index for Eosinophilic Esophagitis: Development, Consensus, and Future Directions. Gastroenterology.. 2022 Jul;163(1):59-76. doi: 10.1053/j.gastro.2022.03.025. Epub 2022 May 20. PMID: 35606197; PMCID: PMC9233087.

For patients with eosinophilic esophagitis (EoE), an allergic inflammatory disease that damages the esophagus, therapeutic options and management are dictated by disease severity. However, the process for determining severity varies among practitioners. Reducing this variability could help improve clinicians’ ability to monitor EoE in an office setting. In this study, researchers aimed to create an international consensus severity scoring index for EoE. First, a group of adult and pediatric EoE researchers and clinicians—as well as non-EoE allergy immunology and gastroenterology experts—reviewed existing literature on EoE in the context of progression and severity. Next, a steering committee reached consensus on important features of severity. These features were then distilled to categorize patients with EoE as having inactive, mild, moderate, or severe disease. This new simplified scoring system, called the Index of Severity for Eosinophilic Esophagitis (I-SEE), can be completed at routine clinic visits. The system can help guide practitioners in EoE management by standardizing features of disease severity beyond eosinophil counts. To increase its utilization and functionality, authors note that I-SEE should be validated and refined using data from future clinical trials and routine clinical practice.

Dellon ES, Khoury P, Muir AB, Liacouras CA, Safroneeva E, Atkins D, Collins MH, Gonsalves N, Falk GW, Spergel JM, Hirano I, Chehade M, Schoepfer AM, Menard-Katcher C, Katzka DA, Bonis PA, Bredenoord AJ, Geng B, Jensen ET, Pesek RD, Feuerstadt P, Gupta SK, Lucendo AJ, Genta RM, Hiremath G, McGowan EC, Moawad FJ, Peterson KA, Rothenberg ME, Straumann A, Furuta GT, Aceves SS. A Clinical Severity Index for Eosinophilic Esophagitis: Development, Consensus, and Future Directions. J Allergy Clin Immunol. 2022 Jul;150(1):33-47. doi: 10.1016/j.jaci.2022.03.015. Epub 2022 May 20.

Daniel N, Larey A, Aknin E, Osswald GA, Caldwell JM, Rochman M, Collins MH, Yang GY, Arva NC, Capocelli KE, Rothenberg ME, Savir Y. A Deep Multi-Label Segmentation Network For Eosinophilic Esophagitis Whole Slide Biopsy Diagnostics. Annu Int Conf IEEE Eng Med Biol Soc. 2022 Jul;2022:3211-3217. doi: 10.1109/EMBC48229.2022.9871086.

Chang JW, Chen VL, Rubenstein JH, Dellon ES, Wallner LP, De Vries R. What patients with eosinophilic esophagitis may not share with their providers: a qualitative assessment of online health communities. Dis Esophagus. 2022 Jun 15;35(6):doab073. doi: 10.1093/dote/doab073. PMID: 34718475.

Eosinophilic esophagitis (EoE) is an allergic inflammatory disease that damages the esophagus. Little is known about how patients with EoE experience their symptoms, receive care, and cope with their disease. Often, patients seek peer support from online communities. As an unfiltered source of patient perspectives, these communities can provide insights on unmet needs and barriers to care. In this study, researchers performed a qualitative analysis of electronic health forums to characterize patient-to-patient conversations about EoE symptoms and the experience of disease. The team analyzed a random sample of conversation threads from three publicly accessible electronic health forums hosting EoE communities. Results showed that patients with EoE interpret their disease as sporadic events and lack reliable sources of knowledge, which may influence how they prioritize treatment. Authors note that providers should equip themselves with evidence-based knowledge, engage in shared decision-making, and look outside of clinical settings in order to recognize barriers to disease management.

Zhang S, Shoda T, Aceves SS, Arva NC, Chehade M, Collins MH, Dellon ES, Falk GW, Gonsalves N, Gupta SK, Hirano I, Khoury P, Leung J, Spergel AKR, Spergel JM, Wechsler JB, Yang GY, Furuta GT, Rothenberg ME; Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) Investigators Group. Mast cell-pain connection in eosinophilic esophagitis. Allergy. 2022 Jun;77(6):1895-1899. doi: 10.1111/all.15260. Epub 2022 Mar 3.

Bon L, Safroneeva E, Bussmann C, Biedermann L, Schreiner P, Vavricka SR, Schoepfer AM, McCright-Gill T, Simon HU, Straumann A, Chehade M, Greuter T. Close follow-up is associated with fewer stricture formation and results in earlier detection of histological relapse in the long-term management of eosinophilic esophagitis. United European Gastroenterol J. 2022 Apr;10(3):308-318. doi: 10.1002/ueg2.12216. Epub 2022 Apr 5. PMID: 35384368.

Eosinophilic esophagitis (EoE) is characterized by immune cells called eosinophils building up in the esophagus, which may cause polyps, tissue break down, inflammation, and ulcers. The follow-up schedule for maintenance treatment of EoE varies, possibly due to a lack of a recommended schedule. In this study, researchers analyzed "close follow-up" (less than 18 months between maintenance visits) and "non-close follow-up" (greater than or equal to 18 months between maintenance visits) for steroid treatment of EoE. They found that close follow-up was associated with less stricture formation (abnormal narrowing) and earlier detection of EoE relapse by histology. Authors note that regular assessment of EoE disease activity (every 12-18 months) may be beneficial in detecting relapsing disease as early as possible, therefore potentially minimizing the risk for EoE complications.

Safroneeva E, Pan Z, King E, Martin LJ, Collins MH, Yang GY, Capocelli KE, Arva NC, Abonia JP, Atkins D, Bonis PA, Dellon ES, Falk GW, Gonsalves N, Gupta SK, Hirano I, Leung J, Menard-Katcher PA, Mukkada VA, Schoepfer AM, Spergel JM, Wershil BK, Rothenberg ME, Aceves SS, Furuta GT; Consortium of Eosinophilic Gastrointestinal Disease Researchers. Long-Lasting Dissociation of Esophageal Eosinophilia and Symptoms After Dilation in Adults With Eosinophilic Esophagitis. Clin Gastroenterol Hepatol. 2022 Apr;20(4):766-775.e4. doi: 10.1016/j.cgh.2021.05.049. Epub 2021 May 29.

Dellon ES, Gonsalves N, Rothenberg ME, Hirano I, Chehade M, Peterson KA, Falk GW, Murray JA, Gehman LT, Chang AT, Singh B, Rasmussen HS, Genta RM. Determination of Biopsy Yield That Optimally Detects Eosinophilic Gastritis and/or Duodenitis in a Randomized Trial of Lirentelimab. Clin Gastroenterol Hepatol. 2022 Mar;20(3):535-545.e15. doi: 10.1016/j.cgh.2021.05.053. Epub 2021 Jun 2.

Rothenberg ME, Hottinger SKB, Gonsalves N, Furuta GT, Collins MH, Talley NJ, Peterson K, Menard-Katcher C, Smith M, Hirano I, Genta RM, Chehade M, Gupta SK, Spergel JM, Aceves SS, Dellon ES. Impressions and aspirations from the FDA GREAT VI Workshop on Eosinophilic Gastrointestinal Disorders Beyond Eosinophilic Esophagitis and Perspectives for Progress in the Field. J Allergy Clin Immunol. 2022 Mar;149(3):844-853. doi: 10.1016/j.jaci.2021.12.768. Epub 2021 Dec 22.

Dellon ES, Gonsalves N, Abonia JP, Alexander JA, Arva NC, Atkins D, Attwood SE, Auth MKH, Bailey DD, Biederman L, Blanchard C, Bonis PA, Bose P, Bredenoord AJ, Chang JW, Chehade M, Collins MH, Di Lorenzo C, Dias JA, Dohil R, Dupont C, Falk GW, Ferreira CT, Fox AT, Genta RM, Greuter T, Gupta SK, Hirano I, Hiremath GS, Horsley-Silva JL, Ishihara S, Ishimura N, Jensen ET, Gutiérrez-Junquera C, Katzka DA, Khoury P, Kinoshita Y, Kliewer KL, Koletzko S, Leung J, Liacouras CA, Lucendo AJ, Martin LJ, McGowan EC, Menard-Katcher C, Metz DC, Miller TL, Moawad FJ, Muir AB, Mukkada VA, Murch S, Nhu QM, Nomura I, Nurko S, Ohtsuka Y, Oliva S, Orel R, Papadopoulou A, Patel DA, Pesek RD, Peterson KA, Philpott H, Putnam PE, Richter JE, Rosen R, Ruffner MA, Safroneeva E, Schreiner P, Schoepfer A, Schroeder SR, Shah N, Souza RF, Spechler SJ, Spergel JM, Straumann A, Talley NJ, Thapar N, Vandenplas Y, Venkatesh RD, Vieira MC, von Arnim U, Walker MM, Wechsler JB, Wershil BK, Wright BL, Yamada Y, Yang GY, Zevit N, Rothenberg ME, Furuta GT, Aceves SS. International Consensus Recommendations for Eosinophilic Gastrointestinal Disease Nomenclature. Clin Gastroenterol Hepatol. 2022 Feb 16:S1542-3565(22)00143-4. doi: 10.1016/j.cgh.2022.02.017. Online ahead of print.

Hiremath G, Sun L, Correa H, Acra S, Collins MH, Bonis P, Arva NC, Capocelli KE, Falk GW, King E, Gonsalves N, Gupta SK, Hirano I, Mukkada VA, Martin LJ, Putnam PE, Spergel JM, Wechsler JB, Yang GY, Aceves SS, Furuta GT, Rothenberg ME, Koyama T, Dellon ES. Development and Validation of Web-Based Tool to Predict Lamina Propria Fibrosis in Eosinophilic Esophagitis. Am J Gastroenterol. 2022 Feb 1;117(2):272-279. doi: 10.14309/ajg.0000000000001587.

Dunn JLM, Rothenberg ME. 2021 year in review: Spotlight on eosinophils. J Allergy Clin Immunol. 2022 Feb;149(2):517-524. doi: 10.1016/j.jaci.2021.11.012. Epub 2021 Nov 25.

COREOS Collaborators:, Ma C, Schoepfer AM, Dellon ES, Bredenoord AJ, Chehade M, Collins MH, Feagan BG, Furuta GT, Gupta SK, Hirano I, Jairath V, Katzka DA, Pai RK, Rothenberg ME, Straumann A, Aceves SS, Alexander JA, Arva NC, Atkins D, Biedermann L, Blanchard C, Cianferoni A, Ciriza de Los Rios C, Clayton F, Davis CM, de Bortoli N, Dias JA, Falk GW, Genta RM, Ghaffari G, Gonsalves N, Greuter T, Hopp R, Hsu Blatman KS, Jensen ET, Johnston D, Kagalwalla AF, Larsson HM, Leung J, Louis H, Masterson JC, Menard-Katcher C, Menard-Katcher PA, Moawad FJ, Muir AB, Mukkada VA, Penagini R, Pesek RD, Peterson K, Putnam PE, Ravelli A, Savarino EV, Schlag C, Schreiner P, Simon D, Smyrk TC, Spergel JM, Taft TH, Terreehorst I, Vanuytsel T, Venter C, Vieira MC, Vieth M, Vlieg-Boerstra B, von Arnim U, Walker MM, Wechsler JB, Woodland P, Woosley JT, Yang GY, Zevit N, Safroneeva E. Development of a core outcome set for therapeutic studies in eosinophilic esophagitis (COREOS). J Allergy Clin Immunol. 2022 Feb;149(2):659-670. doi: 10.1016/j.jaci.2021.07.001. Epub 2021 Jul 6.

Min S, Shoda T, Wen T, Rothenberg ME. Diagnostic merits of the Eosinophilic Esophagitis Diagnostic Panel from a single esophageal biopsy. J Allergy Clin Immunol. 2022 Feb;149(2):782-787.e1. doi: 10.1016/j.jaci.2021.07.032. Epub 2021 Aug 8.

Hara T, Kasagi Y, Wang J, Sasaki M, Aaron B, Karami A, Shimonosono M, Shimonosono R, Maekawa H, Dolinsky L, Wilkins B, Klein J, Wei J, Nunes K, Lynch K, Spergel JM, Hamilton KE, Ruffner MA, Karakasheva TA, Whelan KA, Nakagawa H, Muir AB. CD73(+) Epithelial Progenitor Cells That Contribute to Homeostasis and Renewal Are Depleted in Eosinophilic Esophagitis. Cell Mol Gastroenterol Hepatol. 2022;13(5):1449-1467. doi: 10.1016/j.jcmgh.2022.01.018. Epub 2022 Jan 30.

Shoda T, Collins MH, Rochman M, Wen T, Caldwell JM, Mack LE, Osswald GA, Besse JA, Haberman Y, Aceves SS, Arva NC, Capocelli KE, Chehade M, Davis CM, Dellon ES, Falk GW, Gonsalves N, Gupta SK, Hirano I, Khoury P, Klion A, Menard-Katcher C, Leung J, Mukkada V, Putnam PE, Spergel JM, Wechsler JB, Yang GY, Furuta GT, Denson LA, Rothenberg ME; Consortium of Eosinophilic Gastrointestinal Diseases Researchers (CEGIR). Evaluating Eosinophilic Colitis as a Unique Disease using Colonic Molecular Profiles: A Multi-Site Study. Gastroenterology. 2022 Jan 24:S0016-5085(22)00038-5. doi: 10.1053/j.gastro.2022.01.022. Epub ahead of print. PMID: 35085569.

Eosinphilic colitis (EoC) has been a poorly understood condition with uncertainty whether it is a distinct disease or a manifestation of eosinophilic gastrointestinal disease or inflammatory bowel disease. Researchers from the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) seeking to better understand the condition analyzed samples from more than 60 people treated at multiple medical centers v. controls to compare this rare disease to other conditions. They identified and analyzed 987 differentially expressed genes, established EoC transcriptomic profiles, identified mechanistic pathways, and compared findings with related conditions. They concluded that EoC is a distinct disease, establishing a basis for improved diagnosis and treatment.

Hirano I, Collins MH, King E, Sun Q, Chehade M, Abonia JP, Bonis PA, Capocelli KE, Dellon ES, Falk GW, Gonsalves N, Gupta SK, Leung J, Katzka D, Menard-Katcher P, Khoury P, Klion A, Mukkada VA, Peterson K, Rudman-Spergel AK, Spergel JA, Yang GY, Rothenberg ME, Aceves SS, Furuta GT. Prospective Endoscopic Activity Assessment for Eosinophilic Gastritis in a Multisite Cohort. Am J Gastroenterol. 2022 Jan 20. doi: 10.14309/ajg.0000000000001625. Epub ahead of print. PMID: 35080202.

Eosinophilic gastritis (EG) is a chronic inflammatory disease of the stomach that occurs when certain white blood cells known as eosinophils gather in large numbers in the stomach, causing injury and irritation. In this study, researchers aimed to better understand the endoscopic manifestations of EG and develop a standardized instrument for investigations. Using data prospectively collected as part of CEGIR, the team evaluated endoscopic features of children and adults with EG recorded with the EG Endoscopic Reference System (EG-REFS). Researchers identified a strong correlation between EG-REFS scores and physician global assessment of endoscopy severity. EG-REFS severity was significantly correlated with active histology and a tendency for the gastric antrum (lower portion of the stomach). The authors note that further development of EG-REFS should improve its utility in clinical studies.

Trogen B, Jin H, Cianferoni A, Chehade M, Schultz F, Chavez A, Warren C, Nowak-Wegrzyn AH. A survey examining the impact of COVID-19 on food protein-induced enterocolitis syndrome. J Allergy Clin Immunol Pract. 2022 Jan;10(1):312-314.e3. doi: 10.1016/j.jaip.2021.10.053. Epub 2021 Nov 2.

Zevit N, Chehade M, Leung J, Marderfeld L, Dellon ES. Eosinophilic Esophagitis Patients Are Not at Increased Risk of Severe COVID-19: A Report From a Global Registry. J Allergy Clin Immunol Pract. 2022 Jan;10(1):143-149.e9. doi: 10.1016/j.jaip.2021.10.019. Epub 2021 Oct 22.

McGowan EC, Keller JP, Muir AB, Dellon ES, Peng R, Keet CA, Jensen ET. Distance to pediatric gastroenterology providers is associated with decreased diagnosis of eosinophilic esophagitis in rural populations. J Allergy Clin Immunol Pract. 2021 Dec;9(12):4489-4492.e2. doi: 10.1016/j.jaip.2021.08.034. Epub 2021 Sep 14. PMID: 34534720; PMCID: PMC8671202.

Eosinophilic esophagitis (EoE) is characterized by immune cells called eosinophils building up in the esophagus, which may cause polyps, tissue break down, inflammation, and ulcers. In this cross-sectional study, researchers examined data from children enrolled in Medicaid 2012. They found that the apparent lower prevalence of eosinophilic esophagitis in rural communities was attenuated when adjusting for distance to provider. These results suggest that diagnostic disparities likely exist for eosinophilic esophagitis among children residing in rural areas.

Qeadan F, Chehade M, Tingey B, Egbert J, Dellon ES, Peterson KA. Patients with eosinophilic gastrointestinal disorders have lower in-hospital mortality rates related to COVID-19. J Allergy Clin Immunol Pract. 2021 Dec;9(12):4473-4476.e4. doi: 10.1016/j.jaip.2021.09.022. Epub 2021 Sep 23. PMID: 34563741; PMCID: PMC8459462.

Little is known about eosinophilic gastrointestinal disease (EGID) and COVID-19 outcomes. By reducing viral entry into cells, the mucosal responses of patients with EGID may protect against severe effects of COVID-19. In this study, researchers compared hospitalization rates, ventilator dependence, and death between patients with and without EGID. When compared with non–EGID COVID-19 positive patients, they found that EGID COVID-19 positive individuals stayed longer in the hospital, yet had lower rates of inpatient mortality. This analysis suggests that EGID may provide a protective effect against severe COVID-19 outcomes. In future studies, researchers plan to further explore the protective role of reduced expression of ACE2/TMPRSS2 and the eosinophilic disease itself in COVID-19 mortality.

Hasan SH, Taylor S, Garg S, Buras MR, Doyle AD, Bauer CS, Wright BL, Schroeder S. Diagnosis of Pediatric Non-Esophageal Eosinophilic Gastrointestinal Disorders by Eosinophil Peroxidase Immunohistochemistry. Pediatr Dev Pathol. 2021 Nov-Dec;24(6):513-522. doi: 10.1177/10935266211024552. Epub 2021 Jun 28.

Muir A, Falk GW. Eosinophilic Esophagitis: A Review. JAMA. 2021 Oct 5;326(13):1310-1318. doi: 10.1001/jama.2021.14920.

Researchers affiliated with the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) have published a new review paper examining eosinophilic esophagitis (EoE), an allergic inflammatory disease. EoE is characterized by elevated eosinophils (a type of disease-fighting white blood cell) in the esophagus (the tube connecting the mouth to the stomach). It affects an estimated 34.4/100,000 people in Europe and North America, including both children and adults. To diagnose the disease and evaluate treatment efficacy, a doctor inserts a thin, flexible tube with a light and camera at the end through a patient’s mouth, into the stomach, and sometimes into the upper intestine and collects tissue samples. In this paper, researchers discuss symptoms of the disease along with genetic and environmental factors associated with it. They also examine several current therapies, including proton pump inhibitors, topical steroid preparations, dietary therapy, and endoscopic dilation, and summarize recent systematic reviews of therapy trials.

Zimmermann N, Abonia JP, Dreskin SC, Akin C, Bolton S, Happel CS, Geller M, Larenas-Linnemann D, Nanda A, Peterson K, Wasan A, Wechsler J, Zhang S, Bernstein JA. Developing a standardized approach for assessing mast cells and eosinophils on tissue biopsies: A Work Group Report of the AAAAI Allergic Skin Diseases Committee. J Allergy Clin Immunol. 2021 Oct;148(4):964-983. doi: 10.1016/j.jaci.2021.06.030. Epub 2021 Aug 9. PMID: 34384610.

In human tissue biopsies, mast cells and eosinophils are commonly found. However, for several clinical conditions, there are knowledge gaps in determining diagnostic thresholds and how samples are processed, interpreted, and reported. These discrepancies can delay the correct diagnosis of a patient’s condition. A work group of pathology, allergy, dermatology, hematology/oncology, and gastroenterology stakeholders assembled to address this need. Together, the group developed a standardized approach for assessing mast cells and eosinophils in skin, gastrointestinal, and bone marrow pathologic specimens for the benefit of clinical practice and patients.

Melethil S, Abonia JP. A Gut-Wrenching Case of Hypereosinophilia. J Allergy Clin Immunol Pract. 2021 Sep;9(9):3524-3525. doi: 10.1016/j.jaip.2021.05.039. PMID: 34507713.

In a case study of hypereosinophilia, an allergic inflammatory condition in which white blood cells called eosinophils are at high levels in the body, a pediatric patient had recurrent gastrointestinal symptoms and histology showing elevated eosinophils in biopsy specimens. After excluding secondary causes of gastrointestinal eosinophilia, the clinicians diagnosed the patient with eosinophilic gastroenteritis (EGE). Eosinophilic gastritis (EG) and EGE are a heterogeneous group of rare disorders due to selective eosinophilic infiltration causing inflammation in the stomach and small intestine, in the absence of other secondary causes of eosinophilia. The exact incidence is unknown but is more commonly diagnosed in children younger than 5 years. In adults, the peak age of diagnosis is in the third decade of life. Authors say this case exemplifies two key points for healthcare providers: 1) Refer patients presenting with peripheral eosinophilia and recurrent or persistent gastrointestinal (GI) symptoms for evaluation for an intestinal biopsy and 2) Recognize that eosinophilic gastrointestinal diseases can be diagnosed only after other secondary causes of eosinophilia like parasitic infections or drug-induced causes are ruled out.

Chehade M, Aceves SS. Treatment of Eosinophilic Esophagitis: Diet or Medication?. J Allergy Clin Immunol Pract. 2021 Sep;9(9):3249-3256. doi: 10.1016/j.jaip.2021.07.029. PMID: 34507706.

Eosinophilic esophagitis (EoE) is an allergic inflammatory disease characterized by elevated eosinophils (white blood cells) in the esophagus (the tube connecting the mouth to the stomach). The prevalence of EoE is increasing in children and adults. As a chronic condition currently without a cure, EoE must be carefully managed to prevent complications, such as food impactions in the esophagus or narrowing of the lumen. In this paper, researchers discuss the current approaches for dietary and pharmacologic management of EoE and the need for future clinical trials to help tailor therapies to individual patients with this chronic disease.

Friedlander JA, Fleischer DM, Black JO, Levy M, Rothenberg ME, Smith C, Nguyen N, Pan Z, Furuta GT. Unsedated transnasal esophagoscopy with virtual reality distraction enables earlier monitoring of dietary therapy in eosinophilic esophagitis. J Allergy Clin Immunol Pract. 2021 Sep;9(9):3494-3496. doi: 10.1016/j.jaip.2021.06.030. Epub 2021 Jul 2. PMID: 34224927; PMCID: PMC8459391.

Eosinophilic esophagitis is a chronic, inflammatory disease of the esophagus often treated with an elimination diet, where patients avoid specific foods that are triggering the disease. The current standard of care for diagnosis and symptom monitoring requires repeated sedated endoscopy procedures over time. After the initial diagnostic endoscopy, many assessments may be needed to establish the correct diet. For patients, these repeated diagnostic procedures raise issues of risk, cost, and lost time from school and/or work. They also extend the time patients must wait to reintroduce foods. In this study, researchers seeking to address these concerns tested the use of an emerging technology, less invasive monitoring approach compared with standard endoscopy—unsedated transnasal esophagoscopy (TN-Eso) with virtual reality distraction. Although this was a pilot study involving only five patients, the researchers found that TN-Eso was well-tolerated and preferred by patients and families. Tests using the new technology detected the return of esophagitis as soon as two weeks after single-food exposure, suggesting that the timing of food reintroductions could be shortened by 50% to 75%, compared with the traditional endoscopies (which typically occur at 12-week intervals). Study authors say these findings support a shortened challenge period with the use of TN-Eso, which may lead to faster identification of a suitable treatment. The study also demonstrates that food allergen-induced eosinophilic esophagitis occurs within two weeks following exposure to the triggering food.

Ruffner MA, Zhang Z, Maurer K, Muir AB, Cianferoni A, Sullivan KE, Spergel JM. RNA sequencing identifies global transcriptional changes in peripheral CD4(+) cells during active oesophagitis and following epicutaneous immunotherapy in eosinophilic oesophagitis. Clin Transl Immunology. 2021 Jul 22;10(7):e1314. doi: 10.1002/cti2.1314. eCollection 2021.

Davis CM. Moving FORWARD Toward Racial Equity in Food Allergy. J Allergy Clin Immunol Pract. 2021 Jul;9(7):2874-2875. doi: 10.1016/j.jaip.2021.04.066.

Joshi S, Rubenstein JH, Dellon ES, Worthing N, Stefanadis Z, Chang JW. Variability in Practices of Compounding Budesonide for Eosinophilic Esophagitis. Am J Gastroenterol. 2021 Jun 1;116(6):1336-1338. doi: 10.14309/ajg.0000000000001170.

Sabet C, Klion AD, Bailey D, Jensen E, Chehade M, Abonia JP, Rothenberg ME, Furuta GT, Muir AB; CEGIR Investigator Group. Do rural health disparities affect prevalence data in pediatric eosinophilic esophagitis?. J Allergy Clin Immunol Pract. 2021 Jun;9(6):2549-2551. doi: 10.1016/j.jaip.2021.03.027.

Chang JW, Rubenstein JH, Mellinger JL, Kodroff E, Strobel MJ, Scott M, Mack D, Book W, Sable K, Kyle S, Paliana A, Dellon ES. Motivations, Barriers, and Outcomes of Patient-Reported Shared Decision Making in Eosinophilic Esophagitis. Dig Dis Sci. 2021 Jun;66(6):1808-1817. doi: 10.1007/s10620-020-06438-5. Epub 2020 Jul 3.

Chiang AWT, Duong LD, Shoda T, Nhu QM, Ruffner M, Hara T, Aaron B, Joplin E, Manresa MC, Abonia JP, Dellon ES, Hirano I, Gonsalves N, Gupta SK, Furuta GT, Rothenberg ME, Lewis NE, Muir AB, Aceves SS; CEGIR Investigator Group. Type 2 Immunity and Age Modify Gene Expression of Coronavirus-induced Disease 2019 Receptors in Eosinophilic Gastrointestinal Disorders. J Pediatr Gastroenterol Nutr. 2021 May 1;72(5):718-722. doi: 10.1097/MPG.0000000000003032.

Eosinophilic gastrointestinal disorders are inflammatory conditions caused by chronic type 2 (T2) inflammation. In this study, researchers sought to better understand the impact of this T2 inflammation on susceptibility to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the virus that causes coronavirus-induced disease 2019 (COVID-19). Researchers analyzed gene expression data in pediatric eosinophilic esophagitis, eosinophilic gastritis, and in normal adults using publicly available datasets. They concluded that eosinophilic gastrointestinal diseases are not risk factors for COVID-19. and that T2 immunity & pediatric age could be protective for SARS-CoV-2 infection in the GI tract.

Benitez AJ, Tanes C, Mattei L, Hofstaedter CE, Kim DK, Gross J, Ruffner MA, Albenberg L, Spergel J, Bittinger K, Muir AB. Effect of topical swallowed steroids on the bacterial and fungal esophageal microbiota in eosinophilic esophagitis. Allergy. 2021 May;76(5):1549-1552. doi: 10.1111/all.14602. Epub 2020 Oct 19.

Wechsler JB, Ackerman SJ, Chehade M, Amsden K, Riffle ME, Wang MY, Du J, Kleinjan ML, Alumkal P, Gray E, Kim KA, Wershil BK, Kagalwalla AF. Noninvasive biomarkers identify eosinophilic esophagitis: A prospective longitudinal study in children. Allergy. 2021 Apr 27. doi: 10.1111/all.14874. Online ahead of print.

Jacobsen EA, Jackson DJ, Heffler E, Mathur SK, Bredenoord AJ, Pavord ID, Akuthota P, Roufosse F, Rothenberg ME. Eosinophil Knockout Humans: Uncovering the Role of Eosinophils Through Eosinophil-Directed Biological Therapies. Annu Rev Immunol. 2021 Apr 26;39:719-757. doi: 10.1146/annurev-immunol-093019-125918. Epub 2021 Mar 1.

Wechsler JB, Schwartz S, Arva NC, Kim KA, Chen L, Makhija M, Amsden K, Keeley K, Mohammed S, Dellon ES, Kagalwalla AF. A Single-Food Milk Elimination Diet Is Effective for Treatment of Eosinophilic Esophagitis in Children. Clin Gastroenterol Hepatol. 2021 Apr 3:S1542-3565(21)00384-0. doi: 10.1016/j.cgh.2021.03.049. Online ahead of print.

Moore H, Wechsler J, Frost C, Whiteside E, Baldassano R, Markowitz J, Muir AB. Comorbid Diagnosis of Eosinophilic Esophagitis and Inflammatory Bowel Disease in the Pediatric Population. J Pediatr Gastroenterol Nutr. 2021 Mar 1;72(3):398-403. doi: 10.1097/MPG.0000000000003002.

Hamant L, Freeman C, Garg S, Wright BL, Schroeder S. Eosinophilic esophagitis may persist after discontinuation of oral immunotherapy. Ann Allergy Asthma Immunol. 2021 Mar;126(3):299-302. doi: 10.1016/j.anai.2020.12.007. Epub 2020 Dec 17.

Shoda T, Wen T, Caldwell JM, Ben-Baruch Morgenstern N, Osswald GA, Rochman M, Mack LE, Felton JM, Abonia JP, Arva NC, Atkins D, Bonis PA, Capocelli KE, Collins MH, Dellon ES, Falk GW, Gonsalves N, Gupta SK, Hirano I, Leung J, Menard-Katcher PA, Mukkada VA, Putnam PE, Rudman Spergel AK, Spergel JM, Wechsler JB, Yang GY, Aceves SS, Furuta GT, Rothenberg ME; Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) Investigators Group. Loss of Endothelial TSPAN12 Promotes Fibrostenotic Eosinophilic Esophagitis via Endothelial Cell-Fibroblast Crosstalk. Gastroenterology. 2022 Feb;162(2):439-453. doi: 10.1053/j.gastro.2021.10.016. Epub 2021 Oct 21. PMID: 34687736; PMCID: PMC8792211.

Eosinophilic esophagitis (EoE) is a chronic, antigen-mediated immunologic disease that can progress to fibrostenosis, but the molecular pathogenesis of fibrostenotic EoE is not well understood. This study found that endothelial TSPAN12 contributes to fibrostenotic EoE and is the first molecular correlate of esophageal diameter. These findings provide new insight into previously underrecognized roles of the endothelium in disease pathogenesis. Anti–IL-13 therapy may improve fibrostenotic EoE through normalizing TSPAN12 levels.

Dellon ES, Shaheen O, Koutlas NT, Chang AO, Martin LJ, Rothenberg ME, Jensen ET. Early life factors are associated with risk for eosinophilic esophagitis diagnosed in adulthood. Dis Esophagus. 2021 Feb 10;34(2):doaa074. doi: 10.1093/dote/doaa074.

Schreiner P, Biedermann L, Greuter T, Wright BL, Straumann A. How to approach adult patients with asymptomatic esophageal eosinophilia. Dis Esophagus. 2021 Jan 11;34(1):doaa105. doi: 10.1093/dote/doaa105.

Doyle AD, Masuda MY, Kita H, Wright BL. Eosinophils in Eosinophilic Esophagitis: The Road to Fibrostenosis is Paved With Good Intentions. Front Immunol. 2020 Dec 1;11:603295. doi: 10.3389/fimmu.2020.603295. eCollection 2020.

Hiremath G, Krischer JP, Rothenberg ME, Dellon ES. Validation of self-reported diagnosis of eosinophilic gastrointestinal disorders patients enrolled in the CEGIR contact registry. Clin Res Hepatol Gastroenterol. 2020 Nov 5:101555. doi: 10.1016/j.clinre.2020.10.001. Online ahead of print.

Jensen ET, Aceves SS, Bonis PA, Bray K, Book W, Chehade M, Collins MH, Dellon ES, Falk GW, Gonsalves N, Gupta SK, Hirano I, Katzka DA, Kyle S, Mack D, Kodroff E, Leung J, Mukkada VA, Scott M, Paliana A, Sable K, Spergel JM, Strobel MJ, Krischer J, Rothenberg ME, Abonia P; CEGIR Investigator group. High Patient Disease Burden in a Cross-sectional, Multicenter Contact Registry Study of Eosinophilic Gastrointestinal Diseases. J Pediatr Gastroenterol Nutr. 2020 Oct;71(4):524-529. doi: 10.1097/MPG.0000000000002817.

Greuter T, Godat A, Ringel A, Almonte HS, Schupack D, Mendoza G, McCright-Gill T, Dellon ES, Hirano I, Alexander J, Chehade M, Safroneeva E, Bussmann C, Biedermann L, Schreiner P, Schoepfer AM, Straumann A, Katzka DA. Effectiveness and Safety of High- vs Low-Dose Swallowed Topical Steroids for Maintenance Treatment of Eosinophilic Esophagitis: A Multicenter Observational Study. Clin Gastroenterol Hepatol. 2020 Aug 13:S1542-3565(20)31136-8. doi: 10.1016/j.cgh.2020.08.027. Online ahead of print.

Pesek RD, Reed CC, Collins MH, Muir AB, Fulkerson PC, Menard-Katcher C, Falk GW, Kuhl J, Magier AZ, Ahmed FN, Demarshall M, Gupta A, Gross J, Ashorobi T, Carpenter CL, Krischer JP, Gonsalves N, Hirano I, Spergel JM, Gupta SK, Furuta GT, Rothenberg ME, Dellon ES; Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR). Association Between Endoscopic and Histologic Findings in a Multicenter Retrospective Cohort of Patients with Non-esophageal Eosinophilic Gastrointestinal Disorders. Dig Dis Sci. 2020 Jul;65(7):2024-2035. doi: 10.1007/s10620-019-05961-4. Epub 2019 Nov 26.

Chehade M, Brown S. Elimination diets for eosinophilic esophagitis: making the best choice. Expert Rev Clin Immunol. 2020 Jul;16(7):679-687. doi: 10.1080/1744666X.2020.1801419. Epub 2020 Aug 4.

Slack IF, Schwartz JT, Mukkada VA, Hottinger S, Abonia JP. Eosinophilic Esophagitis: Existing and Upcoming Therapies in an Age of Emerging Molecular and Personalized Medicine. Curr Allergy Asthma Rep. 2020 Jun 6;20(8):30. doi: 10.1007/s11882-020-00928-2.

Dunn JLM, Shoda T, Caldwell JM, Wen T, Aceves SS, Collins MH, Dellon ES, Falk GW, Leung J, Martin LJ, Menard-Katcher P, Rudman-Spergel AK, Spergel JM, Wechsler JB, Yang GY, Furuta GT, Rothenberg ME; Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR). Esophageal type 2 cytokine expression heterogeneity in eosinophilic esophagitis in a multisite cohort. J Allergy Clin Immunol. 2020 Jun;145(6):1629-1640.e4. doi: 10.1016/j.jaci.2020.01.051. Epub 2020 Mar 19.

Spergel JM, Brown-Whitehorn TA, Muir A, Liacouras CA. Medical algorithm: Diagnosis and treatment of eosinophilic esophagitis in children. Allergy. 2020 Jun;75(6):1522-1524. doi: 10.1111/all.14188. Epub 2020 Jan 31.

Whelan KA, Godwin BC, Wilkins B, Elci OU, Benitez A, DeMarshall M, Sharma M, Gross J, Klein-Szanto AJ, Liacouras CA, Dellon ES, Spergel JM, Falk GW, Muir AB, Nakagawa H. Persistent Basal Cell Hyperplasia Is Associated With Clinical and Endoscopic Findings in Patients With Histologically Inactive Eosinophilic Esophagitis. Clin Gastroenterol Hepatol. 2020 Jun;18(7):1475-1482.e1. doi: 10.1016/j.cgh.2019.08.055. Epub 2019 Sep 6.

Hirano I, Chan ES, Rank MA, Sharaf RN, Stollman NH, Stukus DR, Wang K, Greenhawt M, Falck-Ytter YT; AGA Institute Clinical Guidelines Committee; Joint Task Force on Allergy-Immunology Practice Parameters. AGA institute and the joint task force on allergy-immunology practice parameters clinical guidelines for the management of eosinophilic esophagitis. Ann Allergy Asthma Immunol. 2020 May;124(5):416-423. doi: 10.1016/j.anai.2020.03.020.

Hirano I, Chan ES, Rank MA, Sharaf RN, Stollman NH, Stukus DR, Wang K, Greenhawt M, Falck-Ytter YT; AGA Institute Clinical Guidelines Committee; Joint Task Force on Allergy-Immunology Practice Parameters. AGA Institute and the Joint Task Force on Allergy-Immunology Practice Parameters Clinical Guidelines for the Management of Eosinophilic Esophagitis. Gastroenterology. 2020 May;158(6):1776-1786. doi: 10.1053/j.gastro.2020.02.038.

Rank MA, Sharaf RN, Furuta GT, Aceves SS, Greenhawt M, Spergel JM, Falck-Ytter YT, Dellon ES; AGA Institute Electronic address: clinicalpractice@gastroorg; Joint Task Force on Allergy-Immunology Practice Parameters collaborators Electronic address: drdanawallace@gmailcom; AGA Institute; Joint Task Force on Allergy-Immunology Practice Parameters collaborators. Technical review on the management of eosinophilic esophagitis: a report from the AGA institute and the joint task force on allergy-immunology practice parameters. Ann Allergy Asthma Immunol. 2020 May;124(5):424-440.e17. doi: 10.1016/j.anai.2020.03.021.

Rank MA, Sharaf RN, Furuta GT, Aceves SS, Greenhawt M, Spergel JM, Falck-Ytter YT, Dellon ES; AGA Institute. Electronic address: clinicalpractice@gastro.org; Joint Task Force on Allergy-Immunology Practice Parameters collaborators. Electronic address: drdanawallace@gmail.com; AGA Institute; Joint Task Force on Allergy-Immunology Practice Parameters collaborators. Technical Review on the Management of Eosinophilic Esophagitis: A Report From the AGA Institute and the Joint Task Force on Allergy-Immunology Practice Parameters. Gastroenterology. 2020 May;158(6):1789-1810.e15. doi: 10.1053/j.gastro.2020.02.039.

Nhu QM, Hsieh L, Dohil L, Dohil R, Newbury RO, Kurten R, Moawad FJ, Aceves SS. Antifibrotic Effects of the Thiazolidinediones in Eosinophilic Esophagitis Pathologic Remodeling: A Preclinical Evaluation. Clin Transl Gastroenterol. 2020 Apr;11(4):e00164. doi: 10.14309/ctg.0000000000000164.

Cafone J, Ruffner MA, Spergel JM. The role of eosinophils in immunotherapy. Curr Opin Allergy Clin Immunol. 2020 Apr;20(2):329. doi: 10.1097/ACI.0000000000000617.

Applequist J, Burroughs C, Ramirez A Jr, Merkel PA, Rothenberg ME, Trapnell B, Desnick RJ, Sahin M, Krischer JP. A novel approach to conducting clinical trials in the community setting: utilizing patient-driven platforms and social media to drive web-based patient recruitment. BMC Med Res Methodol. 2020 Mar 13;20(1):58. doi: 10.1186/s12874-020-00926-y.

Hirano I, Furuta GT. Approaches and Challenges to Management of Pediatric and Adult Patients With Eosinophilic Esophagitis. Gastroenterology. 2020 Mar;158(4):840-851. doi: 10.1053/j.gastro.2019.09.052. Epub 2019 Dec 10.

Godwin B, Wilkins B, Muir AB. EoE disease monitoring: Where we are and where we are going. Ann Allergy Asthma Immunol. 2020 Mar;124(3):240-247. doi: 10.1016/j.anai.2019.12.004. Epub 2019 Dec 9.

Greuter T, Straumann A. Medical algorithm: Diagnosis and treatment of eosinophilic esophagitis in adults. Allergy. 2020 Mar;75(3):727-730. doi: 10.1111/all.14112. Epub 2019 Dec 5.

Nakagawa H, Kasagi Y, Karakasheva TA, Hara T, Aaron B, Shimonosono M, Kijima T, Giroux V, Bailey D, Wilkins B, Abrams JA, Falk GW, Aceves SS, Spergel JM, Hamilton KE, Whelan KA, Muir AB. Modeling Epithelial Homeostasis and Reactive Epithelial Changes in Human and Murine Three-Dimensional Esophageal Organoids. Curr Protoc Stem Cell Biol. 2020 Mar;52(1):e106. doi: 10.1002/cpsc.106.

Nhu QM, Aceves SS. Unanswered questions in eosinophilic esophagitis. Ann Allergy Asthma Immunol. 2020 Mar;124(3):227-228. doi: 10.1016/j.anai.2019.12.003. Epub 2019 Dec 9.

Bolton SM, Kagalwalla AF, Arva NC, Wang MY, Amsden K, Melin-Aldana H, Dellon ES, Bryce PJ, Wershil BK, Wechsler JB. Mast Cell Infiltration Is Associated With Persistent Symptoms and Endoscopic Abnormalities Despite Resolution of Eosinophilia in Pediatric Eosinophilic Esophagitis. Am J Gastroenterol. 2020 Feb;115(2):224-233. doi: 10.14309/ajg.0000000000000474.

Muir AB, Whelan KA, Dougherty MK, Aaron B, Navarre B, Aceves SS, Dellon ES, Jensen ET. The potential for malignancy from atopic disorders and allergic inflammation: A systematic review and meta-analysis. Clin Exp Allergy. 2020 Feb;50(2):147-159. doi: 10.1111/cea.13537. Epub 2019 Dec 20.

Aceves S, Collins MH, Rothenberg ME, Furuta GT, Gonsalves N; Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR). Advancing patient care through the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR). J Allergy Clin Immunol. 2020 Jan;145(1):28-37. doi: 10.1016/j.jaci.2019.11.012. Epub 2019 Nov 20.

Greuter T, Hirano I, Dellon ES. Emerging therapies for eosinophilic esophagitis. J Allergy Clin Immunol. 2020 Jan;145(1):38-45. doi: 10.1016/j.jaci.2019.10.027. Epub 2019 Nov 6.

Pesek RD, Rothenberg ME. Eosinophilic gastrointestinal disease below the belt. J Allergy Clin Immunol. 2020 Jan;145(1):87-89.e1. doi: 10.1016/j.jaci.2019.10.013. Epub 2019 Oct 24.

Shoda T, Wen T, Caldwell JM, Collins MH, Besse JA, Osswald GA, Abonia JP, Arva NC, Atkins D, Capocelli KE, Dellon ES, Falk GW, Gonsalves N, Gupta SK, Hirano I, Mukkada VA, Putnam PE, Sheridan RM, Rudman Spergel AK, Spergel JM, Wechsler JB, Yang GY, Aceves SS, Furuta GT, Rothenberg ME; Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR). Molecular, endoscopic, histologic, and circulating biomarker-based diagnosis of eosinophilic gastritis: Multi-site study. J Allergy Clin Immunol. 2020 Jan;145(1):255-269. doi: 10.1016/j.jaci.2019.11.007. Epub 2019 Nov 16.

Kottyan LC, Parameswaran S, Weirauch MT, Rothenberg ME, Martin LJ. The genetic etiology of eosinophilic esophagitis. J Allergy Clin Immunol. 2020 Jan;145(1):9-15. doi: 10.1016/j.jaci.2019.11.013.

Bailey DD, Zhang Y, van Soldt BJ, Jiang M, Suresh S, Nakagawa H, Rustgi AK, Aceves SS, Cardoso WV, Que J. Use of hPSC-derived 3D organoids and mouse genetics to define the roles of YAP in the development of the esophagus. Development. 2019 Dec 4;146(23):dev178855. doi: 10.1242/dev.178855.

Ruffner MA, Song L, Maurer K, Shi L, Carroll MC, Wang JX, Muir AB, Spergel JM, Sullivan KE. Toll-like receptor 2 stimulation augments esophageal barrier integrity. Allergy. 2019 Dec;74(12):2449-2460. doi: 10.1111/all.13968. Epub 2019 Jul 25.

Dellon ES, Gupta SK. A Conceptual Approach to Understanding Treatment Response in Eosinophilic Esophagitis. Clin Gastroenterol Hepatol. 2019 Oct;17(11):2149-2160. doi: 10.1016/j.cgh.2019.01.030. Epub 2019 Jan 30.

Groft SC, Gopal-Srivastava R, Dellon ES, Gupta SK. How to Advance Research, Education, and Training in the Study of Rare Diseases. Gastroenterology. 2019 Oct;157(4):917-921. doi: 10.1053/j.gastro.2019.08.010. Epub 2019 Aug 8.

Lyles J, Rothenberg M. Role of genetics, environment, and their interactions in the pathogenesis of eosinophilic esophagitis. Curr Opin Immunol. 2019 Oct;60:46-53. doi: 10.1016/j.coi.2019.04.004. Epub 2019 May 25.

Olbrich CL, Simerly L, de Zoeten EF, Furuta GT, Spencer LA. Climbing New Mountains: How Antibodies Blocking α4β7 Integrins Tamed Eosinophilic Inflammation of the Intestinal Tract. Dig Dis Sci. 2019 Aug;64(8):2068-2071. doi: 10.1007/s10620-019-05706-3.

Muir AB, Jensen ET, Wechsler JB, Menard-Katcher P, Falk GW, Aceves SS, Furuta GT, Dellon ES, Rothenberg ME, Spergel JM. Overestimation of the diagnosis of eosinophilic colitis with reliance on billing codes. J Allergy Clin Immunol Pract. 2019 Sep-Oct;7(7):2434-2436. doi: 10.1016/j.jaip.2019.03.020. Epub 2019 Mar 25.

Muir AB, Brown-Whitehorn T, Godwin B, Cianferoni A. Eosinophilic esophagitis: early diagnosis is the key. Clin Exp Gastroenterol. 2019 Aug 15;12:391-399. doi: 10.2147/CEG.S175061. eCollection 2019.

Hiremath G, Rogers E, Kennedy E, Hemler J, Acra S. A Comparative Analysis of Eating Behavior of School-Aged Children with Eosinophilic Esophagitis and Their Caregivers' Quality of Life: Perspectives of Caregivers. Dysphagia. 2019 Aug;34(4):567-574. doi: 10.1007/s00455-019-09984-x. Epub 2019 Feb 2.

Dellon ES. Cost-effective care in eosinophilic esophagitis. Ann Allergy Asthma Immunol. 2019 Aug;123(2):166-172. doi: 10.1016/j.anai.2019.04.010. Epub 2019 Apr 19.

Cafone J, Capucilli P, Hill DA, Spergel JM. Eosinophilic esophagitis during sublingual and oral allergen immunotherapy. Curr Opin Allergy Clin Immunol. 2019 Aug;19(4):350-357. doi: 10.1097/ACI.0000000000000537.

Masterson JC, Biette KA, Hammer JA, Nguyen N, Capocelli KE, Saeedi BJ, Harris RF, Fernando SD, Hosford LB, Kelly CJ, Campbell EL, Ehrentraut SF, Ahmed FN, Nakagawa H, Lee JJ, McNamee EN, Glover LE, Colgan SP, Furuta GT. Epithelial HIF-1α/claudin-1 axis regulates barrier dysfunction in eosinophilic esophagitis. J Clin Invest. 2019 Jul 2;129(8):3224-3235. doi: 10.1172/JCI126744. eCollection 2019 Jul 2.

Kasagi Y, Dods K, Wang JX, Chandramouleeswaran PM, Benitez AJ, Gambanga F, Kluger J, Ashorobi T, Gross J, Tobias JW, Klein-Szanto AJ, Spergel JM, Cianferoni A, Falk GW, Whelan KA, Nakagawa H, Muir AB. Fibrostenotic eosinophilic esophagitis might reflect epithelial lysyl oxidase induction by fibroblast-derived TNF-α. J Allergy Clin Immunol. 2019 Jul;144(1):171-182. doi: 10.1016/j.jaci.2018.10.067. Epub 2018 Dec 20.

Dellon ES. Editorial: the evolving epidemiology of EoE-up, up, and away?. Aliment Pharmacol Ther. 2019 Jun;49(11):1448-1449. doi: 10.1111/apt.15252.

Chehade M, Meyer R, Beauregard A. Feeding difficulties in children with non-IgE-mediated food allergic gastrointestinal disorders. Ann Allergy Asthma Immunol. 2019 Jun;122(6):603-609. doi: 10.1016/j.anai.2019.03.020. Epub 2019 Mar 26.

Cotton CC, Durban R, Dellon ES. Illuminating Elimination Diets: Controversies Regarding Dietary Treatment of Eosinophilic Esophagitis. Dig Dis Sci. 2019 Jun;64(6):1401-1408. doi: 10.1007/s10620-019-05602-w.

Pesek RD, Reed CC, Muir AB, Fulkerson PC, Menard-Katcher C, Falk GW, Kuhl J, Martin EK, Magier AZ, Ahmed F, Demarshall M, Gupta A, Gross J, Ashorobi T, Carpenter CL, Krischer JP, Gonsalves N, Spergel JM, Gupta SK, Furuta GT, Rothenberg ME, Dellon ES; Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR). Increasing Rates of Diagnosis, Substantial Co-Occurrence, and Variable Treatment Patterns of Eosinophilic Gastritis, Gastroenteritis, and Colitis Based on 10-Year Data Across a Multicenter Consortium. Am J Gastroenterol. 2019 Jun;114(6):984-994. doi: 10.14309/ajg.0000000000000228.

Muir A, Moore H, Spergel JM. Minimally symptomatic patients with eosinophilic esophagitis should still be actively treated-PRO. Ann Allergy Asthma Immunol. 2019 Jun;122(6):572-573. doi: 10.1016/j.anai.2018.09.468. Epub 2018 Oct 5.

Hiremath G, Shilts MH, Boone HH, Correa H, Acra S, Tovchigrechko A, Rajagopala SV, Das SR. The Salivary Microbiome Is Altered in Children With Eosinophilic Esophagitis and Correlates With Disease Activity. Clin Transl Gastroenterol. 2019 Jun;10(6):e00039. doi: 10.14309/ctg.0000000000000039.

Kottyan L, Spergel JM, Cianferoni A. Immunology of the ancestral differences in eosinophilic esophagitis. Ann Allergy Asthma Immunol. 2019 May;122(5):443-444. doi: 10.1016/j.anai.2018.10.026. Epub 2018 Nov 7.

DiTommaso LA, Rosenberg CE, Eby MD, Tasco A, Collins MH, Lyles JL, Putnam PE, Mukkada VA, Rothenberg ME. Prevalence of eosinophilic colitis and the diagnoses associated with colonic eosinophilia. J Allergy Clin Immunol. 2019 May;143(5):1928-1930.e3. doi: 10.1016/j.jaci.2018.12.1002. Epub 2019 Jan 14.

Ruffner MA, Capucilli P, Hill DA, Spergel JM. Screening children for eosinophilic esophagitis: allergic and other risk factors. Expert Rev Clin Immunol. 2019 Apr;15(4):315-318. doi: 10.1080/1744666X.2019.1579643. Epub 2019 Feb 20.

Azouz NP, Rothenberg ME. Mechanisms of gastrointestinal allergic disorders. J Clin Invest. 2019 Mar 11;129(4):1419-1430. doi: 10.1172/JCI124604. eCollection 2019 Mar 11.

Gupta SK, Falk GW, Aceves SS, Chehade M, Collins MH, Dellon ES, Gonsalves N, Hirano I, Mukkuda VA, Peterson KA, Spergel J, Yang GY, Furuta GT, Rothenberg ME; Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR). Consortium of Eosinophilic Gastrointestinal Disease Researchers: Advancing the Field of Eosinophilic GI Disorders Through Collaboration. Gastroenterology. 2019 Mar;156(4):838-842. doi: 10.1053/j.gastro.2018.10.057. Epub 2018 Nov 17.

Schwartz JT, Morris DW, Collins MH, Rothenberg ME, Fulkerson PC. Eosinophil progenitor levels correlate with tissue pathology in pediatric eosinophilic esophagitis. J Allergy Clin Immunol. 2019 Mar;143(3):1221-1224.e3. doi: 10.1016/j.jaci.2018.10.036. Epub 2018 Nov 9.

Nguyen N, Baumgarten A, Wright BL, Capocelli KE, Pan Z, Lee JJ, Furuta GT, Masterson JC. Histologic similarities in children with eosinophilic esophagitis and proton pump inhibitor-responsive esophageal eosinophilia. J Allergy Clin Immunol. 2019 Mar;143(3):1237-1240.e2. doi: 10.1016/j.jaci.2018.10.047. Epub 2018 Nov 14.

Nhu QM, Moawad FJ. New Developments in the Diagnosis and Treatment of Eosinophilic Esophagitis. Curr Treat Options Gastroenterol. 2019 Mar;17(1):48-62. doi: 10.1007/s11938-019-00216-7.

Dellon ES. No Maintenance, No Gain in Long-term Treatment of Eosinophilic Esophagitis. Clin Gastroenterol Hepatol. 2019 Feb;17(3):397-399. doi: 10.1016/j.cgh.2018.07.038.

Muir AB, Wang JX, Nakagawa H. Epithelial-stromal crosstalk and fibrosis in eosinophilic esophagitis. J Gastroenterol. 2019 Jan;54(1):10-18. doi: 10.1007/s00535-018-1498-3. Epub 2018 Aug 12.

Spergel JM, Dellon ES, Liacouras CA, Hirano I, Molina-Infante J, Bredenoord AJ, Furuta GT. Authors' response. Ann Allergy Asthma Immunol. 2018 Dec;121(6):747-748. doi: 10.1016/j.anai.2018.10.015. Epub 2018 Oct 13.

Greuter T, Alexander JA, Straumann A, Katzka DA. Diagnostic and Therapeutic Long-term Management of Eosinophilic Esophagitis- Current Concepts and Perspectives for Steroid Use. Clin Transl Gastroenterol. 2018 Dec;9(12):e212. doi: 10.1038/s41424-018-0074-8.

Hill DA, Spergel JM. Epithelial acid imbalance in patients with eosinophilic esophagitis. J Allergy Clin Immunol. 2018 Dec;142(6):1757-1758. doi: 10.1016/j.jaci.2018.09.026. Epub 2018 Oct 10.

Ruffner MA, Spergel JM. Pediatric eosinophilic esophagitis: updates for the primary care setting. Curr Opin Pediatr. 2018 Dec;30(6):829-836. doi: 10.1097/MOP.0000000000000698.

Inage E, Furuta GT, Menard-Katcher C, Masterson JC. Eosinophilic esophagitis: pathophysiology and its clinical implications. Am J Physiol Gastrointest Liver Physiol. 2018 Nov 1;315(5):G879-G886. doi: 10.1152/ajpgi.00174.2018. Epub 2018 Sep 13.

Hiremath G, Kodroff E, Strobel MJ, Scott M, Book W, Reidy C, Kyle S, Mack D, Sable K, Abonia P, Spergel J, Gupta SK, Furuta TG, Rothenberg ME, Dellon ES. Individuals affected by eosinophilic gastrointestinal disorders have complex unmet needs and frequently experience unique barriers to care. Clin Res Hepatol Gastroenterol. 2018 Oct;42(5):483-493. doi: 10.1016/j.clinre.2018.03.003. Epub 2018 Mar 31.

Dellon ES, Liacouras CA, Molina-Infante J, Furuta GT, Spergel JM, Zevit N, Spechler SJ, Attwood SE, Straumann A, Aceves SS, Alexander JA, Atkins D, Arva NC, Blanchard C, Bonis PA, Book WM, Capocelli KE, Chehade M, Cheng E, Collins MH, Davis CM, Dias JA, Di Lorenzo C, Dohil R, Dupont C, Falk GW, Ferreira CT, Fox A, Gonsalves NP, Gupta SK, Katzka DA, Kinoshita Y, Menard-Katcher C, Kodroff E, Metz DC, Miehlke S, Muir AB, Mukkada VA, Murch S, Nurko S, Ohtsuka Y, Orel R, Papadopoulou A, Peterson KA, Philpott H, Putnam PE, Richter JE, Rosen R, Rothenberg ME, Schoepfer A, Scott MM, Shah N, Sheikh J, Souza RF, Strobel MJ, Talley NJ, Vaezi MF, Vandenplas Y, Vieira MC, Walker MM, Wechsler JB, Wershil BK, Wen T, Yang GY, Hirano I, Bredenoord AJ. Updated International Consensus Diagnostic Criteria for Eosinophilic Esophagitis: Proceedings of the AGREE Conference. Gastroenterology. 2018 Oct;155(4):1022-1033.e10. doi: 10.1053/j.gastro.2018.07.009. Epub 2018 Sep 6.

Wright BL, Spergel JM. Eosinophilic Esophagitis. J Allergy Clin Immunol Pract. 2018 Sep-Oct;6(5):1799-1801. doi: 10.1016/j.jaip.2018.06.019.

Steinbach EC, Hernandez M, Dellon ES. Eosinophilic Esophagitis and the Eosinophilic Gastrointestinal Diseases: Approach to Diagnosis and Management. J Allergy Clin Immunol Pract. 2018 Sep-Oct;6(5):1483-1495. doi: 10.1016/j.jaip.2018.06.012. Epub 2018 Jul 3.

Hill DA, Grundmeier RW, Ramos M, Spergel JM. Eosinophilic Esophagitis Is a Late Manifestation of the Allergic March. J Allergy Clin Immunol Pract. 2018 Sep-Oct;6(5):1528-1533. doi: 10.1016/j.jaip.2018.05.010. Epub 2018 Jun 25.

Naramore S, Gupta SK. Nonesophageal Eosinophilic Gastrointestinal Disorders: Clinical Care and Future Directions. J Pediatr Gastroenterol Nutr. 2018 Sep;67(3):318-321. doi: 10.1097/MPG.0000000000002040.

Chehade M, Jones SM, Pesek RD, Burks AW, Vickery BP, Wood RA, Leung DYM, Furuta GT, Fleischer DM, Henning AK, Dawson P, Lindblad RW, Sicherer SH, Abonia JP, Sherrill JD, Sampson HA, Rothenberg ME. Phenotypic Characterization of Eosinophilic Esophagitis in a Large Multicenter Patient Population from the Consortium for Food Allergy Research. J Allergy Clin Immunol Pract. 2018 Sep-Oct;6(5):1534-1544.e5. doi: 10.1016/j.jaip.2018.05.038. Epub 2018 Aug 1.

Spergel JM, Dellon ES, Liacouras CA, Hirano I, Molina-Infante J, Bredenoord AJ, Furuta GT; participants of AGREE. Summary of the updated international consensus diagnostic criteria for eosinophilic esophagitis: AGREE conference. Ann Allergy Asthma Immunol. 2018 Sep;121(3):281-284. doi: 10.1016/j.anai.2018.05.035. Epub 2018 Jul 18.

Durrani SR, Mukkada VA, Guilbert TW. Eosinophilic Esophagitis: an Important Comorbid Condition of Asthma?. Clin Rev Allergy Immunol. 2018 Aug;55(1):56-64. doi: 10.1007/s12016-018-8670-7.

Ferguson AE, Mukkada VA, Fulkerson PC. Pediatric Eosinophilic Esophagitis Endotypes: Are We Closer to Predicting Treatment Response?. Clin Rev Allergy Immunol. 2018 Aug;55(1):43-55. doi: 10.1007/s12016-017-8658-8.

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Nguyen N, Furuta GT, Masterson JC. Deeper Than the Epithelium: Role of Matrix and Fibroblasts in Pediatric and Adult Eosinophilic Esophagitis. J Pediatr Gastroenterol Nutr. 2016 Aug;63(2):168-9. doi: 10.1097/MPG.0000000000001183.

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Hirano I. 2015 David Y. Graham Lecture: The First Two Decades Of Eosinophilic Esophagitis-From Acid Reflux To Food Allergy. Am J Gastroenterol. 2016 Jun;111(6):770-6. doi: 10.1038/ajg.2016.136. Epub 2016 Apr 12.

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Leung J, Beukema KR, Shen AH. Allergic mechanisms of Eosinophilic oesophagitis. Best Pract Res Clin Gastroenterol. 2015 Oct;29(5):709-720. doi: 10.1016/j.bpg.2015.09.012. Epub 2015 Sep 11.

Spergel JM. An allergist's perspective to the evaluation of Eosinophilic Esophagitis. Best Pract Res Clin Gastroenterol. 2015 Oct;29(5):771-781. doi: 10.1016/j.bpg.2015.06.011. Epub 2015 Jul 8.

Jensen ET, Dellon ES. Environmental and infectious factors in eosinophilic esophagitis. Best Pract Res Clin Gastroenterol. 2015 Oct;29(5):721-729. doi: 10.1016/j.bpg.2015.06.008. Epub 2015 Jul 17.

Cianferoni A, Spergel JM. From genetics to treatment of eosinophilic esophagitis. Curr Opin Allergy Clin Immunol. 2015 Oct;15(5):417-25. doi: 10.1097/ACI.0000000000000200.

Nguyen N, Furuta GT, Menard-Katcher C. Recognition and Assessment of Eosinophilic Esophagitis: The Development of New Clinical Outcome Metrics. Gastroenterol Hepatol (N Y). 2015 Oct;11(10):670-4.

Sodikoff J, Hirano I. Therapeutic strategies in eosinophilic esophagitis: Induction, maintenance and refractory disease. Best Pract Res Clin Gastroenterol. 2015 Oct;29(5):829-839. doi: 10.1016/j.bpg.2015.09.002. Epub 2015 Sep 11.

Mehta P, Furuta GT. Eosinophils in Gastrointestinal Disorders: Eosinophilic Gastrointestinal Diseases, Celiac Disease, Inflammatory Bowel Diseases, and Parasitic Infections. Immunol Allergy Clin North Am. 2015 Aug;35(3):413-37. doi: 10.1016/j.iac.2015.04.003. Epub 2015 Jun 17.

Kia L, Hirano I. Distinguishing GERD from eosinophilic oesophagitis: concepts and controversies. Nat Rev Gastroenterol Hepatol. 2015 Jul;12(7):379-386. doi: 10.1038/nrgastro.2015.75. Epub 2015 May 19.

Eluri S, Dellon ES. Proton pump inhibitor-responsive oesophageal eosinophilia and eosinophilic oesophagitis: more similarities than differences. Curr Opin Gastroenterol. 2015 Jul;31(4):309-15. doi: 10.1097/MOG.0000000000000185.

Benitez AJ, Hoffmann C, Muir AB, Dods KK, Spergel JM, Bushman FD, Wang ML. Inflammation-associated microbiota in pediatric eosinophilic esophagitis. Microbiome. 2015 Jun 1;3:23. doi: 10.1186/s40168-015-0085-6. eCollection 2015.

Rothenberg ME. Molecular, genetic, and cellular bases for treating eosinophilic esophagitis. Gastroenterology. 2015 May;148(6):1143-57. doi: 10.1053/j.gastro.2015.02.002. Epub 2015 Feb 7.

Kochar B, Dellon ES. Management of proton pump inhibitor responsive-esophageal eosinophilia and eosinophilic esophagitis: controversies in treatment approaches. Expert Rev Gastroenterol Hepatol. 2015;9(11):1359-69. doi: 10.1586/17474124.2015.1088384. Epub 2015 Sep 12.

Cianferoni A, Spergel JM, Muir A. Recent advances in the pathological understanding of eosinophilic esophagitis. Expert Rev Gastroenterol Hepatol. 2015;9(12):1501-10. doi: 10.1586/17474124.2015.1094372. Epub 2015 Oct 15.

Yang Z, Teaney NA, Buttermore ED, Sahin M, Afshar-Saber W. Harnessing the potential of human induced pluripotent stem cells, functional assays and machine learning for neurodevelopmental disorders. Front Neurosci. 2025 Jan 8;18:1524577. doi: 10.3389/fnins.2024.1524577. PMID: 39844857; PMCID: PMC11750789.

Neurodevelopmental disorders are associated with delays in brain development and a spectrum of impairments that can lead to lifelong disability and even mortality. Although these disorders affect 4.7% of the global population, there are few biomarkers for accurate diagnosis or medications for effective treatment. Human-induced pluripotent stem cells (hiPSCs) are a promising tool for modeling neurodevelopmental disorders, providing new opportunities to understand mechanisms driving these disorders in human neurons.

In this review, researchers compare two- and three-dimensional hiPSC formats for disease modeling. Authors also discuss the applications of functional assays and offer insights on incorporating machine learning into hiPSC-based research and drug screening for neurodevelopmental disorders. Authors note that these tools present unprecedented opportunities to advance the neurodevelopmental disorder research process.

Frazier TW, Busch RM, Klaas P, Lachlan K, Jeste S, Kolevzon A, Loth E, Harris J, Pepper T, Anthony K, Graglia JM, Helde K, Delagrammatikas C, Bedrosian-Sermone S, Smith-Hicks C, Sahin M, Youngstrom EA, Eng C, Chetcuti L, Hardan AY, Uljarevic M. Remote monitoring of social attention in neurogenetic syndromes and idiopathic neurodevelopmental disability. Autism Res. 2024 Dec 6. doi: 10.1002/aur.3290. Epub ahead of print. PMID: 39643599.

Neurodevelopmental genetic syndromes are conditions that affect the development of brain function. Many individuals with these syndromes experience altered social attention that can impact their ability to accurately perceive social information in their world.

In this study, researchers evaluated remote monitoring of social attention in children, adolescents, and adults with a wide range of neurodevelopmental outcomes. Participants included individuals with three genetic syndromes (PTEN hamartoma tumor syndrome, Malan syndrome, and SYNGAP1-related disorder), a mixed group of other neurodevelopmental genetic syndromes, and individuals with a range of idiopathic neurodevelopmental disorders, as well as neurotypical siblings and unrelated controls. Each participant completed a four-minute social attention paradigm via webcam.

Results show that social attention measures had good scale and test-retest reliability, with the exception of measures of non-social preference and face-specific processing. Findings demonstrate that remote monitoring of social attention may be useful for characterizing phenotypic profiles and tracking the natural history of distinct neurodevelopmental genetic syndromes and idiopathic neurodevelopmental disorders, as well as identifying autism spectrum disorder in patients with neurodevelopmental genetic syndromes. Authors note that global social attention and several distinct social attention measures may also be useful outcomes for future clinical trials.

Farach LS, Richard MA, Wulsin AC, Bebin EM, Krueger DA, Sahin M, Porter BE, McPherson TO, Peters JM, O'Kelley S, Taub KS, Rajaraman R, Randle SC, McClintock WM, Koenig MK, Frost MD, Werner K, Nolan DA, Wong M, Cutter G, Northrup H, Au KS; PREVeNT Study Group. Drug-Resistant Epilepsy in Tuberous Sclerosis Complex Is Associated With TSC2 Genotype: More Findings From the Preventing Epilepsy Using Vigatrin (PREVeNT) Trial. Pediatr Neurol. 2024 Oct;159:62-71. doi: 10.1016/j.pediatrneurol.2024.06.012. Epub 2024 Jul 4.

Srivastava S, Cole JJ, Cohen JS, Chopra M, Smith HS, Deardorff MA, Pedapati E, Corner B, Anixt JS, Jeste S, Sahin M, Gurnett CA, Campbell CA. Survey of the Landscape of Society Practice Guidelines for Genetic Testing of Neurodevelopmental Disorders. Ann Neurol. 2024 Sep 25. doi: 10.1002/ana.27045. Epub ahead of print. PMID: 39319594.

Neurodevelopmental disorders are a spectrum of conditions that affect how the brain functions. These disorders can impact many different areas of childhood development, including motor, problem solving, social-communication, and adaptive skills. Genetic testing of patients with neurodevelopmental disorders is critical for diagnosis, medical management, and access to precision therapies. However, the creation and implementation of professional society practice guidelines for genetic testing can be challenging due to the rapid evolution of approaches.

In this review, authors assessed the current state of United States professional societies' guidelines for genetic testing of neurodevelopmental disorders. The team focused on disorders including unexplained global developmental delay, intellectual disability, autism spectrum disorder, and cerebral palsy. Authors describe several shortcomings of current guidelines and express the need for a unified, frequently updated, and easily accessible cross-specialty society guideline.

Gluckman J, Levy T, Friedman K, Garces F, Filip-Dhima R, Quinlan A, Iannotti I, Pekar M, Hernandez AL, Nava MT, Kravets E, Siegel A, Bernstein JA, Berry-Kravis E, Powell CM, Soorya LV, Thurm A, Srivastava S, Buxbaum JD, Sahin M, Kolevzon A, Gelb BD. Aortic Root Dilation and Genotype Associations in Phelan-McDermid Syndrome. Am J Med Genet A. 2024 Sep 11:e63872. doi: 10.1002/ajmg.a.63872. Epub ahead of print. PMID: 39257296.

Phelan-McDermid syndrome (PMS) is a genetic neurodevelopmental disorder that results from the loss of a small piece of chromosome 22. While many features of PMS are well-understood, less is known about cardiovascular abnormalities.

In this study, researchers evaluated the prevalence and risk of aortic root dilation (ARD) in patients with PMS. Among 59 individuals with PMS, the team analyzed echocardiographic and genetic reports for aortic root measurements and genetic variant data.

Results reveal that eight participants had ARD, which was associated with larger chromosome 22 deletions. Participants with ARD also had significantly more genes deleted on chromosome 22 than participants without ARD. Authors note that these results could help identify individuals with PMS who are at higher risk for ARD.

Ahtam B, Yun HJ, Vyas R, Pienaar R, Wilson JH, Goswami CP, Berto LF, Warfield SK, Sahin M, Grant PE, Peters JM, Im K. Morphological Features of Language Regions in Individuals with Tuberous Sclerosis Complex. J Autism Dev Disord. 2024 Aug;54(8):3155-3175. doi: 10.1007/s10803-023-06004-8. Epub 2023 May 24. Erratum in: J Autism Dev Disord. 2024 Mar;54(3):1232. doi: 10.1007/s10803-023-06098-0. PMID: 37222965.

Tuberous sclerosis complex (TSC) is a genetic condition in which typically benign tumors affect multiple organs including the brain, kidneys, heart, lungs, eyes, and skin. Many individuals with TSC also experience delay in several aspects of development, including language. 

In this structural brain MRI study, researchers examined the morphological features of cortical language regions in individuals with TSC. Participants included seven individuals with TSC and comorbid autism spectrum disorder (ASD), 13 with TSC but no ASD, 10 with ASD-only, and 29 typically developing controls.

Results suggest that comorbid ASD in TSC as well as tuber load in TSC is associated with changes in the morphometry of language regions. Authors note that future studies with larger sample sizes are needed to confirm these findings.

Brown JA, Faley SL, Judge M, Ward P, Ihrie RA, Carson R, Armstrong L, Sahin M, Wikswo JP, Ess KC, Neely MD. Rescue of impaired blood-brain barrier in tuberous sclerosis complex patient derived neurovascular unit. J Neurodev Disord. 2024 May 23;16(1):27. doi: 10.1186/s11689-024-09543-y. PMID: 38783199; PMCID: PMC11112784.

Tuberous sclerosis complex (TSC) is a genetic condition that affects many organs and can cause benign tumors in the skin, kidney, brain, heart, eyes, lungs, and other organs. The most severe symptoms—including seizures, intellectual disability, autism, and behavioral problems—result from complications in the central nervous system. Although these neurological complications are well-understood, less is known about how the genetic mutations that cause TSC might affect different components of the brain, including the blood-brain barrier.

In this study, researchers examined the function of the blood-brain barrier in TSC. The team created TSC patient-specific brain tissue models to explore how mutations in the TSC2 gene affect the blood-brain barrier.

Results show altered function of a blood-brain barrier generated from TSC2 mutant cells, which can improve with treatment of the drug rapamycin or replacement of mutant cells with astrocytes (glial cells in the brain) that do not carry the mutation. Authors note that these findings demonstrate the importance of their methods in ongoing research for TSC and other neurogenetic disorders.

Levy T, Gluckman J, Siper PM, Halpern D, Zweifach J, Filip-Dhima R, Holder JL Jr, Trelles MP, Johnson K, Bernstein JA, Berry-Kravis E, Powell CM, Soorya LV, Thurm A, Buxbaum JD, Sahin M, Kolevzon A, Srivastava S; Developmental Synaptopathies Consortium. Clinical, genetic, and cognitive correlates of seizure occurrences in Phelan-McDermid syndrome. J Neurodev Disord. 2024 May 10;16(1):25. doi: 10.1186/s11689-024-09541-0.

Dhawan A, Baitamouni S, Liu D, Busch R, Klaas P, Frazier TW, Srivastava S, Parikh S, Hsich GE, Friedman NR, Ritter DM, Hardan AY, Martinez-Agosto JA, Sahin M, Eng C. Exploring the neurological features of individuals with germline PTEN variants: A multicenter study. Ann Clin Transl Neurol. 2024 May;11(5):1301-1309. doi: 10.1002/acn3.52046. Epub 2024 Mar 19.

Richard MA, Lupo PJ, Ehli EA, Sahin M, Krueger DA, Wu JY, Bebin EM, Au KS, Northrup H, Farach LS; TACERN Study Group. Common epilepsy variants from the general population are not associated with epilepsy among individuals with tuberous sclerosis complex. Am J Med Genet A. 2024 Jun;194(6):e63569. doi: 10.1002/ajmg.a.63569. Epub 2024 Feb 17.

Macaluso M, Rothenberg ME, Ferkol T, Kuhnell P, Kaminski HJ, Kimberlin DW, Benatar M, Chehade M; Principal Investigators of the Rare Diseases Clinical Research Network – Cycle 4. Impact of the COVID-19 Pandemic on People Living With Rare Diseases and Their Families: Results of a National Survey. JMIR Public Health Surveill. 2024 Feb 14;10:e48430. doi: 10.2196/48430.

Afshar-Saber W, Teaney NA, Winden KD, Jumo H, Shi X, McGinty G, Hubbs J, Chen C, Tokatly Latzer I, Gasparoli F, Ebrahimi-Fakhari D, Buttermore ED, Roullet JB, Pearl PL, Sahin M. ALDH5A1-deficient iPSC-derived excitatory and inhibitory neurons display cell type specific alterations. Neurobiol Dis. 2024 Jan;190:106386. doi: 10.1016/j.nbd.2023.106386. Epub 2023 Dec 16.

Brown JA, Faley SL, Judge M, Ward P, Ihrie RA, Carson R, Armstrong L, Sahin M, Wikswo JP, Ess KC, Neely MD. Rescue of Impaired Blood-Brain Barrier in Tuberous Sclerosis Complex Patient Derived Neurovascular Unit. bioRxiv. 2023 Dec 16:2023.12.15.571738. doi: 10.1101/2023.12.15.571738.

Eng C, Kim A, Yehia L. Genomic diversity in functionally relevant genes modifies neurodevelopmental versus neoplastic risks in individuals with germline PTEN variants. Res Sq. 2023 Dec 14:rs.3.rs-3734368. doi: 10.21203/rs.3.rs-3734368/v1.

Clements CC, Ascunce K, Nelson CA. In Context: A Developmental Model of Reward Processing, With Implications for Autism and Sensitive Periods. J Am Acad Child Adolesc Psychiatry. 2023 Nov;62(11):1200-1216. doi: 10.1016/j.jaac.2022.07.861. Epub 2022 Nov 3.

Heunis TM, Chambers N, Vanclooster S, Bissell S, Byars AW, Capal JK, Cukier S, Davis PE, de Vries MC, De Waele L, Flinn J, Gardner-Lubbe S, Gipson T, Kingswood JC, Krueger DA, Kumm AJ, Sahin M, Schoeters E, Smith C, Srivastava S, Takei M, van Eeghen AM, Waltereit R, Jansen AC, de Vries PJ. Development and Feasibility of the Self-Report Quantified Tuberous Sclerosis Complex-Associated Neuropsychiatric Disorders Checklist (TAND-SQ). Pediatr Neurol. 2023 Oct;147:101-123. doi: 10.1016/j.pediatrneurol.2023.07.001. Epub 2023 Jul 7. PMID: 37598571

Tuberous sclerosis complex (TSC) is a genetic condition in which typically benign tumors affect multiple organs including the brain, kidneys, heart, lungs, eyes, and skin. TSC-associated neuropsychiatric disorders (TAND) include difficulties at the behavioral, psychiatric, intellectual, academic, neuropsychologic, and psychosocial levels. Although TAND are often present in individuals with TSC, they are also underidentified and undertreated.

In this study, researchers developed a self-report quantified TAND Checklist (TAND-SQ). The team conducted feasibility and acceptability testing of the TAND-SQ Checklist with 23 technical experts from the TAND consortium and 58 caregivers and individuals with TSC.

The resulting Checklist can be completed by caregivers or individuals with TSC and used to quantify TAND difficulties. Authors state that next steps include further validation of the checklist and development of a smartphone application.

Srivastava S, Sahin M, Buxbaum JD, Berry-Kravis E, Soorya LV, Thurm A, Bernstein JA, Asante-Otoo A, Bennett WE Jr, Betancur C, Brickhouse TH, Passos Bueno MR, Chopra M, Christensen CK, Cully JL, Dies K, Friedman K, Gummere B, Holder JL Jr, Jimenez-Gomez A, Kerins CA, Khan O, Kohlenberg T, Lacro RV, Levi LA, Levy T, Linnehan D, Eva L, Moshiree B, Neumeyer A, Paul SM, Phelan K, Persico A, Rapaport R, Rogers C, Saland J, Sethuram S, Shapiro J, Tarr PI, White KM, Wickstrom J, Williams KM, Winrow D, Wishart B, Kolevzon A. Updated consensus guidelines on the management of Phelan-McDermid syndrome. Am J Med Genet A. 2023 Jul 1. doi: 10.1002/ajmg.a.63312. Epub ahead of print. PMID: 37392087

Phelan–McDermid syndrome (PMS) is a genetic condition caused by the deletion of a small portion of chromosome 22 or a mutation in the SHANK3 gene resulting in a wide range of neurodevelopmental and systemic characteristics. The first guidelines for assessment and monitoring in individuals with PMS were published in 2014. Due to recent studies and investigations, knowledge about PMS has since grown significantly.

In this study, researchers aimed to update clinical management guidelines for PMS based on the latest knowledge. A taskforce of clinical experts in PMS and representatives from the parent community collaborated to produce specialty-specific guidelines—including genetics, neurology, neurodevelopment, gastroenterology, primary care, physiatry, nephrology, endocrinology, cardiology, gynecology, and dentistry.

These updated guidelines allow for improved assessment and monitoring of individuals with PMS. Authors highlight several areas for future research with plans to update the guidelines as new knowledge becomes available.

Morgan FC, Yehia L, McDonald C, Martinez-Agosto JA, Hardan AY, Tamburro J, Sahin M, Bayart C, Eng C; Developmental Synaptopathies Consortium. Characterizing dermatologic findings among patients with PTEN hamartoma tumor syndrome: Results of a multicenter cohort study. J Am Acad Dermatol. 2023 Jul;89(1):90-98. doi: 10.1016/j.jaad.2022.01.045. Epub 2022 Feb 7.

Levine A, Davis P, Zhang B, Peters J, Filip-Dhima R, Warfield SK, Prohl A, Capal J, Krueger D, Bebin EM, Northrup H, Wu JY, Sahin M; TACERN Study Group. Epilepsy Severity Is Associated With Head Circumference and Growth Rate in Infants With Tuberous Sclerosis Complex. Pediatr Neurol. 2023 Jul;144:26-32. doi: 10.1016/j.pediatrneurol.2023.03.015. Epub 2023 Mar 29.

Patterson AM, O'Boyle M, VanNoy GE, Dies KA. Emerging roles and opportunities for rare disease patient advocacy groups. Ther Adv Rare Dis. 2023 Apr 24;4:26330040231164425. doi: 10.1177/26330040231164425. eCollection 2023 Jan-Dec.

Yehia L, Plitt G, Tushar AM, Joo J, Burke CA, Campbell SC, Heiden K, Jin J, Macaron C, Michener CM, Pederson HJ, Radhakrishnan K, Shin J, Tamburro J, Patil S, Eng C. Longitudinal Analysis of Cancer Risk in Children and Adults With Germline PTEN Variants. JAMA Netw Open. 2023 Apr 3;6(4):e239705. doi: 10.1001/jamanetworkopen.2023.9705.

Yehia L, Heald B, Eng C. Clinical Spectrum and Science Behind the Hamartomatous Polyposis Syndromes. Gastroenterology. 2023 Apr;164(5):800-811. doi: 10.1053/j.gastro.2023.01.026. Epub 2023 Jan 28.

Applequist J, Burroughs C, Merkel PA, Rothenberg M, Trapnell B, Desnick R, Sahin M, Krischer J. Direct-to-Consumer Recruitment Methods via Traditional and Social Media to Aid in Research Accrual for Clinical Trials for Rare Diseases: Comparative Analysis Study. J Med Internet Res. 2023 Mar 14;25:e39262. doi: 10.2196/39262.

Cohen AL, Kroeck MR, Wall J, McManus P, Ovchinnikova A, Sahin M, Krueger DA, Bebin EM, Northrup H, Wu JY, Warfield SK, Peters JM, Fox MD; Tuberous Sclerosis Complex Autism Center of Excellence Network Study Group. Tubers Affecting the Fusiform Face Area Are Associated with Autism Diagnosis. Ann Neurol. 2023 Mar;93(3):577-590. doi: 10.1002/ana.26551. Epub 2022 Nov 30. PMID: 36394118; PMCID: PMC9974824.

Tuberous sclerosis complex (TSC) is a genetic condition in which typically benign tumors affect multiple organs. TSC is associated with tubers—tumors that form in the brain—and a high incidence of autism spectrum disorder (ASD).

In this study, researchers explored the relationship between location of brain tubers and ASD diagnosis. The team began by determining tuber locations for 115 TSC patients with and without ASD. Next, researchers tested for associations between ASD diagnosis and tuber burden within the whole brain and specific locations relevant to ASD. Finally, they created a map of the data to calculate the risk of ASD.  

Results show that tubers involving the right fusiform face area (FFA) were associated with a 3.7-fold increased risk of developing ASD. Authors note that this strong association highlights a potential causal mechanism for developing autism in TSC, which may help guide more general research on ASD symptoms.

Busch RM, Frazier Ii TW, Sonneborn C, Hogue O, Klaas P, Srivastava S, Hardan AY, Martinez-Agosto JA, Sahin M, Eng C. Longitudinal neurobehavioral profiles in children and young adults with PTEN hamartoma tumor syndrome and reliable methods for assessing neurobehavioral change. J Neurodev Disord. 2023 Jan 14;15(1):3. doi: 10.1186/s11689-022-09468-4. PMID: 36641436; PMCID: PMC9840250.

PTEN hamartoma tumor syndrome (PHTS) is a spectrum of disorders caused by mutations in the PTEN gene, which typically suppresses formation of tumors. In addition to its role in cancer, PTEN plays crucial roles in brain function. Individuals with PHTS show distinct neurobehavioral profiles, suggesting primary disruption of frontal lobe systems. More severe cognitive deficits are seen in individuals with associated autism spectrum disorder (ASD) that also extend to other areas of neurobehavioral function, such as adaptive behavior and sensory deficits. In this study, researchers aimed to characterize longitudinal neurobehavioral profiles in individuals with PHTS. Ninety-two children and young adults with PHTS and/or ASD completed two to three neurobehavioral evaluations over a two-year time period. The team used spaghetti plots and linear mixed effects models to visualize individual patient profiles and group trends, examining differences in cognitive and behavioral test scores over time. Results suggest that neurobehavioral characteristics observed in individuals with PHTS remain relatively stable over time, even in those with ASD. Reliable change indices and standardized regression-based change scores were calculated and provided in an easy-to-use Excel calculator that can be used in future research to examine patient outcomes at the individual level and inform intervention strategies.

Srivastava S, Jo B, Zhang B, Frazier T, Gallagher AS, Peck F, Levin AR, Mondal S, Li Z, Filip-Dhima R, Geisel G, Dies KA, Diplock A, Eng C, Hanna R, Sahin M, Hardan A; Developmental Synaptopathies Consortium. A randomized controlled trial of everolimus for neurocognitive symptoms in PTEN hamartoma tumor syndrome. Hum Mol Genet. 2022 Oct 10;31(20):3393-3404. doi: 10.1093/hmg/ddac111. PMID: 35594551.

PTEN hamartoma tumor syndrome (PHTS) is a complex neurodevelopmental disorder characterized by overactivity of the mechanistic target of rapamycin (mTOR) pathway, which serves as a major regulator of growth. Limited data suggest that mTOR inhibitors may be therapeutic for patients with PHTS. However, no placebo-controlled studies have explored the effects of mTOR inhibition on cognition and behavior in PHTS patients with or without autism. In this study, researchers conducted a phase II, placebo-controlled trial to examine the safety and efficacy of everolimus, an mTOR inhibitor, in patients with PHTS. The team measured cognitive and behavioral outcomes in addition to biomarkers of electroencephalography (measurement of electrical activity in different parts of the brain). Results show that everolimus was well tolerated in individuals with PHTS. Electroencephalography supported engagement of the drug target in the brain, and some of the secondary (but not primary) outcome measures moved in the direction of improvement. Although this trial provides early evidence that everolimus is safe for use in patients with PHTS, authors note that further study is needed.

Breen MS, Fan X, Levy T, Pollak RM, Collins B, Osman A, Tocheva AS, Sahin M, Berry-Kravis E, Soorya L, Thurm A, Powell CM, Bernstein JA, Kolevzon A, Buxbaum JD; Developmental Synaptopathies Consortium. Large 22q13.3 deletions perturb peripheral transcriptomic and metabolomic profiles in Phelan-McDermid syndrome. HGG Adv. 2022 Sep 26;4(1):100145. doi: 10.1016/j.xhgg.2022.100145. eCollection 2023 Jan 12.

Chopra M, Modi ME, Dies KA, Chamberlin NL, Buttermore ED, Brewster SJ, Prock L, Sahin M. GENE TARGET: A framework for evaluating Mendelian neurodevelopmental disorders for gene therapy. Mol Ther Methods Clin Dev. 2022 Aug 29;27:32-46. doi: 10.1016/j.omtm.2022.08.007. eCollection 2022 Dec 8.

Siper PM, Rowe MA, Guillory SB, Rouhandeh AA, George-Jones JL, Tavassoli T, Lurie S, Zweifach J, Weissman J, Foss-Feig J, Halpern D, Trelles MP, Mulhern MS, Brittenham C, Gordon J, Zemon V, Buxbaum JD, Kolevzon A. Visual Evoked Potential Abnormalities in Phelan-McDermid Syndrome. J Am Acad Child Adolesc Psychiatry. 2022 Apr;61(4):565-574.e1. doi: 10.1016/j.jaac.2021.07.006. Epub 2021 Jul 22. PMID: 34303785; PMCID: PMC8782912.

Yehia L, Ni Y, Sadler T, Frazier TW, Eng C.. Distinct metabolic profiles associated with autism spectrum disorder versus cancer in individuals with germline PTEN mutations. NPJ Genom Med. 2022 Mar 3;7(1):16. doi: 10.1038/s41525-022-00289-x. PMID: 35241692; PMCID: PMC8894426.

Levy T, Foss-Feig JH, Betancur C, Siper PM, Trelles-Thorne MDP, Halpern D, Frank Y, Lozano R, Layton C, Britvan B, Bernstein JA, Buxbaum JD, Berry-Kravis E, Powell CM, Srivastava S, Sahin M, Soorya L, Thurm A, Kolevzon A; Developmental Synaptopathies Consortium. Strong evidence for genotype-phenotype correlations in Phelan-McDermid syndrome: results from the developmental synaptopathies consortium. Hum Mol Genet. 2022 Feb 21;31(4):625-637. doi: 10.1093/hmg/ddab280. PMID: 34559195; PMCID: PMC8863417.

Guillory SB, Baskett VZ, Grosman HE, McLaughlin CS, Isenstein EL, Wilkinson E, Weissman J, Britvan B, Trelles MP, Halpern DB, Buxbaum JD, Siper PM, Wang AT, Kolevzon A, Foss-Feig JH. Social visual attentional engagement and memory in Phelan-McDermid syndrome and autism spectrum disorder: a pilot eye tracking study. J Neurodev Disord. 2021 Dec 4;13(1):58. doi: 10.1186/s11689-021-09400-2. PMID: 34863106.

Phelan-McDermid Syndrome (PMS) is a rare genetic disorder characterized by intellectual disability and motor delays. It is also one of the most common genetic causes of autism spectrum disorder (ASD). Social deficits are a core feature of ASD. In order to characterize social attention and recognition memory, researchers tested a group of patients with PMS and another group of patients with idiopathic (no cause identified) ASD on a visual paired-comparison task. They analyzed the behavior of test subjects looking at a novel image versus a previously viewed, familiar image. Researchers found differences in attention and memory for social stimuli in the PMS group v. the idiopathic ASD group. Study authors say that these unique patterns could both clarify underlying mechanistic alterations and inform treatment targets for PMS. They could also help stratify individuals with idiopathic ASD and potentially apply knowledge gained in PMS to those individuals.

Cable J, Purcell RH, Robinson E, Vorstman JAS, Chung WK, Constantino JN, Sanders SJ, Sahin M, Dolmetsch RE, Shah BM, Thurm A, Martin CL, Bearden CE, Mulle JG. Harnessing rare variants in neuropsychiatric and neurodevelopment disorders-a Keystone Symposia report. Ann N Y Acad Sci. 2021 Dec;1506(1):5-17. doi: 10.1111/nyas.14658. Epub 2021 Aug 2. PMID: 34342000; PMCID: PMC8688183.

Neurodevelopmental neuropsychiatric disorders—such as autism spectrum disorder and schizophrenia—have strong genetic risk components, but researchers are still deciphering the underlying mechanisms. Rare variants could help us better understand the biological mechanisms for more common idiopathic diseases and reveal new therapeutic targets. This review summarizes insights from the 2021 Keystone eSymposium "Neuropsychiatric and Neurodevelopmental Disorders: Harnessing Rare Variants.” Experts describe progress in genomic discovery and human phenotyping, as well as raise consistent issues.

Capal JK, Williams ME, Pearson DA, Kissinger R, Horn PS, Murray D, Currans K, Kent B, Bebin M, Northrup H, Wu JY, Sahin M, Krueger DA; TACERN Study Group. Profile of Autism Spectrum Disorder in Tuberous Sclerosis Complex: Results from a Longitudinal, Prospective, Multisite Study. Ann Neuro. 2021 Dec;90(6):874-886. doi: 10.1002/ana.26249. Epub 2021 Oct 29. PMID: 34668231; PMCID: PMC8639652.

Tuberous Sclerosis Complex (TSC) is a rare genetic disorder that causes noncancerous tumors to develop in many parts of the body. It is highly associated with autism spectrum disorder (ASD). Researchers seeking to characterize autistic features in young children with TSC evaluated 138 children from ages 3 to 36 months. They used both development and autism-specific assessments. One in four children in the study had been diagnosed with ASD by 36 months. Many individuals with TSC without an autism diagnosis also exhibited a range of autistic behaviors that were below the diagnostic threshold. Study authors report a broader autism phenotype (set of characteristics) that can be identified in young children with TSC, offering an opportunity for early, targeted treatments.

Srivastava S, Condy E, Carmody E, Filip-Dhima R, Kapur K, Bernstein JA, Berry-Kravis E, Powell CM, Soorya L, Thurm A, Buxbaum JD, Sahin M, Kolevzon AL; Developmental Synaptopathies Consortium. Parent-reported measure of repetitive behavior in Phelan-McDermid syndrome. J Neurodev Disord. 2021 Nov 5;13(1):53. doi: 10.1186/s11689-021-09398-7. PMID: 34740315; PMCID: PMC8570010.

Repetitive behaviors are often seen in individuals with autism spectrum disorder as well as intellectual disability. Due to the association of these diagnoses with Phelan-McDermid syndrome (PMS), researchers characterized the severity and profile of repetitive behaviors in PMS relative to previously published scores in other neurodevelopmental disorders. The team used the Repetitive Behavior Scale-Revised (RBS-R) as a parent-report measure of what was collected as part of a natural history study of PMS through the Developmental Synaptopathies Consortium (DSC). Researchers demonstrated that individuals with PMS in this cohort had lower rates of repetitive behaviors compared to previous studies of individuals with autism spectrum disorder and Fragile X syndrome. They also showed that more severe motor repetitive behaviors (e.g., body rocking, finger movements) were associated with lower IQ scores in PMS, but this relationship was not present between IQ and other types of repetitive behaviors. These findings indicate that repetitive behaviors may be milder overall in PMS compared to previous studies characterizing autism spectrum disorder and other genetic conditions. Stereotyped motor behaviors may be related to level of cognitive functioning, and not an autism spectrum disorder diagnosis, in PMS. Authors note the need to better understand these findings by continuing to study repetitive behaviors in PMS using objective measures.

de Vries PJ, Leclezio L, Gardner-Lubbe S, Krueger D, Sahin M, Sparagana S, De Waele L, Jansen A. Multivariate data analysis identifies natural clusters of Tuberous Sclerosis Complex Associated Neuropsychiatric Disorders (TAND). Orphanet J Rare Dis. 2021 Oct 24;16(1):447. doi: 10.1186/s13023-021-02076-w. PMID: 34689816; PMCID: PMC8543869.

Uljarević M, Frazier TW, Rached G, Busch RM, Klaas P, Srivastava S, Martinez-Agosto JA, Sahin M, Eng C, Hardan AY; Developmental Synaptopathies Consortium. Toward better characterization of restricted and repetitive behaviors in individuals with germline heterozygous PTEN mutations. Am J Med Genet A. 2021 Aug 23. doi: 10.1002/ajmg.a.62458. Online ahead of print.

Mutations in the PTEN gene are an important genetic risk factor for autism spectrum disorder (ASD). PTEN mutations are identified in 2% of all ASD cases and 17-20% of cases with both ASD and macrocephaly (larger than typical head size). Restricted and repetitive behaviors (RRB) are a core diagnostic symptom of ASD and one of the earlier predictors of a subsequent ASD diagnosis. RRBs include repetitive motor behaviors (RMB), insistence on sameness (IS), and circumscribed interests (CI). Researchers believe these symptom domains, which have a significant negative impact on affected individuals and their families, likely have distinct mechanisms and might therefore require different treatments. Seeking to develop a more nuanced understanding of RRB in individuals with PTEN mutations, researchers compared RMB, IS, and CI symptoms captured by two different measures across three groups: 38 individuals with PTEN mutations with ASD, 23 with PTEN mutations without ASD, and 25 with ASD and macrocephaly but without PTEN mutations. After adjusting for age and full-scale intelligence quotient (FSIQ) scores, the researchers found that differences between the three study groups were not statistically significant. However, all three symptom domains showed distinct association patterns with sex, age, and FSIQ. Study authors conclude that their findings highlight the importance of comprehensively assessing RRB in people with PTEN mutations. Their findings further support the hypothesis that RMB, IS, and CI are indeed distinct RRB domains that might, therefore, require different treatment approaches in this population. They recommend that future studies are needed to further understand mechanisms behind specific RRB subdomains and inform most optimal strategies for individuation of treatment options. This research offers the largest, most comprehensive comparison of distinct RRB domains in individuals with PTEN mutations to date.

Steele M, Uljarević M, Rached G, Frazier TW, Phillips JM, Libove RA, Busch RM, Klaas P, Martinez-Agosto JA, Srivastava S, Eng C, Sahin M, Hardan AY. Psychiatric Characteristics Across Individuals With PTEN Mutations. Front Psychiatry. 2021 Aug 17;12:672070. doi: 10.3389/fpsyt.2021.672070. eCollection 2021.

Ihnen SKZ, Capal JK, Horn PS, Griffith M, Sahin M, Bebin EM, Wu JY, Northrup H, Krueger DA; TACERN study group. Epilepsy Is Heterogeneous in Early-Life Tuberous Sclerosis Complex. Pediatr Neurol. 2021 Oct;123:1-9. doi: 10.1016/j.pediatrneurol.2021.06.012. Epub 2021 Jul 6.

Tuberous sclerosis complex (TSC) is a multi-system genetic disease that causes benign tumors to grow in vital organs including the brain, kidneys, heart, eyes, lungs, and skin. Epilepsy in TSC typically presents with early onset, multiple seizure types, and intractability. However, this varies among individual patients. In this study, researchers aimed to define epilepsy profiles in the TSC population. The team prospectively collected detailed individual data on seizure characteristics in children aged zero to 36 months. Caregivers kept daily seizure diaries, including onset and daily counts, for each seizure type. Researchers then compared developmental outcomes at 36 months between subgroups. Epilepsy was seen in 79 percent of participants. Hierarchical clustering based on six metrics of seizure burden—age of onset, total seizures, ratio of seizure days to nonseizure days, seizures per seizure day, and worst seven- and 30-day stretches—revealed two distinct groups with broadly favorable and unfavorable epilepsy profiles. Within each group, subpopulations showed clinically meaningful differences in seizure burden, and groups with higher burden had worse developmental outcomes at 36 months. These findings indicate that early and aggressive treatments for epilepsy in TSC may be best leveraged by targeting specific subgroups based on phenotype severity.

Anderson NC, Chen PF, Meganathan K, Afshar Saber W, Petersen AJ, Bhattacharyya A, Kroll KL, Sahin M; Cross-IDDRC Human Stem Cell Working Group. Balancing serendipity and reproducibility: Pluripotent stem cells as experimental systems for intellectual and developmental disorders. Stem Cell Reports. 2021 Jun 8;16(6):1446-1457. doi: 10.1016/j.stemcr.2021.03.025. Epub 2021 Apr 15. PMID: 33861989; PMCID: PMC8190574.

Mariscal MG, Berry-Kravis E, Buxbaum JD, Ethridge LE, Filip-Dhima R, Foss-Feig JH, Kolevzon A, Modi ME, Mosconi MW, Nelson CA, Powell CM, Siper PM, Soorya L, Thaliath A, Thurm A, Zhang B, Sahin M, Levin AR; Developmental Synaptopathies Consortium. Shifted phase of EEG cross-frequency coupling in individuals with Phelan-McDermid syndrome. Mol Autism. 2021 Apr 28;12(1):29. doi: 10.1186/s13229-020-00411-9.

Cohen AL, Mulder BPF, Prohl AK, Soussand L, Davis P, Kroeck MR, McManus P, Gholipour A, Scherrer B, Bebin EM, Wu JY, Northrup H, Krueger DA, Sahin M, Warfield SK, Fox MD, Peters JM; Tuberous Sclerosis Complex Autism Center of Excellence Network Study Group. Tuber Locations Associated with Infantile Spasms Map to a Common Brain Network. Ann Neurol. 2021 Apr;89(4):726-739. doi: 10.1002/ana.26015. Epub 2021 Jan 21.

Uljarević M, Frazier TW, Rached G, Busch RM, Klaas P, Srivastava S, Martinez-Agosto JA, Sahin M, Eng C, Hardan AY; Developmental Synaptopathies Consortium. Brief Report: Role of Parent-Reported Executive Functioning and Anxiety in Insistence on Sameness in Individuals with Germline PTEN Mutations. J Autism Dev Disord. 2021 Feb 17. doi: 10.1007/s10803-021-04881-5. Online ahead of print.

Jia M, Sangwan N, Tzeng A, Eng C.. Interplay Between Class II HLA Genotypes and the Microbiome and Immune Phenotypes in Individuals With PTEN Hamartoma Tumor Syndrome. JCO Precis Oncol. 2021 Feb 9;5:PO.20.00374. doi: 10.1200/PO.20.00374. PMID: 34250407; PMCID: PMC8232567.

Hardan AY, Jo B, Frazier TW, Klaas P, Busch RM, Dies KA, Filip-Dhima R, Snow AV, Eng C, Hanna R, Zhang B, Sahin M. A randomized double-blind controlled trial of everolimus in individuals with PTEN mutations: Study design and statistical considerations. Contemp Clin Trials Commun. 2021 Feb 6;21:100733. doi: 10.1016/j.conctc.2021.100733. eCollection 2021 Mar.

Frazier TW, Jaini R, Busch RM, Wolf M, Sadler T, Klaas P, Hardan AY, Martinez-Agosto JA, Sahin M, Eng C; Developmental Synaptopathies Consortium. Cross-level analysis of molecular and neurobehavioral function in a prospective series of patients with germline heterozygous PTEN mutations with and without autism. Mol Autism. 2021 Jan 28;12(1):5. doi: 10.1186/s13229-020-00406-6.

Although PTEN is a well-established risk gene for autism spectrum disorder (ASD), little is known about how PTEN mutations and associated molecular processes influence neurobehavioral function in mutation carriers with (PTEN-ASD) and without ASD (PTEN no-ASD). In this study, researchers evaluated the influence of PTEN mutation and ASD diagnostic status on relevant pathway protein levels in peripheral blood. They also examined the associations between protein levels and neurobehavioral functions. They found that several canonical PTEN pathway molecules appear to influence the presence of ASD and modify neurobehavioral function in PTEN mutation patients. These results show that protein assays of the PTEN pathway may be useful for predicting neurobehavioral outcomes in PTEN patients. The team notes that future longitudinal analyses are needed to replicate these findings and evaluate relationships between protein and neurobehavioral measures.

Farach LS, Richard MA, Lupo PJ, Sahin M, Krueger DA, Wu JY, Bebin EM, Au KS, Northrup H; TACERN Study Group. Epilepsy Risk Prediction Model for Patients With Tuberous Sclerosis Complex. Pediatr Neurol. 2020 Dec;113:46-50. doi: 10.1016/j.pediatrneurol.2020.07.015. Epub 2020 Jul 29.

Shao DD, Achkar CM, Lai A, Srivastava S, Doan RN, Rodan LH, Chen AY; Brain Development Study Group, Poduri A, Yang E, Walsh CA. Polymicrogyria is Associated With Pathogenic Variants in PTEN. Ann Neurol. 2020 Dec;88(6):1153-1164. doi: 10.1002/ana.25904. Epub 2020 Oct 8.

Sahin M, Sweeney JA, Jones SR. Editorial: Biomarkers to Enable Therapeutics Development in Neurodevelopmental Disorders. Front Integr Neurosci. 2020 Nov 12;14:616641. doi: 10.3389/fnint.2020.616641. PMID: 33262695; PMCID: PMC7686575.

Nariai H, Hussain SA, Bernardo D, Motoi H, Sonoda M, Kuroda N, Asano E, Nguyen JC, Elashoff D, Sankar R, Bragin A, Staba RJ, Wu JY. Scalp EEG interictal high frequency oscillations as an objective biomarker of infantile spasms. Clin Neurophysiol. 2020 Nov;131(11):2527-2536. doi: 10.1016/j.clinph.2020.08.013. Epub 2020 Sep 3.

Yehia L, Eng C. PTEN hamartoma tumour syndrome: what happens when there is no PTEN germline mutation?. Hum Mol Genet. 2020 Oct 20;29(R2):R150-R157. doi: 10.1093/hmg/ddaa127.

More than 400 hereditary cancer syndromes have been described to date and account for 5-10% of all cancers. PTEN hamartoma tumour syndrome (PHTS) is an umbrella term for subsets of four syndromes associated with germline (inherited) PTEN mutations. However, many patients with phenotypes similar to those in PHTS do not carry germline PTEN mutations. This paper reviews gene discovery efforts over the last decade to identify alterations in cancer-predisposing genes in order to facilitate gene-informed molecular diagnosis, cancer risk assessment, and gene-specific clinical management. Authors conclude that validating these discoveries is critical to bringing these patients specific gene-informed risk assessment and subsequent management.

Gergoudis K, Weinberg A, Templin J, Farmer C, Durkin A, Weissman J, Siper P, Foss-Feig J, Del Pilar Trelles M, Bernstein JA, Buxbaum JD, Berry-Kravis E, Powell CM, Sahin M, Soorya L, Thurm A, Kolevzon A; Developmental Synaptopathies Consortium. Psychometric Study of the Social Responsiveness Scale in Phelan-McDermid Syndrome. Autism Res. 2020 Aug;13(8):1383-1396. doi: 10.1002/aur.2299. Epub 2020 May 14.

Bassell J, Srivastava S, Prohl AK, Scherrer B, Kapur K, Filip-Dhima R, Berry-Kravis E, Soorya L, Thurm A, Powell CM, Bernstein JA, Buxbaum JD, Kolevzon A, Warfield SK, Sahin M; Developmental Synaptopathies Consortium. Diffusion Tensor Imaging Abnormalities in the Uncinate Fasciculus and Inferior Longitudinal Fasciculus in Phelan-McDermid Syndrome. Pediatr Neurol. 2020 May;106:24-31. doi: 10.1016/j.pediatrneurol.2020.01.006. Epub 2020 Jan 31.

Scherrer B, Prohl AK, Taquet M, Kapur K, Peters JM, Tomas-Fernandez X, Davis PE, M Bebin E, Krueger DA, Northrup H, Y Wu J, Sahin M, Warfield SK. The Connectivity Fingerprint of the Fusiform Gyrus Captures the Risk of Developing Autism in Infants with Tuberous Sclerosis Complex. Cereb Cortex. 2020 Apr 14;30(4):2199-2214. doi: 10.1093/cercor/bhz233.

Karimi D, Peters JM, Ouaalam A, Prabhu SP, Sahin M, Krueger DA, Kolevzon A, Eng C, Warfield SK, Gholipour A. LEARNING TO DETECT BRAIN LESIONS FROM NOISY ANNOTATIONS. Proc IEEE Int Symp Biomed Imaging. 2020 Apr;2020:1910-1914. doi: 10.1109/isbi45749.2020.9098599. Epub 2020 May 22.

Applequist J, Burroughs C, Ramirez A Jr, Merkel PA, Rothenberg ME, Trapnell B, Desnick RJ, Sahin M, Krischer JP. A novel approach to conducting clinical trials in the community setting: utilizing patient-driven platforms and social media to drive web-based patient recruitment. BMC Med Res Methodol. 2020 Mar 13;20(1):58. doi: 10.1186/s12874-020-00926-y.

Afshar Saber W, Sahin M. Recent advances in human stem cell-based modeling of Tuberous Sclerosis Complex. Mol Autism. 2020 Feb 19;11(1):16. doi: 10.1186/s13229-020-0320-2.

Kohlenberg TM, Trelles MP, McLarney B, Betancur C, Thurm A, Kolevzon A. Psychiatric illness and regression in individuals with Phelan-McDermid syndrome. J Neurodev Disord. 2020 Feb 12;12(1):7. doi: 10.1186/s11689-020-9309-6.

Schoenberger A, Capal JK, Ondracek A, Horn PS, Murray D, Byars AW, Pearson DA, Williams ME, Bebin M, Northrup H, Wu JY, Sahin M, Krueger DA. Language predictors of autism spectrum disorder in young children with tuberous sclerosis complex. Epilepsy Behav. 2020 Feb;103(Pt A):106844. doi: 10.1016/j.yebeh.2019.106844. Epub 2019 Dec 18.

Yehia L, Seyfi M, Niestroj LM, Padmanabhan R, Ni Y, Frazier TW, Lal D, Eng C. Copy Number Variation and Clinical Outcomes in Patients With Germline PTEN Mutations. JAMA Netw Open. 2020 Jan 3;3(1):e1920415. doi: 10.1001/jamanetworkopen.2019.20415.

Peters JM, Hyde DE, Chu CJ, Boom M, Scherrer B, Madsen JR, Stone SS, Ouaalam H, Prabhu SP, Sahin M, Warfield SK. Lesion-Constrained Electrical Source Imaging: A Novel Approach in Epilepsy Surgery for Tuberous Sclerosis Complex. J Clin Neurophysiol. 2020 Jan;37(1):79-86. doi: 10.1097/WNP.0000000000000615.

Kolevzon A, Delaby E, Berry-Kravis E, Buxbaum JD, Betancur C. Neuropsychiatric decompensation in adolescents and adults with Phelan-McDermid syndrome: a systematic review of the literature. Mol Autism. 2019 Dec 24;10:50. doi: 10.1186/s13229-019-0291-3. eCollection 2019.

Modi ME, Sahin M. A unified circuit for social behavior. Neurobiol Learn Mem. 2019 Nov;165:106920. doi: 10.1016/j.nlm.2018.08.010. Epub 2018 Aug 24.

Nariai H, Hussain SA, Bernardo D, Fallah A, Murata KK, Nguyen JC, Rajaraman RR, Rao LM, Matsumoto JH, Lerner JT, Salamon N, Elashoff D, Sankar R, Wu JY. Prospective observational study: Fast ripple localization delineates the epileptogenic zone. Clin Neurophysiol. 2019 Nov;130(11):2144-2152. doi: 10.1016/j.clinph.2019.08.026. Epub 2019 Sep 17.

Ahtam B, Dehaes M, Sliva DD, Peters JM, Krueger DA, Bebin EM, Northrup H, Wu JY, Warfield SK, Sahin M, Grant PE; TACERN Study Group. Resting-State fMRI Networks in Children with Tuberous Sclerosis Complex. J Neuroimaging. 2019 Nov;29(6):750-759. doi: 10.1111/jon.12653. Epub 2019 Jul 14.

Busch RM, Srivastava S, Hogue O, Frazier TW, Klaas P, Hardan A, Martinez-Agosto JA, Sahin M, Eng C; Developmental Synaptopathies Consortium. Neurobehavioral phenotype of autism spectrum disorder associated with germline heterozygous mutations in PTEN. Transl Psychiatry. 2019 Oct 8;9(1):253. doi: 10.1038/s41398-019-0588-1.

Yehia L, Ni Y, Feng F, Seyfi M, Sadler T, Frazier TW, Eng C. Distinct Alterations in Tricarboxylic Acid Cycle Metabolites Associate with Cancer and Autism Phenotypes in Cowden Syndrome and Bannayan-Riley-Ruvalcaba Syndrome. Am J Hum Genet. 2019 Oct 3;105(4):813-821. doi: 10.1016/j.ajhg.2019.09.004. Epub 2019 Sep 26.

Witmer C, Mattingly A, DʼSouza P, Thurm A, Hadigan C. Incontinence in Phelan-McDermid Syndrome. J Pediatr Gastroenterol Nutr. 2019 Aug;69(2):e39-e42. doi: 10.1097/MPG.0000000000002342.

Davis PE, Kapur K, Filip-Dhima R, Trowbridge SK, Little E, Wilson A, Leuchter A, Bebin EM, Krueger D, Northrup H, Wu JY, Sahin M, Peters JM; Tuberous Sclerosis Autism Centers of Excellence Research Network. Increased electroencephalography connectivity precedes epileptic spasm onset in infants with tuberous sclerosis complex. Epilepsia. 2019 Aug;60(8):1721-1732. doi: 10.1111/epi.16284. Epub 2019 Jul 12.

Farach LS, Pearson DA, Woodhouse JP, Schraw JM, Sahin M, Krueger DA, Wu JY, Bebin EM, Lupo PJ, Au KS, Northrup H; TACERN Study Group. Tuberous Sclerosis Complex Genotypes and Developmental Phenotype. Pediatr Neurol. 2019 Jul;96:58-63. doi: 10.1016/j.pediatrneurol.2019.03.003. Epub 2019 Mar 13.

Peters JM, Struyven RR, Prohl AK, Vasung L, Stajduhar A, Taquet M, Bushman JJ, Lidov H, Singh JM, Scherrer B, Madsen JR, Prabhu SP, Sahin M, Afacan O, Warfield SK. White matter mean diffusivity correlates with myelination in tuberous sclerosis complex. Ann Clin Transl Neurol. 2019 Jul;6(7):1178-1190. doi: 10.1002/acn3.793. Epub 2019 Jun 23.

Smith IN, Thacker S, Seyfi M, Cheng F, Eng C. Conformational Dynamics and Allosteric Regulation Landscapes of Germline PTEN Mutations Associated with Autism Compared to Those Associated with Cancer. Am J Hum Genet. 2019 May 2;104(5):861-878. doi: 10.1016/j.ajhg.2019.03.009. Epub 2019 Apr 18.

Marami B, Scherrer B, Khan S, Afacan O, Prabhu SP, Sahin M, Warfield SK, Gholipour A. Motion-robust diffusion compartment imaging using simultaneous multi-slice acquisition. Magn Reson Med. 2019 May;81(5):3314-3329. doi: 10.1002/mrm.27613. Epub 2018 Nov 16.

Smith IN, Thacker S, Jaini R, Eng C. Dynamics and structural stability effects of germline PTEN mutations associated with cancer versus autism phenotypes. J Biomol Struct Dyn. 2019 Apr;37(7):1766-1782. doi: 10.1080/07391102.2018.1465854. Epub 2018 May 14.

Yehia L, Ngeow J, Eng C. PTEN-opathies: from biological insights to evidence-based precision medicine. J Clin Invest. 2019 Feb 1;129(2):452-464. doi: 10.1172/JCI121277. Epub 2019 Jan 7.

The tumor suppressor phosphatase and tensin homolog (PTEN) classically counteracts the PI3K/AKT/mTOR signaling cascade. Germline pathogenic PTEN mutations cause PTEN hamartoma tumor syndrome (PHTS), featuring various benign and malignant tumors, as well as neurodevelopmental disorders such as autism spectrum disorder. Germline and somatic mosaic mutations in genes encoding components of the PI3K/AKT/mTOR pathway downstream of PTEN predispose to syndromes with partially overlapping clinical features, termed the "PTEN-opathies." Experimental models of PTEN pathway disruption uncover the molecular and cellular processes influencing clinical phenotypic manifestations. Such insights not only teach us about biological mechanisms in states of health and disease, but also enable more accurate gene-informed cancer risk assessment, medical management, and targeted therapeutics. Hence, the PTEN-opathies serve as a prototype for bedside to bench, and back to the bedside, practice of evidence-based precision medicine.

Peters JM, Prohl A, Kapur K, Nath A, Scherrer B, Clancy S, Prabhu SP, Sahin M, Franz DN, Warfield SK, Krueger DA. Longitudinal Effects of Everolimus on White Matter Diffusion in Tuberous Sclerosis Complex. Pediatr Neurol. 2019 Jan;90:24-30. doi: 10.1016/j.pediatrneurol.2018.10.005. Epub 2018 Oct 18.

Srivastava S, Scherrer B, Prohl AK, Filip-Dhima R, Kapur K, Kolevzon A, Buxbaum JD, Berry-Kravis E, Soorya L, Thurm A, Powell CM, Bernstein JA, Warfield SK, Sahin M; Developmental Synaptopathies Consortium. Volumetric Analysis of the Basal Ganglia and Cerebellar Structures in Patients with Phelan-McDermid Syndrome. Pediatr Neurol. 2019 Jan;90:37-43. doi: 10.1016/j.pediatrneurol.2018.09.008. Epub 2018 Sep 21.

Hussain SA, Schmid E, Peters JM, Goyal M, Bebin EM, Northrup H, Sahin M, Krueger DA, Wu JY; Tuberous Sclerosis Complex Autism Center of Excellence Network. High vigabatrin dosage is associated with lower risk of infantile spasms relapse among children with tuberous sclerosis complex. Epilepsy Res. 2018 Dec;148:1-7. doi: 10.1016/j.eplepsyres.2018.09.016. Epub 2018 Oct 2.

Nariai H, Wu JY, Bernardo D, Fallah A, Sankar R, Hussain SA. Interrater reliability in visual identification of interictal high-frequency oscillations on electrocorticography and scalp EEG. Epilepsia Open. 2018 Nov 2;3(Suppl Suppl 2):127-132. doi: 10.1002/epi4.12266. eCollection 2018 Dec.

Frazier TW, Klingemier EW, Parikh S, Speer L, Strauss MS, Eng C, Hardan AY, Youngstrom EA. Development and Validation of Objective and Quantitative Eye Tracking-Based Measures of Autism Risk and Symptom Levels. J Am Acad Child Adolesc Psychiatry. 2018 Nov;57(11):858-866. doi: 10.1016/j.jaac.2018.06.023. Epub 2018 Sep 13.

Baumer FM, Peters JM, Clancy S, Prohl AK, Prabhu SP, Scherrer B, Jansen FE, Braun KPJ, Sahin M, Stamm A, Warfield SK. Corpus Callosum White Matter Diffusivity Reflects Cumulative Neurological Comorbidity in Tuberous Sclerosis Complex. Cereb Cortex. 2018 Oct 1;28(10):3665-3672. doi: 10.1093/cercor/bhx247.

Modi ME, Sahin M. The Way Forward for Mechanism-Based Therapeutics in Genetically Defined Neurodevelopmental Disorders. Clin Pharmacol Ther. 2018 Oct;104(4):603-606. doi: 10.1002/cpt.1181. Epub 2018 Aug 12.

Jacobs J, Wu JY, Perucca P, Zelmann R, Mader M, Dubeau F, Mathern GW, Schulze-Bonhage A, Gotman J. Removing high-frequency oscillations: A prospective multicenter study on seizure outcome.. Neurology. 2018 Sep 11;91(11):e1040-e1052. doi: 10.1212/WNL.0000000000006158. Epub 2018 Aug 17. PMID: 30120133; PMCID:PMC6140372

de Vries PJ, Wilde L, de Vries MC, Moavero R, Pearson DA, Curatolo P. A clinical update on tuberous sclerosis complex-associated neuropsychiatric disorders (TAND). Am J Med Genet C Semin Med Genet. 2018 Sep;178(3):309-320. doi: 10.1002/ajmg.c.31637. Epub 2018 Aug 16.

Peron A, Au KS, Northrup H. Genetics, genomics, and genotype-phenotype correlations of TSC: Insights for clinical practice. Am J Med Genet C Semin Med Genet. 2018 Sep;178(3):281-290. doi: 10.1002/ajmg.c.31651. Epub 2018 Sep 26.

Peron A, Northrup H. Tuberous sclerosis complex. Am J Med Genet C Semin Med Genet. 2018 Sep;178(3):274-277. doi: 10.1002/ajmg.c.31657. Epub 2018 Oct 16.

Soorya L, Leon J, Trelles MP, Thurm A. Framework for assessing individuals with rare genetic disorders associated with profound intellectual and multiple disabilities (PIMD): the example of Phelan McDermid Syndrome. Clin Neuropsychol. 2018 Aug-Oct;32(7):1226-1255. doi: 10.1080/13854046.2017.1413211. Epub 2017 Dec 21.

van der Poest Clement EA, Sahin M, Peters JM. Vigabatrin for Epileptic Spasms and Tonic Seizures in Tuberous Sclerosis Complex. J Child Neurol. 2018 Jul;33(8):519-524. doi: 10.1177/0883073818768309. Epub 2018 Apr 24.

Bernardo D, Nariai H, Hussain SA, Sankar R, Salamon N, Krueger DA, Sahin M, Northrup H, Bebin EM, Wu JY; UCLA Pediatric Epilepsy Group; TACERN Study Group. Visual and semi-automatic non-invasive detection of interictal fast ripples: A potential biomarker of epilepsy in children with tuberous sclerosis complex. Clin Neurophysiol. 2018 Jul;129(7):1458-1466. doi: 10.1016/j.clinph.2018.03.010. Epub 2018 Apr 3.

Curtin P, Austin C, Curtin A, Gennings C, Arora M; (for the Emergent Dynamical Systems Group), Tammimies K, Willfors C, Berggren S, Siper P, Rai D, Meyering K, Kolevzon A, Mollon J, David AS, Lewis G, Zammit S, Heilbrun L, Palmer RF, Wright RO, Bölte S, Reichenberg A. Dynamical features in fetal and postnatal zinc-copper metabolic cycles predict the emergence of autism spectrum disorder. Sci Adv. 2018 May 30;4(5):eaat1293. doi: 10.1126/sciadv.aat1293. eCollection 2018 May.

De Rubeis S, Siper PM, Durkin A, Weissman J, Muratet F, Halpern D, Trelles MDP, Frank Y, Lozano R, Wang AT, Holder JL Jr, Betancur C, Buxbaum JD, Kolevzon A. Delineation of the genetic and clinical spectrum of Phelan-McDermid syndrome caused by SHANK3 point mutations. Mol Autism. 2018 Apr 27;9:31. doi: 10.1186/s13229-018-0205-9. eCollection 2018.

Srivastava S, Prohl AK, Scherrer B, Kapur K, Krueger DA, Warfield SK, Sahin M; TACERN Study Group. Cerebellar volume as an imaging marker of development in infants with tuberous sclerosis complex. Neurology. 2018 Apr 24;90(17):e1493-e1500. doi: 10.1212/WNL.0000000000005352. Epub 2018 Mar 23.

Rensonnet G, Scherrer B, Warfield SK, Macq B, Taquet M. Assessing the validity of the approximation of diffusion-weighted-MRI signals from crossing fascicles by sums of signals from single fascicles. Magn Reson Med. 2018 Apr;79(4):2332-2345. doi: 10.1002/mrm.26832. Epub 2017 Jul 16.

Khan OI, Zhou X, Leon J, Kessler R, Gaughan T, D'Souza P, Gropman A, Cohen N, Rennert O, Buckley A, Inati S, Thurm A. Prospective longitudinal overnight video-EEG evaluation in Phelan-McDermid Syndrome. Epilepsy Behav. 2018 Mar;80:312-320. doi: 10.1016/j.yebeh.2017.11.034. Epub 2018 Feb 3.

Byrd V, Getz T, Padmanabhan R, Arora H, Eng C. The microbiome in PTEN hamartoma tumor syndrome. Endocr Relat Cancer. 2018 Mar;25(3):233-243. doi: 10.1530/ERC-17-0442. Epub 2017 Dec 12.

Farach LS, Little ME, Duker AL, Logan CV, Jackson A, Hecht JT, Bober M. The expanding phenotype of RNU4ATAC pathogenic variants to Lowry Wood syndrome. Am J Med Genet A. 2018 Feb;176(2):465-469. doi: 10.1002/ajmg.a.38581. Epub 2017 Dec 19.

Frazier TW, Strauss M, Klingemier EW, Zetzer EE, Hardan AY, Eng C, Youngstrom EA. A Meta-Analysis of Gaze Differences to Social and Nonsocial Information Between Individuals With and Without Autism. J Am Acad Child Adolesc Psychiatry. 2017 Jul;56(7):546-555. doi: 10.1016/j.jaac.2017.05.005. Epub 2017 May 11.

Srivastava S, Sahin M. Autism spectrum disorder and epileptic encephalopathy: common causes, many questions. J Neurodev Disord. 2017 Jun 23;9:23. doi: 10.1186/s11689-017-9202-0. PMID: 28649286; PMCID: PMC5481888.

Martin KR, Zhou W, Bowman MJ, Shih J, Au KS, Dittenhafer-Reed KE, Sisson KA, Koeman J, Weisenberger DJ, Cottingham SL, DeRoos ST, Devinsky O, Winn ME, Cherniack AD, Shen H, Northrup H, Krueger DA, MacKeigan JP. The genomic landscape of tuberous sclerosis complex. Nat Commun. 2017 Jun 15;8:15816. doi: 10.1038/ncomms15816.

Siper PM, Kolevzon A, Wang AT, Buxbaum JD, Tavassoli T. A clinician-administered observation and corresponding caregiver interview capturing DSM-5 sensory reactivity symptoms in children with ASD. Autism Res. 2017 Jun;10(6):1133-1140. doi: 10.1002/aur.1750. Epub 2017 Mar 11.

Rankine J, Li E, Lurie S, Rieger H, Fourie E, Siper PM, Wang AT, Buxbaum JD, Kolevzon A. Language ENvironment Analysis (LENA) in Phelan-McDermid Syndrome: Validity and Suggestions for Use in Minimally Verbal Children with Autism Spectrum Disorder. J Autism Dev Disord. 2017 Jun;47(6):1605-1617. doi: 10.1007/s10803-017-3082-8.

Capal JK, Bernardino-Cuesta B, Horn PS, et al. Influence of seizures on early development in tuberous sclerosis complex. Epilepsy Behav. 2017;70(Pt A):245-252. PMID: 28457992, PMCID: PMC5497719.

Hussain SA, Mathern GW, Hung P, Weng J, Sankar R, Wu JY. Intraoperative fast ripples independently predict postsurgical epilepsy outcome: Comparison with other electrocorticographic phenomena. Epilepsy Res. 2017;135:79-86. PMID: 28644979, PMCID: PMC5568451.

Davis PE, Filip-Dhima R, Sideridis G, Peters JM, Au KS, Northrup H, Bebin EM, Wu JY, Krueger D, Sahin M; Tuberous Sclerosis Complex Autism Center of Excellence Research Network. Presentation and Diagnosis of Tuberous Sclerosis Complex in Infants. Pediatrics. 2017;140(6). PMID: 29101226, PMCID: PMC5703775.

Capal JK, Horn PS, Murray DS, Byars AW, Bing NM, Kent B, Bucher LA, Williams ME, O'Kelley S, Pearson DA, Sahin M, Krueger DA; TACERN Study Group. Utility of the Autism Observation Scale for Infants in Early Identification of Autism in Tuberous Sclerosis Complex. Pediatr Neurol. 2017;75:80-86. PMID: 28844798, PMCID: PMC5610103.

Krueger DA, Wilfong AA, Mays M, Talley CM, Agricola K, Tudor C, Capal J, Holland-Bouley K, Franz DN. Long-term treatment of epilepsy with everolimus in tuberous sclerosis. Neurology. 2016 Dec 6;87(23):2408-2415. doi: 10.1212/WNL.0000000000003400. Epub 2016 Nov 4. PMID: 27815402; PMCID: PMC5177677.

Markowitz LA, Reyes C, Embacher RA, Speer LL, Roizen N, Frazier TW. Development and psychometric evaluation of a psychosocial quality-of-life questionnaire for individuals with autism and related developmental disorders. Autism. 2016 Oct;20(7):832-44. doi: 10.1177/1362361315611382. Epub 2015 Dec 10.

Scherrer B, Schwartzman A, Taquet M, Sahin M, Prabhu SP, Warfield SK. Characterizing brain tissue by assessment of the distribution of anisotropic microstructural environments in diffusion-compartment imaging (DIAMOND). Magn Reson Med. Sep 12 2015. PMID: 26362832.

Sahin M, Henske EP, Manning BD, Ess KC, Bissler JJ, Klann E, Kwiatkowski DJ, Roberds SL, Silva AJ, Hillaire-Clarke CS, Young LR, Zervas M, Mamounas LA; Tuberous Sclerosis Complex Working Group to Update the Research Plan. Advances and Future Directions for Tuberous Sclerosis Complex Research: Recommendations From the 2015 Strategic Planning Conference. Pediatr Neurol. 2016 Jul;60:1-12. doi: 10.1016/j.pediatrneurol.2016.03.015. Epub 2016 Apr 2. PMID: 27267556; PMCID: PMC4921275.

Im K, Ahtam B, Haehn D, Peters JM, Warfield SK, Sahin M, Ellen Grant P. Altered Structural Brain Networks in Tuberous Sclerosis Complex. Cereb Cortex. 2016 May;26(5):2046-58. doi: 10.1093/cercor/bhv026. Epub 2015 Mar 5. PMID: 25750257; PMCID: PMC4830286.

Dölen G, Sahin M. Editorial: Essential Pathways and Circuits of Autism Pathogenesis. Front Neurosci. 2016 Apr 26;10:182. doi: 10.3389/fnins.2016.00182. eCollection 2016.

Frazier TW, Klingemier EW, Beukemann M, Speer L, Markowitz L, Parikh S, Wexberg S, Giuliano K, Schulte E, Delahunty C, Ahuja V, Eng C, Manos MJ, Hardan AY, Youngstrom EA, Strauss MS. Development of an Objective Autism Risk Index Using Remote Eye Tracking. J Am Acad Child Adolesc Psychiatry. Apr 2016;55(4):301-309. PMID: 27015721, PMCID: PMC4808563.

Ebrahimi-Fakhari D, Saffari A, Wahlster L, Lu J, Byrne S, Hoffmann GF, Jungbluth H, Sahin M. Congenital disorders of autophagy: an emerging novel class of inborn errors of neuro-metabolism. Brain. 2016 Feb;139(Pt 2):317-37. doi: 10.1093/brain/awv371. Epub 2015 Dec 29. PMID: 26715604; PMCID: PMC5841365.

Marami B, Scherrer B, Afacan O, Erem B, Warfield SK, Gholipour A. Motion-Robust Diffusion-Weighted Brain MRI Reconstruction Through Slice-Level Registration-Based Motion Tracking. IEEE Trans Med Imaging. 2016;35(10):2258-2269. PMID: 27834639, PMCID: PMC5108524.

Siper PM, Zemon V, Gordon J, et al. Siper PM. PLoS ONE. 2016;11(10):e0164422. PMID: 27716799, PMCID: PMC5055293.

Keppler-Noreuil KM, Parker VE, Darling TN, Martinez-Agosto JA. Somatic overgrowth disorders of the PI3K/AKT/mTOR pathway & therapeutic strategies. Am J Med Genet C Semin Med Genet. 2016;172(4):402-421. PMID: 27860216, PMCID: PMC5592089.

The phosphatidylinositol-3-kinase (PI3K)/AKT/mTOR signaling pathway plays an essential role in regulation of normal cell growth, metabolism, and survival. Somatic activating mutations in the PI3K/AKT/mTOR pathway are among the most common mutations identified in cancer, and have been shown to cause a spectrum of overgrowth syndromes including PIK3CA-Related Overgrowth Spectrum, Proteus syndrome, and brain overgrowth conditions. Clinical findings in these disorders may be isolated or multiple, including sporadic or mosaic overgrowth (adipose, skeletal, muscle, brain, vascular, or lymphatic), and skin abnormalities (including epidermal nevi, hyper-, and hypopigmented lesions), and have the potential risk of tumorigenesis. Key negative regulators of the PI3K-AKT signaling pathway include PTEN and TSC1/TSC2 and germline loss-of function mutations of these genes are established to cause PTEN Hamartoma Tumor Syndrome and Tuberous Sclerosis Complex. Mosaic forms of these conditions lead to increased activation of PI3K and mTOR at affected sites and there is phenotypic overlap between these conditions. All are associated with significant morbidity with limited options for treatment other than symptomatic therapies and surgeries. As dysregulation of the PI3K/AKT/mTOR pathway has been implicated in cancer, several small molecule inhibitors targeting different components of the PI3K/AKT/mTOR signaling pathway are under clinical investigation. The development of these therapies brings closer the prospect of targeting treatment for somatic PI3K/AKT/mTOR-related overgrowth syndromes. This review describes the clinical findings, gene function and pathogenesis of these mosaic overgrowth syndromes, and presents existing and future treatment strategies to reduce or prevent associated complications of these disorders. © 2016 Wiley Periodicals, Inc.

Costales J, Kolevzon A. The therapeutic potential of insulin-like growth factor-1 in central nervous system disorders. Neurosci Biobehav Rev. 2016;63:207-222. PMID: 26780584, PMCID: PMC4790729.

Taquet M, Scherrer B, Boumal N, Peters JM, Macq B, Warfield SK. Improved fidelity of brain microstructure mapping from single-shell diffusion MRI. Med Image Anal. Dec 2015;26(1):268- 286. PMID: 26529580, PMCID: PMC4679640.

Sahin M, Sur M. Genes, circuits, and precision therapies for autism and related neurodevelopmental disorders. Science. Nov 20 2015;350(6263). PMID: 26472761, PMCID: PMC4739545.

He X, Thacker S, Romigh T, Yu Q, Frazier TW Jr, Eng C. Cytoplasm-predominant Pten associates with increased region-specific brain tyrosine hydroxylase and dopamine D2 receptors in mouse model with autistic traits. Mol Autism. 2015 Nov 17;6:63. doi: 10.1186/s13229-015-0056-6. eCollection 2015.

Tyburczy ME, Dies KA, Glass J, Camposano S, Chekaluk Y, Thorner AR, Lin L, Krueger D, Franz DN, Thiele EA, Sahin M, Kwiatkowski DJ. Mosaic and Intronic Mutations in TSC1/TSC2 Explain the Majority of TSC Patients with No Mutation Identified by Conventional Testing. PLoS Genet. 2015 Nov 5;11(11):e1005637. doi: 10.1371/journal.pgen.1005637. eCollection 2015 Nov.

Frazier TW, Youngstrom EA, Hardan AY, Georgiades S, Constantino JN, Eng C. Quantitative autism symptom patterns recapitulate differential mechanisms of genetic transmission in single and multiple incidence families. Mol Autism. 2015 Oct 27;6:58. doi: 10.1186/s13229-015-0050-z. eCollection 2015.

Tilot AK, Frazier TW 2nd, Eng C. Balancing Proliferation and Connectivity in PTEN-associated Autism Spectrum Disorder. Neurotherapeutics. 2015 Jul;12(3):609-19. doi: 10.1007/s13311-015-0356-8. PMID: 25916396; PMCID: PMC4489960.

Neul JL, Sahin M. Therapeutic Advances in Autism and Other Neurodevelopmental Disorders. Neurotherapeutics. Jul 2015;12(3):519-520. PMID: 26076992, PMCID: PMC4489958.

Davis PE, Peters JM, Krueger DA, Sahin M. Tuberous Sclerosis: A New Frontier in Targeted Treatment of Autism. Neurotherapeutics. Jul 2015;12(3):572-583. PMID: 25986747, PMCID: PMC4489948.

Baumer FM, Song JW, Mitchell PD, Pienaar R, Sahin M, Grant PE, Takahashi E. Longitudinal changes in diffusion properties in white matter pathways of children with tuberous sclerosis complex. Pediatr Neurol. Jun 2015;52(6):615-623. PMID: 25817702, PMCID: PMC4442035.

Ebrahimi-Fakhari D, Sahin M. Autism and the synapse: emerging mechanisms and mechanism-based therapies. Curr Opin Neurol. Apr 2015;28(2):91-102. PMID: 25695134.

Sundberg M, Sahin M. Cerebellar Development and Autism Spectrum Disorder in Tuberous Sclerosis Complex. J Child Neurol. Aug 24 2015. PMID: 26303409, PMCID: PMC4644486.

Hussain SA, Kwong G, Millichap JJ, Mytinger JR, Ryan N, Matsumoto JH, Wu JY, Lerner JT, Sankar R. Hypsarrhythmia assessment exhibits poor interrater reliability: a threat to clinical trial validity. Epilepsia. 2015 Jan;56(1):77-81. doi: 10.1111/epi.12861. Epub 2014 Nov 10.

Lipton JO, Sahin M. The neurology of mTOR. Neuron. Oct 22 2014;84(2):275-291. PMID: 25374355, PMCID: PMC4223653.

The mechanistic target of rapamycin (mTOR) signaling pathway is a crucial cellular signaling hub that, like the nervous system itself, integrates internal and external cues to elicit critical outputs including growth control, protein synthesis, gene expression, and metabolic balance. The importance of mTOR signaling to brain function is underscored by the myriad disorders in which mTOR pathway dysfunction is implicated, such as autism, epilepsy, and neurodegenerative disorders. Pharmacological manipulation of mTOR signaling holds therapeutic promise and has entered clinical trials for several disorders. Here, we review the functions of mTOR signaling in the normal and pathological brain, highlighting ongoing efforts to translate our understanding of cellular physiology into direct medical benefit for neurological disorders.

Hoffmeister JD, Konczak J, Misono SN. Characterization of Upper Esophageal Sphincter Pressures Relative to Vocal Acoustics. J Appl Physiol (1985). 2024 Dec 6. doi: 10.1152/japplphysiol.00385.2024. Online ahead of print.

Thomsen M, Ott F, Loens S, Kilic-Berkmen G, Tan AH, Lim SY, Lohmann E, Schröder KM, Ipsen L, Nothacker LA, Welzel L, Rudnik AS, Hinrichs F, Odorfer T, Zeuner KE, Schumann F, Kühn AA, Zittel S, Moeller M, Pfister R, Kamm C, Lang AE, Tay YW, Vidailhet M, Roze E, Perlmutter JS, Feuerstein JS, Fung VSC, Chang F, Barbano RL, Bellows S, Shukla AAW, Espay AJ, LeDoux MS, Berman BD, Reich S, Deik A, Franke A, Wittig M, Franzenburg S, Volkmann J, Brüggemann N, Jinnah HA, Bäumer T, Klein C, Busch H, Lohmann K. Genetic Diversity and Expanded Phenotypes in Dystonia: Insights from Large-Scale Exome Sequencing. medRxiv [Preprint]. 2024 Dec 5:2024.12.02.24316741. doi: 10.1101/2024.12.02.24316741.

Laabs BH, Lohmann K, Vollstedt EJ, Reinberger T, Nuxoll LM, Kilic-Berkmen G, Perlmutter JS, Loens S, Cruchaga C, Franke A, Dobricic V, Hinrichs F, Grözinger A, Altenmüller E, Bellows S, Boesch S, Bressman SB, Duque KR, Espay AJ, Ferbert A, Feuerstein JS, Frank S, Gasser T, Haslinger B, Jech R, Kaiser F, Kamm C, Kollewe K, Kühn AA, LeDoux MS, Lohmann E, Mahajan A, Münchau A, Multhaupt-Buell T, Pantelyat A, Pirio Richardson SE, Raymond D, Reich SG, Saunders Pullman R, Schormair B, Sharma N, Sichani AH, Simonyan K, Volkmann J, Wagle Shukla A, Winkelmann J, Wright LJ, Zech M, Zeuner KE, Zittel S, Kasten M, Sun YV, Bäumer T, Brüggemann N, Ozelius LJ, Jinnah HA, Klein C, König IR. Genetic Risk Factors in Isolated Dystonia Escape Genome-Wide Association Studies. Mov Disord. 2024 Sep 17. doi: 10.1002/mds.29968. Online ahead of print.

Rocchi L, Latorre A, Menozzi E, Rispoli V, Rothwell JC, Berardelli A, Bhatia KP. Amelioration of Focal Hand Dystonia via Low-Frequency Repetitive Somatosensory Stimulation. Mov Disord. 2024 Sep 10. doi: 10.1002/mds.30011. Online ahead of print.

Timsina J, Dinasarapu A, Kilic-Berkmen G, Budde J, Sung YJ, Klein AM, Cruchaga C, Jinnah HA. Blood-Based Proteomics for Adult-Onset Focal Dystonias. Ann Neurol. 2024 Jul;96(1):110-120. doi: 10.1002/ana.26929. Epub 2024 Apr 5. PMID: 38578115; PMCID: PMC11186717.

Adult-onset focal dystonias are neurological disorders characterized by overactive muscles leading to involuntary, sometimes painful movements in one part of the body. In most cases, the cause and development of these disorders are unknown.

In this study, researchers used proteomics methods to identify potential changes in blood plasma proteins in patients with adult-onset focal dystonias. The team compared over 6,000 proteins in the blood plasma of participants with cervical dystonia, laryngeal dystonia, and blepharospasm, as well as healthy controls. Next, researchers identified relevant biological pathways and used protein changes to build a prediction model for dystonia.

Results show that 15 proteins were associated with adult-onset focal dystonia, with some proteins shared across multiple subgroups and others unique to just one. The top biological pathways involved changes in the immune system, metal ion transport, and reactive oxygen species. Finally, the prediction model showed high accuracy in discriminating control participants from those with dystonia. Authors note that this study provides new insights into the cause and development of dystonia, as well as new potential biomarkers.

Castagna A, Jinnah HA, Albanese A. Duration of botulinum toxin efficacy in cervical dystonia clinical trials: A scoping review. Parkinsonism Relat Disord. 2024 May 29;125:107011. doi: 10.1016/j.parkreldis.2024.107011. Online ahead of print.

Cash TV, Lessov-Schlaggar CN, Foster ER, Myers PS, Jackson JJ, Maiti B, Kotzbauer PT, Perlmutter JS, Campbell MC. Replication and reliability of Parkinson's disease clinical subtypes. Parkinsonism Relat Disord. 2024 May 22;124:107016. doi: 10.1016/j.parkreldis.2024.107016. Online ahead of print.

Kilic-Berkmen G, Scorr LM, McKay L, Thayani M, Donsante Y, Perlmutter JS, Norris SA, Wright L, Klein C, Feuerstein JS, Mahajan A, Wagle-Shukla A, Malaty I, LeDoux MS, Pirio-Richardson S, Pantelyat A, Moukheiber E, Frank S, Ondo W, Saunders-Pullman R, Lohman K, Hess EJ, Jinnah HA. Sex Differences in Dystonia. Mov Disord Clin Pract. 2024 May 22. doi: 10.1002/mdc3.14059. Epub ahead of print. PMID: 38778444.

Dystonia is a neurological disorder characterized by excessive muscle contractions leading to abnormal postures, movements, and pain. Previous studies have suggested that there are more female individuals with certain types of dystonia compared to male individuals. However, not much is known about the factors that impact these differences or the mechanisms behind them.

In this study, researchers explored the factors and mechanisms underlying differences between males and females with dystonia. The team analyzed data from two different sources, including 3,222 individuals from the Dystonia Coalition database and 1,377 individuals from the Movement Disorder Society Genetic mutation (MDSGene) database.

Results show that female individuals outnumber male individuals for both adult-onset idiopathic and early onset monogenic (single-gene) dystonias, with females making up about two-thirds of all cases. In addition, these findings reveal that the ratio of females to males with dystonia depends on the type of dystonia, age, and underlying genetics.

Di Luca DG, Perlmutter JS. Time for Clinical Dopamine Transporter Scans in Parkinsonism?: Not DAT Yet. Neurology. 2024 Jun 11;102(11):e209558. doi: 10.1212/WNL.0000000000209558. Epub 2024 May 17.

Thayani M, Jinnah HA. Can symptoms or signs of cervical dystonia occur without abnormal movements of the head or neck?. Parkinsonism Relat Disord. 2024 Jun;123:106958. doi: 10.1016/j.parkreldis.2024.106958. Epub 2024 Apr 16.

Kilic-Berkmen G, Scorr LM, Defazio G, Jinnah HA. Thyroid disease and cervical dystonia. Parkinsonism Relat Disord. 2024 Mar 2:106082. doi: 10.1016/j.parkreldis.2024.106082. Epub ahead of print. PMID: 38458834.

Scorr LM, Kilic-Berkmen G, Sutcliffe DJ, Dinasarapu AR, McKay JL, Bagchi P, Powell MD, Boss JM, Cereb N, Little M, Gragert L, Hanfelt J, McKeon A, Tyor W, Jinnah HA. Exploration of potential immune mechanisms in cervical dystonia. Parkinsonism Relat Disord. 2024 Feb 17:106036. doi: 10.1016/j.parkreldis.2024.106036. Epub ahead of print. PMID: 38462403.

Kilic-Berkmen G, Kim H, Chen D, Yeo CI, Dinasarapu AR, Scorr LM, Yeo WH, Peterson DA, Williams H, Ruby A, Mills R, Jinnah HA. An Exploratory, Randomized, Double-Blind Clinical Trial of Dipraglurant for Blepharospasm. Mov Disord. 2024 Feb 3. doi: 10.1002/mds.29734. Epub ahead of print. PMID: 38310362.

Blepharospasm is a type of dystonia (involuntary muscle twitching) which affects the muscles surrounding both eyes, causing forced blinking, eye irritation, and involuntary closure of the eyes. Although blepharospasm can be treated with a medication called botulinum toxin, outcomes are often inconsistent.

In this study, researchers conducted an exploratory, randomized, double-blind clinical trial of the oral drug dipraglurant for blepharospasm. Fifteen individuals with blepharospasm received either a placebo or dipraglurant. The team used multiple scales rated by clinicians or participants, digital video, and a wearable sensor to assess outcomes.

Results show that although dipraglurant was well tolerated in study participants, it did not produce an obvious benefit. Authors note that these results provide valuable information for planning future trials in blepharospasm.

Beylergil SB, Mukunda KN, Elkasaby M, Perlmutter JS, Factor S, Bäumer T, Feurestein J, Shelton E, Bellows S, Jankovic J, Mahajan A, Wamer-Rosen T, Reich SG, Shukla AW, Malaty I, Espay A, Duque K, LeDoux MS, Saunders-Pullman R, Leaver K, Frank S, Pantelyat A, Fung V, Richardson SP, Berman B, Stover N, Deik A, Ondo W, Groth C, Jinnah HA, Shaikh AG. Tremor in cervical dystonia. Dystonia. 2024;3:11309. doi: 10.3389/dyst.2024.11309. Epub 2024 Mar 21.

Boz D, Kilic-Berkmen G, Perlmutter JS, Norris SA, Wright LJ, Klein C, Bäumer T, Löns S, Feuerstein JS, Mahajan A, Wagle-Shukla A, Malaty I, LeDoux MS, Ondo W, Pantelyat A, Frank S, Saunders-Pullman R, Jinnah HA. An Empirical Comparison of Commonly Used Universal Rating Scales for Dystonia. Mov Disord Clin Pract. 2023 Nov 12;10(12):1777-1786. doi: 10.1002/mdc3.13909. eCollection 2023 Dec.

Ghanouni A, Jona N, Jinnah HA, Kilic-Berkmen G, Shelly S, Klein AM. Demographics and Clinical Characteristics Associated with the Spread of New-Onset Laryngeal Dystonia. Laryngoscope. 2024 May;134(5):2295-2299. doi: 10.1002/lary.31146. Epub 2023 Nov 1.

Junker J, Hall J, Berman BD, Vidailhet M, Roze E, Bäumer T, Malaty IA, Shukla AW, Jankovic J, Reich SG, Espay AJ, Duque KR, Patel N, Perlmutter JS, Jinnah HA; Dystonia Coalition Study Group; Brandt V, Brüggemann N. Longitudinal predictors of health-related quality of life in isolated dystonia. J Neurol. 2023 Oct 15. doi: 10.1007/s00415-023-12022-4. Online ahead of print.

Lee HY, Park I, Luu MP, Zhao J, Vu JP, Cisneros E, Berman BD, Jinnah HA, Kim HJ, Liu CY, Perlmutter JS, Richardson SP, Weissbach A, Stebbins GT, Peterson DA. Interrater reliability of motor severity scales for hemifacial spasm. J Neural Transm (Vienna). 2023 Oct;130(10):1269-1279. doi: 10.1007/s00702-023-02667-w. Epub 2023 Jul 19.

Cotton AC, Scorr L, McDonald W, Comella C, Perlmutter JS, Goetz CG, Jankovic J, Marsh L, Factor S, Jinnah HA. Assessing the Severity of Cervical Dystonia: Ask the Doctor or Ask the Patient. Mov Disord Clin Pract. 2023 Aug 3;10(9):1399-1403. doi: 10.1002/mdc3.13827. PMID: 37772296; PMCID: PMC10525044

Cervical dystonia is a rare, often painful, movement disorder associated with characteristic sustained or jerky involuntary muscle contractions of the neck. The severity of cervical dystonia can be assessed using either clinician-rated scales (CRS) or patient-rated outcome (PRO) tools. However, these two measures are often poorly correlated.   

In this study, researchers aimed to determine if the correlation between a CRS and PRO for the movement disorder of cervical dystonia improves by accounting for non-movement features. The team evaluated 209 patients with cervical dystonia using a CRS and a PRO.

The results revealed a weak correlation between the two measures, even when considering only the movement. However, the correlation improved with a model that included non-motor symptoms of pain, depression, and disability. These results suggest that assessing the movement disorder with a PRO should also include assessments of non-motor symptoms that may contribute to the patient’s perception of the disorder. Findings may apply to other disorders, especially those with frequent non-motor co-morbidities.

Aravamuthan BR, Pearson TS, Ueda K, Miao H, Zerafati-Jahromi G, Gilbert L, Comella C, Perlmutter JS. Determinants of gait dystonia severity in cerebral palsy. Dev Med Child Neurol. 2023 Jul;65(7):968-977. doi: 10.1111/dmcn.15524. Epub 2023 Jan 26.

Younce JR, Cascella RH, Berman BD, Jinnah HA, Bellows S, Feuerstein J, Wagle Shukla A, Mahajan A, Chang FCF, Duque KR, Reich S, Richardson SP, Deik A, Stover N, Luna JM, Norris SA. Anatomical categorization of isolated non-focal dystonia: novel and existing patterns using a data-driven approach. Dystonia. 2023;2:11305. doi: 10.3389/dyst.2023.11305. Epub 2023 Jun 8. PMID: 37920445; PMCID: PMC10621194

Dystonia is a neurological disorder characterized by excessive muscle contractions leading to abnormal postures, movements, and pain. Any region of the body can be involved, either in isolation or in combination with another region of the body. Although accurate classification of these combinations is important to providing care, it can sometimes be inconsistent.

In this study, researchers used a data-driven clustering approach to investigate which combinations are most common in dystonia. The team analyzed 1,618 participants with isolated non-focal dystonia from the Dystonia Coalition database to explore which body regions were affected together.

Results reinforce common patterns in cranial and cervical regions. However, findings also show unexpectedly strong associations between bilateral upper or lower limbs, revealing new patterns that may represent an underrecognized dystonia subtype.

Albanese A, Wissel J, Jost WH, Castagna A, Althaus M, Comes G, Scheschonka A, Vacchelli M, Jinnah HA. Pain Reduction in Cervical Dystonia Following Treatment with IncobotulinumtoxinA: A Pooled Analysis. Toxins (Basel). 2023 May 12;15(5):333. doi: 10.3390/toxins15050333.

Vizcarra JA, Jinnah HA. What Is Hemidystonia. Mov Disord Clin Pract. 2023 Feb 3;10(3):477-481. doi: 10.1002/mdc3.13659. eCollection 2023 Mar.

Kilic-Berkmen G, Scorr L, Rosen A, Wu E, Freeman A, Silver M, Hanfelt J, Jinnah HA. Thyroid disease in cervical dystonia. Parkinsonism Relat Disord. 2023 Feb;107:105274. doi: 10.1016/j.parkreldis.2022.105274. Epub 2022 Dec 30. PMID: 36621155.

Bukhari-Parlakturk N, Lutz MW, Al-Khalidi HR, Unnithan S, Wang JE, Scott B, Termsarasab P, Appelbaum LG, Calakos N. Suitability of Automated Writing Measures for Clinical Trial Outcome in Writer's Cramp. Mov Disord. 2023 Jan;38(1):123-132. doi: 10.1002/mds.29237. Epub 2022 Oct 13.

Corp DT, Greenwood CJ, Morrison-Ham J, Pullinen J, McDowall GM, Younger EFP, Jinnah HA, Fox MD, Joutsa J. Clinical and Structural Findings in Patients With Lesion-Induced Dystonia: Descriptive and Quantitative Analysis of Published Cases. Neurology. 2022 Nov 1;99(18):e1957-e1967. doi: 10.1212/WNL.0000000000201042. Epub 2022 Aug 17.

Defazio G, Gigante AF, Hallett M, Berardelli A, Perlmutter JS, Berman BD, Jankovic J, Bäumer T, Comella C, Ercoli T, Ferrazzano G, Fox SH, Kim HJ, Moukheiber ES, Richardson SP, Weissbach A, Jinnah HA.. Motor and psychiatric features in idiopathic blepharospasm: A data-driven cluster analysis. Parkinsonism Relat Disord. 2022 Nov;104:94-98. doi: 10.1016/j.parkreldis.2022.10.008. Epub 2022 Oct 13.

Seifar F, Dinasarapu AR, Jinnah HA.. Uric Acid in Parkinson's Disease: What Is the Connection?. Mov Disord. 2022 Nov;37(11):2173-2183. doi: 10.1002/mds.29209. Epub 2022 Sep 3.

Peterson QA, Fei T, Sy LE, Froeschke LLO, Mendelsohn AH, Berke GS, Peterson DA. Correlating perceptual voice quality in ADSD with computer vision assessment of glottal geometry dynamics. J Speech Lang Hear Res. 2022 Oct 17;65(10):3695-3708. doi: 10.1044/2022_JSLHR-22-00053. Epub 2022 Sep 21.

Vu JP, Cisneros E, Zhao J, Lee HY, Jankovic J, Factor SA, Goetz CG, Barbano RL, Perlmutter JS, Jinnah HA, Richardson SP, Stebbins GT, Elble RJ, Comella CL, Peterson DA. From null to midline: changes in head posture do not predictably change head tremor in cervical dystonia. Dystonia. 2022;1:10684. doi: 10.3389/dyst.2022.10684. Epub 2022 Sep 1. PMID: 37101941; PMCID: PMC10128866.

Kilic-Berkmen G, Defazio G, Hallett M, Berardelli A, Ferrazzano G, Belvisi D, Klein C, Bäumer T, Weissbach A, Perlmutter JS, Feuerstein J, Jinnah HA; Dystonia Coalition Investigators. Diagnosis and classification of blepharospasm: Recommendations based on empirical evidence. J Neurol Sci. 2022 Aug 15;439:120319. doi: 10.1016/j.jns.2022.120319. Epub 2022 Jun 10. PMID: 35716653; PMCID: PMC9357089.

Blepharospasm is a rare disorder characterized by spasms of muscles surrounding both eyes with excessive blinking and squinting. It is the second most common form of dystonia (involuntary muscle twitching) and often spreads to other regions of the body. Currently, guidelines for diagnosis and classification are ambiguous. In this study, researchers aimed to provide more specific recommendations for diagnosis and classification of blepharospasm. Data were obtained from the Dystonia Coalition for patients diagnosed with all types of isolated dystonia. The team evaluated these data to determine how examinations recorded by movement disorder specialists were used to classify blepharospasm as focal, segmental, or multifocal. Results showed much variability in expert opinion regarding the diagnosis of blepharospasm, which was often inconsistent with existing guidelines for the diagnosis and classification of focal blepharospasm. This study highlights the need for more specific guidelines, which are provided in the publication.

Defazio G, Hallett M, Berardelli A, Perlmutter JS, Berman BD, Jankovic J, Bäumer T, Comella C, Ercoli T, Ferrazzano G, Fox SH, Kim HJ, Moukheiber ES, Pirio Richardson S, Weissbach A, Gigante AF, Jinnah HA. Measurement Properties of Clinical Scales Rating the Severity of Blepharospasm: A Multicenter Observational Study. Mov Disord Clin Pract. 2022 Aug 15;9(7):949-955. doi: 10.1002/mdc3.13530. eCollection 2022 Oct.

Di Fonzo A, Albanese A, Jinnah HA. The apparent paradox of phenotypic diversity and shared mechanisms across dystonia syndromes. Curr Opin Neurol.. 2022 Aug 1;35(4):502-509. doi: 10.1097/WCO.0000000000001076. Epub 2022 Jul 5. PMID: 35856917; PMCID: PMC9309988.

The dystonias are a group of movement disorders characterized by uncontrollable, sometimes painful, involuntary muscle contractions, resulting in repetitive shaking, turning, and twisting of affected body parts. As new genetic causes continue to be discovered, researchers have found that these different genetic forms share unexpectedly common underlying mechanisms. In this review article, authors explore the phenotypic diversity and shared mechanisms across dystonia syndromes. They also describe how these mechanisms can give rise to motor performance dysfunctions with a clinical aspect of dystonia. Authors state that this relationship between dystonia genes could revolutionize current dystonia classification systems. In the future, these advances could have promising effects on mechanism-based therapeutic approaches.

Couto B, Martinez-Valbuena I, Lee S, Alfradique-Dunham I, Perrin RJ, Perlmutter JS, Cruchaga C, Kim A, Visanji N, Sato C, Rogaeva E, Lang AE, Kovacs GG. Protracted course progressive supranuclear palsy. Eur J Neurol. 2022 Aug;29(8):2220-2231. doi: 10.1111/ene.15346. Epub 2022 Apr 21.

Reid EW, Nobriga CV. Reid EW. Clin Linguist Phon. 2022 Jul 12:1-16. doi: 10.1080/02699206.2022.2096483. Online ahead of print.

Scorr LM, Cho HJ, Kilic-Berkmen G, McKay JL, Hallett M, Klein C, Baumer T, Berman BD, Feuerstein JS, Perlmutter JS, Berardelli A, Ferrazzano G, Wagle-Shukla A, Malaty IA, Jankovic J, Bellows ST, Barbano RL, Vidailhet M, Roze E, Bonnet C, Mahajan A, LeDoux MS, Fung VSC, Chang FCF, Defazio G, Ercoli T, Factor S, Wojno T, Jinnah HA. Clinical Features and Evolution of Blepharospasm: A Multicenter International Cohort and Systematic Literature Review. Dystonia. 2022;1:10359. doi: 10.3389/dyst.2022.10359. Epub 2022 May 16. PMID: 36248010; PMCID: PMC9557246.

Kilic-Berkmen G, Jinnah HA. Cervical Dystonia with Tremor: One Movement Disorder or Two?. Mov Disord Clin Pract. 2022 Apr 15;9(5):719-720. doi: 10.1002/mdc3.13443. eCollection 2022 Jul.

Panyakaew P, Jinnah HA, Shaikh AG. Clinical features, pathophysiology, treatment, and controversies of tremor in dystonia. J Neurol Sci. 2022 Apr 15;435:120199. doi: 10.1016/j.jns.2022.120199. Epub 2022 Feb 22. PMID: 35259651.

Dystonia is a general term for a group of movement disorders characterized by uncontrollable, sometimes painful, involuntary muscle contractions, resulting in repetitive shaking, turning, and twisting of affected body parts. Dystonia is a rare disorder, but it often coexists with a more common disorder, tremor. The reasons for the frequent co-occurrence of dystonia and tremor are not clear. In this review article, researchers outline the differences in definitions, subtypes, and pathophysiology of dystonia and tremor. They outline some controversial topics, such as whether these two problems share a similar pathophysiology.

Hauser RA, Meyer JM, Factor SA, Comella CL, Tanner CM, Xavier RM, Caroff SN, Lundt L. Differentiating tardive dyskinesia: a video-based review of antipsychotic-induced movement disorders in clinical practice. CNS Spectr. 2022 Apr;27(2):208-217. doi: 10.1017/S109285292000200X. Epub 2020 Nov 20.

Zhang Z, Cisneros E, Lee HY, Vu JP, Chen Q, Benadof CN, Whitehill J, Rouzbehani R, Sy DT, Huang JS, Sejnowski TJ, Jankovic J, Factor S, Goetz CG, Barbano RL, Perlmutter JS, Jinnah HA, Berman BD, Richardson SP, Stebbins GT, Comella CL, Peterson DA. Hold that pose: capturing cervical dystonia's head deviation severity from video. Ann Clin Transl Neurol. 2022 Mar 25. doi: 10.1002/acn3.51549. Epub ahead of print. PMID: 35333449.

Cervical dystonia (CD) is a movement disorder resulting in characteristic, sustained, or tremor-like involuntary muscle contractions of the neck. It is characterized by excessive pulling of the muscles of the neck and shoulder, which causes the head to turn or tilt involuntarily. Typically, head posture severity is quantified with clinical rating scales that are susceptible to variability, reducing their sensitivity as outcome measures. Previously used objective methods require specialized equipment and have been limited to studies with a small number of cases. In this study, researchers evaluated a novel software system—the Computational Motor Objective Rater (CMOR)—to quantify multi-axis directionality and severity of head posture in CD using only conventional video camera recordings. They found that CMOR’s metrics for head posture severity correlated with clinical rating scales. Authors note that CMOR’s reliance upon only conventional video recordings supports its future potential for large-scale multisite clinical trials.

Vu JP, Cisneros E, Lee HY, Le L, Chen Q, Guo XA, Rouzbehani R, Jankovic J, Factor S, Goetz CG, Barbano RL, Perlmutter JS, Jinnah HA, Pirio Richardson S, Stebbins GT, Elble R, Comella CL, Peterson DA. Head tremor in cervical dystonia: Quantifying severity with computer vision. J Neurol Sci. 2022 Mar 15;434:120154. doi: 10.1016/j.jns.2022.120154. Epub 2022 Jan 22.

Dinasarapu AR, Sutcliffe DJ, Seifar F, Visser JE, Jinnah HA. Abnormalities of neural stem cells in Lesch-Nyhan disease. J Neurogenet. 2022 Mar-Jun;36(2-3):81-87. doi: 10.1080/01677063.2022.2129632. Epub 2022 Oct 13.

Del Bene VA, Crawford JL, Gómez-Gastiasoro A, Vannorsdall TD, Buchholz A, Ojeda N, Harris JC, Jinnah HA, Schretlen DJ. Microstructural white matter abnormalities in Lesch-Nyhan disease. Eur J Neurosci. 2022 Jan;55(1):264-276. doi: 10.1111/ejn.15512. Epub 2021 Dec 6.

Perlmutter JS. Bidding for a Grateful Patient. Narrat Inq Bioeth. 2022;12(1):7-9. doi: 10.1353/nib.2022.0003.

Kilic-Berkmen G, Pirio Richardson S, Perlmutter JS et al. Current Guidelines for Classifying and Diagnosing Cervical Dystonia: Empirical Evidence and Recommendations. Mov Disord Clin Pract. 2021 Dec 1;9(2):183-190. doi: 10.1002/mdc3.13376. PMID: 35146058; PMCID: PMC8810420.

Fagan M, Scorr L, Bernhardt D, Hess EJ, Perlmutter JS, Pardo CA, Jinnah HA. Neuropathology of blepharospasm. Exp Neurol. 2021 Dec;346:113855. doi: 10.1016/j.expneurol.2021.113855. Epub 2021 Aug 28. PMID: 34464652; PMCID: PMC8490317.

The dystonias are a group of disorders characterized by excessive muscle contractions leading to abnormal repetitive movements or postures. Blepharospasm is a subtype of dystonia characterized by overactive facial muscles. Previous brain imaging studies have implied subtle structural changes in blepharospasm, but the nature of these changes is not well understood. In this study, researchers found subtle loss of cerebellar Purkinje neurons in histopathological studies of brains from blepharospasm cases. These findings are similar to those reported for subjects with cervical dystonia. “To focus on what we should be looking for in blepharospasm, we used what we learned about cervical dystonia published in 2013 in a prior funding cycle,” says H. A. Jinnah, MD, PhD, principal investigator of the DC. “Thus, the RDCRN strategy of combining similar disorders under the same research umbrella is successful in facilitating both the research questions and methodologies.”

Sedov A, Popov V, Gamaleya A, Semenova U, Tomskiy A, Jinnah HA, Shaikh AG. Pallidal neuron activity determines responsiveness to deep brain stimulation in cervical dystonia. Clin Neurophysiol. 2021 Dec;132(12):3190-3196. doi: 10.1016/j.clinph.2021.07.032. Epub 2021 Sep 27. PMID: 34627682; PMCID: PMC9195244.

Wang M, Sajobi T, Morgante F, Adler C, Agarwal P, Bäumer T, Berardelli A, Berman BD, Blumin J, Borsche M, Brashear A, Deik A, Duque K, Espay AJ, Ferrazzano G, Feuerstein J, Fox S, Frank S, Hallett M, Jankovic J, LeDoux MS, Leegwater-Kim J, Mahajan A, Malaty IA, Ondo W, Pantelyat A, Pirio-Richardson S, Roze E, Saunders-Pullman R, Suchowersky O, Truong D, Vidailhet M, Shukla AW, Perlmutter JS, Jinnah HA, Martino D. Predictive modeling of spread in adult-onset isolated dystonia: key properties and effect of tremor inclusion. European Journal of Neurology. 2021 Dec;28(12):3999-4009. doi: 10.1111/ene.15031. Epub 2021 Aug 4. PMID: 34296504; PMCID: PMC9100858.

Parra SP, Heckers SH, Wilcox WR, Mcknight CD, Jinnah HA.. The emerging neurological spectrum of AARS2-associated disorders. Parkinsonism Relat Disord. 2021 Dec;93:50-54. doi: 10.1016/j.parkreldis.2021.10.031. Epub 2021 Nov 10.

Maiti B, Rawson KS, Tanenbaum AB, Koller JM, Snyder AZ, Campbell MC, Earhart GM, Perlmutter JS. Functional Connectivity of Vermis Correlates with Future Gait Impairments in Parkinson's Disease. Mov Disord. 2021 Nov;36(11):2559-2568. doi: 10.1002/mds.28684. Epub 2021 Jun 10.

Defazio G, Jinnah HA, Berardelli A, Perlmutter JS, Berkmen GK, Berman BD, Jankovic J, Bäumer T, Comella C, Cotton AC, Ercoli T, Ferrazzano G, Fox S, Kim HJ, Moukheiber ES, Richardson SP, Weissbach A, Wrigth LJ, Hallett M. Diagnostic criteria for blepharospasm: A multicenter international study. Parkinsonism Relat Disord. 2021 Oct;91:109-114. doi: 10.1016/j.parkreldis.2021.09.004. Epub 2021 Sep 8. PMID: 34583301.

Blepharospasm (BSP) is a form of focal dystonia that manifests with eyelid spasms, involuntary eyelid closures, and spontaneous blinking. To date, there are no widely accepted criteria to diagnose BSP. In this study, researchers validate the use of new diagnostic criteria for BSP in a diverse international population. “This was a huge, multicenter effort aimed at establishing internationally acceptable diagnostic criteria for BSP,” says H. A. Jinnah, MD, PhD, principal investigator of the DC. “Such criteria did not exist before. What we do in the USA with RDCRN funding must ultimately go to the rest of the world.”

Scorr LM, Factor FA, Parra SP et al and Jinnah HA for the Dystonia Coalition Investigators. Oromandibular Dystonia: A Clinical Examination of 2,020 Cases. Front Neurol. 2021 Sep 16;12:700714. doi: 10.3389/fneur.2021.700714. PMID: 34603182; PMCID: PMC8481678.

Myers PS, Jackson JJ, Clover AK, Lessov-Schlaggar CN, Foster ER, Maiti B, Perlmutter JS, Campbell MC. Distinct progression patterns across Parkinson disease clinical subtypes. Ann Clin Transl Neurol. 2021 Aug;8(8):1695-1708. doi: 10.1002/acn3.51436. Epub 2021 Jul 26.

Megan E Wadon, Grace A Bailey, Zehra Yilmaz, Emily Hubbard, Meshari AlSaeed, Amy Robinson, Duncan McLauchlan, Richard L Barbano, Laura Marsh, Stewart A Factor, Susan H Fox, Charles H Adler, Ramon L Rodriguez, Cynthia L Comella, Stephen G Reich, William L Severt, Christopher G Goetz, Joel S Perlmutter, Hyder A Jinnah, Katharine E Harding, Cynthia Sandor, Kathryn J Peall. Non-motor phenotypic subgroups in adult-onset idiopathic, isolated, focal cervical dystonia. Wiley Online Library. 2021 Aug;11(8):e2292. doi: 10.1002/brb3.2292. Epub 2021 Jul 21. PMID: 34291595; PMCID: PMC8413761.

Adult-onset idiopathic, isolated, focal cervical dystonia (AOIFCD) is a disorder characterized by involuntary muscle contractions that cause repetitive movements or abnormal postures. These movements can be painful and cause considerable disability. Although patients most commonly present to clinical services due to their motor symptoms, increasing evidence suggests a significant non-motor phenotype to be associated with most forms of dystonia, including AOIFCD. Improved understanding of these non-motor symptoms is needed to better target therapeutic interventions. In this study, researchers examined non-motor phenotypic features to identify possible AOIFCD subgroups. Non-motor symptoms were assessed in participants with AOIFCD, including psychiatric symptoms, pain, sleep disturbance, and quality of life. To investigate the relationship between these symptoms and determine phenotypic subgroups, researchers used Cluster and Bayesian multiple mixed model phenotype analyses. They identified two phenotypic subgroups of non-motor symptoms accompanying AOIFCD, with differences in psychiatric symptoms, pain catastrophizing, sleep quality, and quality of life. Researchers say that improved understanding of these symptom groups will enable better targeted pathophysiological investigation and future therapeutic intervention.

Sun YV, Li C, Hui Q, Huang Y, Barbano R, Rodriguez R, Malaty IA, Reich S, Bambarger K, Holmes K, Jankovic J, Patel NJ, Roze E, Vidailhet M, Berman BD, LeDoux MS, Espay AJ, Agarwal P, Pirio-Richardson S, Frank SA, Ondo WG, Saunders-Pullman R, Chouinard S, Natividad S, Berardelli A, Pantelyat AY, Brashear A, Fox SH, Kasten M, Krämer UM, Neis M, Bäumer T, Loens S, Borsche M, Zittel S, Maurer A, Gelderblom M, Volkmann J, Odorfer T, Kühn AA, Borngräber F, König IR, Cruchaga C, Cotton AC, Kilic-Berkmen G, Freeman A, Factor SA, Scorr L, Bremner JD, Vaccarino V, Quyyumi AA, Klein C, Perlmutter JS, Lohmann K, Jinnah HA. A Multi-center Genome-wide Association Study of Cervical Dystonia. Mov Disord. 2021 Jul 28. doi: 10.1002/mds.28732. Online ahead of print.

Cervical dystonia is a painful condition in which a patient’s neck muscles contract involuntarily, causing the head to twist or turn to one side. In this multi-center international study, researchers conducted a Genome-Wide Association Study (GWAS) using samples from the Dystonia Coalition Biorepository. They compared 919 cervical dystonia patients with 1491 controls, seeking to identify genetic loci—fixed positions on a chromosome where a particular gene or genetic marker is located—related to the disorder. They identified one genome-wide significant variant that was however not replicated in an independent sample of 473 cervical dystonia cases and 481 controls. Gene-based analysis identified DENND1A to be significantly associated with cervical dystonia. One low-frequency variant located within the GABBR2 gene on chromosome 9 was associated with lower age-at-onset. Authors concluded that the genetic underpinnings of cervical dystonia are heterogeneous and likely consist of multiple distinct variants of small effect sizes, rather than one gene that is responsible for many cases. Larger GWAS sample sizes may be needed to understand the genetic causes of cervical dystonia.

Cisneros E, Vu JP, Lee HY et al. Does raising the arms modify head tremor severity in cervical dystonia?. Tremor and Other Hyperkinetic Movements. 2021 Jun 23;11:21. doi: 10.5334/tohm.623. PMID: 34221696; PMCID: PMC8231450.

Thakur N, Klopstock T, Jackowski S, Kuscer E, Tricta F, Videnovic A, Jinnah HA. Rational Design of Novel Therapies for Pantothenate Kinase-Associated Neurodegeneration. Mov Disord. 2021 Sep;36(9):2005-2016. doi: 10.1002/mds.28642. Epub 2021 May 18.

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive neurogenetic disorder in which specific regions of the central nervous system progressively degenerate, causing progressive, abnormal, involuntary movements. PKAN is caused by genetic variants in the PANK2 gene that result in dysfunction in enzyme activity. This disruption allows iron to accumulate in the brain. Increased understanding of the molecular and biochemical mechanisms of the disease has allowed researchers to use these insights to begin designing new therapeutics for the disorder. Study authors review the results of recent clinical trials and pre-clinical studies of several compounds currently being evaluated. They say that these trials have helped improve trial designs and allowed the development of PKAN-specific measures to monitor outcomes. They conclude that PKAN provides a good model for targeted drug development and clinical trial design for rare disorders.

Vu JP, Lee HY, Chen Q, Cisneros E, Barbano RL, Goetz CG, Jankovic J, Jinnah HA, Perlmutter JS, Berman BD, Appelbaum MI, Stebbins GT, Comella CL, Peterson DA. Head tremor and pain in cervical dystonia. J Neurol. 2021 May;268(5):1945-1950. doi: 10.1007/s00415-020-10378-5. Epub 2021 Jan 8.

To determine how head tremor and pain are associated with cervical dystonia, researchers undertook a retrospective review of severity and pain rating scales from 188 patients. They examined associations of head trauma and pain with age at onset, disease duration, and head tremor subtype, finding that head tremor severity was associated with longer disease duration while pain severity was associated with younger age at onset. Researchers said these associations further characterize the heterogeneity of cervical dystonia’s clinical presentation and suggest similarly heterogenous underlying mechanisms.

Sutcliffe DJ, Dinasarapu AR, Visser JE, Hoed JD, Seifar F, Joshi P, Ceballos-Picot I, Sardar T, Hess EJ, Sun YV, Wen Z, Zwick ME, Jinnah HA. Induced pluripotent stem cells from subjects with Lesch-Nyhan disease. Sci Rep. 2021 Apr 19;11(1):8523. doi: 10.1038/s41598-021-87955-9.

Kilic-Berkmen G, Wright LJ, Perlmutter JS, Comella C, Hallett M, Teller J, Pirio Richardson S, Peterson DA, Cruchaga C, Lungu C, Jinnah HA. The Dystonia Coalition: A Multicenter Network for Clinical and Translational Studies. Front Neurol. 2021 Apr 8;12:660909. doi: 10.3389/fneur.2021.660909. PMID: 33897610; PMCID: PMC8060489.

Sedov A, Usova S, Popov V, Tomskiy A, Jinnah HA, Shaikh AG. Feedback-dependent neuronal properties make focal dystonias so focal. Eur J Neurosci. 2021 Apr;53(7):2388-2397. doi: 10.1111/ejn.14933. Epub 2020 Aug 31.

Seeking to better understand the neuron activity responsible for dystonia, researchers tested the hypothesis that focal dystonia (a condition that causes abnormal movements in a single body part) may be associated with specific vs broad neuronal abnormalities. They measured the activity of individual neurons of the basal ganglia during deep brain stimulation surgery in 12 patients with dystonia limited to the neck. They found abnormal neuronal activity for both neck and hand neurons, even though the hand was unaffected. These results imply abnormalities of neuronal activity are not restricted to neurons associated with the affected body region, but appear to be more widespread. Symptoms may appear in only in specific body regions, such as the neck, when a second abnormality is added, such as sensory feedback from the affected region.

Martin WRW, Miles M, Zhong Q, Hartlein J, Racette BA, Norris SA, Ushe M, Maiti B, Criswell S, Davis AA, Kotzbauer PT, Cairns NJ, Perrin RJ, Perlmutter JS. Is Levodopa Response a Valid Indicator of Parkinson's Disease?. Mov Disord. 2021 Apr;36(4):948-954. doi: 10.1002/mds.28406. Epub 2020 Nov 30.

Visser JE, Cotton AC, Schretlen DJ, Bloch J, Tedroff K, Schechtmann G, Radu Djurfeldt D, Gonzalez V, Cif L, Jinnah HA. Deep brain stimulation in Lesch-Nyhan disease: outcomes from the patient's perspective. Dev Med Child Neurol. 2021 Mar 10. doi: 10.1111/dmcn.14852. Online ahead of print.

Younce JR, Campbell MC, Hershey T, Tanenbaum AB, Milchenko M, Ushe M, Karimi M, Tabbal SD, Kim AE, Snyder AZ, Perlmutter JS, Norris SA. Resting-State Functional Connectivity Predicts STN DBS Clinical Response. Mov Disord. 2021 Mar;36(3):662-671. doi: 10.1002/mds.28376. Epub 2020 Nov 19.

Groth CL, Brown M, Honce JM et al. Cervical Dystonia Is Associated with Aberrant Inhibitory Signaling Within the Thalamus. Front Neurol. 2021 Feb 9;11:575879. doi: 10.3389/fneur.2020.575879. PMID: 33633655; PMCID: PMC7900407.

Junker J, Berman BD, Hall J, Wahba DW, Brandt V, Perlmutter JS, Jankovic J, Malaty IA, Wagle Shukla A, Reich SG, Espay AJ, Duque KR, Patel N, Roze E, Vidailhet M, Jinnah HA, Brüggemann N. Quality of life in isolated dystonia: non-motor manifestations matter. J Neurol Neurosurg Psychiatry. 2021 Feb 9; jnnp-2020-325193. doi: 10.1136/jnnp-2020-325193. Online ahead of print. PMCID: PMC8356023.

Shaikh AG, Beylergil SB, Scorr L, Kilic-Berkmen G, Freeman A, Klein C, Junker J, Loens S, Brüggemann N, Münchau A, Bäumer T, Vidailhet M, Roze E, Bonnet C, Jankovic J, Jimenez-Shahed J, Patel N, Marsh L, Comella C, Barbano RL, Berman BD, Malaty I, Wagle Shukla A, Reich SG, Ledoux MS, Berardelli A, Ferrazzano G, Stover N, Ondo W, Pirio Richardson S, Saunders-Pullman R, Mari Z, Agarwal P, Adler C, Chouinard S, Fox SH, Brashear A, Truong D, Suchowersky O, Frank S, Factor S, Perlmutter J, Jinnah HA. Dystonia and Tremor: A Cross-Sectional Study of the Dystonia Coalition Cohort. Neurology. 2021 Jan 26;96(4):e563-e574. doi: 10.1212/WNL.0000000000011049. Epub 2020 Oct 12.

Cisneros E, Stebbins GT, Chen Q, Vu JP, Benadof CN, Zhang Z, Barbano RL, Fox SH, Goetz CG, Jankovic J, Jinnah HA, Perlmutter JS, Adler CH, Factor SA, Reich SG, Rodriguez R, Severt LL, Stover NP, Berman BD, Comella CL, Peterson DA. It's tricky: Rating alleviating maneuvers in cervical dystonia. J Neurol Sci. 2020 Dec 15;419:117205. doi: 10.1016/j.jns.2020.117205. Epub 2020 Nov 1.

Norris SA, Jinnah HA, Klein C, Jankovic J, Berman BD, Roze E, Mahajan A, Espay AJ, Murthy AV, Fung VSC, LeDoux MS, Chang FCF, Vidailhet M, Testa C, Barbano R, Malaty IA, Bäumer T, Loens S, Wright LJ, Perlmutter JS. Clinical and Demographic Characteristics of Upper Limb Dystonia. Mov Disord. 2020 Nov;35(11):2086-2090. doi: 10.1002/mds.28223. Epub 2020 Aug 26.

Mahmood M, Kwon S, Berkmen GK, Kim YS, Scorr L, Jinnah HA, Yeo WH. Soft Nanomembrane Sensors and Flexible Hybrid Bioelectronics for Wireless Quantification of Blepharospasm. IEEE Trans Biomed Eng. 2020 Nov;67(11):3094-3100. doi: 10.1109/TBME.2020.2975773. Epub 2020 Feb 21.

Norris SA, Morris AE, Campbell MC, Karimi M, Adeyemo B, Paniello RC, Snyder AZ, Petersen SE, Mink JW, Perlmutter JS. Regional, not global, functional connectivity contributes to isolated focal dystonia. Neurology. 2020 Oct 20;95(16):e2246-e2258. doi: 10.1212/WNL.0000000000010791. Epub 2020 Sep 10.

Laura LO Froeschke. The Influence of Linguistic Demand on Symptom Expression in Adductor Spasmodic Dysphonia. Journal of Voice. 2020 Sep;34(5):807.e11-807.e21. doi: 10.1016/j.jvoice.2019.04.003. Epub 2019 Apr 30. PMID: 31047737.

Sedov A, Usova S, Semenova U, Gamaleya A, Tomskiy A, Beylergil SB, Jinnah HA, Shaikh AG. Pallidal Activity in Cervical Dystonia with and Without Head Tremor. Cerebellum. 2020 Jun;19(3):409-418. doi: 10.1007/s12311-020-01119-5.

Jinnah HA. Medical and Surgical Treatments for Dystonia. Neurol Clin. 2020 May;38(2):325-348. doi: 10.1016/j.ncl.2020.01.003. Epub 2020 Mar 2.

Berman BD, Groth CL, Shelton E, Sillau SH, Sutton B, Legget KT, Tregellas JR. Hemodynamic responses are abnormal in isolated cervical dystonia. J Neurosci Res. 2020 Apr;98(4):692-703. doi: 10.1002/jnr.24547. Epub 2019 Nov 6.

Berman BD, Groth CL, Sillau SH, Pirio Richardson S, Norris SA, Junker J, Brüggemann N, Agarwal P, Barbano RL, Espay AJ, Vizcarra JA, Klein C, Bäumer T, Loens S, Reich SG, Vidailhet M, Bonnet C, Roze E, Jinnah HA, Perlmutter JS. Risk of spread in adult-onset isolated focal dystonia: a prospective international cohort study. J Neurol Neurosurg Psychiatry. 2020 Mar;91(3):314-320. doi: 10.1136/jnnp-2019-321794. Epub 2019 Dec 17.

Chen Q, Vu JP, Cisneros E, Benadof CN, Zhang Z, Barbano RL, Goetz CG, Jankovic J, Jinnah HA, Perlmutter JS, Appelbaum MI, Stebbins GT, Comella CL, Peterson DA. Postural Directionality and Head Tremor in Cervical Dystonia. Tremor Other Hyperkinet Mov (N Y). 2020 Jan 20;10. doi: 10.7916/tohm.v0.745. eCollection 2020.

Liu C, Scorr L, Kilic-Berkmen G, Cotton A, Factor SA, Freeman A, Tran V, Liu K, Uppal K, Jones D, Jinnah HA, Sun YV. A metabolomic study of cervical dystonia. Parkinsonism Relat Disord. 2021 Jan;82:98-103. doi: 10.1016/j.parkreldis.2020.11.020. Epub 2020 Nov 26. PMID: 33271463; PMCID: PMC7856090.

Cervical dystonia is the most common adult-onset focal dystonia. Researchers currently believe that cervical dystonia may be caused by a combination of genetic and environmental factors. Although genetic factors have been studied extensively, other factors have not. To identify potentially abnormal metabolites or altered biological pathways, researchers conducted an exploratory metabolomics analysis of cervical dystonia. The team compared plasma samples from 100 idiopathic cervical dystonia patients and 100 controls. Results showed that altered biological pathways may relate to carbohydrate and lipid metabolism. Study authors say this may provide novel insights into the biology of cervical dystonia.

Fernandez HH, Stamler D, Davis MD, Factor SA, Hauser RA, Jimenez-Shahed J, Ondo WG, Jarskog LF, Woods SW, Bega D, LeDoux MS, Shprecher DR, Anderson KE. Long-term safety and efficacy of deutetrabenazine for the treatment of tardive dyskinesia. J Neurol Neurosurg Psychiatry. 2019 Dec;90(12):1317-1323. doi: 10.1136/jnnp-2018-319918. Epub 2019 Jul 10.

Kwon YT, Lee Y, Berkmen GK, Lim HR, Scorr L, Jinnah HA, Yeo WH. Soft Material-Enabled, Active Wireless, Thin-Film Bioelectronics for Quantitative Diagnostics of Cervical Dystonia. Adv Mater Technol. 2019 Oct;4(10):1900458. doi: 10.1002/admt.201900458. Epub 2019 Aug 16.

Beylergil SB, Singh AP, Zee DS, Jinnah HA, Shaikh AG. Relationship between jerky and sinusoidal oscillations in cervical dystonia. Parkinsonism Relat Disord. 2019 Sep;66:130-137. doi: 10.1016/j.parkreldis.2019.07.024. Epub 2019 Jul 20.

Mencacci NE and Jinnah HA. Naming Genes for Dystonia: DYT-z or Ditzy?. Tremor Other Hyperkinet Mov. 2019 Aug 28;9. doi: 10.7916/tohm.v0.710. PMID: 31523486; PMCID: PMC6714488.

Kim CY, Petersen MS, Eliasen EH et al. Involuntary Thumb Flexion on Neurological Examination: An Unusual Form of Upper Limb Dystonia in the Faroe Islands. Tremor Other Hyperkinet Mov. 2019 Aug 20;9. doi: 10.7916/tohm.v0.686. PMID: 31440418; PMCID: PMC6702791.

Merola A, Dwivedi AK, Shaikh AG, Tareen TK, Da Prat GA, Kauffman MA, Hampf J, Mahajan A, Marsili L, Jankovic J, Comella CL, Berman BD, Perlmutter JS, Jinnah HA, Espay AJ. Head tremor at disease onset: an ataxic phenotype of cervical dystonia. J Neurol. 2019 Aug;266(8):1844-1851. doi: 10.1007/s00415-019-09341-w. Epub 2019 Apr 26.

Jinnah HA. The Dystonias. Continuum (Minneap Minn). 2019 Aug;25(4):976-1000. doi: 10.1212/CON.0000000000000747.

Marshall RD, Collins A, Escolar ML, Jinnah HA, Klopstock T, Kruer MC, Videnovic A, Robichaux-Viehoever A, Burns C, Swett LL, Revicki DA, Bender RH, Lenderking WR.. Diagnostic and clinical experience of patients with pantothenate kinase-associated neurodegeneration. Orphanet J Rare Dis. 2019 Jul 12;14(1):174. doi: 10.1186/s13023-019-1142-1.

Benadof CN, Cisneros E, Appelbaum MI, Stebbins GT, Comella CL, Peterson DA. Sensory Tricks Are Associated with Higher Sleep-Related Quality of Life in Cervical Dystonia. Tremor Other Hyperkinet Mov (N Y). 2019 Jun 17;9. doi: 10.7916/4q53-vt23. eCollection 2019.

Tang SY, Shaikh AG. Past and Present of Eye Movement Abnormalities in Ataxia-Telangiectasia. Cerebellum. 2019 Jun;18(3):556-564. doi: 10.1007/s12311-018-0990-x.

Corp DT, Joutsa J, Darby RR, Delnooz CCS, van de Warrenburg BPC, Cooke D, Prudente CN, Ren J, Reich MM, Batla A, Bhatia KP, Jinnah HA, Liu H, Fox MD. Network localization of cervical dystonia based on causal brain lesions. Brain. 2019 Jun 1;142(6):1660-1674. doi: 10.1093/brain/awz112.

Sedov A, Usova S, Semenova U, Gamaleya A, Tomskiy A, Crawford JD, Corneil B, Jinnah HA, Shaikh AG. The role of pallidum in the neural integrator model of cervical dystonia. Neurobiol Dis. 2019 May;125:45-54. doi: 10.1016/j.nbd.2019.01.011. Epub 2019 Jan 22.

Sedov A, Semenova U, Usova S et al. Implications of asymmetric neural activity patterns in the basal ganglia outflow in the integrative neural network model for cervical dystonia. Prog Brain Res. 2019;249:261-268. doi: 10.1016/bs.pbr.2019.03.030. Epub 2019 Apr 30. PMID: 31325985.

Feldman D, Otero-Millan J, Shaikh AG. Gravity-Independent Upbeat Nystagmus in Syndrome of Anti-GAD Antibodies. Cerebellum. 2019 Apr;18(2):287-290. doi: 10.1007/s12311-018-0972-z.

Witek N, Hebert C, Gera A, Comella C. Progressive Encephalomyelitis with Rigidity and Myoclonus Syndrome Presenting as Catatonia. Psychosomatics. 2019 Jan-Feb;60(1):83-87. doi: 10.1016/j.psym.2018.05.005. Epub 2018 May 17. PMID: 30143326.

Pyatka N, Sedov A, Walter BL et al. Tremor in chronic inflammatory demyelinating polyneuropathy: Proof of unifying network model for dystonia. Prog Brain Res. 2019; 249: 285-294. PMCID: In progress.

Wagle Shukla A, Ostrem JL, Vaillancourt DE et al. Physiological effects of subthalamic nucleus deep brain stimulation surgery in cervical dystonia. J Neurol Neurosurg Psychiatry. 2018 Dec;89(12):1296-1300. doi: 10.1136/jnnp-2017-317098. Epub 2018 Jan 11. PMID: 29326293; PMCID: PMC7498178.

Junker J, Brandt V, BD B, Vidailhet M et al. Predictors of alcohol responsiveness in dystonia. Neurology . 2018 Nov 20;91(21):e2020-e2026. doi: 10.1212/WNL.0000000000006551. Epub 2018 Oct 19. PMID: 30341158; PMCID: PMC6260199.

Ludlow CL, Domangue R, Sharma D, Jinnah HA, Perlmutter JS, Berke G, Sapienza C, Smith ME, Blumin JH, Kalata CE, Blindauer K, Johns M, Hapner E, Harmon A, Paniello R, Adler CH, Crujido L, Lott DG, Bansberg SF, Barone N, Drulia T, Stebbins G. Consensus-Based Attributes for Identifying Patients With Spasmodic Dysphonia and Other Voice Disorders. JAMA Otolaryngol Head Neck Surg. 2018 Aug 1;144(8):657-665. doi: 10.1001/jamaoto.2018.0644.

George EB, Cotton AC, Shneyder N, Jinnah HA. A strategy for managing flu-like symptoms after botulinum toxin injections. J Neurol. 2018 Aug;265(8):1932-1933. doi: 10.1007/s00415-018-8934-4. Epub 2018 Jun 20.

Rizvi MT, Cameron L, Kilbane C, Shaikh AG. Paraneoplastic seesaw nystagmus and opsoclonus provides evidence for hyperexcitable reciprocally innervating mesencephalic network. J Neurol Sci. 2018 Jul 15;390:239-245. doi: 10.1016/j.jns.2018.05.002. Epub 2018 May 3.

Espay AJ, Trosch R, Suarez G et al. Minimal clinically important change in the Toronto Western Spasmodic Torticollis Rating Scale. Parkinsonism Relat Disord. 2018 Jul;52:94-97. doi: 10.1016/j.parkreldis.2018.03.002. Epub 2018 Mar 7. PMID: 29530726.

Shaikh AG, Antoniades C, Fitzgerald J et al. Effects of deep brain stimulation on eye movements and vestibular function. Front Neurol. 2018 Jun 12;9:444. doi: 10.3389/fneur.2018.00444. PMID: 29946295; PMCID: PMC6005881.

Jinnah HA, Comella CL, Perlmutter J, Lungu C, Hallett M; Dystonia Coalition Investigators. Longitudinal studies of botulinum toxin in cervical dystonia: Why do patients discontinue therapy?. Toxicon. 2018 Jun 1;147:89-95. doi: 10.1016/j.toxicon.2017.09.004. Epub 2017 Sep 6.

Shaikh AG, Zee DS. Eye movement research in the twenty-first century-a window to the brain, mind, and more. Cerebellum. 2018 Jun;17(3):252-258. doi: 10.1007/s12311-017-0910-5. PMID: 29260439.

Norris SA, Perlmutter JS. Functional imaging in dystonia. In Treatment of Dystonia, ed Dressler, Altenmuller, & Krauss, Cambridge University Press, Cambridge, UK. June 2018, ISBN: 9781107132863. [Chapter]

Liu H, Jin H, Luo Z, Yue X, Zhang X, Flores H, Su Y, Perlmutter JS, Tu Z. In Vivo Characterization of Two (18)F-Labeled PDE10A PET Radioligands in Nonhuman Primate Brains. ACS Chem Neurosci. 2018 May 16;9(5):1066-1073. doi: 10.1021/acschemneuro.7b00458. Epub 2018 Feb 19.

Mahajan A, Jankovic J, Marsh L, Patel A, Jinnah HA, Comella C, Barbano R, Perlmutter J, Patel N; members of the Dystonia Coalition. Cervical dystonia and substance abuse. J Neurol. 2018 Apr;265(4):970-975. doi: 10.1007/s00415-018-8840-9. Epub 2018 Mar 22.

Scorr LM, Silver MR, Hanfelt J, Sperin E, Freeman A, Jinnah HA, Factor SA. Pilot Single-Blind Trial of AbobotulinumtoxinA in Oromandibular Dystonia. Neurotherapeutics. 2018 Apr;15(2):452-458. doi: 10.1007/s13311-018-0620-9.

Shi LL, Simpson CB, Hapner ER, Jinnah HA, Johns MM 3rd. Pharyngeal Dystonia Mimicking Spasmodic Dysphonia. J Voice. 2018 Mar;32(2):234-238. doi: 10.1016/j.jvoice.2017.05.004. Epub 2017 Jun 23.

Morris AE, Norris SA, Perlmutter JS, Mink JW. Quantitative, clinically relevant acoustic measurements of focal embouchure dystonia. Mov Disord. 2018 Mar;33(3):449-458. doi: 10.1002/mds.27298. Epub 2018 Feb 20.

Popa T, Hubsch C, James P et al. Abnormal cerebellar processing of the neck proprioceptive information drives dysfunctions in cervical dystonia. Nat Sci Rep. 2018 Feb 2;8(1):2263. doi: 10.1038/s41598-018-20510-1. PMID: 29396401; PMCID: PMC5797249.

Espay AJ, Maloney T, Vannest J et al. Dysfunction in emotion processing underlies functional (psychogenic) dystonia. Mov Disord. 2018 Jan;33(1):136-145. doi: 10.1002/mds.27217. Epub 2017 Nov 10. PMID: 29124784; PMCID: PMC5767134.

Jinnah HA, Hess EJ. Evolving concepts in the pathogenesis of dystonia. Parkinsonism Relat Disord. 2018 Jan;46 Suppl 1(Suppl 1):S62-S65. doi: 10.1016/j.parkreldis.2017.08.001. Epub 2017 Aug 2.

Jinnah HA, Albanese A, Bhatia KP, Cardoso F, Da Prat G, de Koning TJ, Espay AJ, Fung V, Garcia-Ruiz PJ, Gershanik O, Jankovic J, Kaji R, Kotschet K, Marras C, Miyasaki JM, Morgante F, Munchau A, Pal PK, Rodriguez Oroz MC, Rodríguez-Violante M, Schöls L, Stamelou M, Tijssen M, Uribe Roca C, de la Cerda A, Gatto EM; International Parkinson's Disease Movement Disorders Society Task Force on Rare Movement Disorders. Treatable inherited rare movement disorders. Mov Disord. 2018 Jan;33(1):21-35. doi: 10.1002/mds.27140. Epub 2017 Sep 1.

Cotton AC, Bell RB, Jinnah HA. Expert Opinion vs Patient Perspective in Treatment of Rare Disorders: Tooth Removal in Lesch-Nyhan Disease as an Example. JIMD Rep. 2018;41:25-27. doi: 10.1007/8904_2017_80. Epub 2017 Dec 15. PMID: 29243037; PMCID: PMC6122048.

Jinnah HA, Hess EJ. The motor network model for dystonia. In Treatment of dystonia: Cambridge University Press, 1st ED. 2018. [Book chapter]

Kang SL, Shaikh AG, Ghasia FF. Vergence and strabismus in neurodegenerative disorders. Front Neurol. 2018; 9: 299. PMCID: PMC5964131.

Puri S, Shaikh AG. Basic and translational neuro-ophthalmology of visually guided saccades: disorders of velocity. Expert Rev Ophthalmol. 2017;12(6):457-473. doi: 10.1080/17469899.2017.1395695. Epub 2017 Nov 28.

Shaikh AG, Finkelstein SR, Schuchard R, Ross G, Juncos JL. Fixational eye movements in Tourette syndrome. Neurol Sci. 2017 Nov;38(11):1977-1984. doi: 10.1007/s10072-017-3069-4. Epub 2017 Aug 16.

Jinnah HA, Neychev V, Hess EJ. The anatomical basis for dystonia: The motor network model. Tremor Other Hyperkinet Mov (N Y). 2017 Oct 23;7:506. doi: 10.7916/D8V69X3S. PMID: 29123945; PMCID: PMC5673689.

Alsinaidi O, Shaikh AG. Diffusion-Weighted Magnetic Resonance Imaging in Acute Retinal Pathology. Neuroophthalmology. 2017 Oct 13;42(3):191-193. doi: 10.1080/01658107.2017.1354385. eCollection 2018 Jun.

Conte A, Ferrazzano G, Defazio G et al. Increased blinking may be a precursor of blepharospasm: a longitudinal study. Mov Disord Clin Pract. 2017 Sep-Oct;4(5):733-736. doi: 10.1002/mdc3.12499. Epub 2017 Jun 2. PMID: 29082270; PMCID: PMC5654574.

Shaikh AG, Factor SA, Juncos J. Saccades in progressive supranuclear palsy - maladapted, irregular, curved, and slow. Mov Disord Clin Pract. 2017 Sep-Oct;4(5):671-681. doi: 10.1002/mdc3.12491. Epub 2017 Aug 11.

Li Z, Prudente CN, Stilla R, Sathian K, Jinnah HA, Hu X. Alterations of resting-state fMRI measurements in individuals with cervical dystonia. Hum Brain Mapp. 2017 Aug;38(8):4098-4108. doi: 10.1002/hbm.23651. Epub 2017 May 15.

Shaikh AG, Ghasia FF. Novel Eye Movement Disorders in Whipple's Disease-Staircase Horizontal Saccades, Gaze-Evoked Nystagmus, and Esotropia. Front Neurol. 2017 Jul 11;8:321. doi: 10.3389/fneur.2017.00321. eCollection 2017.

Berman BD, Junker J, Shelton E, Sillau SH, Jinnah HA, Perlmutter JS, Espay AJ, Jankovic J, Vidailhet M, Bonnet C, Ondo W, Malaty IA, Rodríguez R, McDonald WM, Marsh L, Zurowski M, Bäumer T, Brüggemann N. Psychiatric associations of adult-onset focal dystonia phenotypes. J Neurol Neurosurg Psychiatry. 2017 Jul;88(7):595-602. doi: 10.1136/jnnp-2016-315461. Epub 2017 Apr 24.

Shaikh AG, Straumann D, Palla A. Motion Illusion-Evidence towards Human Vestibulo-Thalamic Projections. Cerebellum. 2017 Jun;16(3):656-663. doi: 10.1007/s12311-017-0844-y.

Sedov A, Popov V, Shabalov V, Raeva S, Jinnah HA, Shaikh AG. Physiology of midbrain head movement neurons in cervical dystonia. Mov Disord. 2017 Jun;32(6):904-912. doi: 10.1002/mds.26948. Epub 2017 Feb 20.

Pirio Richardson S, Altenmüller E, Alter K, Alterman RL, Chen R, Frucht S, Furuya S, Jankovic J, Jinnah HA, Kimberley TJ, Lungu C, Perlmutter JS, Prudente CN, Hallett M. Research Priorities in Limb and Task-Specific Dystonias. Front Neurol. 2017 May 3;8:170. doi: 10.3389/fneur.2017.00170. eCollection 2017.

Kang S, Shaikh AG. Acquired pendular nystagmus. J Neurol Sci. 2017 Apr 15;375:8-17. doi: 10.1016/j.jns.2017.01.033. Epub 2017 Jan 10.

Shaikh AG, Ghasia FF. Fixational saccades are more disconjugate in adults than in children. PLoS One. 2017 Apr 13;12(4):e0175295. doi: 10.1371/journal.pone.0175295. eCollection 2017.

Defazio G, Hallett M, Jinnah HA, Conte A, Berardelli A. Blepharospasm 40 years later. Mov Disord. 2017 Apr;32(4):498-509. doi: 10.1002/mds.26934. Epub 2017 Feb 10.

Shakkottai VG, Batla A, Bhatia K, Dauer WT, Dresel C, Niethammer M, Eidelberg D, Raike RS, Smith Y, Jinnah HA, Hess EJ, Meunier S, Hallett M, Fremont R, Khodakhah K, LeDoux MS, Popa T, Gallea C, Lehericy S, Bostan AC, Strick PL. Current Opinions and Areas of Consensus on the Role of the Cerebellum in Dystonia. Cerebellum. 2017 Apr;16(2):577-594. doi: 10.1007/s12311-016-0825-6.

Jinnah HA, Alterman R, Klein C, Krauss JK, Moro E, Vidailhet M, Raike R. Deep brain stimulation for dystonia: a novel perspective on the value of genetic testing. J Neural Transm (Vienna). 2017 Apr;124(4):417-430. doi: 10.1007/s00702-016-1656-9. Epub 2017 Feb 3.

Nibbeling EA, Delnooz CC, de Koning TJ, Sinke RJ, Jinnah HA, Tijssen MA, Verbeek DS. Using the shared genetics of dystonia and ataxia to unravel their pathogenesis. Neurosci Biobehav Rev. 2017 Apr;75:22-39. doi: 10.1016/j.neubiorev.2017.01.033. Epub 2017 Jan 28.

Peterson DA, Sejnowski TJ. A Dynamic circuit hypothesis for the pathogenesis of blepharospasm. Front Comput Neurosci. 2017 Mar 7;11:11. doi: 10.3389/fncom.2017.00011. PMID: 28326032; PMCID: PMC5340098.

Pirio Richardson S, Wegele A, Skipper B et al. Dystonia treatment: patterns of medication use in an international cohort. Neurology. 2017 Feb 7;88(6):543-550. doi: 10.1212/WNL.0000000000003596. Epub 2017 Jan 11. PMID: 28077492; PMCID: PMC5304465.

Shaikh AG, Zee DS, Crawford JD et al. Reply: Contributions of visual and motor signals in cervical dystonia. Brain. 2017 Jan;140(1):e5. doi: 10.1093/brain/aww292. Epub 2016 Dec 19. PMID: 27993889.

Norris SA, Jinnah HA, Espay AJ, Klein C, Brüggemann N, Barbano RL, Malaty IA, Rodriguez RL, Vidailhet M, Roze E, Reich SG, Berman BD, LeDoux MS, Richardson SP, Agarwal P, Mari Z, Ondo WG, Shih LC, Fox SH, Berardelli A, Testa CM, Cheng FC, Truong D, Nahab FB, Xie T, Hallett M, Rosen AR, Wright LJ, Perlmutter JS. Clinical and demographic characteristics related to onset site and spread of cervical dystonia. Mov Disord. 2016 Dec;31(12):1874-1882. doi: 10.1002/mds.26817. Epub 2016 Oct 18.

Paudel R, Li A, Hardy J, Bhatia KP, Houlden H, Holton J. DYT6 Dystonia: A Neuropathological Study. Neurodegener Dis. 2016;16(3-4):273-8. doi: 10.1159/000440863. Epub 2015 Nov 27.

Peterson DA, Littlewort GC, Bartlett MS, Macerollo A, Perlmutter JS, Jinnah HA, Hallett M, Sejnowski TJ. Objective, computerized video-based rating of blepharospasm severity. Neurology. 2016 Nov 15;87(20):2146-2153. doi: 10.1212/WNL.0000000000003336. Epub 2016 Oct 21. PMID: 27770067; PMCID: PMC5109937.

Albanese A, Bhatia K, DeLong MR, Fahn S, Fung VS, Hallett M, Jankovic J, Jinnah HA, Mink JW, Teller JK. "Complex" dystonia is not a category in the new 2013 consensus classification. Mov Disord. 2016 Nov;31(11):1758-1759. doi: 10.1002/mds.26764. Epub 2016 Sep 10.

Bologna M, Paparella G, Fabbrini A, Leodori G, Rocchi L, Hallett M, Berardelli A. Effects of cerebellar theta-burst stimulation on arm and neck movement kinematics in patients with focal dystonia. Clin Neurophysiol. 2016 Nov;127(11):3472-3479. doi: 10.1016/j.clinph.2016.09.008. Epub 2016 Sep 15.

Jinnah HA. Locus Pocus. Mov Disord. 2016 Nov;31(11):1759-1760. doi: 10.1002/mds.26765. Epub 2016 Aug 22.

Shaikh AG, Zee DS, Crawford JD, Jinnah HA. Cervical dystonia: a neural integrator disorder. Brain. 2016 Oct;139(Pt 10):2590-2599. doi: 10.1093/brain/aww141. Epub 2016 Jun 20.

Jinnah HA, Factor S. The role of polymyography in the treatment of cervical dystonia: the authors reply. J Neurol. 2016 Aug;263(8):1665. doi: 10.1007/s00415-016-8222-0. Epub 2016 Jul 8.

Arkadir D, Radulescu A, Raymond D et al. DYT1 dystonia increases risk taking in humans. eLife. 2016 Jun 1;5:e14155. doi: 10.7554/eLife.14155. PMID: 27249418; PMCID: PMC4951192.

Jinnah HA, Goodmann E, Rosen AR, Evatt M, Freeman A, Factor S. Botulinum toxin treatment failures in cervical dystonia: causes, management, and outcomes. J Neurol. 2016 Jun;263(6):1188-94. doi: 10.1007/s00415-016-8136-x. Epub 2016 Apr 25.

Merkel PA, Manion M, Gopal-Srivastava R, Groft S, Jinnah HA, Robertson D, Krischer JP; Rare Diseases Clinical Research Network. The partnership of patient advocacy groups and clinical investigators in the rare diseases clinical research network. Orphanet J Rare Dis. 2016 May 18;11(1):66. doi: 10.1186/s13023-016-0445-8.

LeDoux MS, Vemula SR, Xiao J, Thompson MM, Perlmutter JS, Wright LJ, Jinnah HA, Rosen AR, Hedera P, Comella CL, Weissbach A, Junker J, Jankovic J, Barbano RL, Reich SG, Rodriguez RL, Berman BD, Chouinard S, Severt L, Agarwal P, Stover NP. Clinical and genetic features of cervical dystonia in a large multicenter cohort. Neurol Genet. 2016 Apr 11;2(3):e69. doi: 10.1212/NXG.0000000000000069. eCollection 2016 Jun.

Bäumer T, Schmidt A, Heldmann M, Landwehr M, Simmer A, Tönniges D, Münte T, Lohmann K, Altenmüller E, Klein C, Münchau A. Abnormal interhemispheric inhibition in musician's dystonia - Trait or state?. Parkinsonism Relat Disord. 2016 Apr;25:33-8. doi: 10.1016/j.parkreldis.2016.02.018. Epub 2016 Feb 20.

Comella CL, Perlmutter JS, Jinnah HA, Waliczek TA, Rosen AR, Galpern WR, Adler CA, Barbano RL, Factor SA, Goetz CG, Jankovic J, Reich SG, Rodriguez RL, Severt WL, Zurowski M, Fox SH, Stebbins GT. Clinimetric testing of the comprehensive cervical dystonia rating scale. Mov Disord. 2016 Apr;31(4):563-9. doi: 10.1002/mds.26534. Epub 2016 Mar 12.

Xiao J, Thompson MM, Vemula SR et al. Blepharospasm in a multiplex African-American pedigree. J Neurol Sci. 2016 Mar 15;362:299-303. doi: 10.1016/j.jns.2016.02.003. Epub 2016 Feb 2. PMID: 26944167; PMCID: PMC4779500.

Fraint A, Vittal P, Comella C. Considerations on patient-related outcomes with the use of botulinum toxins: is switching products safe?. Ther Clin Risk Manag. 2016 Feb 5;12:147-54. doi: 10.2147/TCRM.S99239. PMID: 26917963; PMCID: PMC4751901.

Justicz N, Hapner ER, Josephs JS, Boone BC, Jinnah HA, Johns MM 3rd. Comparative effectiveness of propranolol and botulinum for the treatment of essential voice tremor. Laryngoscope. 2016 Jan;126(1):113-7. doi: 10.1002/lary.25485. Epub 2015 Jul 21.

Shaikh AG, Ghasia FF, DeLong MR, Jinnah HA, Freeman A, Factor SA. Ocular palatal tremor plus dystonia - new syndromic association. Mov Disord Clin Pract. 2015 Sep 1;2(3):267-270. doi: 10.1002/mdc3.12193. Epub 2015 Jun 17.

Creighton FX, Hapner E, Klein A, Rosen A, Jinnah HA, Johns MM. Diagnostic Delays in Spasmodic Dysphonia: A Call for Clinician Education. J Voice. 2015 Sep;29(5):592-4. doi: 10.1016/j.jvoice.2013.10.022. Epub 2015 Apr 11.

Ludlow CL. Central Nervous System Control of Voice and Swallowing. J Clin Neurophysiol. 2015 Aug;32(4):294-303. doi: 10.1097/WNP.0000000000000186.

Ludlow CL. Laryngeal Reflexes: Physiology, Technique, and Clinical Use. J Clin Neurophysiol. 2015 Aug;32(4):284-93. doi: 10.1097/WNP.0000000000000187.

Jinnah HA, Teller JK, Galpern WR. Recent developments in dystonia. Curr Opin Neurol. 2015 Aug;28(4):400-5. doi: 10.1097/WCO.0000000000000213.

Kimberley TJ, Schmidt RL, Chen M et al. Mixed effectiveness of rTMS and retraining in the treatment of focal hand dystonia. Front Hum Neurosci. 2015 Jul 9;9:385. doi: 10.3389/fnhum.2015.00385. PMID: 26217209; PMCID: PMC4496570.

Prudente CN, Stilla R, Buetefisch CM, Singh S, Hess EJ, Hu X, Sathian K, Jinnah HA. Neural Substrates for Head Movements in Humans: A Functional Magnetic Resonance Imaging Study. J Neurosci. 2015 Jun 17;35(24):9163-72. doi: 10.1523/JNEUROSCI.0851-15.2015.

Comella CL, Fox SH, Bhatia KP, Perlmutter JS, Jinnah HA, Zurowski M, McDonald WM, Marsh L, Rosen AR, Waliczek T, Wright LJ, Galpern WR, Stebbins GT. Development of the Comprehensive Cervical Dystonia Rating Scale: Methodology. Mov Disord Clin Pract. 2015 Jun;2(2):135-141. doi: 10.1002/mdc3.12131. Epub 2015 Apr 6.

Berman BD, Jinnah HA. Dystonia: Five new things. Neurol Clin Pract. 2015 Jun;5(3):232-240. doi: 10.1212/CPJ.0000000000000128.

Shaikh AG, Wong A, Zee DS, Jinnah HA. Why are voluntary head movements in cervical dystonia slow?. Parkinsonism Relat Disord. 2015 Jun;21(6):561-6. doi: 10.1016/j.parkreldis.2015.03.005. Epub 2015 Mar 14.

Shaikh AG, Zee DS, Jinnah HA. Oscillatory head movements in cervical dystonia: Dystonia, tremor, or both?. Mov Disord. 2015 May;30(6):834-42. doi: 10.1002/mds.26231. Epub 2015 Apr 16.

Pirio Richardson S, Tinaz S, Chen R. Repetitive transcranial magnetic stimulation in cervical dystonia:  effect of site and repetition in a randomized pilot trial. PLoS One. 2015 Apr 29;10(4):e0124937. doi: 10.1371/journal.pone.0124937. PMID: 25923718; PMCID: PMC4414555.

Defazio G, Hallett M, Jinnah HA, Stebbins GT, Gigante AF, Ferrazzano G, Conte A, Fabbrini G, Berardelli A. Development and validation of a clinical scale for rating the severity of blepharospasm. Mov Disord. 2015 Apr;30(4):525-30. doi: 10.1002/mds.26156.

Yan L, Hicks M, Winslow K, Comella C, Ludlow C, Jinnah HA, Rosen AR, Wright L, Galpern WR, Perlmutter JS. Secured web-based video repository for multicenter studies. Parkinsonism Relat Disord. 2015 Apr;21(4):366-71. doi: 10.1016/j.parkreldis.2015.01.011. Epub 2015 Jan 20.

Brüggemann N, Kühn A, Schneider SA, Kamm C, Wolters A, Krause P, Moro E, Steigerwald F, Wittstock M, Tronnier V, Lozano AM, Hamani C, Poon YY, Zittel S, Wächter T, Deuschl G, Krüger R, Kupsch A, Münchau A, Lohmann K, Volkmann J, Klein C. Short- and long-term outcome of chronic pallidal neurostimulation in monogenic isolated dystonia. Neurology. 2015 Mar 3;84(9):895-903. doi: 10.1212/WNL.0000000000001312. Epub 2015 Feb 4.

Schottlaender LV, Polke JM, Ling H, MacDoanld ND, Tucci A, Nanji T, Pittman A, de Silva R, Holton JL, Revesz T, Sweeney MG, Singleton AB, Lees AJ, Bhatia KP, Houlden H. Analysis of C9orf72 repeat expansions in a large series of clinically and pathologically diagnosed cases with atypical parkinsonism. Neurobiol Aging. 2015 Feb;36(2):1221.e1-6. doi: 10.1016/j.neurobiolaging.2014.08.024. Epub 2014 Aug 27.

Jinnah HA, Factor SA. Diagnosis and treatment of dystonia. Neurol Clin. 2015 Feb;33(1):77-100. doi: 10.1016/j.ncl.2014.09.002.

Shaikh AG, Mewes K, DeLong MR, Gross RE, Triche SD, Jinnah HA, Boulis N, Willie JT, Freeman A, Alexander GE, Aia P, Butefisch CM, Esper CD, Factor SA. Temporal profile of improvement of tardive dystonia after globus pallidus deep brain stimulation. Parkinsonism Relat Disord. 2015 Feb;21(2):116-9. doi: 10.1016/j.parkreldis.2014.11.013. Epub 2014 Nov 20.

Tanner CM, Comella CL. When brawn benefits brain: physical activity and Parkinson's disease risk. Brain. 2015 Feb;138(Pt 2):238-9. doi: 10.1093/brain/awu351.

Karimi M, Perlmutter JS. The role of dopamine and dopaminergic pathways in dystonia: insights from neuroimaging. Tremor Other Hyperkinet Mov (N Y). 2015 Jan 29;5:280. doi: 10.7916/D8J101XV. eCollection 2015.

Jinnah HA, Prudente CN, Rose SJ et al. The neurobiology of dystonia. In Neurobiology of Disease, 2nd Ed. 2015. [Chapter]

Jinnah HA, Albanese A. The New Classification System for the Dystonias: Why Was it Needed and How was it Developed?. Mov Disord Clin Pract. 2014 Dec 1;1(4):280-284. doi: 10.1002/mdc3.12100.

Perlmutter JS, Norris SA. Neuroimaging biomarkers for Parkinson disease: facts and fantasy. Ann Neurol. 2014 Dec;76(6):769-83. doi: 10.1002/ana.24291. Epub 2014 Nov 7.

Luciano AY, Jinnah HA, Pfeiffer RF, Truong DD, Nance MA, LeDoux MS. Treatment of myoclonus-dystonia syndrome with tetrabenazine. Parkinsonism Relat Disord. 2014 Dec;20(12):1423-6. doi: 10.1016/j.parkreldis.2014.09.029. Epub 2014 Oct 5.

Paudel R, Kiely A, Li A, Lashley T, Bandopadhyay R, Hardy J, Jinnah HA, Bhatia K, Houlden H, Holton JL. Neuropathological features of genetically confirmed DYT1 dystonia: investigating disease-specific inclusions. Acta Neuropathol Commun. 2014 Nov 18;2:159. doi: 10.1186/s40478-014-0159-x.

Shaikh AG, Mewes K, Jinnah HA, DeLong MR, Gross RE, Triche S, Freeman A, Factor SA. Globus pallidus deep brain stimulation for adult-onset axial dystonia. Parkinsonism Relat Disord. 2014 Nov;20(11):1279-82. doi: 10.1016/j.parkreldis.2014.09.005. Epub 2014 Sep 16.

Hershey LA, Perlmutter JS. Smoking and Parkinson disease: where there is smoke there may not be fire. Neurology. 2014 Oct 14;83(16):1392-3. doi: 10.1212/WNL.0000000000000896. Epub 2014 Sep 12.

Patel N, Hanfelt J, Marsh L, Jankovic J; members of the Dystonia Coalition. Alleviating manoeuvres (sensory tricks) in cervical dystonia. J Neurol Neurosurg Psychiatry. 2014 Aug;85(8):882-4. doi: 10.1136/jnnp-2013-307316. Epub 2014 May 14.

Broccard FD, Mullen T, Chi YM, Peterson D, Iversen JR, Arnold M, Kreutz-Delgado K, Jung TP, Makeig S, Poizner H, Sejnowski T, Cauwenberghs G. Closed-loop brain-machine-body interfaces for noninvasive rehabilitation of movement disorders. Ann Biomed Eng. 2014 Aug;42(8):1573-93. doi: 10.1007/s10439-014-1032-6. Epub 2014 May 15.

Xiao J, Vemula SR, LeDoux MS. Recent advances in the genetics of dystonia. Curr Neurol Neurosci Rep. 2014 Aug;14(8):462. doi: 10.1007/s11910-014-0462-8.

Göttle M, Prudente CN, Fu R, Sutcliffe D, Pang H, Cooper D, Veledar E, Glass JD, Gearing M, Visser JE, Jinnah HA. Loss of dopamine phenotype among midbrain neurons in Lesch-Nyhan disease. Ann Neurol. 2014 Jul;76(1):95-107. doi: 10.1002/ana.24191. Epub 2014 Jun 20.

Revuelta GJ, Montilla J, Benatar M, Freeman A, Wichmann T, Jinnah HA, Delong MR, Factor SA. An ¹⁸F-FDG PET study of cervical muscle in parkinsonian anterocollis. J Neurol Sci. 2014 May 15;340(1-2):174-7. doi: 10.1016/j.jns.2014.03.023. Epub 2014 Mar 18.

Vemula SR, Xiao J, Zhao Y, Bastian RW, Perlmutter JS, Racette BA, Paniello RC, Wszolek ZK, Uitti RJ, Van Gerpen JA, Hedera P, Truong DD, Blitzer A, Rudzińska M, Momčilović D, Jinnah HA, Frei K, Pfeiffer RF, LeDoux MS. A rare sequence variant in intron 1 of THAP1 is associated with primary dystonia. Mol Genet Genomic Med. 2014 May;2(3):261-72. doi: 10.1002/mgg3.67. Epub 2014 Feb 11.

Vemula SR, Xiao J, Bastian RW, Momčilović D, Blitzer A, LeDoux MS. Pathogenic variants in TUBB4A are not found in primary dystonia. Neurology. 2014 Apr 8;82(14):1227-30. doi: 10.1212/WNL.0000000000000294. Epub 2014 Mar 5.

Albanese A, Bhatia K, Bressman SB, Delong MR, Fahn S, Fung VS, Hallett M, Jankovic J, Jinnah HA, Klein C, Lang AE, Mink JW, Teller JK. Reply: dystonia after severe head injuries. Mov Disord. 2014 Apr;29(4):578-9. doi: 10.1002/mds.25861. Epub 2014 Mar 3.

Prudente CN, Hess EJ, Jinnah HA. Dystonia as a network disorder: what is the role of the cerebellum?. Neuroscience. 2014 Feb 28;260:23-35. doi: 10.1016/j.neuroscience.2013.11.062. Epub 2013 Dec 11.

Fregosi RF, Ludlow CL. Activation of upper airway muscles during breathing and swallowing. J Appl Physiol (1985). 2014 Feb 1;116(3):291-301. doi: 10.1152/japplphysiol.00670.2013. Epub 2013 Oct 3.

Galpern WR, Coffey CS, Albanese A, Cheung K, Comella CL, Ecklund DJ, Fahn S, Jankovic J, Kieburtz K, Lang AE, McDermott MP, Shefner JM, Teller JK, Thompson JL, Yeatts SD, Jinnah HA. Designing clinical trials for dystonia. Neurotherapeutics. 2014 Jan;11(1):117-27. doi: 10.1007/s13311-013-0221-6.

Comella CL. Treatment of restless legs syndrome. Neurotherapeutics. 2014 Jan;11(1):177-87. doi: 10.1007/s13311-013-0247-9.

Jinnah HA, Albanese A. New concepts for dystonia. Moving Along: The Official Newsletter of the International Parkinson and Movement Disorder Society. 2014; 18: 6-7. [Feature article]

Tiderington E, Goodman EM, Rosen AR, Hapner ER, Johns MM 3rd, Evatt ML, Freeman A, Factor S, Jinnah HA. How long does it take to diagnose cervical dystonia?. J Neurol Sci. 2013 Dec 15;335(1-2):72-4. doi: 10.1016/j.jns.2013.08.028. Epub 2013 Aug 30.

Marsh L. Depression and Parkinson's disease: current knowledge. Curr Neurol Neurosci Rep. 2013 Dec;13(12):409. doi: 10.1007/s11910-013-0409-5.

Ceballos-Picot I, Augé F, Fu R, Olivier-Bandini A, Cahu J, Chabrol B, Aral B, de Martinville B, Lecain JP, Jinnah HA. Phenotypic variation among seven members of one family with deficiency of hypoxanthine-guanine phosphoribosyltransferase. Mol Genet Metab. 2013 Nov;110(3):268-74. doi: 10.1016/j.ymgme.2013.08.016. Epub 2013 Sep 8.

Khooshnoodi MA, Factor SA, Jinnah HA. Secondary blepharospasm associated with structural lesions of the brain. J Neurol Sci. 2013 Aug 15;331(1-2):98-101. doi: 10.1016/j.jns.2013.05.022. Epub 2013 Jun 6.

Peterson DA, Berque P, Jabusch HC, Altenmüller E, Frucht SJ. Rating scales for musician's dystonia: the state of the art. Neurology. 2013 Aug 6;81(6):589-98. doi: 10.1212/WNL.0b013e31829e6f72. Epub 2013 Jul 24.

Defazio G, Hallett M, Jinnah HA, Berardelli A. Development and validation of a clinical guideline for diagnosing blepharospasm. Neurology. 2013 Jul 16;81(3):236-40. doi: 10.1212/WNL.0b013e31829bfdf6. Epub 2013 Jun 14.

Moscovich M, LeDoux MS, Xiao J, Rampon GL, Vemula SR, Rodriguez RL, Foote KD, Okun MS. Dystonia, facial dysmorphism, intellectual disability and breast cancer associated with a chromosome 13q34 duplication and overexpression of TFDP1: case report. BMC Med Genet. 2013 Jul 13;14:70. doi: 10.1186/1471-2350-14-70.

Shaikh AG, Wong AL, Zee DS, Jinnah HA. Keeping your head on target. J Neurosci. 2013 Jul 3;33(27):11281-95. doi: 10.1523/JNEUROSCI.3415-12.2013.

Hubsch C, Roze E, Popa T, Russo M, Balachandran A, Pradeep S, Mueller F, Brochard V, Quartarone A, Degos B, Vidailhet M, Kishore A, Meunier S. Defective cerebellar control of cortical plasticity in writer's cramp. Brain. 2013 Jul;136(Pt 7):2050-62. doi: 10.1093/brain/awt147. PMID: 23801734; PMCID: PMC3692031.

Fung VS, Jinnah HA, Bhatia K, Vidailhet M. Assessment of patients with isolated or combined dystonia: an update on dystonia syndromes. Mov Disord. 2013 Jun 15;28(7):889-98. doi: 10.1002/mds.25549.

Albanese A, Sorbo FD, Comella C, Jinnah HA, Mink JW, Post B, Vidailhet M, Volkmann J, Warner TT, Leentjens AF, Martinez-Martin P, Stebbins GT, Goetz CG, Schrag A. Dystonia rating scales: critique and recommendations. Mov Disord. 2013 Jun 15;28(7):874-83. doi: 10.1002/mds.25579.

Lohmann K, Klein C. Genetics of dystonia: What's known? What's new? What's next?. Mov Disord. 2013 Jun 15;28(7):899-905. doi: 10.1002/mds.25536. PMID: 23893446.

Albanese A, Bhatia K, Bressman SB, Delong MR, Fahn S, Fung VS, Hallett M, Jankovic J, Jinnah HA, Klein C, Lang AE, Mink JW, Teller JK. Phenomenology and classification of dystonia: a consensus update. Mov Disord. 2013 Jun 15;28(7):863-73. doi: 10.1002/mds.25475. Epub 2013 May 6.

Zurowski M, McDonald WM, Fox S, Marsh L. Psychiatric comorbidities in dystonia: emerging concepts. Mov Disord. 2013 Jun 15;28(7):914-20. doi: 10.1002/mds.25501.

Mink JW. Special concerns in defining, studying, and treating dystonia in children. Mov Disord. 2013 Jun 15;28(7):921-5. doi: 10.1002/mds.25548.

Jinnah HA, Delong MR, Hallett M. The dystonias: past, present, and future. Mov Disord. 2013 Jun 15;28(7):849-50. doi: 10.1002/mds.25564.

Jinnah HA, Berardelli A, Comella C, Defazio G, Delong MR, Factor S, Galpern WR, Hallett M, Ludlow CL, Perlmutter JS, Rosen AR; Dystonia Coalition Investigators. The focal dystonias: current views and challenges for future research. Mov Disord. 2013 Jun 15;28(7):926-43. doi: 10.1002/mds.25567.

Klein C, Fahn S. Translation of Oppenheim's 1911 paper on dystonia. Mov Disord. 2013 Jun 15;28(7):851-62. doi: 10.1002/mds.25546. PMID: 23893442. [Translation from German]

Prudente CN, Pardo CA, Xiao J, Hanfelt J, Hess EJ, Ledoux MS, Jinnah HA. Neuropathology of cervical dystonia. Exp Neurol. 2013 Mar;241:95-104. doi: 10.1016/j.expneurol.2012.11.019. Epub 2012 Nov 27.

Popa T, Velayudhan B, Hubsch C, Pradeep S, Roze E, Vidailhet M, Meunier S, Kishore A. Cerebellar processing of sensory inputs primes motor cortex plasticity. Cereb Cortex. 2013 Feb;23(2):305-14. doi: 10.1093/cercor/bhs016. Epub 2012 Feb 20.

Ushe M, Perlmutter JS. Oromandibular and lingual dystonia associated with spinocerebellar ataxia type 8. Mov Disord. 2012 Dec;27(14):1741-2. doi: 10.1002/mds.25295.

Hedera P, Xiao J, Puschmann A, Momčilović D, Wu SW, LeDoux MS. Novel PRRT2 mutation in an African-American family with paroxysmal kinesigenic dyskinesia. BMC Neurol. 2012 Sep 18;12:93. doi: 10.1186/1471-2377-12-93.

White LJ, Hapner ER, Klein AM, Delgaudio JM, Hanfelt JJ, Jinnah HA, Johns MM 3rd. Coprevalence of anxiety and depression with spasmodic dysphonia: a case-control study. J Voice. 2012 Sep;26(5):667.e1-6. doi: 10.1016/j.jvoice.2011.08.011. Epub 2011 Dec 29.

Fleming BM, Schwab EL, Nouer SS, Wan JY, LeDoux MS. Prevalence, predictors, and perceived effectiveness of complementary, alternative and integrative medicine in adult-onset primary dystonia. Parkinsonism Relat Disord. 2012 Sep;18(8):936-40. doi: 10.1016/j.parkreldis.2012.04.027. Epub 2012 May 25.

LeDoux MS, Xiao J, Rudzińska M, Bastian RW, Wszolek ZK, Van Gerpen JA, Puschmann A, Momčilović D, Vemula SR, Zhao Y. Genotype-phenotype correlations in THAP1 dystonia: molecular foundations and description of new cases. Parkinsonism Relat Disord. 2012 Jun;18(5):414-25. doi: 10.1016/j.parkreldis.2012.02.001. Epub 2012 Feb 28.

Revuelta GJ, Benatar M, Freeman A, Wichmann T, Jinnah HA, DeLong MR, Factor SA. Clinical subtypes of anterocollis in parkinsonian syndromes. J Neurol Sci. 2012 Apr 15;315(1-2):100-3. doi: 10.1016/j.jns.2011.11.017. Epub 2011 Nov 30.

Xiao J, Uitti RJ, Zhao Y, Vemula SR, Perlmutter JS, Wszolek ZK, Maraganore DM, Auburger G, Leube B, Lehnhoff K, LeDoux MS. Mutations in CIZ1 cause adult onset primary cervical dystonia. Ann Neurol. 2012 Apr;71(4):458-69. doi: 10.1002/ana.23547. Epub 2012 Mar 23.

LeDoux MS. Dystonia: phenomenology. Parkinsonism Relat Disord. 2012 Jan;18 Suppl 1(Suppl 1):S162-4. doi: 10.1016/S1353-8020(11)70050-5.

LeDoux MS. The genetics of dystonias. Adv Genet. 2012;79:35-85. doi: 10.1016/B978-0-12-394395-8.00002-5. PMID: 22989765; PMCID: PMC4879967.

Thompson VB, Jinnah HA, Hess EJ. Convergent mechanisms in etiologically-diverse dystonias. Expert Opin Ther Targets. 2011 Dec;15(12):1387-403. doi: 10.1517/14728222.2011.641533. Epub 2011 Dec 3.

Shamim EA, Chu J, Scheider LH, Savitt J, Jinnah HA, Hallett M. Extreme task specificity in writer's cramp. Mov Disord. 2011 Sep;26(11):2107-9. doi: 10.1002/mds.23827. Epub 2011 Jun 28.

Jinnah HA, Hallett M. In the wink of an eye: nature and nurture in blepharospasm. Neurology. 2011 Aug 16;77(7):616-7. doi: 10.1212/WNL.0b013e3182299f84. Epub 2011 Jul 20.

Puschmann A, Xiao J, Bastian RW, Searcy JA, LeDoux MS, Wszolek ZK. An African-American family with dystonia. Parkinsonism Relat Disord. 2011 Aug;17(7):547-50. doi: 10.1016/j.parkreldis.2011.04.019. Epub 2011 May 20.

White LJ, Klein AM, Hapner ER, Delgaudio JM, Hanfelt JJ, Jinnah HA, Johns MM 3rd. Coprevalence of tremor with spasmodic dysphonia: a case-control study. Laryngoscope. 2011 Aug;121(8):1752-5. doi: 10.1002/lary.21872.

LeDoux MS. Animal models of dystonia: Lessons from a mutant rat. Neurobiol Dis. 2011 May;42(2):152-61. doi: 10.1016/j.nbd.2010.11.006. Epub 2010 Nov 21.

Neychev VK, Gross RE, Lehéricy S, Hess EJ, Jinnah HA. The functional neuroanatomy of dystonia. Neurobiol Dis. 2011 May;42(2):185-201. doi: 10.1016/j.nbd.2011.01.026. Epub 2011 Feb 12.

Xiao J, Zhao Y, Bastian RW, Perlmutter JS, Racette BA, Tabbal SD, Karimi M, Paniello RC, Wszolek ZK, Uitti RJ, Van Gerpen JA, Simon DK, Tarsy D, Hedera P, Truong DD, Frei KP, Blitzer A, Rudzińska M, Pfeiffer RF, Le C, LeDoux MS. The c.-237_236GA>TT THAP1 sequence variant does not increase risk for primary dystonia. Mov Disord. 2011 Feb 15;26(3):549-52. doi: 10.1002/mds.23551. Epub 2011 Mar 2.

Ludlow CL. Spasmodic dysphonia: a laryngeal control disorder specific to speech. J Neurosci. 2011 Jan 19;31(3):793-7. doi: 10.1523/JNEUROSCI.2758-10.2011.

Jinnah HA. Needles in haystacks: the challenges of rare diseases. Dev Med Child Neurol. 2011 Jan;53(1):6-7. doi: 10.1111/j.1469-8749.2010.03791.x.

Hess EJ, Jen JC, Jinnah HA, Benarroch EE. Neuronal voltage-gated calcium channels: brief overview of their function and clinical implications in neurology. Neurology. 2010 Sep 7;75(10):937; author reply 937-8. doi: 10.1212/WNL.0b013e3181eee9e8.

Xiao J, Zhao Y, Bastian RW, Perlmutter JS, Racette BA, Tabbal SD, Karimi M, Paniello RC, Wszolek ZK, Uitti RJ, Van Gerpen JA, Simon DK, Tarsy D, Hedera P, Truong DD, Frei KP, Dev Batish S, Blitzer A, Pfeiffer RF, Gong S, LeDoux MS. Novel THAP1 sequence variants in primary dystonia. Neurology. 2010 Jan 19;74(3):229-38. doi: 10.1212/WNL.0b013e3181ca00ca.

Cloud LJ, Jinnah HA. Treatment strategies for dystonia. Expert Opin Pharmacother. 2010 Jan;11(1):5-15. doi: 10.1517/14656560903426171.

Hess EJ, Jinnah HA. Rodent models of dystonia. In Animal models for movement disorders, LeDoux MS, Ed Elsevier Academic Press, Amsterdam. 2005. [Book chapter]

Verberkmoes S, Mazza GL, Edmondson AC, Scaglia F, Horikoshi S, Kuschel B, Janssen MCH, Mousa J, Larson A, Shah R, McDonald G, Sarafoglou K, Berry G, Kozicz T, Lam C, Morava E. Goal attainment in PMM2-CDG: A new approach measuring meaningful clinical outcomes. Mol Genet Metab. 2025 Mar 19;145(1):109087. doi: 10.1016/j.ymgme.2025.109087. Epub ahead of print. PMID: 40121796.

Patient-centered outcomes, including patient-reported outcomes (PROs), are increasingly important in healthcare and to appropriately design clinical trials. Unfortunately using PROs in rare diseases is still limited.

Patients with Phosphomannomutase 2-CDG (PMM2-CDG) have highly variable clinical severity, underscoring the need for personalized outcome measures. We used a so far unexplored, individualized approach, the so called Goal Attainment Scaling (GAS), in our natural history study for CDG, which allowed patients to set and track personal goals over time.

We evaluated 93 PMM2-CDG patients assessing goal achievement prospectively. We also analyzed potential associations between GAS and factors such as age, sex, genetic background, and disease severity measured by the Nijmegen Progression CDG Rating Scale (NPCRS).

The most common goals set by patients were related to mobility (31.5 %) and communication (26.8 %), with additional goals focused on body function (22.8 %) and independence (18.8 %). Of the 68 patients with follow-up data, 23.5 % showed no improvement in their goals, while 20.6 % improved in all three personal goals.

It is very important to note, that there was no significant correlation between NPCRS score changes assessed by medical providers, and GAS improvement. Emphasizing the importance of patient set goals in severity scaling

GAS is a valuable additional outcome measure that ensures clinical improvements are meaningful for patients and their representatives, helping to assess individual goals and overall wellbeing.

Aryal RP, Ramanujan A, Bucci C, Neckelmann C, Heimburg-Molinaro J, Cummings SF, Erger F, Beck BB, Seaver LH, Cummings RD. C1GALT1C1-Associated Mosaic Disorder of Glycosylation in a Female. J Inherit Metab Dis. 2025 Mar;48(2):e70006. doi: 10.1002/jimd.70006.

Alharbi H, Horikoshi S, Jenkins SM, Scaglia F, Lam C, Morava E, Larson A, Edmondson AC. Causes of mortality in the congenital disorders of glycosylation. Mol Genet Metab. 2025 Mar;144(3):109052. doi: 10.1016/j.ymgme.2025.109052. Epub 2025 Feb 4.

Muffels IJJ, Kozicz T, Perlstein EO, Morava E. The Therapeutic Future for Congenital Disorders of Glycosylation. J Inherit Metab Dis. 2025 Mar;48(2):e70011. doi: 10.1002/jimd.70011.

García-Cazorla Á, Morava E, Saudubray JM. "Trafficking Disorders: Phenotypical Similarities and Differences With Other IMDs". J Inherit Metab Dis. 2025 Mar;48(2):e70004. doi: 10.1002/jimd.70004.

Matheny-Rabun C, Mokashi SS, Radenkovic S, Wiggins K, Dukes-Rimsky L, Angel P, Ghesquiere B, Kozicz T, Steet R, Morava E, Flanagan-Steet H. O-GlcNAcylation modulates expression and abundance of N-glycosylation machinery in an inherited glycosylation disorder. Cell Rep. 2024 Nov 26;43(11):114976. doi: 10.1016/j.celrep.2024.114976. Epub 2024 Nov 18.

Muffels IJJ, Sadek M, Kozicz T, Morava E. Assessing age of onset and clinical symptoms over time in patients with heterozygous pathogenic DHDDS variants. J Inherit Metab Dis. 2024 Sep;47(5):935-944. doi: 10.1002/jimd.12769. Epub 2024 Jun 21.

Mayfield JM, Hitefield NL, Czajewski I, Vanhye L, Holden L, Morava E, van Aalten DMF, Wells L. O-GlcNAc transferase congenital disorder of glycosylation (OGT-CDG): Potential mechanistic targets revealed by evaluating the OGT interactome. J Biol Chem. 2024 Sep;300(9):107599. doi: 10.1016/j.jbc.2024.107599. Epub 2024 Jul 24. PMID: 39059494; PMCID: PMC11381892.

O-GlcNAc transferase congenital disorder of glycosylation (OGT-CDG) is an inherited disorder caused by dysfunction of the OGT enzyme that affects a complex process in the body called glycosylation. Pathogenic variants associated with OGT-CDG are thought to disrupt the OGT interactome, which consists of interactions between thousands of proteins.

In this review paper, researchers evaluated the OGT interactome to identify potential mechanistic targets for OGT-CDG studies. The team also discussed clinical features of OGT-CDG and the biochemical effects of mutations.

Authors note that as more OGT variants are characterized and additional patients are identified, it may become possible to identify a set of common alterations in OGT function as well as a core set of clinical features of OGT-CDG, which could help improve diagnosis.

Marquez J, Cech JN, Paschal CR, Dingmann B, Scott AI, Thies JM, Mills MR, Albert CM, Beck AE, Beckman E, Bonkowski ES, Earl DL, Lam CT, Mefford HC, Merritt JL 2nd, Nelson Z, Ohlsen TJ, Taylor MR, Perlman SJ, Rudzinski ER, Sikes MC, Waligorski N, Wenger TL, Adam MP, Mirzaa GM, Bennett JT, Glass IA, Sternen DL, Miller DE. Clinical RNA sequencing clarifies variants of uncertain significance identified by prior testing. Genet Med Open. 2024;2:101886. doi: 10.1016/j.gimo.2024.101886. Epub 2024 Aug 9. PMID: 39484203; PMCID: PMC11526042.

RNA sequencing (RNA-seq) is a technique used to evaluate the sequence and quantity of messenger RNA, which can provide insights on gene expression. Although RNA-seq can help identify pathogenic variants in individuals with suspected genetic conditions, technological complexities and limited experience might affect its use in clinical practice.

In this study, researchers evaluated the use of RNA-seq to clarify variants of uncertain significance (VUS) in a clinical setting. The team developed a process to identify individuals who might benefit from clinical RNA-seq. Over a two-year period, genetics providers referred 26 cases for clinical RNA-seq, of which nine cases met the criteria for sequencing.

Results show that clinical RNA-seq was useful in clarifying uncertain results in about one-third of cases, including a new diagnosis of NGLY1 congenital disorder of deglycosylation. Authors note that demonstrating the clinical utility of RNA-seq may improve access to this new testing technique.

Sidpra J, Sudhakar S, Biswas A, Massey F, Turchetti V, Lau T, Cook E, Alvi JR, Elbendary HM, Jewell JL, Riva A, Orsini A, Vignoli A, Federico Z, Rosenblum J, Schoonjans AS, de Wachter M, Delgado Alvarez I, Felipe-Rucián A, Haridy NA, Haider S, Zaman M, Banu S, Anwaar N, Rahman F, Maqbool S, Yadav R, Salpietro V, Maroofian R, Patel R, Radhakrishnan R, Prabhu SP, Lichtenbelt K, Stewart H, Murakami Y, Löbel U, D'Arco F, Wakeling E, Jones W, Hay E, Bhate S, Jacques TS, Mirsky DM, Whitehead MT, Zaki MS, Sultan T, Striano P, Jansen AC, Lequin M, de Vries LS, Severino M, Edmondson AC, Menzies L, Campeau PM, Houlden H, McTague A, Efthymiou S, Mankad K. The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders. Brain. 2024 Aug 1;147(8):2775-2790. doi: 10.1093/brain/awae056.

Zemet R, Hope KD, Edmondson AC, Shah R, Patino M, Yesso AM, Berger JH, Sarafoglou K, Larson A, Lam C, Morava E, Scaglia F. Cardiomyopathy, an uncommon phenotype of congenital disorders of glycosylation: Recommendations for baseline screening and follow-up evaluation. Mol Genet Metab. 2024 Aug;142(4):108513. doi: 10.1016/j.ymgme.2024.108513. Epub 2024 Jun 13.

Bosnyak I, Sadek M, Ranatunga W, Kozicz T, Morava E. Normal transferrin glycosylation does not rule out severe ALG1 deficiency. JIMD Rep. 2024 Apr 16;65(3):135-143. doi: 10.1002/jmd2.12415. eCollection 2024 May.

Lam C, Scaglia F, Berry GT, Larson A, Sarafoglou K, Andersson HC, Sklirou E, Tan QKG, Starosta RT, Sadek M, Wolfe L, Horikoshi S, Ali M, Barone R, Campbell T, Chang IJ, Coles K, Cook E, Eklund EA, Engelhardt NM, Freeman M, Friedman J, Fu DYT, Botzo G, Rawls B, Hernandez C, Johnsen C, Keller K, Kramer S, Kuschel B, Leshinski A, Martinez-Duncker I, Mazza GL, Mercimek-Andrews S, Miller BS, Muthusamy K, Neira J, Patterson MC, Pogorelc N, Powers LN, Ramey E, Reinhart M, Squire A, Thies J, Vockley J, Vreugdenhil H, Witters P, Youbi M, Zeighami A, Zemet R, Edmondson AC, Morava E. Frontiers in congenital disorders of glycosylation consortium, a cross-sectional study report at year 5 of 280 individuals in the natural history cohort. Mol Genet Metab. 2024 Jun 6;142(4):108509. doi: 10.1016/j.ymgme.2024.108509. Epub ahead of print. PMID: 38959600.

Congenital disorders of glycosylation (CDG) are a large group of rare, inherited disorders that affect a complex process in the body called glycosylation. Because the many different types of CDG are rare and vary widely, not much is known about the progression of this group of disorders.

In this study, researchers are exploring the natural history of CDG. The team is gathering data from 280 individuals with CDG across 9 clinical sites. Now at year 5 of the study, the team is sharing an overview of participant characteristics.

Initial findings include insights on liver function, patient-reported outcomes, and neurological features, as well as information on ultra-rare genetic causes of CDG. Authors note that this study serves as an important resource to build future research studies, improve clinical care, and prepare for clinical trial readiness.

Shah R, Eklund EA, Radenkovic S, Sadek M, Shammas I, Verberkmoes S, Ng BG, Freeze HH, Edmondson AC, He M, Kozicz T, Altassan R, Morava E. ALG13-Congenital Disorder of Glycosylation (ALG13-CDG): Updated clinical and molecular review and clinical management guidelines. Mol Genet Metab. 2024 Jun;142(2):108472. doi: 10.1016/j.ymgme.2024.108472. Epub 2024 Apr 23.

Starosta RT, Lee AJ, Toolan ER, He M, Wongkittichote P, Daniel EJP, Radenkovic S, Budhraja R, Pandey A, Sharma J, Morava E, Nguyen H, Dickson PI. D-mannose as a new therapy for fucokinase deficiency-related congenital disorder of glycosylation (FCSK-CDG). Mol Genet Metab. 2024 Jun;142(2):108488. doi: 10.1016/j.ymgme.2024.108488. Epub 2024 May 9.

Budhraja R, Radenkovic S, Jain A, Muffels IJJ, Ismaili MHA, Kozicz T, Pandey A, Morava E. Liposome-encapsulated mannose-1-phosphate therapy improves global N-glycosylation in different congenital disorders of glycosylation. Mol Genet Metab. 2024 Jun;142(2):108487. doi: 10.1016/j.ymgme.2024.108487. Epub 2024 May 7.

Martínez Duncker I, Mata-Salgado D, Shammas I, Ranatunga W, Daniel EJP, Cruz Muñoz ME, Abreu M, Mora-Montes H, He M, Morava E, Zafra de la Rosa G. Case report: Novel genotype of ALG2-CDG and confirmation of the heptasaccharide glycan (NeuAc-Gal-GlcNAc-Man2-GlcNAc2) as a specific diagnostic biomarker. Front Genet. 2024 May 6;15:1363558. doi: 10.3389/fgene.2024.1363558. eCollection 2024.

Daniel EJP, Edmondson AC, Argon Y, Alsharhan H, Lam C, Freeze HH, He M. Deficient glycan extension and endoplasmic reticulum stresses in ALG3-CDG. J Inherit Metab Dis. 2024 Apr 10. doi: 10.1002/jimd.12739. Epub ahead of print. PMID: 38597022.

ALG3-CDG is a rare congenital disorder of glycosylation (CDG) characterized by neurological symptoms, transaminitis (elevated liver enzymes), and frequent infections. When the endoplasmic reticulum—a network of membranes inside a cell that plays a major role in protein synthesis and transport—is under stress, one of the earliest and fastest responses in cells is glycan extension. The first step of this process is catalyzed by the ALG3 enzyme, which is deficient in patients with ALG3-CDG.  

In this study, researchers investigated the effects of glycan extension deficiency in ALG3-CDG. The team explored the biochemical consequences of this deficiency and associated response to endoplasmic reticulum stress.

These results provide a better understanding of how glycan extension deficiency affects patients with ALG3-CDG. Authors note that these findings also have important implications for the development of personalized medicine for other types of CDG.

Garapati K, Budhraja R, Saraswat M, Kim J, Joshi N, Sachdeva GS, Jain A, Ligezka AN, Radenkovic S, Ramarajan MG, Udainiya S, Raymond K, He M, Lam C, Larson A, Edmondson AC, Sarafoglou K, Larson NB, Freeze HH, Schultz MJ, Kozicz T, Morava E, Pandey A. A complement C4-derived glycopeptide is a biomarker for PMM2-CDG. JCI Insight. 2024 Apr 8;9(7):e172509. doi: 10.1172/jci.insight.172509.

Budhraja R, Joshi N, Radenkovic S, Kozicz T, Morava E, Pandey A. Dysregulated proteome and N-glycoproteome in ALG1-deficient fibroblasts. Proteomics. 2024 Mar 12:e2400012. doi: 10.1002/pmic.202400012. Epub ahead of print. PMID: 38470198.

ALG1-congenital disorder of glycosylation (ALG1-CDG) is an inherited disorder caused by variants in the ALG1 gene. These variants affect N-glycosylation, which is the body’s process of creating, changing, and attaching sugar blocks to proteins and lipids. However, not much is known about how these variants affect the cellular proteome (proteins expressed in cells) and the process of glycosylation.

In this study, researchers explored proteomics and N-glycoproteomics in ALG1-CDG. The team studied fibroblasts (connective tissue cells) from three individuals with different ALG1 variants.

Results revealed altered protein levels and a reduction of mature forms of glycopeptides. Authors note that these results can help us understand the biology and molecular mechanisms of ALG1-CDG, differentiate CDG types, and identify potential biomarkers.

Radenkovic S, Budhraja R, Klein-Gunnewiek T, King AT, Bhatia TN, Ligezka AN, Driesen K, Shah R, Ghesquière B, Pandey A, Kasri NN, Sloan SA, Morava E, Kozicz T. Neural and metabolic dysregulation in PMM2-deficient human in vitro neural models. Cell Rep. 2024 Mar 1;43(3):113883. doi: 10.1016/j.celrep.2024.113883. Epub ahead of print. PMID: 38430517.

PMM2-congenital disorder of glycosylation (PMM2-CDG) is an inherited condition caused by mutations in the PMM2 gene. Most individuals with PMM2-CDG experience neurological symptoms. However, not much is known about the specific brain-related changes caused by PMM2 deficiency.

In this study, researchers explored the neurological characteristics of PMM2-CDG using human in vitro neural models. The team created human induced pluripotent stem cell (hiPSC)-derived neural models to observe changes in neural function and metabolic dynamics.

Results revealed disrupted functioning of PMM2-deficient neuronal networks, as well as widespread changes in metabolite composition, RNA expression, protein abundance, and protein glycosylation. Authors note that these findings introduce potentially critical factors contributing to the early neural issues in patients with PMM2-CDG, paving the way for exploring innovative treatment approaches.

Madan-Khetarpal S, He M, Wongkittichote P, Dobrowolski SF. Congenital Disorder of Glycosylation in a Child with Macrosomia. Clin Chem. 2023 Dec 1;69(12):1432-1434. doi: 10.1093/clinchem/hvad166.

Muthusamy K, Perez-Ortiz JM, Ligezka AN, Altassan R, Johnsen C, Schultz MJ, Patterson MC, Morava E. Neurological manifestations in PMM2-congenital disorders of glycosylation (PMM2-CDG): Insights into clinico-radiological characteristics, recommendations for follow-up, and future directions. Genet Med. 2023 Nov 10;26(2):101027. doi: 10.1016/j.gim.2023.101027. Online ahead of print.

Duan R, Marafi D, Xia ZJ, Ng BG, Maroofian R, Sumya FT, Saad AK, Du H, Fatih JM, Hunter JV, Elbendary HM, Baig SM, Abdullah U, Ali Z, Efthymiou S, Murphy D, Mitani T, Withers MA, Jhangiani SN, Coban-Akdemir Z, Calame DG, Pehlivan D, Gibbs RA, Posey JE, Houlden H, Lupashin VV, Zaki MS, Freeze HH, Lupski JR. Biallelic missense variants in COG3 cause a congenital disorder of glycosylation with impairment of retrograde vesicular trafficking. J Inherit Metab Dis. 2023 Nov;46(6):1195-1205. doi: 10.1002/jimd.12679. Epub 2023 Oct 5.

Altassan R, Allers MM, De Graef D, Shah R, de Vries M, Larson A, Glamuzina E, Morava E. Defining the phenotype of PGAP3-congenital disorder of glycosylation; a review of 65 cases. Mol Genet Metab. 2023 Nov;140(3):107688. doi: 10.1016/j.ymgme.2023.107688. Epub 2023 Aug 23.

Del Caño-Ochoa F, Ng BG, Rubio-Del-Campo A, Mahajan S, Wilson MP, Vilar M, Rymen D, Sánchez-Pintos P, Kenny J, Martos ML, Campos T, Wortmann SB, Freeze HH, Ramón-Maiques S. Beyond genetics: Deciphering the impact of missense variants in CAD deficiency. J Inherit Metab Dis. 2023 Nov;46(6):1170-1185. doi: 10.1002/jimd.12667. Epub 2023 Sep 11.

CAD deficiency is a rare congenital disorder of glycosylation characterized by epileptic encephalopathy (disease affecting the brain). Because symptoms are non-specific, there is no biomarker, and the CAD protein has over 1,000 known variants, CAD deficiency is difficult to diagnose.

In this study, researchers aimed to improve diagnosis of CAD deficiency. The team assessed the disease-causing ability of both previously reported and unreported CAD variants. Additionally, researchers studied the impact of disease-causing variants at the protein level.

Authors note that combining these functional and protein structural analysis methods can help refine clinical diagnostic workflow for CAD variants.

Starosta RT, Kerashvili N, Pruitt C, Schultz MJ, Boyer SW, Morava E, Lasio MLD, Grange DK. PIGO-CDG: A case study with a new genotype, expansion of the phenotype, literature review, and nosological considerations. JIMD Rep. 2023 Sep 20;64(6):424-433. doi: 10.1002/jmd2.12396. eCollection 2023 Nov.

Wang R, Helbig I, Edmondson AC, Lin L, Xing Y. Splicing defects in rare diseases: transcriptomics and machine learning strategies towards genetic diagnosis. Brief Bioinform. 2023 Sep 20;24(5):bbad284. doi: 10.1093/bib/bbad284. PMID: 37580177; PMCID: PMC10516351

Many rare diseases are caused by genomic variants that affect the process of pre-messenger RNA splicing and its regulation. However, these splice-altering variants are often overlooked by common workflows for genetic diagnosis and clinical variant interpretation.

In this review, researchers summarized recent developments and challenges in using RNA sequencing technologies to investigate rare diseases. Discussion included the use of new computational splicing prediction tools to reveal splice-altering variants.

Authors predict that continuous improvements to sequencing technologies and predictive modeling will expand our understanding of splicing regulation and improve diagnoses for rare disease patients.

Monticelli M, D'Onofrio T, Jaeken J, Morava E, Andreotti G, Cubellis MV. Congenital disorders of glycosylation: narration of a story through its patents. Orphanet J Rare Dis. 2023 Aug 29;18(1):247. doi: 10.1186/s13023-023-02852-w.

Hong X, Edmondson AC, Strong A, Pomerantz D, Michl E, Berry G, He M. Combined PMM2-CDG and hereditary fructose intolerance in a patient with mild clinical presentation. Mol Genet Metab. 2023 Aug 9;140(3):107682. doi: 10.1016/j.ymgme.2023.107682. Online ahead of print.

Ligezka AN, Budhraja R, Nishiyama Y, Fiesel FC, Preston G, Edmondson A, Ranatunga W, Van Hove JLK, Watzlawik JO, Springer W, Pandey A, Morava E, Kozicz T. Interplay of Impaired Cellular Bioenergetics and Autophagy in PMM2-CDG. Genes (Basel). 2023 Aug 4;14(8):1585. doi: 10.3390/genes14081585. PMID: 37628636; PMCID: PMC10454768

PMM2-CDG is a type of congenital disorder of glycosylation caused by mutations in the PMM2 gene. Some types of CDG are associated with dysfunction of the mitochondria, which generate energy to power cells. However, not much is known about cellular bioenergetics (how cells transform energy) in PMM2-CDG. 

In this study, researchers evaluated mitochondrial function and autophagy (the process of breaking down cellular contents) in PMM2-CDG. The team evaluated fibroblasts (skin cell-derived connective tissue cells) with different genotypes from a natural history study of individuals with PMM2-CDG. 

Results reveal secondary mitochondrial dysfunction in PMM2-CDG, as well as altered autophagy, which may act as a marker of disease severity. Authors note that manipulating these processes could offer therapeutic benefits when combined with existing treatments for PMM2-CDG. 

Radenkovic S, Ligezka AN, Mokashi SS, Driesen K, Dukes-Rimsky L, Preston G, Owuocha LF, Sabbagh L, Mousa J, Lam C, Edmondson A, Larson A, Schultz M, Vermeersch P, Cassiman D, Witters P, Beamer LJ, Kozicz T, Flanagan-Steet H, Ghesquière B, Morava E. Tracer metabolomics reveals the role of aldose reductase in glycosylation. Cell Rep Med. 2023 Jun 20;4(6):101056. doi: 10.1016/j.xcrm.2023.101056. Epub 2023 May 30.

De Graef D, Ligezka AN, Rezents J, Mazza GL, Preston G, Schwartz K, Krzysciak W, Lam C, Edmondson AC, Johnsen C, Kozicz T, Morava E. Coagulation abnormalities in a prospective cohort of 50 patients with PMM2-congenital disorder of glycosylation. Mol Genet Metab. 2023 Jun;139(2):107606. doi: 10.1016/j.ymgme.2023.107606. Epub 2023 May 9.

Shah R, Johnsen C, Pletcher BA, Edmondson AC, Kozicz T, Morava E. Long-term outcomes in ALG13-Congenital Disorder of Glycosylation. Am J Med Genet A. 2023 Jun;191(6):1626-1631. doi: 10.1002/ajmg.a.63179. Epub 2023 Mar 17.

Sitek A, Ligezka A, Budhraja R, Morava E, Chiarella SE. Pathogenic DDOST Variant Is Associated with Humoral Immune Deficiency. J Clin Immunol. 2023 May;43(4):692-694. doi: 10.1007/s10875-023-01429-3. Epub 2023 Jan 12.

Tahata S, Weckwerth J, Ligezka A, He M, Lee HE, Heimbach J, Ibrahim SH, Kozicz T, Furuya K, Morava E. Liver transplantation recovers hepatic N-glycosylation with persistent IgG glycosylation abnormalities: Three-year follow-up in a patient with phosphomannomutase-2-congenital disorder of glycosylation. Mol Genet Metab. 2023 Apr;138(4):107559. doi: 10.1016/j.ymgme.2023.107559. Epub 2023 Mar 17.

Alharbi H, Daniel EJP, Thies J, Chang I, Goldner DL, Ng BG, Witters P, Aqul A, Velez-Bartolomei F, Enns GM, Hsu E, Kichula E, Lee E, Lourenco C, Poskanzer SA, Rasmussen S, Saarela K, Wang YM, Raymond KM, Schultz MJ, Freeze HH, Lam C, Edmondson AC, He M. Fractionated plasma N-glycan profiling of novel cohort of ATP6AP1-CDG subjects identifies phenotypic association. J Inherit Metab Dis. 2023 Mar;46(2):300-312. doi: 10.1002/jimd.12589. Epub 2023 Jan 29.

Radenkovic S, Laerdahl JK, Backe PH, Morava E. The role of PGM1isoform 2 in PGM1-CDG: One step closer to genotype-phenotype correlation?. J Inherit Metab Dis. 2023 Mar;46(2):159-160. doi: 10.1002/jimd.12601.

Balakrishnan B, Altassan R, Budhraja R, Liou W, Lupo A, Bryant S, Mankouski A, Radenkovic S, Preston GJ, Pandey A, Boudina S, Kozicz T, Morava-Kozicz E, Lai K. AAV-based gene therapy prevents and halts the progression of dilated cardiomyopathy in a mouse model of phosphoglucomutase 1 deficiency (PGM1-CDG). Transl Res. 2023 Jul;257:1-14. doi: 10.1016/j.trsl.2023.01.004. Epub 2023 Jan 26.

Altassan R, Albert-Brotons DC, Alowain M, Al-Halees Z, Jaeken J, Morava E. Successful heart transplantation in an infant with phosphoglucomutase 1 deficiency (PGM1-CDG). JIMD Rep. 2022 Nov 22;64(2):123-128. doi: 10.1002/jmd2.12350. eCollection 2023 Mar.

Sosicka P, Ng BG, Freeze HH. Chemical Therapies for Congenital Disorders of Glycosylation. ACS Chem Biol. 2022 Nov 18;17(11):2962-2971. doi: 10.1021/acschembio.1c00601. Epub 2021 Nov 17.

Mahajan S, Ng BG, AlAbdi L, Earnest PDJ, Sosicka P, Patel N, Helaby R, Abdulwahab F, He M, Alkuraya FS, Freeze HH. Homozygous truncating variant in MAN2A2 causes a novel congenital disorder of glycosylation with neurological involvement. J Med Genet. 2022 Nov 10:jmg-2022-108821. doi: 10.1136/jmg-2022-108821. Epub ahead of print. PMID: 36357165.

Congenital disorders of glycosylation (CDG) are a large group of rare, inherited disorders that affect a complex process in the body called glycosylation. Defects in Golgi enzymes, which play a critical role in N-glycan processing and brain development, are often defined as types of CDG. However, defects in the Golgi enzyme MAN2A2 have not been known to cause defects in glycosylation. In this study, researchers investigated the effects of variants in MAN2A2. In a family of affected individuals, the team performed exome sequencing, analyzed N-glycans, and designed a cell-based complementation assay to evaluate the disease-causing effects of the variant. Findings show that variants in MAN2A2 cause a new type of CDG, which is characterized by neurological involvement and facial dysmorphism. Authors note that the cell-based complementation assay designed in this study can also help diagnose patients with potentially pathogenic variants in a very similar enzyme, MAN2A1.

Elsharkawi I, Wongkittichote P, Daniel EJP, Starosta RT, Ueda K, Ng BG, Freeze HH, He M, Shinawi M. DDOST-CDG. Clinical and molecular characterization of a third patient with a milder and a predominantly movement disorder phenotype. J Inherit Metab Dis. 2022 Oct 10. doi: 10.1002/jimd.12565. Epub ahead of print. PMID: 36214423.

DDOST-CDG is an ultra-rare type of congenital disorder of glycosylation (CDG) that is caused by mutations in the gene DDOST. The metabolic disorder was previously reported in just two patients, whose clinical features included severe developmental delay, failure to thrive, and hypotonia (low muscle tone). Both patients also had abnormal transferrin glycosylation. In this study, researchers describe a new patient with DDOST-CDG. The 18-year-old male presented with moderate developmental delay, progressive opsoclonus (involuntary, rapid eye movements), myoclonus (involuntary, sudden muscle spasms), ataxia (impaired balance or coordination), tremor, and dystonia (involuntary muscle contractions that cause repetitive or twisting movements). The team performed several tests, including biochemical studies, exome sequencing, plasma N-glycan profiling, and western blot analysis, to learn more about the patient’s clinical features. Authors state that these insights—including new findings on the clinical variability, phenotypes, and genotypes of DDOST-CDG—are essential for diagnosing and managing patients with DDOST-CDG.

Sosicka P, Ng BG, Pepi LE, Shajahan A, Wong M, Scott DA, Matsumoto K, Xia ZJ, Lebrilla CB, Haltiwanger RS, Azadi P, Freeze HH. Origin of cytoplasmic GDP-fucose determines its contribution to glycosylation reactions. J Cell Biol. 2022 Oct 3;221(10):e202205038. doi: 10.1083/jcb.202205038. Epub 2022 Sep 2. PMID: 36053214.

Congenital disorders of glycosylation (CDG) are a group of inherited metabolic disorders that affect a process called glycosylation. This process uses monosaccharides (simple sugars) from multiple sources to produce nucleotide sugars (activated forms of monosaccharides). Since these sources of monosaccharides are assumed to contribute to one similar pool, their individual contributions are often overlooked. In this study, researchers explored the hypothesis that fucose (a type of monosaccharide) exists in multiple, distinct pools. The team measured the contribution of fucose from different sources. Findings show that cells identify and select from different pools of fucose for the process of glycosylation. Authors also present new perspectives on monosaccharide metabolism, which may have other applications beyond glycosylation.

Budhraja R, Saraswat M, De Graef D, Ranatunga W, Ramarajan MG, Mousa J, Kozicz T, Pandey A, Morava E. N-glycoproteomics reveals distinct glycosylation alterations in NGLY1-deficient patient-derived dermal fibroblasts. J Inherit Metab Dis. 2022 Sep 14. doi: 10.1002/jimd.12557. Epub ahead of print. PMID: 36102038.

NGLY1-CDDG (congenital disorder of deglycosylation) is a multisystemic, inherited condition caused by a mutation in the NGLY1 gene. Although the NGLY1 enzyme plays an essential role in the process of deglycosylation, the effects of NGLY1 deficiency on protein glycosylation are not yet understood. In this study, researchers explored the hypothesis that NGLY1 deficiency leads to accumulation of misfolded glycoproteins. Using glycoproteomics and proteomics methods, the team analyzed fibroblasts from four patients with NGLY1 deficiency carrying different variants in NGLY1. Results showed no significant accumulation of glycoproteins in the NGLY1-deficient fibroblasts. However, researchers found distinct changes in specific glycoproteins. As the first study of its kind, authors note that these findings highlight new insights for understanding NGLY1-CDDG.

Shimada S, Ng BG, White AL, Nickander KK, Turgeon C, Liedtke KL, Lam CT, Font-Montgomery E, Lourenco CM, He M, Peck DS, Umana LA, Uhles CL, Haynes D, Wheeler PG, Bamshad MJ, Nickerson DA, Cushing T, Gates R, Gomez-Ospina N, Byers HM; UW Center for Mendelian Genomics; Scalco FB, Martinez NN, Sachdev R, Smith L, Poduri A, Malone S, Harris RV, Scheffer IE, Rosenzweig SD, Adams DR, Gahl WA, Malicdan MCV, Raymond KM, Freeze HH, Wolfe LA. Clinical, biochemical and genetic characteristics of MOGS-CDG: a rare congenital disorder of glycosylation. J Med Genet. 2022 Jul 5:jmedgenet-2021-108177. doi: 10.1136/jmedgenet-2021-108177. Online ahead of print.

Albokhari D, Ng BG, Guberinic A, Daniel EJP, Engelhardt NM, Barone R, Fiumara A, Garavelli L, Trimarchi G, Wolfe L, Raymond KM, Morava E, He M, Freeze HH, Lam C, Edmondson AC. ALG8-CDG: Molecular and phenotypic expansion suggests clinical management guidelines. J Inherit Metab Dis.. 2022 Jun 18. doi: 10.1002/jimd.12527. Epub ahead of print. PMID: 35716054.

ALG8-congenital disorder of glycosylation (ALG8-CDG) is a rare, inherited disorder that affects multiple systems in the body. Patients with ALG8-CDG commonly present with decreased muscle tone, intestinal problems, and liver problems. In this study, researchers describe seven new individuals with ALG8-CDG, bringing the total to 26 individuals reported in medical literature. The team diagnosed these patients based on biochemical and molecular testing, identifying nine novel variants in ALG8. The cohort also includes the two oldest patients reported to date. This study expands the phenotype of ALG8-CDG to include stable intellectual disability, autism spectrum disorder, and other neuropsychiatric symptoms. Researchers also expand the clinical features in a variety of organ systems. To improve clinical management, authors suggest a comprehensive evaluation and monitoring strategy.

Geiculescu I, Dranove J, Cosper G, Edmondson AC, Morava-Kozicz E, Carter LB. A rare cause of infantile achalasia: GMPPA-congenital disorder of glycosylation with two novel compound heterozygous variants. Am J Med Genet A. 2022 Jun 4. doi: 10.1002/ajmg.a.62859. Epub ahead of print. PMID: 35665995.

Achalasia is a disorder of the esophagus, the tube that carries food from the mouth to the stomach. It is characterized by enlargement of the esophagus, impaired ability of the esophagus to push food down toward the stomach (peristalsis), and failure of the ring-shaped muscle at the bottom of the esophagus (the lower esophageal sphincter) to relax. Because achalasia is rare in the pediatric population, clinicians should consider associated genetic disorders. This includes GMPPA-congenital disorder of glycosylation (CDG), a rare type of CDG that is caused by variants in the GMPPA gene. In this study, researchers describe a 9-month-old female with achalasia and alacrima (reduced or absent ability to produce tears). The patient was found to have two novel compound heterozygous variants in the GMPPA gene that are associated with GMPPA-CDG. Authors provide a brief review of GMPPA-CDG, including management of this condition.

Ritter AL, Gold J, Hayashi H, Ackermann AM, Hanke S, Skraban C, Cuddapah S, Bhoj E, Li D, Kuroda Y, Wen J, Takeda R, Bibb A, El Chehadeh S, Piton A, Ohl J, Kukolich MK, Nagasaki K, Kato K, Ogi T, Bhatti T, Russo P, Krock B, Murrell JR, Sullivan JA, Shashi V, Stong N, Hakonarson H, Sawano K, Torti E, Willaert R, Si Y, Wilcox WR, Wirgenes KV, Thomassen K, Carlotti K, Erwin A, Lazier J, Marquardt T, He M, Edmondson AC, Izumi K. Expanding the phenotypic spectrum of ARCN1-related syndrome. Genet Med. 2022 Jun;24(6):1227-1237. doi: 10.1016/j.gim.2022.02.005. Epub 2022 Mar 14.

Boyer SW, Johnsen C, Morava E. Nutrition interventions in congenital disorders of glycosylation. Trends Mol Med. 2022 Jun;28(6):463-481. doi: 10.1016/j.molmed.2022.04.003. Epub 2022 May 10.

Ligezka AN, Mohamed A, Pascoal C, Ferreira VDR, Boyer S, Lam C, Edmondson A, Krzysciak W, Golebiowski R, Perez-Ortiz J, Morava E. Patient-reported outcomes and quality of life in PMM2-CDG. Mol Genet Metab. 2022 Jun;136(2):145-151. doi: 10.1016/j.ymgme.2022.04.002. Epub 2022 Apr 20.

Freeze HH, Jaeken J, Matthijs G. CDG or not CDG. J Inherit Metab Dis.. 2022 May;45(3):383-385. doi: 10.1002/jimd.12498. Epub 2022 Apr 1. PMID: 35338706; PMCID: PMC9121739.

In this letter to the editor, an expert team of authors explores a consensus on which genetic conditions should be identified as congenital disorders of glycosylation (CDG). “They are aiming to be inclusive; CDG should be used as the correct nomenclature in any disorders where the synthesis of glycans, glycoproteins, or glycolipids—including oligosaccharide transfer, glycan maturation, or trafficking—is affected,” says Eva Morava-Kozicz, MD, PhD, principal investigator of the Frontiers in Congenital Disorders of Glycosylation Consortium (FCDGC). “This is demonstrated by abnormal glycosylation in functional studies, and should be called a CDG.”

Tahata S, Raymond K, Quade M, Barnes S, Boyer S, League S, Kumanovics A, Abraham R, Jacob E, Menon P, Morava E. Defining the mild variant of leukocyte adhesion deficiency type II (SLC35C1-congenital disorder of glycosylation) and response to l-fucose therapy: Insights from two new families and review of the literature. Am J Med Genet A. 2022 Mar 26. doi: 10.1002/ajmg.a.62737. Epub ahead of print. PMID: 35338746.

Leukocyte adhesion deficiency type II (LAD II, also known as SLC35C1-congenital disorder of glycosylation) is an autosomal recessive disorder characterized by growth and cognitive impairment, peripheral neutrophilia, recurrent infections, and the Bombay blood phenotype. Among a subset of patients with a milder presentation, descriptions have also included short stature and developmental delay with minimal immune and hematologic (relating to blood) features. While some patients with LAD II benefit from oral fucose therapy, this has not yet been studied in patients with milder disease. In this study, researchers describe three new patients from two separate families with the milder variant of LAD II and review the published literature. After 27 months of oral fucose supplementation, one patient showed improvements in speech and cognition, CD15 expression, and core fucosylation of serum glycoproteins. Authors note that these patients support classification of this disorder into distinct subtypes—a classical severe and an attenuated variant—and provide preliminary evidence of benefit of fucose therapy in the latter group.

Tiwary H, Hecht LE, Brucker WJ, Berry GT, Rodig NM. The development of end stage renal disease in two patients with PMM2-CDG. JIMD Rep. 2022 Jan 10;63(2):131-136. doi: 10.1002/jmd2.12269. eCollection 2022 Mar.

Hong X, Alharbi H, Albokhari D, Edmondson AC, He M. A 6-Month-Old Infant with Severe Failure to Thrive during COVID-19 Pandemic. Clin Chem. 2022 Jul 3;68(7):987-989. doi: 10.1093/clinchem/hvac012.

Ligezka AN, Radenkovic S, Saraswat M, Garapati K, Ranatunga W, Krzysciak W, Yanaihara H, Preston G, Brucker W, McGovern RM, Reid JM, Cassiman D, Muthusamy K, Johnsen C, Mercimek-Andrews S, Larson A, Lam C, Edmondson AC, Ghesquière B, Witters P, Raymond K, Oglesbee D, Pandey A, Perlstein EO, Kozicz T, Morava E. Sorbitol Is a Severity Biomarker for PMM2-CDG with Therapeutic Implications. Ann Neurol. 2021 Dec;90(6):887-900. doi: 10.1002/ana.26245. Epub 2021 Oct 26.

Vaes L, Rymen D, Cassiman D, Ligezka A, Vanhoutvin N, Quelhas D, Morava E, Witters P Genotype-Phenotype Correlations in PMM2-CDG . Genotype-Phenotype Correlations in PMM2-CDG. Genes (Basel). 2021 Oct 21;12(11):1658. doi: 10.3390/genes12111658. PMID: 34828263; PMCID: PMC8620515.

PMM2-CDG is a rare disease that causes hypoglycosylation of multiple proteins. Direct genotype-phenotype correlations are not yet identified. In this paper, researchers carried out a retrospective cohort study on 26 PMM2-CDG patients. They collected the identified genotype, as well as variables indicating the disease severity and patients' phenotype. By studying the phenotypic effects of patients' genotype, researchers gained a better insight in the phenotypic prognosis of PMM2-CDG, according to their molecular base. They concluded that specific pathogenic variants (p.Pro113Leu and p.Phe119Leu) have a significantly higher total NPCRS disease severity score which indicates a more severe clinical outcome. The Nijmegen Paediatric CDG Rating Scale (NPCRS) is a tool to objectively follow the clinical disease progression in clinical disorders of glycosylation (CDG). Pathogenic variants affecting the folding or stabilization domain of the PMM2 enzyme protein have a significantly lower total NPCRS and thus the genetic results could provide a good prognostic clinical outcome.

Johnsen C, Edmondson AC.. Manifestations and Management of Hepatic Dysfunction in Congenital Disorders of Glycosylation. Clin Liver Dis (Hoboken). 2021 Sep 19;18(2):54-66. doi: 10.1002/cld.1105. eCollection 2021 Aug.

Čechová A, Honzík T, Edmondson AC, Ficicioglu C, Serrano M, Barone R, De Lonlay P, Schiff M, Witters P, Lam C, Patterson M, Janssen MCH, Correia J, Quelhas D, Sykut-Cegielska J, Plotkin H, Morava E, Sarafoglou K. Should patients with Phosphomannomutase 2-CDG (PMM2-CDG) be screened for adrenal insufficiency?. Mol Genet Metab. 2021 Aug;133(4):397-399. doi: 10.1016/j.ymgme.2021.06.003. Epub 2021 Jun 11.

Polla DL, Edmondson AC, Duvet S, March ME, Sousa AB, Lehman A; CAUSES Study, Niyazov D, van Dijk F, Demirdas S, van Slegtenhorst MA, Kievit AJA, Schulz C, Armstrong L, Bi X, Rader DJ, Izumi K, Zackai EH, de Franco E, Jorge P, Huffels SC, Hommersom M, Ellard S, Lefeber DJ, Santani A, Hand NJ, van Bokhoven H, He M, de Brouwer APM. Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation. Am J Hum Genet. 2021 Jul 1;108(7):1342-1349. doi: 10.1016/j.ajhg.2021.05.010. Epub 2021 Jun 17.

Morava E, Schatz UA, Torring PM, Abbott MA, Baumann M, Brasch-Andersen C, Chevalier N, Dunkhase-Heinl U, Fleger M, Haack TB, Nelson S, Potelle S, Radenkovic S, Bommer GT, Van Schaftingen E, Veiga-da-Cunha M. Impaired glucose-1,6-biphosphate production due to bi-allelic PGM2L1 mutations is associated with a neurodevelopmental disorder. Am J Hum Genet. 2021 Jun 3;108(6):1151-1160. doi: 10.1016/j.ajhg.2021.04.017. Epub 2021 May 11.

Study authors describe a genetic syndrome due to PGM2L1 deficiency. The gene PGM2L1 is highly expressed in the brain. They report the identification of four children with PGM2L1 deficiency sharing a largely neurological phenotype. All four children had severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris. Early obesity and seizures were present in three individuals. Study authors concluded that, while analyses indicated PGM2L1 deficiency does not appear to be a glycosylation defect, the discovery of this developmental disorder highlights the importance of glucose-1,6-biophosphate in the brain.

Perales-Clemente E, Liedtke K, Studinski A, Radenkovic S, Gavrilov D, Oglesbee D, Matern D, Rinaldo P, Tortorelli S, Morava E, Raymond K. A new D-galactose treatment monitoring index for PGM1-CDG. J Inherit Metab Dis. 2021 Sep;44(5):1263-1271. doi: 10.1002/jimd.12406. Epub 2021 Jun 22.

Witters P, Andersson H, Jaeken J, Tseng L, van Karnebeek CDM, Lefeber DJ, Cassiman D, Morava E. D-galactose supplementation in individuals with PMM2-CDG: results of a multicenter, open label, prospective pilot clinical trial. Orphanet J Rare Dis. 2021 Mar 20;16(1):138. doi: 10.1186/s13023-020-01609-z.

Alsharhan H, He M, Edmondson AC, Daniel EJP, Chen J, Donald T, Bakhtiari S, Amor DJ, Jones EA, Vassallo G, Vincent M, Cogné B, Deb W, Werners AH, Jin SC, Bilguvar K, Christodoulou J, Webster RI, Yearwood KR, Ng BG, Freeze HH, Kruer MC, Li D, Raymond KM, Bhoj EJ, Sobering AK. ALG13 X-linked intellectual disability: New variants, glycosylation analysis, and expanded phenotypes. J Inherit Metab Dis. 2021 Mar 18. doi: 10.1002/jimd.12378. Online ahead of print.

Witters P, Edmondson AC, Lam C, Johnsen C, Patterson MC, Raymond KM, He M, Freeze HH, Morava E. Spontaneous improvement of carbohydrate-deficient transferrin in PMM2-CDG without mannose observed in CDG natural history study. Orphanet J Rare Dis. 2021 Feb 25;16(1):102. doi: 10.1186/s13023-021-01751-2.

Alsharhan H, Ng BG, Daniel EJP, Friedman J, Pivnick EK, Al-Hashem A, Faqeih EA, Liu P, Engelhardt NM, Keller KN, Chen J, Mazzeo PA; University of Washington Center for Mendelian Genomics (UW-CMG), Rosenfeld JA, Bamshad MJ, Nickerson DA, Raymond KM, Freeze HH, He M, Edmondson AC, Lam C. Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG. J Inherit Metab Dis. 2021 Feb 13. doi: 10.1002/jimd.12367. Online ahead of print.

Berry GT, Freeze HH, Morava E. Is X-linked, infantile onset ALG13-related developmental and epileptic encephalopathy a congenital disorder of glycosylation?. Epilepsia. 2021 Feb;62(2):335-336. doi: 10.1111/epi.16817. Epub 2021 Feb 11.

Starosta RT, Boyer S, Tahata S, Raymond K, Lee HE, Wolfe LA, Lam C, Edmondson AC, Schwartz IVD, Morava E. Liver manifestations in a cohort of 39 patients with congenital disorders of glycosylation: pin-pointing the characteristics of liver injury and proposing recommendations for follow-up. Orphanet J Rare Dis. 2021 Jan 7;16(1):20. doi: 10.1186/s13023-020-01630-2.

Radenkovic S, Fitzpatrick-Schmidt T, Byeon SK, Madugundu AK, Saraswat M, Lichty A, Wong SYW, McGee S, Kubiak K, Ligezka A, Ranatunga W, Zhang Y, Wood T, Friez MJ, Clarkson K, Pandey A, Jones JR, Morava E. Expanding the clinical and metabolic phenotype of DPM2 deficient congenital disorders of glycosylation. Mol Genet Metab. 2021 Jan;132(1):27-37. doi: 10.1016/j.ymgme.2020.10.007. Epub 2020 Oct 17.

Poskanzer SA, Schultz MJ, Turgeon CT, Vidal-Folch N, Liedtke K, Oglesbee D, Gavrilov DK, Tortorelli S, Matern D, Rinaldo P, Bennett JT, Thies JM, Chang IJ, Beck AE, Raymond K, Allenspach EJ, Lam C. Immune dysfunction in MGAT2-CDG: A clinical report and review of the literature. Am J Med Genet A. 2021 Jan;185(1):213-218. doi: 10.1002/ajmg.a.61914. Epub 2020 Oct 12.

Altassan R, Radenkovic S, Edmondson AC, Barone R, Brasil S, Cechova A, Coman D, Donoghue S, Falkenstein K, Ferreira V, Ferreira C, Fiumara A, Francisco R, Freeze H, Grunewald S, Honzik T, Jaeken J, Krasnewich D, Lam C, Lee J, Lefeber D, Marques-da-Silva D, Pascoal C, Quelhas D, Raymond KM, Rymen D, Seroczynska M, Serrano M, Sykut-Cegielska J, Thiel C, Tort F, Vals MA, Videira P, Voermans N, Witters P, Morava E. International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management. J Inherit Metab Dis. 2021 Jan;44(1):148-163. doi: 10.1002/jimd.12286. Epub 2020 Sep 15.

Wilson MP, Garanto A, Pinto E Vairo F, Ng BG, Ranatunga WK, Ventouratou M, Baerenfaenger M, Huijben K, Thiel C, Ashikov A, Keldermans L, Souche E, Vuillaumier-Barrot S, Dupré T, Michelakakis H, Fiumara A, Pitt J, White SM, Lim SC, Gallacher L, Peters H, Rymen D, Witters P, Ribes A, Morales-Romero B, Rodríguez-Palmero A, Ballhausen D, de Lonlay P, Barone R, Janssen MCH, Jaeken J, Freeze HH, Matthijs G, Morava E, Lefeber DJ. Active site variants in STT3A cause a dominant type I congenital disorder of glycosylation with neuromusculoskeletal findings. Am J Hum Genet. 2021 Nov 4;108(11):2130-2144. doi: 10.1016/j.ajhg.2021.09.012. Epub 2021 Oct 14. PMID: 34653363; PMCID: PMC8595932.

Congenital disorders of glycosylation (CDGs) are a group of rare diseases characterized by hypoglycosylation. The STT3A gene plays an essential role in protein N-glycosylation. In this study, researchers identified 16 individuals from nine families who have variants in STT3A, leading to an autosomal-dominant CDG. They describe the features of these individuals including variable skeletal anomalies, short stature, large head, muscle cramps, and in some, intellectual disability. The authors also present data to support a dominant form of STT3A-CDG that is unusual among type I CDGs.

Ferrer A, Starosta RT, Ranatunga W, Ungar D, Kozicz T, Klee E, Rust LM, Wick M, Morava E. Fetal glycosylation defect due to ALG3 and COG5 variants detected via amniocentesis: Complex glycosylation defect with embryonic lethal phenotype. Mol Genet Metab. 2020 Dec;131(4):424-429. doi: 10.1016/j.ymgme.2020.11.003. Epub 2020 Nov 7.

Ng BG, Eklund EA, Shiryaev SA, Dong YY, Abbott MA, Asteggiano C, Bamshad MJ, Barr E, Bernstein JA, Chelakkadan S, Christodoulou J, Chung WK, Ciliberto MA, Cousin J, Gardiner F, Ghosh S, Graf WD, Grunewald S, Hammond K, Hauser NS, Hoganson GE, Houck KM, Kohler JN, Morava E, Larson AA, Liu P, Madathil S, McCormack C, Meeks NJL, Miller R, Monaghan KG, Nickerson DA, Palculict TB, Papazoglu GM, Pletcher BA, Scheffer IE, Schenone AB, Schnur RE, Si Y, Rowe LJ, Serrano Russi AH, Russo RS, Thabet F, Tuite A, Villanueva MM, Wang RY, Webster RI, Wilson D, Zalan A; Undiagnosed Diseases Network, University of Washington Center for Mendelian Genomics (UW-CMG), Wolfe LA, Rosenfeld JA, Rhodes L, Freeze HH. Predominant and novel de novo variants in 29 individuals with ALG13 deficiency: Clinical description, biomarker status, biochemical analysis, and treatment suggestions. J Inherit Metab Dis. 2020 Nov;43(6):1333-1348. doi: 10.1002/jimd.12290. Epub 2020 Aug 5.

Del Caño-Ochoa F, Ng BG, Abedalthagafi M, Almannai M, Cohn RD, Costain G, Elpeleg O, Houlden H, Karimiani EG, Liu P, Manzini MC, Maroofian R, Muriello M, Al-Otaibi A, Patel H, Shimon E, Sutton VR, Toosi MB, Wolfe LA, Rosenfeld JA, Freeze HH, Ramón-Maiques S. Cell-based analysis of CAD variants identifies individuals likely to benefit from uridine therapy. Genet Med. 2020 Oct;22(10):1598-1605. doi: 10.1038/s41436-020-0833-2. Epub 2020 May 28.

Qian Z, Van den Eynde J, Heymans S, Mertens L, Morava E. Vascular ring anomaly in a patient with phosphomannomutase 2 deficiency: A case report and review of the literature. JIMD Rep. 2020 Aug 19;56(1):27-33. doi: 10.1002/jmd2.12160. eCollection 2020 Nov.

Čechová A, Altassan R, Borgel D, Bruneel A, Correia J, Girard M, Harroche A, Kiec-Wilk B, Mohnike K, Pascreau T, Pawliński Ł, Radenkovic S, Vuillaumier-Barrot S, Aldamiz-Echevarria L, Couce ML, Martins EG, Quelhas D, Morava E, de Lonlay P, Witters P, Honzík T. Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation. J Inherit Metab Dis. 2020 Jul;43(4):671-693. doi: 10.1002/jimd.12241. Epub 2020 Apr 21.

Witters P, Tahata S, Barone R, Õunap K, Salvarinova R, Grønborg S, Hoganson G, Scaglia F, Lewis AM, Mori M, Sykut-Cegielska J, Edmondson A, He M, Morava E. Clinical and biochemical improvement with galactose supplementation in SLC35A2-CDG. Genet Med. 2020 Jun;22(6):1102-1107. doi: 10.1038/s41436-020-0767-8. Epub 2020 Feb 27.

Vaes L, Tiller GE, Pérez B, Boyer SW, Berry SA, Sarafoglou K, Morava E. PMM2-CDG caused by uniparental disomy: Case report and literature review. JIMD Rep. 2020 Apr 28;54(1):16-21. doi: 10.1002/jmd2.12122. eCollection 2020 Jul.

Zilmer M, Edmondson AC, Khetarpal SA, Alesi V, Zaki MS, Rostasy K, Madsen CG, Lepri FR, Sinibaldi L, Cusmai R, Novelli A, Issa MY, Fenger CD, Abou Jamra R, Reutter H, Briuglia S, Agolini E, Hansen L, Petäjä-Repo UE, Hintze J, Raymond KM, Liedtke K, Stanley V, Musaev D, Gleeson JG, Vitali C, O'Brien WT, Gardella E, Rubboli G, Rader DJ, Schjoldager KT, Møller RS. Novel congenital disorder of O-linked glycosylation caused by GALNT2 loss of function. Brain. 2020 Apr 1;143(4):1114-1126. doi: 10.1093/brain/awaa063.

Verheijen J, Wong SY, Rowe JH, Raymond K, Stoddard J, Delmonte OM, Bosticardo M, Dobbs K, Niemela J, Calzoni E, Pai SY, Choi U, Yamazaki Y, Comeau AM, Janssen E, Henderson L, Hazen M, Berry G, Rosenzweig SD, Aldhekri HH, He M, Notarangelo LD, Morava E. Defining a new immune deficiency syndrome: MAN2B2-CDG. J Allergy Clin Immunol. 2020 Mar;145(3):1008-1011. doi: 10.1016/j.jaci.2019.11.016. Epub 2019 Nov 24.

Verheijen J, Tahata S, Kozicz T, Witters P, Morava E. Therapeutic approaches in Congenital Disorders of Glycosylation (CDG) involving N-linked glycosylation: an update. Genet Med. 2020 Feb;22(2):268–279. doi: 10.1038/s41436-019-0647-2. Epub 2019 Sep 19. PMID: 31534212.

Moravej H, Altassan R, Jaeken J, Enns GM, Ellaway C, Balasubramaniam S, De Lonlay P, Coman D, Mercimek-Andrews S, Witters P, Morava E. Hypoglycemia in CDG patients due to PMM2 mutations: Follow up on hyperinsulinemic patients. JIMD Rep. 2019 Nov 25;51(1):76-81. doi: 10.1002/jmd2.12085. eCollection 2020 Jan.

Iyer S, Sam FS, DiPrimio N, Preston G, Verheijen J, Murthy K, Parton Z, Tsang H, Lao J, Morava E, Perlstein EO. Repurposing the aldose reductase inhibitor and diabetic neuropathy drug epalrestat for the congenital disorder of glycosylation PMM2-CDG. Dis Model Mech. 2019 Nov 11;12(11):dmm040584. doi: 10.1242/dmm.040584.

Eisenhuth F, Agbonze JE, Groh AMR, Klostranec JM, Rudko DA, Stratton JA, Shapiro AJ. Age-related cerebral ventriculomegaly occurs in patients with primary ciliary dyskinesia. Fluids Barriers CNS. 2025 Jan 31;22(1):12. doi: 10.1186/s12987-024-00614-9. PMID: 39891273; PMCID: PMC11783799.

Primary ciliary dyskinesia (PCD) is a genetic condition in which mucociliary clearance of the lungs is impaired, leading to accumulation of harmful particles and pathogens trapped within mucus. Although PCD is known to affect the respiratory and reproductive systems, less is known about its impact on the central nervous system.

In this study, researchers investigated cerebral ventriculomegaly (enlarged brain ventricles) in patients with PCD. The team analyzed computed tomography sinus images from 33 patients with PCD and 64 healthy control subjects to assess ventricular size.

Findings suggest that patients with PCD may have unrecognized, mild ventriculomegaly which correlates with aging. This ventriculomegaly may be caused by ependymal ciliary dysfunction. Authors note that further study is required to determine causality and whether ventricular enlargement contributes to neuropsychiatric, neurological, or other factors in PCD.

Gardner RA, Ferkol TW, Davis SD, Rosenfeld M, Sagel SD, Dell SD, Milla CE, Li L, Lin FC, Sullivan KM, Zariwala MA, Knowles MR, Leigh MW. Therapies Used by Children With Primary Ciliary Dyskinesia: A Natural History Study. Pediatr Pulmonol. 2025 Jan;60(1):e27412. doi: 10.1002/ppul.27412. Epub 2024 Nov 22. PMID: 39575633; PMCID: PMC11750599.

Primary ciliary dyskinesia (PCD) is a genetic condition in which mucociliary clearance of the lungs is impaired, leading to accumulation of harmful particles and pathogens trapped within mucus. Since management of PCD has not been closely evaluated, most of what is known about therapies relies on patient observation alone or extrapolated from other diseases. The goal of this study was to understand which therapies were commonly used and determine factors that influenced treatment choices.

In this natural history study, researchers investigated therapies used by children with PCD. The team followed 137 pediatric subjects over the course of 13 years, recording and categorizing therapies at 897 annual visits. Analysis techniques were used to reveal trends in therapy prevalence. Results show that more therapies were reported by older participants and those with inner dynein arm and microtubular disorganization defects, likely due to disease progression and severity. Antibiotics were the most reported treatment. Inhaled medications, including inhaled corticosteroids, were more frequently used as participants grew older, despite limited evidence supporting their effectiveness.

Authors note that a wide range of therapies are used in PCD without disease-specific studies defining benefits and risks, underscoring the need for well-designed clinical trials to establish effective, evidence-based treatment strategies.

Despotes KA, Davis SD. Added complexity to genotype-phenotype relationships in primary ciliary dyskinesia: TAS2R38 as a gene modifier. Thorax. 2024 Nov 14;79(12):1109-1111. doi: 10.1136/thorax-2024-222333.

Beaman MM, Yin W, Smith AJ, Sears PR, Leigh MW, Ferkol TW, Kearney B, Olivier KN, Kimple AJ, Clarke S, Huggins E, Nading E, Jung SH, Iyengar AK, Zou X, Dang H, Barrera A, Majoros WH, Rehder CW, Reddy TE, Ostrowski LE, Allen AS, Knowles MR, Zariwala MA, Crawford GE. Promoter Deletion Leading to Allele Specific Expression in a Genetically Unsolved Case of Primary Ciliary Dyskinesia. Am J Med Genet A. 2024 Oct 4:e63880. doi: 10.1002/ajmg.a.63880. Epub ahead of print. PMID: 39364610.

Primary ciliary dyskinesia (PCD) is a genetic condition in which mucociliary clearance of the lungs is impaired, leading to accumulation of harmful particles and pathogens trapped within mucus. Variation in the non-coding genome can sometimes cause genetic diseases like PCD. However, it can be challenging to predict whether these variants will lead to disease.

In this study, researchers identified a pathogenic non-coding variant in a genetically unsolved case of PCD. The team used complementary RNA sequencing and targeted long-read DNA sequencing approaches to uncover a non-coding deletion in the 5’ untranslated region of the SPAG1 gene in a patient with PCD.

Results highlight the importance of investigating the non-coding genome in patients with “missing” disease-causing variants. Authors note that both RNA and long-read DNA sequencing can be used to identify pathogenic non-coding variants in patients with unexplained genetic diseases.

Wee WB, Gatt D, Seidl E, Santyr G, To T, Dell SD. Estimates of primary ciliary dyskinesia prevalence: a scoping review. ERJ Open Res. 2024 Aug 5;10(4):00989-2023. doi: 10.1183/23120541.00989-2023. PMID: 39104959; PMCID: PMC11299005.

Primary ciliary dyskinesia (PCD) is an inherited multisystem disease involving dysfunctional motile cilia that can impact mucociliary clearance, fertility, and organogenesis. Although PCD is considered the second-most common inherited airway disease after cystic fibrosis, it is not well-recognized globally due to its nonspecific clinical features and the lack of gold standard diagnostic testing.

In this article, the authors conducted a scoping review (using PRISMA-ScR methodology) of the current PCD literature to better understand the global prevalence of PCD. Authors also identify key considerations of different study designs and inform the reader about the potential unmet health service needs in PCD. 

Results found that the current best estimate for PCD global prevalence is one in 7,554, which was based on a genomic approach. Although this estimate is still considered conservative, this finding suggests that PCD is much more prevalent than previously thought and that there is an urgent need for more healthcare policies to accelerate improvements in PCD care, as well as expand services to underserved populations. 

Dougherty GW, Ostrowski LE, Nöthe-Menchen T, Raidt J, Schramm A, Olbrich H, Yin W, Sears PR, Dang H, Smith AJ, Beule AG, Hjeij R, Rutjes N, Haarman EG, Maas SM, Ferkol TW, Noone PG, Olivier KN, Bracht DC, Barbry P, Zaragosi LE, Fierville M, Kliesch S, Wohlgemuth K, König J, George S, Loges NT, Ceppe A, Markovetz MR, Luo H, Guo T, Rizk H, Eldesoky T, Dahlke K, Boldt K, Ueffing M, Hill DB, Pang YP, Knowles MR, Zariwala MA, Omran H. Recessively Inherited Deficiency of Secreted WFDC2 (HE4) Causes Nasal Polyposis and Bronchiectasis. Am J Respir Crit Care Med. 2024 Jul 1;210(1):63-76. doi: 10.1164/rccm.202308-1370OC. PMID: 38626355; PMCID: PMC11197063.

Bronchiectasis is a progressive disorder in which the bronchi (air passages within the lungs that diverge from the windpipe) are permanently dilated and irreversibly scarred. Chronic respiratory disorders—including cystic fibrosis, primary ciliary dyskinesia, and primary immunodeficiency disorders—characterized by bronchiectasis have underlying genetic or environmental causes. However, most cases of bronchiectasis have unknown causes. 

In this study, researchers identified a new genetic cause in unsolved cases of bronchiectasis. The team performed next-generation sequencing to explore possible genetic defects in individuals with chronic respiratory symptoms who were not suspected to have cystic fibrosis or primary ciliary dyskinesia based on previous genetic testing.

Results revealed disease-causing variants in the WFDC2 gene in 11 individuals presenting with a unique and severe respiratory disorder characterized by bronchiectasis in all lung fields, chronic rhinosinusitis, and lung infection. This new cause of chronic destructive airway disease results from deficiency of the secreted WFDC2 protein. Authors note that the identification of this disease—which can be diagnosed with a commercially available blood test and genetic testing—adds to our understanding of the causes of bronchiectasis and may lead to improved treatment.

Despotes KA, Zariwala MA, Davis SD, Ferkol TW. Primary Ciliary Dyskinesia: A Clinical Review. Cells. 2024 Jun 4;13(11):974. doi: 10.3390/cells13110974.

Wee WB, Kinghorn B, Davis SD, Ferkol TW, Shapiro AJ. Primary Ciliary Dyskinesia. Pediatrics. 2024 Jun 1;153(6):e2023063064. doi: 10.1542/peds.2023-063064. PMID: 38695103; PMCID: PMC11153322.

Primary ciliary dyskinesia (PCD) is an inherited condition in which mucociliary clearance of the lungs is impaired, leading to accumulation of harmful particles and pathogens trapped within mucus. In the past two decades, research and international collaborations have led to a better understanding of PCD. However, PCD is still not well-known in clinical settings, with only a fraction of patients receiving an accurate diagnosis.

In this review paper, authors describe the latest advancements in PCD research. Topics include the range of clinical manifestations, cutting-edge diagnostic practices, new genotype-phenotype associations, and the latest management techniques for individuals with PCD.

Authors note that sharing these advancements will have important clinical impacts, including improved disease recognition, diagnostic testing, and management. Additionally, increased awareness of PCD could help boost enrollment in upcoming clinical trials for new therapies.

Kaspy KR, Dell SD, Davis SD, Ferkol TW, Rosenfeld M, Sagel SD, Milla C, Olivier KN, Barber AT, Wee W, Lin FC, Li L, Rampakakis E, Zariwala MA, Knowles MR, Leigh MW, Shapiro AJ. Situs Ambiguus Is Associated With Adverse Clinical Outcomes in Children With Primary Ciliary Dyskinesia. Chest. 2024 May;165(5):1070-1081. doi: 10.1016/j.chest.2023.12.005. Epub 2023 Dec 9. PMID: 38072392.

Primary ciliary dyskinesia (PCD) is a genetic disorder in which mucociliary clearance of the lungs is impaired. While most individuals with PCD have normal arrangement of organs in the abdomen and chest (situs solitus), some present with situs ambiguus (abnormal arrangement) or situs inversus totalis (mirror image of normal arrangement).

In this study, researchers compared the clinical outcomes of children with PCD and situs ambiguus to those with situs solitus or situs inversus totalis. The team categorized 397 participants with PCD aged 21 years or younger into situs groups, then evaluated markers of disease severity.

Results show that children with PCD and situs ambiguus have worse nutritional and pulmonary outcomes with more hospitalizations for acute respiratory illnesses than those with situs solitus or situs inversus totalis combined. Authors also note that these outcomes are associated with cardiovascular malformations requiring cardiac surgery, splenic anomalies, or both.

Dodd DO, Mechaussier S, Yeyati PL, McPhie F, Anderson JR, Khoo CJ, Shoemark A, Gupta DK, Attard T, Zariwala MA, Legendre M, Bracht D, Wallmeier J, Gui M, Fassad MR, Parry DA, Tennant PA, Meynert A, Wheway G, Fares-Taie L, Black HA, Mitri-Frangieh R, Faucon C, Kaplan J, Patel M, McKie L, Megaw R, Gatsogiannis C, Mohamed MA, Aitken S, Gautier P, Reinholt FR, Hirst RA, O'Callaghan C, Heimdal K, Bottier M, Escudier E, Crowley S, Descartes M, Jabs EW, Kenia P, Amiel J, Bacci GM, Calogero C, Palazzo V, Tiberi L, Blümlein U, Rogers A, Wambach JA, Wegner DJ, Fulton AB, Kenna M, Rosenfeld M, Holm IA, Quigley A, Hall EA, Murphy LC, Cassidy DM, von Kriegsheim A; Scottish Genomes Partnership16; Genomics England Research Consortium45; Undiagnosed Diseases Network46; Papon JF, Pasquier L, Murris MS, Chalmers JD, Hogg C, Macleod KA, Urquhart DS, Unger S, Aitman TJ, Amselem S, Leigh MW, Knowles MR, Omran H, Mitchison HM, Brown A, Marsh JA, Welburn JPI, Ti SC, Horani A, Rozet JM, Perrault I, Mill P. Ciliopathy patient variants reveal organelle-specific functions for TUBB4B in axonemal microtubules. Science. 2024 Apr 26;384(6694):eadf5489. doi: 10.1126/science.adf5489. Epub 2024 Apr 26.

Gardner RA, Sagel SD, Knowles MR, Ferkol TW, Davis SD, Leigh MW, Zariwala MA. Decoding negative genetic panels in primary ciliary dyskinesia. Pediatr Pulmonol. 2024 Mar;59(3):784-787. doi: 10.1002/ppul.26790. Epub 2023 Dec 5.

Macaluso M, Rothenberg ME, Ferkol T, Kuhnell P, Kaminski HJ, Kimberlin DW, Benatar M, Chehade M; Principal Investigators of the Rare Diseases Clinical Research Network – Cycle 4. Impact of the COVID-19 Pandemic on People Living With Rare Diseases and Their Families: Results of a National Survey. JMIR Public Health Surveill. 2024 Feb 14;10:e48430. doi: 10.2196/48430.

Kim S, Li L, Lin FC, Stack T, Lamb MM, Mohammad I, Norris M, Klatt-Cromwell C, Thorp BD, Ebert CS Jr, Masters D, Senior BA, Askin FB, Kimple AJ. Histologic characterization of primary ciliary dyskinesia chronic rhinosinusitis. Int Forum Allergy Rhinol. 2023 Nov 23. doi: 10.1002/alr.23303. Epub ahead of print. PMID: 37997295

Primary ciliary dyskinesia (PCD) is an inherited condition in which mucociliary clearance of the lungs is impaired, leading to accumulation of harmful particles and pathogens trapped within mucus. In addition to lung disease, this results in chronic rhinosinusitis, where the lining of the sinuses becomes swollen, creates extra mucus, and interferes with drainage.

In this study, researchers characterized the histologic change (microscopic changes in tissues) of PCD-related chronic rhinosinusitis (PCD-CRS) in individuals with PCD who underwent sinus surgery. The team compared tissue samples from patients with PCD-CRS to those with cystic fibrosis-related chronic rhinosinusitis (CF-CRS), routine chronic rhinosinusitis without nasal polyps, and healthy controls.  

While sinus disease is generally mediated by eosinophils (a specific white blood cell) in PCD-CRS, neutrophils were the dominant immune cell in sinus tissue, similar to CF-CRS. As targeted therapies become available for CRS, understanding the pathogenesis of PCD-CRS becomes increasingly important.  

Stack TJ, Norris M, Mohammad I, Thorp BD, Klatt-Cromwell C, Ebert CS Jr, Senior BA, Kimple AJ. Response to letter to the editor regarding "Sinonasal quality of life in primary ciliary dyskinesia". Int Forum Allergy Rhinol. 2023 Nov 8. doi: 10.1002/alr.23297. Online ahead of print.

Ringshausen FC, Shapiro AJ, Nielsen KG, Mazurek H, Pifferi M, Donn KH, van der Eerden MM, Loebinger MR, Zariwala MA, Leigh MW, Knowles MR, Ferkol TW; CLEAN-PCD investigators and study team. Safety and efficacy of the epithelial sodium channel blocker idrevloride in people with primary ciliary dyskinesia (CLEAN-PCD): a multinational, phase 2, randomised, double-blind, placebo-controlled crossover trial. Lancet Respir Med. 2023 Aug 31:S2213-2600(23)00226-6. doi: 10.1016/S2213-2600(23)00226-6. Online ahead of print.

Chaskes MB, Lopez EM, Kong KA, Ebert CS Jr, Senior BA, Thorp BD, Kimple AJ. Primary ciliary dyskinesia: An update on contemporary diagnosis. Int Forum Allergy Rhinol. 2023 Aug 11. doi: 10.1002/alr.23254. Epub ahead of print. PMID: 37565263

Primary ciliary dyskinesia (PCD) is an inherited condition in which mucociliary clearance of the lungs is impaired. Symptoms include chronic sinusitis, frequent respiratory and middle ear infections, hearing loss, chronic cough, severe lung damage, and bronchiectasis (irreversible scarring and dilation of the bronchi).

Individuals with PCD often receive a delayed diagnosis due to multiple factors, including the commonality of symptoms, variability of severity, number of clinicians involved in their care, limitations of diagnostic tests, and lack of standards. Both diagnosed and undiagnosed individuals with PCD require frequent care of the ear, nose, and throat (ENT). However, there is limited published guidance for the proper diagnosis of PCD.  

This clinical letter for ENT clinicians educates ENTs about modern diagnostic criteria and considerations through two cases: a new diagnosis in an adult and a misdiagnosis of PCD as a child that was carried into adulthood. 

Hunter-Schouela J, Geraghty MT, Hegele RA, Dyment DA, St Pierre D, Richer J, Sheffield H, Zariwala MA, Knowles MR, Lehman A, Dell S, Shapiro AJ, Kovesi TA. First reports of primary ciliary dyskinesia caused by a shared DNAH11 allele in Canadian Inuit. Pediatr Pulmonol. 2023 Jul;58(7):1942-1949. doi: 10.1002/ppul.26414. Epub 2023 Apr 23.

Stack T, Norris M, Kim S, Lamb M, Zeatoun A, Mohammad I, Worden C, Thorp BD, Klatt-Cromwell C, Ebert CS Jr, Senior BA, Kimple AJ. Sinonasal quality of life in primary ciliary dyskinesia. Int Forum Allergy Rhinol. 2023 May 19. doi: 10.1002/alr.23180. Online ahead of print.

Beydon N, Kouis P, Marthin JK, Latzin P, Colas M, Davis SD, Haarman E, Harris AL, Hogg C, Kilbride E, Kuehni CE, Marangu D, Nielsen KG, Pendergrast C, Robinson P, Rumman N, Rutter M, Walker WT, Ferkol T, Lucas JS. Nasal nitric oxide measurement in children for the diagnosis of primary ciliary dyskinesia: European Respiratory Society technical standard. Eur Respir J. 2023 Apr 20;61(4):2202031. doi: 10.1183/13993003.02031-2022. Print 2023 Apr.

Kinghorn B, Rosenfeld M, Sullivan E, Onchiri F, Ferkol TW, Sagel SD, Dell SD, Milla C, Shapiro AJ, Sullivan KM, Zariwala MA, Pittman JE, Mollica F, Tiddens HAWM, Kemner-van de Corput M, Knowles MR, Davis SD, Leigh MW. Airway Disease in Children with Primary Ciliary Dyskinesia: Impact of Ciliary Ultrastructure Defect and Genotype. Ann Am Thorac Soc. 2023 Apr;20(4):539-547. doi: 10.1513/AnnalsATS.202206-524OC.

Barber AT, Shapiro AJ, Davis SD, Ferkol TW, Atkinson JJ, Sagel SD, Dell SD, Olivier KN, Milla CE, Rosenfeld M, Li L, Lin FC, Sullivan KM, Capps NA, Zariwala MA, Knowles MR, Leigh MW. Laterality Defects in Primary Ciliary Dyskinesia: Relationship to Ultrastructural Defect or Genotype. Ann Am Thorac Soc. 2023 Mar;20(3):397-405. doi: 10.1513/AnnalsATS.202206-487OC. PMID: 36342963; PMCID: PMC9993158.

Primary ciliary dyskinesia (PCD) is an inherited disorder which affects the movement of tiny hair-like structures on body cells known as cilia, impairing mucociliary clearance of the lungs. Approximately 50 percent of PCD patients have a laterality defect (right-left placement of organs in the chest and abdomen) attributable to impaired ciliary motility in the early embryo. The association between abnormalities in organ laterality and the PCD-associated defect of ciliary ultrastructure (fine, detailed structure) or genotype is not well understood.

In this study, researchers investigated the association between presence and/or type of laterality abnormality and ciliary ultrastructural defect or genotype in PCD. First, the team grouped 559 participants with PCD based on ciliary ultrastructural defect or genotype. Next, researchers analyzed the data to evaluate the association of ciliary ultrastructural defect or genotype and likelihood of a laterality abnormality.

Results show that in patients with PCD, risk of a laterality abnormality differs by ciliary ultrastructural defect. Authors note that further research is needed to understand the pathophysiologic mechanisms underlying these differences.

Sagel SD, Kupfer O, Wagner BD, Davis SD, Dell SD, Ferkol TW, Hoppe JE, Rosenfeld M, Sullivan KM, Tiddens HAWM, Knowles MR, Leigh MW. Airway Inflammation in Children with Primary Ciliary Dyskinesia. Ann Am Thorac Soc. 2023 Jan;20(1):67-74. doi: 10.1513/AnnalsATS.202204-314OC. PMID: 35984413; PMCID: PMC9819265.

Primary ciliary dyskinesia (PCD) is an inherited condition in which mucociliary clearance of the lungs is impaired. In this disorder, cilia (hairlike structures) lining the airway, sinuses, and middle ears have defective movements, leading to accumulation of harmful particles and pathogens trapped within mucus. Currently, not much is known about the role of airway inflammation in the development of PCD in children. In this study, researchers investigated the relationships between sputum (mucus) inflammation measurements, age, lung function, bronchiectasis, airway infection, and ultrastructural defects in children with PCD. The team collected spontaneously expectorated sputum from clinically stable children and adolescents with PCD ages six years and older. Next, the team correlated sputum protease and inflammatory cytokine concentrations with age, lung function, and chest computed tomography measures of structural lung disease. Results show that in this multicenter cohort of pediatric patients with PCD, elevated concentrations of sputum proteases and cytokines were associated with impaired lung function and structural damage as determined by chest computed tomography. These results establish an important linkage between airway inflammation and lung disease in PCD. Authors note that these findings also suggest sputum inflammatory measurements could serve as biomarkers in PCD and could be used to assess the efficacy of anti-inflammatory therapies.

Shapiro AJ, Sillon G, D'Agostino D, Baret L, López-Giráldez F, Mane S, Leigh MW, Davis SD, Knowles MR, Zariwala MA. HYDIN Variants Are a Common Cause of Primary Ciliary Dyskinesia in French Canadians. Ann Am Thorac. 2023 Jan;20(1):140-144. doi: 10.1513/AnnalsATS.202203-253RL. PMID: 36112114; PMCID: PMC9819264.

Primary ciliary dyskinesia (PCD) is a genetic disorder in which mucociliary clearance of the lungs is impaired. In the past two decades, more than 50 PCD-related genes have been discovered. However, most commercial genetic panels do not include variant analysis of the large, complex PCD gene HYDIN. In this letter to the editor, researchers discuss a study of 28 patients in 21 families with probable but undiagnosed PCD from the PCD clinic at McGill University Health Centre in Montreal, Quebec, Canada. To investigate whether HYDIN played a role in these unsolved cases, the team utilized whole-exome sequencing and next-generation sequencing analyses. Results show that pathogenic variants in HYDIN aided diagnosis in six of 21 families with previously unsolved PCD. These findings show that HYDIN variants are responsible for a large percentage of PCD in Quebec. Although it is not clear if increased HYDIN prevalence will be observed in populations outside of Quebec, authors state that transitioning to commercial panels that analyze HYDIN seems critical to accurately diagnose patients with PCD.

Wee WB, Leigh MW, Davis SD, Rosenfeld M, Sullivan KM, Sawras MG, Ferkol TW, Knowles MR, Milla C, Sagel SD, Zariwala MA, Pullenayegum E, Dell SD. Association of Neonatal Hospital Length of Stay with Lung Function in Primary Ciliary Dyskinesia. Ann Am Thorac Soc. 2022 Nov;19(11):1865-1870. doi: 10.1513/AnnalsATS.202202-116OC. PMID: 35657736.

Primary ciliary dyskinesia (PCD) is an inherited, multisystem disease affecting the airways, sinuses, and middle ear that arises from dysfunctional cilia (hairlike structures). This in turn can lead to hearing loss, chronic cough, severe lung damage, and bronchiectasis (irreversible scarring and dilation of the bronchi). Patients with PCD have ranging disease variability and severity, with some clinical manifestations presenting soon after birth. In this study, researchers evaluated the association between neonatal hospital length of stay and supplemental oxygen duration with lung function in pediatric PCD. They used data from a Genetic Disorders of Mucociliary Clearance Consortium (GDMCC) multicenter study consisting of 123 pediatric patients with PCD followed over 5 years. Study results showed that neonatal hospital length of stay was associated with worse lung function, independent of age and ultrastructural defects. However, supplemental oxygen duration was not associated with lung function. These findings highlight the need for future research into the mechanisms and management of neonatal respiratory distress in PCD patients to better understand the variability in lung health outcomes in this patient population.

Shapiro AJ, Stonebraker JR, Knowles MR, Zariwala MA. A Deep Intronic, Pathogenic Variant in DNAH11 Causes Primary Ciliary Dyskinesia. Am J Respir Cell Mol Biol. 2022 Oct;67(4):511-514. doi: 10.1165/rcmb.2022-0176LE.

Wee WB, Kaspy KR, Sawras MG, Knowles MR, Zariwala MA, Leigh MW, Dell SD, Shapiro AJ. Going beyond the chest X-ray: Investigating laterality defects in primary ciliary dyskinesia. Pediatr Pulmonol. 2022 May;57(5):1318-1324. doi: 10.1002/ppul.25853. Epub 2022 Feb 21. PMID: 35122416.

Primary ciliary dyskinesia (PCD) is an inherited condition in which mucociliary clearance is impaired in the upper and lower airways. Organ laterality defects are common in patients with PCD, ranging from situs inversus totalis (SIT, complete mirror image organ arrangement), to situs ambiguus (SA, any laterality defect other than SI). However, targeted investigations for these defects are not universally recommended in PCD consensus statements. Without investigations beyond chest radiography (CXR), clinically significant defects may go undetected, leading to increased morbidity. In this study, researchers reviewed CXR images and reports of add-on, targeted investigations (computed tomography scans, abdominal ultrasounds, upper GI contrast studies, and splenic scintigraphy) from medical records collected at two PCD clinics. They compared situs classifications from CXR alone versus CXR with add-on, targeted investigations. Results showed that situs classification differed significantly from CXR images alone versus CXR with add-on, targeted investigations. Some of these additional organ laterality defects resulted in significant patient morbidity and even mortality when splenic dysfunction was present. Authors conclude that in PCD patients, clinically significant SA defects may not be detected by CXR alone. These results suggest that the routine use of CXR with add-on, targeted investigations may be justified.

Costain G, Liu Z, Mennella V, Radicioni G, Goczi AN, Albulescu A, Walker S, Ngan B, Manson D, Vali R, Khan M, Palaniyar N, Hill DB, Hall DA, Marshall CR, Knowles M, Zariwala MA, Kesimer M, Dell SD. Hereditary Mucin Deficiency Caused by Biallelic Loss of Function of MUC5B. Am J Respir Crit Care Med. 2022 Apr 1;205(7):761-768. doi: 10.1164/rccm.202106-1456OC. PMID: 35023825.

Mucins (the major protein component of mucus) are fundamental to airway health. Upregulation of mucin 5B (MUC5B) is observed in common lung diseases, making it a potential therapeutic target. In mice, Muc5b is required for mucociliary clearance and for controlling inflammation after microbial exposure, although the consequences of its loss in humans are unclear. In this study, researchers aimed to identify and characterize a family with congenital absence of MUC5B. The team performed whole-genome sequencing in an adult proband, deep phenotyping, and genotyping with reverse phenotyping for 8 family members. Across accessible sample types, the team performed immunofluorescence staining and mass spectrometry for mucins. Results show that congenital absence of MUC5B defines a new category of genetic respiratory disease. In addition, the human phenotype is consistent with the Muc5b mouse model. Authors note that further study of individuals with decreased MUC5B production could provide unique insights into airway mucus biology.

Smith AJ, Bustamante-Marin XM, Yin W, Sears PR, Herring LE, Dicheva NN, López-Giráldez F, Mane S, Tarran R, Leigh MW, Knowles MR, Zariwala MA, Ostrowski LE. The role of SPAG1 in the assembly of axonemal dyneins in human airway epithelia. J Cell Sci. 2022 Mar 15;135(6):jcs259512. doi: 10.1242/jcs.259512. Epub 2022 Mar 31.

Zawawi F, Shapiro AJ, Dell S, Wolter NE, Marchica CL, Knowles MR, Zariwala MA, Leigh MW, Smith M, Gajardo P, Daniel SJ. Otolaryngology Manifestations of Primary Ciliary Dyskinesia: A Multicenter Study. Otolaryngol Head Neck Surg. 2022 Mar;166(3):540-547. doi: 10.1177/01945998211019320. Epub 2021 Jun 22.

Ostrowski LE, Yin W, Smith AJ, Sears PR, Bustamante-Marin XM, Dang H, Hildebrandt F, Daniels LA, Capps NA, Sullivan KM, Leigh MW, Zariwala MA, Knowles MR Expression of a Truncated Form of ODAD1 Associated with an Unusually Mild Primary Ciliary Dyskinesia Phenotype. Expression of a Truncated Form of ODAD1 Associated with an Unusually Mild Primary Ciliary Dyskinesia Phenotype. Int J Mol Sci. 2022 Feb 3;23(3):1753. doi: 10.3390/ijms23031753. PMID: 35163670; PMCID: PMC8835943.

Primary ciliary dyskinesia (PCD) is a rare lung disease caused by mutations that impair the movement of cilia, tiny hair-like structures on airway cells that beat rhythmically to move mucus out of the airways. Defects in cilia structure or function result in chronic upper and lower respiratory disease. Mutations in the ODAD1 gene result in a failure to assemble outer dynein arms (ODAs), the molecular motors that provide the force for ciliary beating. In the absence of ODAD1, cilia are mostly immotile cilia, and subjects suffer from a typical PCD phenotype. In this study, researchers identified a patient with an unusually mild phenotype and a mutation in ODAD1. To investigate the mechanisms behind this unusual phenotype, they performed molecular and functional studies of cultured nasal epithelial cells. Their findings indicate that the mutant protein retains partial function, allowing for the assembly of some ODAs and a significant level of ciliary activity that may result in the unusually mild phenotype. These findings also suggest that partial restoration of ciliary function by therapeutic agents could lead to significant improvement of PCD symptoms.

Barber AT, Davis SD, Boutros H, Zariwala M, Knowles MR, Leigh MW. Use caution interpreting nasal nitric oxide – overlap in primary ciliary dyskinesia and primary immunodeficiency. Pediatr Pulmonol. 2021 Sep 2. doi: 10.1002/ppul.25636. Online ahead of print.

This case report highlights the difficulty distinguishing primary ciliary dyskinesia (PCD) from primary immunodeficiency (PID) with particular emphasis on the potential overlap in nasal nitric oxide levels between the two disorders. An 11-year-old female with history of chronic wet cough, chronic nasal congestion, and recurrent lower respiratory tract infections was referred for evaluation of possible PCD. Her nasal nitric oxide level was low (9.8 nL/min) and remained low at follow-up one year later (17.5 nL/min). Ciliary ultrastructure on transmission electron microscopy (TEM) was normal and PCD genetic testing was unrevealing, but given her clinical history and low nasal nitric oxide, she was classified as “probable PCD.” Later, at the age of 21, she became acutely ill, was diagnosed with hemophagocytic lymphohistiocytosis, and died secondary to this. She was subsequently found to have a pathogenic variant in GATA2 resulting in GATA2 deficiency, a syndrome characterized by immunodeficiency and predisposition to myelodysplastic syndrome. This case illustrates how individuals with PID can also have persistent low nasal nitric oxide levels. In those with suspicion for PCD but without a definitive diagnosis (confirmed by either PCD genetic testing and/or abnormal ciliary ultrastructure on TEM), clinicians should consider genetic testing for PID.

Brennan SK, Ferkol TW, Davis SD. Emerging Genotype-Phenotype Relationships in Primary Ciliary Dyskinesia. Int J Mol Sci. 2021 Jul 31;22(15):8272. doi: 10.3390/ijms22158272.

Primary ciliary dyskinesia (PCD) is a rare inherited condition that affects cilia—tiny, hair-like structures—in the lungs, nose and ears of affected individuals, both impairing their ability to remove germs and pollutants and allowing mucus buildup and infections. Abnormal cilia can alter fluid flow in the fallopian tubes and ventricles within the brain, and defects in analogous structures, flagella, can result in abnormal sperm movement. Approximately 50% of people with PCD will present with a laterality defect, like situs inversus totalis, in which the arrangement of the internal organs is a mirror image of normal anatomy. Heterotaxy, in which many organs in the body can be formed abnormally, in the wrong position, or even missing, is also more common in this disease. In this review paper, authors provide an overview of PCD and describe its impacts on cilia structure and function as well as diagnostic approaches. They summarize the various types and presentations (phenotypes) of PCD along with causative genes (genotypes) and the relationships that have emerged over 20 years of research into the condition. Authors also state that the increasing availability of genetic panels for PCD are now refining their understanding of those genotype-phenotype relationships and revealing milder forms of the disease.

Shapiro AJ, Kaspy K, Daniels MLA, Stonebraker JR, Nguyen VH, Joyal L, Knowles MR, Zariwala MA. Autosomal dominant variants in FOXJ1 causing primary ciliary dyskinesia in two patients with obstructive hydrocephalus. Mol Genet Genomic Med. 2021 Jul;9(7):e1726. doi: 10.1002/mgg3.1726. Epub 2021 Jun 15.

Two patients with chronic oto-sino-pulmonary disease and hydrocephalus underwent candidate testing of FOXJ1, a gene that controls the production of motile cilia (miniature, whip-like organelles in the lungs, respiratory tract and middle ear, whose beating generates a directional fluid flow). Upon sequencing, heterozygous, pathogenic variants were discovered in two patients. Study authors concluded that FOXJ1 pathogenic variants cause primary ciliary dyskinesia (PCD) in a de novo, autosomal dominant inheritance pattern, and are associated with hydrocephalus. Physicians treating patients with hydrocephalus and chronic oto-sino-pulmonary disease should be aware of this PCD association and test for FOXJ1 variants.

Zhao Y, Pinskey J, Lin J, Yin W, Sears PR, Daniels LA, Zariwala MA, Knowles MR, Ostrowski LE, Nicastro D. Structural insights into the cause of human RSPH4A primary ciliary dyskinesia. Mol Biol Cell. 2021 Jun 1;32(12):1202-1209. doi: 10.1091/mbc.E20-12-0806. Epub 2021 Apr 14.

Brennan SK, Molter D, Menezes M, Dunsky K, Leonard D, Lieu J, Hirose K, Hazan G, Horani A, Ferkol T, Brody SL. Implementation of a screening tool for primary ciliary dyskinesia (PCD) in a pediatric otolaryngology clinic. Int J Pediatr Otorhinolaryngol. 2021 Mar;142:110586. doi: 10.1016/j.ijporl.2020.110586. Epub 2020 Dec 31.

Horani A, Ferkol TW. Understanding Primary Ciliary Dyskinesia and Other Ciliopathies. J Pediatr. 2021 Mar;230:15-22.e1. doi: 10.1016/j.jpeds.2020.11.040. Epub 2020 Nov 23.

Coverstone AM, Ferkol TW. Early Diagnosis and Intervention in Cystic Fibrosis: Imagining the Unimaginable. Front Pediatr. 2021 Jan 11;8:608821. doi: 10.3389/fped.2020.608821. eCollection 2020.

Pappa AK, Sullivan KM, Lopez EM, Adams KN, Zanation AM, Ebert CS Jr, Thorp BD, Senior BA, Leigh MW, Knowles MR, Kimple AJ. Sinus Development and Pneumatization in a Primary Ciliary Dyskinesia Cohort. Am J Rhinol Allergy. 2021 Jan;35(1):72-76. doi: 10.1177/1945892420933175. Epub 2020 Jun 19.

Wallmeier J, Nielsen KG, Kuehni CE, Lucas JS, Leigh MW, Zariwala MA, Omran H. Motile ciliopathies. Nat Rev Dis Primers. 2020 Sep 17;6(1):77. doi: 10.1038/s41572-020-0209-6.

Crowley S, Azevedo I, Boon M, Bush A, Eber E, Haarman E, Karadag B, Kötz K, Leigh M, Moreno-Galdó A, Mussaffi H, Nielsen KG, Omran H, Papon JF, Pohunek P, Priftis K, Rindlisbacher B, Santamaria F, Valiulis A, Witt M, Yiallouros P, Zivkovic Z, Kuehni CE, Lucas JS. Access to medicines for rare diseases: beating the drum for primary ciliary dyskinesia. ERJ Open Res. 2020 Sep 14;6(3):00377-2020. doi: 10.1183/23120541.00377-2020. eCollection 2020 Jul.

Kinghorn B, McNamara S, Genatossio A, Sullivan E, Siegel M, Bauer I, Clem C, Johnson RC, Davis M, Griffiths A, Wheeler W, Johnson K, Davis SD, Leigh MW, Rosenfeld M, Pittman J. Comparison of Multiple Breath Washout and Spirometry in Children with Primary Ciliary Dyskinesia and Cystic Fibrosis and Healthy Controls. Ann Am Thorac Soc. 2020 Sep;17(9):1085-1093. doi: 10.1513/AnnalsATS.201905-375OC.

Bustamante-Marin XM, Horani A, Stoyanova M, Charng WL, Bottier M, Sears PR, Yin WN, Daniels LA, Bowen H, Conrad DF, Knowles MR, Ostrowski LE, Zariwala MA, Dutcher SK. Mutation of CFAP57, a protein required for the asymmetric targeting of a subset of inner dynein arms in Chlamydomonas, causes primary ciliary dyskinesia. PLoS Genet. 2020 Aug 7;16(8):e1008691. doi: 10.1371/journal.pgen.1008691. eCollection 2020 Aug.

Shapiro AJ, Davis SD, Leigh MW, Knowles MR, Lavergne V, Ferkol T. Limitations of Nasal Nitric Oxide Testing in Primary Ciliary Dyskinesia. Am J Respir Crit Care Med. 2020 Aug 1;202(3):476-477. doi: 10.1164/rccm.202003-0835LE.

Gaston B, Laguna TA, Noah TL, Hagood J, Voynow J, Ferkol T, Hershenson M, Boyne K, Delecaris A, Ross K, Gozal D, Celedón JC, Abman SH, Moore P, Davis S, Cornfield DN, Murphy T. A proposal for the addressing the needs of the pediatric pulmonary work force. Pediatr Pulmonol. 2020 Aug;55(8):1859-1867. doi: 10.1002/ppul.24856. Epub 2020 Jun 12.

Dutcher SK, Brody SL. HY-DIN' in the Cilia: Discovery of Central Pair-related Mutations in Primary Ciliary Dyskinesia. Am J Respir Cell Mol Biol. 2020 Mar;62(3):281-282. doi: 10.1165/rcmb.2019-0316ED.

Fowler C, Wu UI, Shaffer R, Smith C, Barnhart L, Bryant C, Olivier K, Holland SM. The effects of sildenafil on ciliary beat frequency in patients with pulmonary non-tuberculous mycobacteria disease: phase I/II trial. BMJ Open Respir Res. 2020 Mar;7(1):e000574. doi: 10.1136/bmjresp-2020-000574.

Chivukula RR, Montoro DT, Leung HM, Yang J, Shamseldin HE, Taylor MS, Dougherty GW, Zariwala MA, Carson J, Daniels MLA, Sears PR, Black KE, Hariri LP, Almogarri I, Frenkel EM, Vinarsky V, Omran H, Knowles MR, Tearney GJ, Alkuraya FS, Sabatini DM. A human ciliopathy reveals essential functions for NEK10 in airway mucociliary clearance. Nat Med. 2020 Feb;26(2):244-251. doi: 10.1038/s41591-019-0730-x. Epub 2020 Jan 20.

Chivukula RR, Montoro DT, Leung HM, Yang J, Shamseldin HE, Taylor MS, Dougherty GW, Zariwala MA, Carson J, Daniels MLA, Sears PR, Black KE, Hariri LP, Almogarri I, Frenkel EM, Vinarsky V, Omran H, Knowles MR, Tearney GJ, Alkuraya FS, Sabatini DM. Author Correction: A human ciliopathy reveals essential functions for NEK10 in airway mucociliary clearance. Nat Med. 2020 Feb;26(2):300. doi: 10.1038/s41591-020-0773-z.

Shapiro AJ, Dell SD, Gaston B, O'Connor M, Marozkina N, Manion M, Hazucha MJ, Leigh MW. Nasal Nitric Oxide Measurement in Primary Ciliary Dyskinesia. A Technical Paper on Standardized Testing Protocols. Ann Am Thorac Soc. 2020 Feb;17(2):e1-e12. doi: 10.1513/AnnalsATS.201904-347OT.

Lucas JS, Davis SD, Omran H, Shoemark A. Primary ciliary dyskinesia in the genomics age. Lancet Respir Med. 2020 Feb;8(2):202-216. doi: 10.1016/S2213-2600(19)30374-1. Epub 2019 Oct 14.

Sergeev V, Chou FY, Lam GY, Hamilton CM, Wilcox PG, Quon BS. The Extrapulmonary Effects of Cystic Fibrosis Transmembrane Conductance Regulator Modulators in Cystic Fibrosis. Ann Am Thorac Soc. 2020 Feb;17(2):147-154. doi: 10.1513/AnnalsATS.201909-671CME.

Shapiro AJ, Ferkol TW, Manion M, Leigh MW, Davis SD, Knowles MR. High-Speed Videomicroscopy Analysis Presents Limitations in Diagnosis of Primary Ciliary Dyskinesia. Am J Respir Crit Care Med. 2020 Jan 1;201(1):122-123. doi: 10.1164/rccm.201907-1366LE.

Vece TJ, Sagel SD, Zariwala MA, Sullivan KM, Burns KA, Dutcher SK, Yusupov R, Leigh MW, Knowles MR. Cytoplasmic "ciliary inclusions" in isolation are not sufficient for the diagnosis of primary ciliary dyskinesia. Pediatr Pulmonol. 2020 Jan;55(1):130-135. doi: 10.1002/ppul.24528. Epub 2019 Sep 23.

Bustamante-Marin XM, Shapiro A, Sears PR, Charng WL, Conrad DF, Leigh MW, Knowles MR, Ostrowski LE, Zariwala MA. Identification of genetic variants in CFAP221 as a cause of primary ciliary dyskinesia. J Hum Genet. 2020 Jan;65(2):175-180. doi: 10.1038/s10038-019-0686-1. Epub 2019 Oct 21.

Vali R, Ghandourah H, Charron M, Nezhad KV, Omarkhail Y, Khazaee A, Shammas A, Dell SD. Evaluation of the pulmonary radioaerosol mucociliary clearance scan as an adjunctive test for the diagnosis of primary ciliary dyskinesia in children. Pediatr Pulmonol. 2019 Dec;54(12):2021-2027. doi: 10.1002/ppul.24509. Epub 2019 Sep 12.

Behan L, Leigh MW, Dell SD, Quittner AL, Hogg C, Lucas JS. Validation of pediatric health-related quality of life instruments for primary ciliary dyskinesia (QOL-PCD). Pediatr Pulmonol. 2019 Dec;54(12):2011-2020. doi: 10.1002/ppul.24507. Epub 2019 Sep 1.

Wu UI, Olivier KN, Kuhns DB, Fink DL, Sampaio EP, Zelazny AM, Shallom SJ, Marciano BE, Lionakis MS, Holland SM. Patients with Idiopathic Pulmonary Nontuberculous Mycobacterial Disease Have Normal Th1/Th2 Cytokine Responses but Diminished Th17 Cytokine and Enhanced Granulocyte-Macrophage Colony-Stimulating Factor Production. Open Forum Infect Dis. 2019 Nov 28;6(12):ofz484. doi: 10.1093/ofid/ofz484. eCollection 2019 Dec.

Wallmeier J, Frank D, Shoemark A, Nöthe-Menchen T, Cindric S, Olbrich H, Loges NT, Aprea I, Dougherty GW, Pennekamp P, Kaiser T, Mitchison HM, Hogg C, Carr SB, Zariwala MA, Ferkol T, Leigh MW, Davis SD, Atkinson J, Dutcher SK, Knowles MR, Thiele H, Altmüller J, Krenz H, Wöste M, Brentrup A, Ahrens F, Vogelberg C, Morris-Rosendahl DJ, Omran H. De Novo Mutations in FOXJ1 Result in a Motile Ciliopathy with Hydrocephalus and Randomization of Left/Right Body Asymmetry. Am J Hum Genet. 2019 Nov 7;105(5):1030-1039. doi: 10.1016/j.ajhg.2019.09.022. Epub 2019 Oct 17.

Shapiro AJ, Leigh MW, Omran H, Lavergne V, Knowles MR. Errors in Methodology Affect Diagnostic Accuracy of High-Speed Videomicroscopy Analysis in Primary Ciliary Dyskinesia. Chest. 2019 Nov;156(5):1032-1033. doi: 10.1016/j.chest.2019.06.021.

Nöthe-Menchen T, Wallmeier J, Pennekamp P, Höben IM, Olbrich H, Loges NT, Raidt J, Dougherty GW, Hjeij R, Dworniczak B, Omran H. Randomization of Left-right Asymmetry and Congenital Heart Defects: The Role of DNAH5 in Humans and Mice. Circ Genom Precis Med. 2019 Oct 22:10.1161/CIRCGEN.119.002686. doi: 10.1161/CIRCGEN.119.002686. Online ahead of print.

Horani A, Brody SL. Frequenting Sequencing: How Genetics Teaches Us Cilia Biology. Am J Respir Cell Mol Biol. 2019 Oct;61(4):403-404. doi: 10.1165/rcmb.2019-0103ED.

Takeda AJ, Maher TJ, Zhang Y, Lanahan SM, Bucklin ML, Compton SR, Tyler PM, Comrie WA, Matsuda M, Olivier KN, Pittaluga S, McElwee JJ, Long Priel DA, Kuhns DB, Williams RL, Mustillo PJ, Wymann MP, Koneti Rao V, Lucas CL. Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology. Nat Commun. 2019 Sep 25;10(1):4364. doi: 10.1038/s41467-019-12311-5.

Hannah WB, DeBrosse S, Kinghorn B, Strausbaugh S, Aitken ML, Rosenfeld M, Wolf WE, Knowles MR, Zariwala MA. The expanding phenotype of OFD1-related disorders: Hemizygous loss-of-function variants in three patients with primary ciliary dyskinesia. Mol Genet Genomic Med. 2019 Sep;7(9):e911. doi: 10.1002/mgg3.911. Epub 2019 Aug 1.

Morimoto K, Hijikata M, Zariwala MA, Nykamp K, Inaba A, Guo TC, Yamada H, Truty R, Sasaki Y, Ohta K, Kudoh S, Leigh MW, Knowles MR, Keicho N. Recurring large deletion in DRC1 (CCDC164) identified as causing primary ciliary dyskinesia in two Asian patients. Mol Genet Genomic Med. 2019 Aug;7(8):e838. doi: 10.1002/mgg3.838. Epub 2019 Jul 4.

Ferré EMN, Break TJ, Burbelo PD, Allgäuer M, Kleiner DE, Jin D, Xu Z, Folio LR, Mollura DJ, Swamydas M, Gu W, Hunsberger S, Lee CR, Bondici A, Hoffman KW, Lim JK, Dobbs K, Niemela JE, Fleisher TA, Hsu AP, Snow LN, Darnell DN, Ojaimi S, Cooper MA, Bozzola M, Kleiner GI, Martinez JC, Deterding RR, Kuhns DB, Heller T, Winer KK, Rajan A, Holland SM, Notarangelo LD, Fennelly KP, Olivier KN, Lionakis MS. Lymphocyte-driven regional immunopathology in pneumonitis caused by impaired central immune tolerance. Sci Transl Med. 2019 Jun 5;11(495):eaav5597. doi: 10.1126/scitranslmed.aav5597.

Liou TG, Adler FR, Argel N, Asfour F, Brown PS, Chatfield BA, Daines CL, Durham D, Francis JA, Glover B, Heynekamp T, Hoidal JR, Jensen JL, Keogh R, Kopecky CM, Lechtzin N, Li Y, Lysinger J, Molina O, Nakamura C, Packer KA, Poch KR, Quittner AL, Radford P, Redway AJ, Sagel SD, Sprandel S, Taylor-Cousar JL, Vroom JB, Yoshikawa R, Clancy JP, Elborn JS, Olivier KN, Cox DR. Prospective multicenter randomized patient recruitment and sample collection to enable future measurements of sputum biomarkers of inflammation in an observational study of cystic fibrosis. BMC Med Res Methodol. 2019 Apr 26;19(1):88. doi: 10.1186/s12874-019-0705-0.

Bustamante-Marin XM, Yin WN, Sears PR, Werner ME, Brotslaw EJ, Mitchell BJ, Jania CM, Zeman KL, Rogers TD, Herring LE, Refabért L, Thomas L, Amselem S, Escudier E, Legendre M, Grubb BR, Knowles MR, Zariwala MA, Ostrowski LE. Lack of GAS2L2 Causes PCD by Impairing Cilia Orientation and Mucociliary Clearance. Am J Hum Genet. 2019 Feb 7;104(2):229-245. doi: 10.1016/j.ajhg.2018.12.009. Epub 2019 Jan 18.

Zysman-Colman ZN, Kaspy KR, Alizadehfar R, NyKamp KR, Zariwala MA, Knowles MR, Vinh DC, Shapiro AJ. Nasal Nitric Oxide in Primary Immunodeficiency and Primary Ciliary Dyskinesia: Helping to Distinguish Between Clinically Similar Diseases. J Clin Immunol. 2019 Feb;39(2):216-224. doi: 10.1007/s10875-019-00613-8. Epub 2019 Mar 26.

O'Connor MG, Griffiths A, Iyer NP, Shapiro AJ, Wilson KC, Thomson CC. Summary for Clinicians: Diagnosis of Primary Ciliary Dyskinesia. Ann Am Thorac Soc. 2019 Feb;16(2):171-174. doi: 10.1513/AnnalsATS.201810-693CME.

Davis SD, Rosenfeld M, Lee HS, Ferkol TW, Sagel SD, Dell SD, Milla C, Pittman JE, Shapiro AJ, Sullivan KM, Nykamp KR, Krischer JP, Zariwala MA, Knowles MR, Leigh MW. Primary Ciliary Dyskinesia: Longitudinal Study of Lung Disease by Ultrastructure Defect and Genotype. Am J Respir Crit Care Med. 2019 Jan 15;199(2):190-198. doi: 10.1164/rccm.201803-0548OC.

Leigh MW, Horani A, Kinghorn B, O'Connor MG, Zariwala MA, Knowles MR. Primary Ciliary Dyskinesia (PCD): A genetic disorder of motile cilia. Transl Sci Rare Dis. 2019;4(1-2):51-75. doi: 10.3233/TRD-190036. Epub 2019 Jul 4.

Sanders CD, Leigh MW, Chao KC, Weck KE, King I, Wolf WE, Campbell DJ, Knowles MR, Zariwala MA, Shapiro AJ. The prevalence of the defining features of primary ciliary dyskinesia within a cri du chat syndrome cohort. Pediatr Pulmonol. 2018 Nov;53(11):1565-1573. doi: 10.1002/ppul.24159. Epub 2018 Sep 20.

Ghandourah H, Dell SD. Severe disease due to CCDC40 gene variants and the perils of late diagnosis in primary ciliary dyskinesia. BMJ Case Rep. 2018 Sep 12;2018:bcr2018224964. doi: 10.1136/bcr-2018-224964.

Horani A, Ferkol TW. Advances in the Genetics of Primary Ciliary Dyskinesia: Clinical Implications. Chest. 2018 Sep;154(3):645-652. doi: 10.1016/j.chest.2018.05.007. Epub 2018 May 22.

Shapiro AJ, Davis SD, Polineni D, Manion M, Rosenfeld M, Dell SD, Chilvers MA, Ferkol TW, Zariwala MA, Sagel SD, Josephson M, Morgan L, Yilmaz O, Olivier KN, Milla C, Pittman JE, Daniels MLA, Jones MH, Janahi IA, Ware SM, Daniel SJ, Cooper ML, Nogee LM, Anton B, Eastvold T, Ehrne L, Guadagno E, Knowles MR, Leigh MW, Lavergne V; American Thoracic Society Assembly on Pediatrics. Diagnosis of Primary Ciliary Dyskinesia. An Official American Thoracic Society Clinical Practice Guideline. Am J Respir Crit Care Med. 2018 Jun 15;197(12):e24-e39. doi: 10.1164/rccm.201805-0819ST.

Metersky ML, Aksamit TR, Barker A, Choate R, Daley CL, Daniels LA, DiMango A, Eden E, Griffith D, Johnson M, Knowles M, O'Donnell AE, Olivier K, Salathe M, Thomashow B, Tino G, Turino G, Winthrop KL, Mannino D. The Prevalence and Significance of Staphylococcus aureus in Patients with Non-Cystic Fibrosis Bronchiectasis. Ann Am Thorac Soc. 2018 Mar;15(3):365-370. doi: 10.1513/AnnalsATS.201706-426OC.

Horani A, Ustione A, Huang T, Firth AL, Pan J, Gunsten SP, Haspel JA, Piston DW, Brody SL. Establishment of the early cilia preassembly protein complex during motile ciliogenesis. Proc Natl Acad Sci U S A. 2018 Feb 6;115(6):E1221-E1228. doi: 10.1073/pnas.1715915115. Epub 2018 Jan 22.

Rosenfeld M, Ostrowski LE, Zariwala MA. Primary ciliary dyskinesia: keep it on your radar. Thorax. 2018 Feb;73(2):101-102. doi: 10.1136/thoraxjnl-2017-210776. Epub 2017 Nov 13.

Goutaki M, Halbeisen FS, Spycher BD, Maurer E, Belle F, Amirav I, Behan L, Boon M, Carr S, Casaulta C, Clement A, Crowley S, Dell S, Ferkol T, Haarman EG, Karadag B, Knowles M, Koerner-Rettberg C, Leigh MW, Loebinger MR, Mazurek H, Morgan L, Nielsen KG, Phillipsen M, Sagel SD, Santamaria F, Schwerk N, Yiallouros P, Lucas JS, Kuehni CE; PCD Israeli Consortium; Swiss PCD Group; French Reference Centre for Rare Lung Diseases. Growth and nutritional status, and their association with lung function: a study from the international Primary Ciliary Dyskinesia Cohort. Eur Respir J. 2017 Dec 21;50(6):1701659. doi: 10.1183/13993003.01659-2017. Print 2017 Dec.

Deschamp AR, Schornick L, Clem C, Hazucha M, Shapiro AJ, Davis SD. A comparison of nasal nitric oxide measurement modes. Pediatr Pulmonol. 2017 Nov;52(11):1381-1382. doi: 10.1002/ppul.23780. Epub 2017 Aug 16.

Shapiro AJ, Leigh MW. Value of transmission electron microscopy for primary ciliary dyskinesia diagnosis in the era of molecular medicine: Genetic defects with normal and non-diagnostic ciliary ultrastructure. Ultrastruct Pathol. 2017 Nov-Dec;41(6):373-385. doi: 10.1080/01913123.2017.1362088. Epub 2017 Sep 15.

Damseh N, Quercia N, Rumman N, Dell SD, Kim RH. Primary ciliary dyskinesia: mechanisms and management. Appl Clin Genet. 2017 Sep 19;10:67-74. doi: 10.2147/TACG.S127129. eCollection 2017.

Behan L, Leigh MW, Dell SD, Dunn Galvin A, Quittner AL, Lucas JS. Validation of a health-related quality of life instrument for primary ciliary dyskinesia (QOL-PCD). Thorax. 2017 Sep;72(9):832-839. doi: 10.1136/thoraxjnl-2016-209356. Epub 2017 Feb 28.

Kristof AS, Petrof BJ, Hamid Q, Kolb M, Landry JS, MacKenzie A, McCormack FX, Murawski IJ, Moss J, Rauch F, Rosas IO, Shapiro AJ, Smith BM, Thomas DY, Trapnell BC, Young LR, Zariwala MA; ATS Assembly on Respiratory Cell and Molecular Biology. An Official American Thoracic Society Workshop Report: Translational Research in Rare Respiratory Diseases. Ann Am Thorac Soc. 2017 Aug;14(8):1239-1247. doi: 10.1513/AnnalsATS.201705-406WS.

Shapiro AJ, Josephson M, Rosenfeld M, Yilmaz O, Davis SD, Polineni D, Guadagno E, Leigh MW, Lavergne V. Accuracy of Nasal Nitric Oxide Measurement as a Diagnostic Test for Primary Ciliary Dyskinesia. A Systematic Review and Meta-analysis. Ann Am Thorac Soc. 2017 Jul;14(7):1184-1196. doi: 10.1513/AnnalsATS.201701-062SR.

Blackburn K, Bustamante-Marin X, Yin W, Goshe MB, Ostrowski LE. Quantitative Proteomic Analysis of Human Airway Cilia Identifies Previously Uncharacterized Proteins of High Abundance. J Proteome Res. 2017 Apr 7;16(4):1579-1592. doi: 10.1021/acs.jproteome.6b00972. Epub 2017 Mar 27.

Bustamante-Marin XM, Ostrowski LE. Cilia and Mucociliary Clearance. Cold Spring Harb Perspect Biol. 2017 Apr 3;9(4):a028241. doi: 10.1101/cshperspect.a028241.

Boerwinkle C, Marshall JD, Bryant J, Gahl WA, Olivier KN, Gunay-Aygun M. Respiratory manifestations in 38 patients with Alström syndrome. Pediatr Pulmonol. 2017 Apr;52(4):487-493. doi: 10.1002/ppul.23607. Epub 2016 Dec 28.

Lucas JS, Barbato A, Collins SA, Goutaki M, Behan L, Caudri D, Dell S, Eber E, Escudier E, Hirst RA, Hogg C, Jorissen M, Latzin P, Legendre M, Leigh MW, Midulla F, Nielsen KG, Omran H, Papon JF, Pohunek P, Redfern B, Rigau D, Rindlisbacher B, Santamaria F, Shoemark A, Snijders D, Tonia T, Titieni A, Walker WT, Werner C, Bush A, Kuehni CE. European Respiratory Society guidelines for the diagnosis of primary ciliary dyskinesia. Eur Respir J. 2017 Jan 4;49(1):1601090. doi: 10.1183/13993003.01090-2016. Print 2017 Jan.

Goutaki M, Meier AB, Halbeisen FS, Lucas JS, Dell SD, Maurer E, Casaulta C, Jurca M, Spycher BD, Kuehni CE. Clinical manifestations in primary ciliary dyskinesia: systematic review and meta-analysis. Eur Respir J. 2016 Oct;48(4):1081-1095. doi: 10.1183/13993003.00736-2016. Epub 2016 Aug 4.

Daniels ML, Birchard KR, Lowe JR, Patrone MV, Noone PG, Knowles MR. Enlarged Dural Sac in Idiopathic Bronchiectasis Implicates Heritable Connective Tissue Gene Variants. Ann Am Thorac Soc. 2016 Oct;13(10):1712-1720. doi: 10.1513/AnnalsATS.201603-161OC.

Dell SD, Leigh MW, Lucas JS, Ferkol TW, Knowles MR, Alpern A, Behan L, Morris AM, Hogg C, DunnGalvin A, Quittner AL. Primary Ciliary Dyskinesia: First Health-related Quality-of-Life Measures for Pediatric Patients. Ann Am Thorac Soc. 2016 Oct;13(10):1726-1735. doi: 10.1513/AnnalsATS.201603-198OC.

Knowles MR, Zariwala M, Leigh M. Primary Ciliary Dyskinesia. Clin Chest Med. 2016 Sep;37(3):449-61. doi: 10.1016/j.ccm.2016.04.008. Epub 2016 Jun 30.

Leigh MW, Ferkol TW, Davis SD, Lee HS, Rosenfeld M, Dell SD, Sagel SD, Milla C, Olivier KN, Sullivan KM, Zariwala MA, Pittman JE, Shapiro AJ, Carson JL, Krischer J, Hazucha MJ, Knowles MR. Clinical Features and Associated Likelihood of Primary Ciliary Dyskinesia in Children and Adolescents. Ann Am Thorac Soc. 2016 Aug;13(8):1305-13. doi: 10.1513/AnnalsATS.201511-748OC.

Milla CE. The evolving spectrum of ciliopathies and respiratory disease. Curr Opin Pediatr. 2016 Jun;28(3):339-47. doi: 10.1097/MOP.0000000000000358.

Merkel PA, Manion M, Gopal-Srivastava R, Groft S, Jinnah HA, Robertson D, Krischer JP; Rare Diseases Clinical Research Network. The partnership of patient advocacy groups and clinical investigators in the rare diseases clinical research network. Orphanet J Rare Dis. 2016 May 18;11(1):66. doi: 10.1186/s13023-016-0445-8.

Horani A, Ferkol TW, Dutcher SK, Brody SL. Genetics and biology of primary ciliary dyskinesia. Paediatr Respir Rev. 2016 Mar;18:18-24. doi: 10.1016/j.prrv.2015.09.001. Epub 2015 Sep 11.

Shapiro AJ, Zariwala MA, Ferkol T, Davis SD, Sagel SD, Dell SD, Rosenfeld M, Olivier KN, Milla C, Daniel SJ, Kimple AJ, Manion M, Knowles MR, Leigh MW; Genetic Disorders of Mucociliary Clearance Consortium. Diagnosis, monitoring, and treatment of primary ciliary dyskinesia: PCD foundation consensus recommendations based on state of the art review. Pediatr Pulmonol. 2016 Feb;51(2):115-32. doi: 10.1002/ppul.23304. Epub 2015 Sep 29.

Horani A, Ferkol TW. Primary ciliary dyskinesia and associated sensory ciliopathies. Expert Rev Respir Med. 2016;10(5):569-76. doi: 10.1586/17476348.2016.1165612. Epub 2016 Mar 28.

Szymanski EP, Leung JM, Fowler CJ, Haney C, Hsu AP, Chen F, Duggal P, Oler AJ, McCormack R, Podack E, Drummond RA, Lionakis MS, Browne SK, Prevots DR, Knowles M, Cutting G, Liu X, Devine SE, Fraser CM, Tettelin H, Olivier KN, Holland SM. Pulmonary Nontuberculous Mycobacterial Infection. A Multisystem, Multigenic Disease. Am J Respir Crit Care Med. 2015 Sep 1;192(5):618-28. doi: 10.1164/rccm.201502-0387OC.

Lucas JS, Behan L, Dunn Galvin A, Alpern A, Morris AM, Carroll MP, Knowles MR, Leigh MW, Quittner AL. A quality-of-life measure for adults with primary ciliary dyskinesia: QOL-PCD. Eur Respir J. 2015 Aug;46(2):375-83. doi: 10.1183/09031936.00216214. Epub 2015 May 14.

Pittman JE, Ferkol TW. The Evolution of Cystic Fibrosis Care. Chest. 2015 Aug;148(2):533-542. doi: 10.1378/chest.14-1997.

Marshall CR, Scherer SW, Zariwala MA, Lau L, Paton TA, Stockley T, Jobling RK, Ray PN, Knowles MR; FORGE Canada Consortium, Hall DA, Dell SD, Kim RH. Whole-Exome Sequencing and Targeted Copy Number Analysis in Primary Ciliary Dyskinesia. G3 (Bethesda). 2015 Jul 2;5(8):1775-81. doi: 10.1534/g3.115.019851.

Lobo J, Zariwala MA, Noone PG. Primary ciliary dyskinesia. Semin Respir Crit Care Med. 2015 Apr;36(2):169-79. doi: 10.1055/s-0035-1546748. Epub 2015 Mar 31.

Shapiro AJ, Tolleson-Rinehart S, Zariwala MA, Knowles MR, Leigh MW. The prevalence of clinical features associated with primary ciliary dyskinesia in a heterotaxy population: results of a web-based survey. Cardiol Young. 2015 Apr;25(4):752-9. doi: 10.1017/S1047951114000912. Epub 2014 Jun 6.

Daniels ML, Noone PG. Genetics, diagnosis, and future treatment strategies for primary ciliary dyskinesia. Expert Opin Orphan Drugs. 2015 Mar 1;3(1):31-44. doi: 10.1517/21678707.2015.989212. Epub 2014 Nov 29.

Fedick AM, Jalas C, Treff NR, Knowles MR, Zariwala MA. Carrier frequencies of eleven mutations in eight genes associated with primary ciliary dyskinesia in the Ashkenazi Jewish population. Mol Genet Genomic Med. 2015 Mar;3(2):137-42. doi: 10.1002/mgg3.124. Epub 2014 Dec 6.

Davis SD, Ferkol TW, Rosenfeld M, Lee HS, Dell SD, Sagel SD, Milla C, Zariwala MA, Pittman JE, Shapiro AJ, Carson JL, Krischer JP, Hazucha MJ, Cooper ML, Knowles MR, Leigh MW. Clinical features of childhood primary ciliary dyskinesia by genotype and ultrastructural phenotype. Am J Respir Crit Care Med. 2015 Feb 1;191(3):316-24. doi: 10.1164/rccm.201409-1672OC.

Daniels ML, Lowe JR, Roy P, Patrone MV, Conyers JM, Fine JP, Knowles MR, Birchard KR. Standardization and validation of a novel and simple method to assess lumbar dural sac size. Clin Radiol. 2015 Feb;70(2):146-52. doi: 10.1016/j.crad.2014.10.009. Epub 2014 Nov 27.

Lin J, Yin W, Smith MC, Song K, Leigh MW, Zariwala MA, Knowles MR, Ostrowski LE, Nicastro D. Cryo-electron tomography reveals ciliary defects underlying human RSPH1 primary ciliary dyskinesia. Nat Commun. 2014 Dec 4;5:5727. doi: 10.1038/ncomms6727.

Mullowney T, Manson D, Kim R, Stephens D, Shah V, Dell S. Primary ciliary dyskinesia and neonatal respiratory distress. Pediatrics. 2014 Dec;134(6):1160-6. doi: 10.1542/peds.2014-0808.

Shapiro AJ, Davis SD, Ferkol T, Dell SD, Rosenfeld M, Olivier KN, Sagel SD, Milla C, Zariwala MA, Wolf W, Carson JL, Hazucha MJ, Burns K, Robinson B, Knowles MR, Leigh MW; Genetic Disorders of Mucociliary Clearance Consortium. Laterality defects other than situs inversus totalis in primary ciliary dyskinesia: insights into situs ambiguus and heterotaxy. Chest. 2014 Nov;146(5):1176-1186. doi: 10.1378/chest.13-1704.

Teves ME, Sears PR, Li W, Zhang Z, Tang W, van Reesema L, Costanzo RM, Davis CW, Knowles MR, Strauss JF 3rd, Zhang Z. Sperm-associated antigen 6 (SPAG6) deficiency and defects in ciliogenesis and cilia function: polarity, density, and beat. PLoS One. 2014 Oct 21;9(10):e107271. doi: 10.1371/journal.pone.0107271. eCollection 2014.

Shapiro AJ, Weck KE, Chao KC, Rosenfeld M, Nygren AO, Knowles MR, Leigh MW, Zariwala MA. Cri du chat syndrome and primary ciliary dyskinesia: a common genetic cause on chromosome 5p. J Pediatr. 2014 Oct;165(4):858-61. doi: 10.1016/j.jpeds.2014.06.048. Epub 2014 Jul 25.

Prevots DR, Adjemian J, Fernandez AG, Knowles MR, Olivier KN. Environmental risks for nontuberculous mycobacteria. Individual exposures and climatic factors in the cystic fibrosis population. Ann Am Thorac Soc. 2014 Sep;11(7):1032-8. doi: 10.1513/AnnalsATS.201404-184OC.

Funkhouser WK 3rd, Niethammer M, Carson JL, Burns KA, Knowles MR, Leigh MW, Zariwala MA, Funkhouser WK Jr. A new tool improves diagnostic test performance for transmission em evaluation of axonemal dynein arms. Ultrastruct Pathol. 2014 Aug;38(4):248-55. doi: 10.3109/01913123.2013.815081. Epub 2013 Aug 19.

Knowles MR, Ostrowski LE, Leigh MW, Sears PR, Davis SD, Wolf WE, Hazucha MJ, Carson JL, Olivier KN, Sagel SD, Rosenfeld M, Ferkol TW, Dell SD, Milla CE, Randell SH, Yin W, Sannuti A, Metjian HM, Noone PG, Noone PJ, Olson CA, Patrone MV, Dang H, Lee HS, Hurd TW, Gee HY, Otto EA, Halbritter J, Kohl S, Kircher M, Krischer J, Bamshad MJ, Nickerson DA, Hildebrandt F, Shendure J, Zariwala MA. Mutations in RSPH1 cause primary ciliary dyskinesia with a unique clinical and ciliary phenotype. Am J Respir Crit Care Med. 2014 Mar 15;189(6):707-17. doi: 10.1164/rccm.201311-2047OC.

Kim RH, A Hall D, Cutz E, Knowles MR, Nelligan KA, Nykamp K, Zariwala MA, Dell SD. The role of molecular genetic analysis in the diagnosis of primary ciliary dyskinesia. Ann Am Thorac Soc. 2014 Mar;11(3):351-9. doi: 10.1513/AnnalsATS.201306-194OC.

Horani A, Brody SL, Ferkol TW. Picking up speed: advances in the genetics of primary ciliary dyskinesia. Pediatr Res. 2014 Jan;75(1-2):158-64. doi: 10.1038/pr.2013.200. Epub 2013 Nov 5.

Leigh MW, Hazucha MJ, Chawla KK, Baker BR, Shapiro AJ, Brown DE, Lavange LM, Horton BJ, Qaqish B, Carson JL, Davis SD, Dell SD, Ferkol TW, Atkinson JJ, Olivier KN, Sagel SD, Rosenfeld M, Milla C, Lee HS, Krischer J, Zariwala MA, Knowles MR. Standardizing nasal nitric oxide measurement as a test for primary ciliary dyskinesia. Ann Am Thorac Soc. 2013 Dec;10(6):574-81. doi: 10.1513/AnnalsATS.201305-110OC.

Knowles MR, Daniels LA, Davis SD, Zariwala MA, Leigh MW. Primary ciliary dyskinesia. Recent advances in diagnostics, genetics, and characterization of clinical disease. Am J Respir Crit Care Med. 2013 Oct 15;188(8):913-22. doi: 10.1164/rccm.201301-0059CI.

Knowles MR, Ostrowski LE, Loges NT, Hurd T, Leigh MW, Huang L, Wolf WE, Carson JL, Hazucha MJ, Yin W, Davis SD, Dell SD, Ferkol TW, Sagel SD, Olivier KN, Jahnke C, Olbrich H, Werner C, Raidt J, Wallmeier J, Pennekamp P, Dougherty GW, Hjeij R, Gee HY, Otto EA, Halbritter J, Chaki M, Diaz KA, Braun DA, Porath JD, Schueler M, Baktai G, Griese M, Turner EH, Lewis AP, Bamshad MJ, Nickerson DA, Hildebrandt F, Shendure J, Omran H, Zariwala MA. Mutations in SPAG1 cause primary ciliary dyskinesia associated with defective outer and inner dynein arms. Am J Hum Genet. 2013 Oct 3;93(4):711-20. doi: 10.1016/j.ajhg.2013.07.025. Epub 2013 Sep 19.

Daniels ML, Leigh MW, Davis SD, Armstrong MC, Carson JL, Hazucha M, Dell SD, Eriksson M, Collins FS, Knowles MR, Zariwala MA. Founder mutation in RSPH4A identified in patients of Hispanic descent with primary ciliary dyskinesia. Hum Mutat. 2013 Oct;34(10):1352-6. doi: 10.1002/humu.22371. Epub 2013 Aug 6.

Tarkar A, Loges NT, Slagle CE, Francis R, Dougherty GW, Tamayo JV, Shook B, Cantino M, Schwartz D, Jahnke C, Olbrich H, Werner C, Raidt J, Pennekamp P, Abouhamed M, Hjeij R, Köhler G, Griese M, Li Y, Lemke K, Klena N, Liu X, Gabriel G, Tobita K, Jaspers M, Morgan LC, Shapiro AJ, Letteboer SJ, Mans DA, Carson JL, Leigh MW, Wolf WE, Chen S, Lucas JS, Onoufriadis A, Plagnol V, Schmidts M, Boldt K; UK10K, Roepman R, Zariwala MA, Lo CW, Mitchison HM, Knowles MR, Burdine RD, Loturco JJ, Omran H. DYX1C1 is required for axonemal dynein assembly and ciliary motility. Nat Genet. 2013 Sep;45(9):995-1003. doi: 10.1038/ng.2707. Epub 2013 Jul 21.

Hjeij R, Lindstrand A, Francis R, Zariwala MA, Liu X, Li Y, Damerla R, Dougherty GW, Abouhamed M, Olbrich H, Loges NT, Pennekamp P, Davis EE, Carvalho CM, Pehlivan D, Werner C, Raidt J, Köhler G, Häffner K, Reyes-Mugica M, Lupski JR, Leigh MW, Rosenfeld M, Morgan LC, Knowles MR, Lo CW, Katsanis N, Omran H. ARMC4 mutations cause primary ciliary dyskinesia with randomization of left/right body asymmetry. Am J Hum Genet. 2013 Aug 8;93(2):357-67. doi: 10.1016/j.ajhg.2013.06.009. Epub 2013 Jul 11.

Zariwala MA, Gee HY, Kurkowiak M, Al-Mutairi DA, Leigh MW, Hurd TW, Hjeij R, Dell SD, Chaki M, Dougherty GW, Adan M, Spear PC, Esteve-Rudd J, Loges NT, Rosenfeld M, Diaz KA, Olbrich H, Wolf WE, Sheridan E, Batten TF, Halbritter J, Porath JD, Kohl S, Lovric S, Hwang DY, Pittman JE, Burns KA, Ferkol TW, Sagel SD, Olivier KN, Morgan LC, Werner C, Raidt J, Pennekamp P, Sun Z, Zhou W, Airik R, Natarajan S, Allen SJ, Amirav I, Wieczorek D, Landwehr K, Nielsen K, Schwerk N, Sertic J, Köhler G, Washburn J, Levy S, Fan S, Koerner-Rettberg C, Amselem S, Williams DS, Mitchell BJ, Drummond IA, Otto EA, Omran H, Knowles MR, Hildebrandt F. ZMYND10 is mutated in primary ciliary dyskinesia and interacts with LRRC6. Am J Hum Genet. 2013 Aug 8;93(2):336-45. doi: 10.1016/j.ajhg.2013.06.007. Epub 2013 Jul 25.

Ferkol TW, Puffenberger EG, Lie H, Helms C, Strauss KA, Bowcock A, Carson JL, Hazucha M, Morton DH, Patel AC, Leigh MW, Knowles MR, Zariwala MA. Primary ciliary dyskinesia-causing mutations in Amish and Mennonite communities. J Pediatr. 2013 Aug;163(2):383-7. doi: 10.1016/j.jpeds.2013.01.061. Epub 2013 Mar 7.

Fowler CJ, Olivier KN, Leung JM, Smith CC, Huth AG, Root H, Kuhns DB, Logun C, Zelazny A, Frein CA, Daub J, Haney C, Shelhamer JH, Bryant CE, Holland SM. Abnormal nasal nitric oxide production, ciliary beat frequency, and Toll-like receptor response in pulmonary nontuberculous mycobacterial disease epithelium. Am J Respir Crit Care Med. 2013 Jun 15;187(12):1374-81. doi: 10.1164/rccm.201212-2197OC.

Antony D, Becker-Heck A, Zariwala MA, Schmidts M, Onoufriadis A, Forouhan M, Wilson R, Taylor-Cox T, Dewar A, Jackson C, Goggin P, Loges NT, Olbrich H, Jaspers M, Jorissen M, Leigh MW, Wolf WE, Daniels ML, Noone PG, Ferkol TW, Sagel SD, Rosenfeld M, Rutman A, Dixit A, O'Callaghan C, Lucas JS, Hogg C, Scambler PJ, Emes RD; Uk10k, Chung EM, Shoemark A, Knowles MR, Omran H, Mitchison HM. Mutations in CCDC39 and CCDC40 are the major cause of primary ciliary dyskinesia with axonemal disorganization and absent inner dynein arms. Hum Mutat. 2013 Mar;34(3):462-72. doi: 10.1002/humu.22261. Epub 2013 Feb 11.

Sears PR, Thompson K, Knowles MR, Davis CW. Human airway ciliary dynamics. Am J Physiol Lung Cell Mol Physiol. 2013 Feb 1;304(3):L170-83. doi: 10.1152/ajplung.00105.2012. Epub 2012 Nov 9.

Knowles MR, Leigh MW, Ostrowski LE, Huang L, Carson JL, Hazucha MJ, Yin W, Berg JS, Davis SD, Dell SD, Ferkol TW, Rosenfeld M, Sagel SD, Milla CE, Olivier KN, Turner EH, Lewis AP, Bamshad MJ, Nickerson DA, Shendure J, Zariwala MA; Genetic Disorders of Mucociliary Clearance Consortium. Exome sequencing identifies mutations in CCDC114 as a cause of primary ciliary dyskinesia. Am J Hum Genet. 2013 Jan 10;92(1):99-106. doi: 10.1016/j.ajhg.2012.11.003. Epub 2012 Dec 20.

Horani A, Druley TE, Zariwala MA, Patel AC, Levinson BT, Van Arendonk LG, Thornton KC, Giacalone JC, Albee AJ, Wilson KS, Turner EH, Nickerson DA, Shendure J, Bayly PV, Leigh MW, Knowles MR, Brody SL, Dutcher SK, Ferkol TW. Whole-exome capture and sequencing identifies HEATR2 mutation as a cause of primary ciliary dyskinesia. Am J Hum Genet. 2012 Oct 5;91(4):685-93. doi: 10.1016/j.ajhg.2012.08.022.

Nakhleh N, Francis R, Giese RA, Tian X, Li Y, Zariwala MA, Yagi H, Khalifa O, Kureshi S, Chatterjee B, Sabol SL, Swisher M, Connelly PS, Daniels MP, Srinivasan A, Kuehl K, Kravitz N, Burns K, Sami I, Omran H, Barmada M, Olivier K, Chawla KK, Leigh M, Jonas R, Knowles M, Leatherbury L, Lo CW. High prevalence of respiratory ciliary dysfunction in congenital heart disease patients with heterotaxy. Circulation. 2012 May 8;125(18):2232-42. doi: 10.1161/CIRCULATIONAHA.111.079780. Epub 2012 Apr 12.

Knowles MR, Leigh MW, Zariwala MA. Cutting edge genetic studies in primary ciliary dyskinesia. Thorax. 2012 May;67(5):464; author reply 464. doi: 10.1136/thoraxjnl-2012-201609. Epub 2012 Feb 10.

Knowles MR, Leigh MW, Carson JL, Davis SD, Dell SD, Ferkol TW, Olivier KN, Sagel SD, Rosenfeld M, Burns KA, Minnix SL, Armstrong MC, Lori A, Hazucha MJ, Loges NT, Olbrich H, Becker-Heck A, Schmidts M, Werner C, Omran H, Zariwala MA; Genetic Disorders of Mucociliary Clearance Consortium. Mutations of DNAH11 in patients with primary ciliary dyskinesia with normal ciliary ultrastructure. Thorax. 2012 May;67(5):433-41. doi: 10.1136/thoraxjnl-2011-200301. Epub 2011 Dec 18.

Ferkol TW, Leigh MW. Ciliopathies: the central role of cilia in a spectrum of pediatric disorders. J Pediatr. 2012 Mar;160(3):366-71. doi: 10.1016/j.jpeds.2011.11.024. Epub 2011 Dec 16.

Leigh MW, O'Callaghan C, Knowles MR. The challenges of diagnosing primary ciliary dyskinesia. Proc Am Thorac Soc. 2011 Sep;8(5):434-7. doi: 10.1513/pats.201103-028SD.

Zariwala MA, Omran H, Ferkol TW. The emerging genetics of primary ciliary dyskinesia. Proc Am Thorac Soc. 2011 Sep;8(5):430-3. doi: 10.1513/pats.201103-023SD.

Sagel SD, Davis SD, Campisi P, Dell SD. Update of respiratory tract disease in children with primary ciliary dyskinesia. Proc Am Thorac Soc. 2011 Sep;8(5):438-43. doi: 10.1513/pats.201103-024SD.

Olin JT, Burns K, Carson JL, Metjian H, Atkinson JJ, Davis SD, Dell SD, Ferkol TW, Milla CE, Olivier KN, Rosenfeld M, Baker B, Leigh MW, Knowles MR, Sagel SD; Genetic Disorders of Mucociliary Clearance Consortium. Diagnostic yield of nasal scrape biopsies in primary ciliary dyskinesia: a multicenter experience. Pediatr Pulmonol. 2011 May;46(5):483-8. doi: 10.1002/ppul.21402. Epub 2011 Jan 31.

Berg JS, Evans JP, Leigh MW, Omran H, Bizon C, Mane K, Knowles MR, Weck KE, Zariwala MA. Next generation massively parallel sequencing of targeted exomes to identify genetic mutations in primary ciliary dyskinesia: implications for application to clinical testing. Genet Med. 2011 Mar;13(3):218-29. doi: 10.1097/GIM.0b013e318203cff2.

Lie H, Zariwala MA, Helms C, Bowcock AM, Carson JL, Brown DE 3rd, Hazucha MJ, Forsen J, Molter D, Knowles MR, Leigh MW, Ferkol TW. Primary ciliary dyskinesia in Amish communities. J Pediatr. 2010 Jun;156(6):1023-1025. doi: 10.1016/j.jpeds.2010.01.054. Epub 2010 Mar 29.

Loges NT, Olbrich H, Becker-Heck A, Häffner K, Heer A, Reinhard C, Schmidts M, Kispert A, Zariwala MA, Leigh MW, Knowles MR, Zentgraf H, Seithe H, Nürnberg G, Nürnberg P, Reinhardt R, Omran H. Deletions and point mutations of LRRC50 cause primary ciliary dyskinesia due to dynein arm defects. Am J Hum Genet. 2009 Dec;85(6):883-9. doi: 10.1016/j.ajhg.2009.10.018.

Leigh MW, Pittman JE, Carson JL, Ferkol TW, Dell SD, Davis SD, Knowles MR, Zariwala MA. Clinical and genetic aspects of primary ciliary dyskinesia/Kartagener syndrome. Genet Med. 2009 Jul;11(7):473-87. doi: 10.1097/GIM.0b013e3181a53562.

Leigh MW, Zariwala MA, Knowles MR. Primary ciliary dyskinesia: improving the diagnostic approach. Curr Opin Pediatr. 2009 Jun;21(3):320-5. doi: 10.1097/MOP.0b013e328329cddb.

Griggs RC, Batshaw M, Dunkle M, Gopal-Srivastava R, Kaye E, Krischer J, Nguyen T, Paulus K, Merkel PA; Rare Diseases Clinical Research Network. Clinical research for rare disease: opportunities, challenges, and solutions. Mol Genet Metab. 2009 Jan;96(1):20-6. doi: 10.1016/j.ymgme.2008.10.003. Epub 2008 Nov 13.

Brown DE, Pittman JE, Leigh MW, Fordham L, Davis SD. Early lung disease in young children with primary ciliary dyskinesia. Pediatr Pulmonol. 2008 May;43(5):514-6. doi: 10.1002/ppul.20792.

Zhang Z, Zariwala MA, Mahadevan MM, Caballero-Campo P, Shen X, Escudier E, Duriez B, Bridoux AM, Leigh M, Gerton GL, Kennedy M, Amselem S, Knowles MR, Strauss JF 3rd. A heterozygous mutation disrupting the SPAG16 gene results in biochemical instability of central apparatus components of the human sperm axoneme. Biol Reprod. 2007 Nov;77(5):864-71. doi: 10.1095/biolreprod.107.063206. Epub 2007 Aug 15.

Kennedy MP, Coakley RD, Donaldson SH, Aris RM, Hohneker K, Wedd JP, Knowles MR, Gilligan PH, Yankaskas JR. Burkholderia gladioli: five year experience in a cystic fibrosis and lung transplantation center. J Cyst Fibros. 2007 Jul;6(4):267-73. doi: 10.1016/j.jcf.2006.10.007. Epub 2006 Nov 29.

Kennedy MP, Omran H, Leigh MW, Dell S, Morgan L, Molina PL, Robinson BV, Minnix SL, Olbrich H, Severin T, Ahrens P, Lange L, Morillas HN, Noone PG, Zariwala MA, Knowles MR. Congenital heart disease and other heterotaxic defects in a large cohort of patients with primary ciliary dyskinesia. Circulation. 2007 Jun 5;115(22):2814-21. doi: 10.1161/CIRCULATIONAHA.106.649038. Epub 2007 May 21.

Kennedy MP, Noone PG, Leigh MW, Zariwala MA, Minnix SL, Knowles MR, Molina PL. High-resolution CT of patients with primary ciliary dyskinesia. AJR Am J Roentgenol. 2007 May;188(5):1232-8. doi: 10.2214/AJR.06.0965.

Kennedy MP, Noone PG, Carson J, Molina PL, Ghio A, Zariwala MA, Minnix SL, Knowles MR. Calcium stone lithoptysis in primary ciliary dyskinesia. Respir Med. 2007 Jan;101(1):76-83. doi: 10.1016/j.rmed.2006.04.007. Epub 2006 Jun 6.

Zariwala MA, Knowles MR, Omran H. Genetic defects in ciliary structure and function. Annu Rev Physiol. 2007;69:423-50. doi: 10.1146/annurev.physiol.69.040705.141301.

Lie H, Ferkol T. Primary ciliary dyskinesia: recent advances in pathogenesis, diagnosis and treatment. Drugs. 2007;67(13):1883-92. doi: 10.2165/00003495-200767130-00006.

Ferkol T, Leigh M. Primary ciliary dyskinesia and newborn respiratory distress. Semin Perinatol. 2006 Dec;30(6):335-40. doi: 10.1053/j.semperi.2005.11.001.

Zariwala MA, Leigh MW, Ceppa F, Kennedy MP, Noone PG, Carson JL, Hazucha MJ, Lori A, Horvath J, Olbrich H, Loges NT, Bridoux AM, Pennarun G, Duriez B, Escudier E, Mitchison HM, Chodhari R, Chung EM, Morgan LC, de Iongh RU, Rutland J, Pradal U, Omran H, Amselem S, Knowles MR. Mutations of DNAI1 in primary ciliary dyskinesia: evidence of founder effect in a common mutation. Am J Respir Crit Care Med. 2006 Oct 15;174(8):858-66. doi: 10.1164/rccm.200603-370OC. Epub 2006 Jul 20.

Sheridan MB, Fong P, Groman JD, Conrad C, Flume P, Diaz R, Harris C, Knowles M, Cutting GR. Mutations in the beta-subunit of the epithelial Na+ channel in patients with a cystic fibrosis-like syndrome. Hum Mol Genet. 2005 Nov 15;14(22):3493-8. doi: 10.1093/hmg/ddi374. Epub 2005 Oct 5.

Lentini L, Toutounchi H, Chapleau A, Le A, Fournier S, Emari F, Flamini R, Rossi A, Gentile A, Bertini E, Nicita F, Pohl D, Venkateswaran S, Keller S, Rossignol E, Renaud D, Assis Pereira D, Chen X, Vanderver A, Bernard G. Stress and Quality of Life of Parents of Children With POLR3-Related Leukodystrophy: A Cross-Sectional Pilot Study. J Child Neurol. 2025 Jan;40(1):26-38. doi: 10.1177/08830738241283171. Epub 2024 Oct 21.

Mutua S, Sevagamoorthy A, Woidill S, Orchard PJ, Gavazzi F, MacFarland SP, Russo P, Vanderver A, Adang LA. Characterization of gallbladder disease in metachromatic leukodystrophy across the lifespan. Mol Genet Metab. 2025 Jan;144(1):109003. doi: 10.1016/j.ymgme.2024.109003. Epub 2024 Dec 22. PMID: 39733668.

Metachromatic leukodystrophy (MLD) is an inherited lysosomal disorder caused by a missing or abnormal enzyme that cannot break down sulfatides (complex, fat-sugar molecules containing a sulfate group). While the neurological symptoms of MLD are well understood, less is known about how MLD affects other areas of the body. Learning more about how gallbladder complications in MLD affect neurological progression could help identify cases of active disease before neurological symptoms appear.

In this study, researchers characterized gallbladder disease in MLD across the lifespan. The team used natural history study data from 40 individuals with MLD as well as 87 published cases in medical literature to learn more about the disease course—including gallbladder abnormalities—and neurological function.

Results reveal a high prevalence of gallbladder complications in MLD. These complications were commonly found at first evaluation, even in pre- or early symptomatic disease. Authors note that since gallbladder disease can potentially progress to malignancy, regular gallbladder monitoring should be integrated with clinical care, as well as considered a potential predictive biomarker for disease onset.

Nagy A, Eichler F, Bley A, Bredow J, Fay A, Townsend EL, Leiro B, Shaywitz A, Laforet G, Crippen-Harmon D, Williams R. Urine N-Acetylaspartate Distinguishes Phenotypes in Canavan Disease. Hum Gene Ther. 2024 Jan;36(1-2):45-56. doi: 10.1089/hum.2024.168. Epub 2024 Dec 4. PMID: 39628365; PMCID: PMC11807896.

Canavan disease is a progressive, genetic type of leukodystrophy affecting the central nervous system, muscles, and eyes. This disorder is caused by mutations in ASPA—the gene that encodes the enzyme aspartoacylase (ASPA)—leading to accumulation of N-acetylaspartate (NAA), one of the most concentrated metabolites in the brain. While most patients with Canavan disease experience psychomotor deficits within the first 6 months of life and meet few motor milestones, some patients show milder symptoms and meet more milestones.

In this study, researchers explored the relationship between urine NAA levels and disease severity in Canavan disease. The team used data from a natural history study and literature search to compare urine NAA levels and associated genotypes in patients with mild or typical Canavan disease.

Results show that on average, patients with mild disease had lower urine NAA levels than patients with typical disease. Variants R71H and Y288C in the ASPA gene may have higher residual activity in the ASPA enzyme and were unique to patients with mild disease. Authors note that urine NAA levels can distinguish between mild and typical Canavan disease, suggesting the ability to reflect ASPA activity.

Kotes E, Gavazzi F, Woidill S, Sevagamoorthy A, Yang E, Smith V, Dubbs H, Pierce SR, Pucci K, Vithayathil J, Thakur N, Adang LA. Determination of Health Concepts in β-Propeller Protein-Associated Neurodegeneration. J Child Neurol. 2024 Oct 8:8830738241283932. doi: 10.1177/08830738241283932. Epub ahead of print. PMID: 39376195.

β-propeller protein–associated neurodegeneration (BPAN) is a progressive, neurodegenerative disease characterized by buildup of iron in the brain, leading to severe neurologic impairments. Future clinical trials are anticipated to identify new therapies for BPAN.

In this natural history study, researchers characterized family perspectives to define health concepts in BPAN. Among 42 caregivers of children diagnosed with BPAN, the team administered the Vineland Adaptive Behavior Scales, Third Edition—a tool which supports diagnosis of intellectual and developmental disabilities—along with health-related quality of life questionnaires.

Results highlight the effects of BPAN on both patient and caregiver quality of life. Key health concepts identified by families included overall health, comfort, and communication. Authors note that these health concepts will help inform future clinical outcome assessments.

Chen Y, Dawes R, Kim HC, Ljungdahl A, Stenton SL, Walker S, Lord J, Lemire G, Martin-Geary AC, Ganesh VS, Ma J, Ellingford JM, Delage E, D'Souza EN, Dong S, Adams DR, Allan K, Bakshi M, Baldwin EE, Berger SI, Bernstein JA, Bhatnagar I, Blair E, Brown NJ, Burrage LC, Chapman K, Coman DJ, Compton AG, Cunningham CA, D'Souza P, Danecek P, Délot EC, Dias KR, Elias ER, Elmslie F, Evans CA, Ewans L, Ezell K, Fraser JL, Gallacher L, Genetti CA, Goriely A, Grant CL, Haack T, Higgs JE, Hinch AG, Hurles ME, Kuechler A, Lachlan KL, Lalani SR, Lecoquierre F, Leitão E, Fevre AL, Leventer RJ, Liebelt JE, Lindsay S, Lockhart PJ, Ma AS, Macnamara EF, Mansour S, Maurer TM, Mendez HR, Metcalfe K, Montgomery SB, Moosajee M, Nassogne MC, Neumann S, O'Donoghue M, O'Leary M, Palmer EE, Pattani N, Phillips J, Pitsava G, Pysar R, Rehm HL, Reuter CM, Revencu N, Riess A, Rius R, Rodan L, Roscioli T, Rosenfeld JA, Sachdev R, Shaw-Smith CJ, Simons C, Sisodiya SM, Snell P, St Clair L, Stark Z, Stewart HS, Tan TY, Tan NB, Temple SEL, Thorburn DR, Tifft CJ, Uebergang E, VanNoy GE, Vasudevan P, Vilain E, Viskochil DH, et al. De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome. Nature. 2024 Aug;632(8026):832-840. doi: 10.1038/s41586-024-07773-7. Epub 2024 Jul 11.

Ferreira da Silva J, Tou CJ, King EM, Eller ML, Rufino-Ramos D, Ma L, Cromwell CR, Metovic J, Benning FMC, Chao LH, Eichler FS, Kleinstiver BP. Click editing enables programmable genome writing using DNA polymerases and HUH endonucleases. Nat Biotechnol. 2024 Jul 22. doi: 10.1038/s41587-024-02324-x. Online ahead of print.

Nomakuchi TT, Teferedegn EY, Li D, Muirhead KJ, Dubbs H, Leonard J, Muraresku C, Sergio E, Arnold K, Pizzino A, Skraban CM, Zackai EH, Wang K, Ganetzky RD, Vanderver AL, Ahrens-Nicklas RC, Bhoj EJK. Utility of genome sequencing in exome-negative pediatric patients with neurodevelopmental phenotypes. Am J Med Genet A. 2024 Jul 19:e63817. doi: 10.1002/ajmg.a.63817. Epub ahead of print. PMID: 39031459.

Neurodevelopmental disorders have a wide range of causes, which can lead to diagnostic challenges. Patients are often subjected to a long course of tests with frequently inconclusive results. Exome sequencing is a comprehensive genetic test that can help evaluate undiagnosed neurodevelopmental disorders. However, these tests may miss rare diagnoses due to technical limitations. While genome sequencing addresses many of these limitations, it is less commonly used due to higher cost and more intense analysis.

In this study, researchers illustrate the diagnostic utility of genome sequencing in pediatric cases of neurodevelopmental disorders following non-diagnostic exome sequencing. The team describes nine cases of individuals presenting with global developmental delay or regression who were diagnosed with genome sequencing after inconclusive exome sequencing tests.

Results show that in these cases, exome sequencing was limited by poor sensitivity for structural variants and non-coding variants, as well as biased coverage of coding regions. Authors note that these findings suggest that individuals presenting with neurodevelopmental disability could benefit from genome sequencing, either as a follow-up or in place of non-diagnostic exome sequencing.

Thorpe E, Williams T, Shaw C, Chekalin E, Ortega J, Robinson K, Button J, Jones MC, Campo MD, Basel D, McCarrier J, Keppen LD, Royer E, Foster-Bonds R, Duenas-Roque MM, Urraca N, Bosfield K, Brown CW, Lydigsen H, Mroczkowski HJ, Ward J, Sirchia F, Giorgio E, Vaux K, Salguero HP, Lumaka A, Mubungu G, Makay P, Ngole M, Lukusa PT, Vanderver A, Muirhead K, Sherbini O, Lah MD, Anderson K, Bazalar-Montoya J, Rodriguez RS, Cornejo-Olivas M, Milla-Neyra K, Shinawi M, Magoulas P, Henry D, Gibson K, Wiafe S, Jayakar P, Salyakina D, Masser-Frye D, Serize A, Perez JE, Taylor A, Shenbagam S, Abou Tayoun A, Malhotra A, Bennett M, Rajan V, Avecilla J, Warren A, Arseneault M, Kalista T, Crawford A, Ajay SS, Perry DL, Belmont J, Taft RJ. The impact of clinical genome sequencing in a global population with suspected rare genetic disease. Am J Hum Genet. 2024 Jul 11;111(7):1271-1281. doi: 10.1016/j.ajhg.2024.05.006. Epub 2024 Jun 5.

Gavazzi F, Vaia Y, Woidill S, Formanowski B, Peixoto de Barcelos I, Sevagamoorthy A, Modesti NB, Charlton L, Cusack SV, Vincent A, D'Aiello R, Jawad A, Galli J, Varesio C, Fazzi E, Orcesi S, Glanzman AM, Lorch S, DeMauro SB, Guez-Barber D, Waldman AT, Vanderver A, Adang LA. Nonverbal Cognitive Skills in Children With Aicardi Goutières Syndrome. Neurology. 2024 Jul 9;103(1):e209541. doi: 10.1212/WNL.0000000000209541. Epub 2024 Jun 10.

Kissell J, Rochmann C, Minini P, Eichler F, Stephen CD, Lau H, Toro C, Johnston JM, Krupnick R, Hamed A, Cox GF. Clinical outcome assessments of disease burden and progression in late-onset GM2 gangliosidoses. Mol Genet Metab. 2024 Jul;142(3):108512. doi: 10.1016/j.ymgme.2024.108512. Epub 2024 Jun 6.

Adang LA, Bonkowsky JL, Boelens JJ, Mallack E, Ahrens-Nicklas R, Bernat JA, Bley A, Burton B, Darling A, Eichler F, Eklund E, Emrick L, Escolar M, Fatemi A, Fraser JL, Gaviglio A, Keller S, Patterson MC, Orchard P, Orthmann-Murphy J, Santoro JD, Schöls L, Sevin C, Srivastava IN, Rajan D, Rubin JP, Van Haren K, Wasserstein M, Zerem A, Fumagalli F, Laugwitz L, Vanderver A. Consensus guidelines for the monitoring and management of metachromatic leukodystrophy in the United States. Cytotherapy. 2024 Jul;26(7):739-748. doi: 10.1016/j.jcyt.2024.03.487. Epub 2024 Apr 1.

Adang LA, Groeschel S, Grzyb C, D'Aiello R, Gavazzi F, Sherbini O, Bronner N, Patel A, Vincent A, Sevagamoorthy A, Mutua S, Muirhead K, Schmidt J, Pizzino A, Yu E, Jin D, Eichler F, Fraser JL, Emrick L, Van Haren K, Boulanger JM, Ruzhnikov M, Sylvain M, Nguyen CÉ, Potic A, Keller S, Fatemi A, Uebergang E, Poe M, Yazdani PA, Bernat J, Lindstrom K, Bonkowsky JL, Bernard G, Stutterd CA, Orchard P, Gupta AO, Ljungberg M, Groenborg S, Zambon A, Locatelli S, Fumagalli F, Elguen S, Kehrer C, Krägeloh-Mann I, Shults J, Vanderver A, Escolar ML. Developmental delay can precede neurologic regression in early onset metachromatic leukodystrophy. Mol Genet Metab. 2024 Aug;142(4):108521. doi: 10.1016/j.ymgme.2024.108521. Epub 2024 Jun 29. PMID: 38964050; PMCID: PMC11348664.

Metachromatic leukodystrophy (MLD) is an inherited lysosomal disorder caused by a missing or abnormal enzyme that cannot break down sulfatides (complex, fat-sugar molecules containing a sulfate group). Since therapies are most effective before patients begin experiencing symptoms, there is a critical need to define this window early in the disease course.  

In this study, researchers explored the relationship between early development delay and neurologic regression in late-infantile MLD. The team studied medical records of 351 patients, including the specific ages of gain and loss of developmental milestones.

Results show that early developmental delay precedes regression in a subset of children affected by late-infantile MLD, defining an earlier onset of neurologic dysfunction than previously understood. As real-world data prior to diagnosis revealed early differences from typical development, authors note that close monitoring for early development delay in presymptomatic individuals may help with earlier diagnosis, leading to improved treatment decisions.

Adang LA, D'Aiello R, Takanohashi A, Woidill S, Gavazzi F, Behrens EM, Sullivan KE, Goldbach-Mansky R, de Jesus AA; AGS Clinical Trial Readiness Workgroup; Vanderver A, Shults J. IFN-signaling gene expression as a diagnostic biomarker for monogenic interferonopathies. JCI Insight. 2024 Jun 17;9(14):e178456. doi: 10.1172/jci.insight.178456.

Armangue T, Whitehead MT, Tonduti D, Farina L, Tavasoli AR, Vossough A, Bennett ML, Vaia Y, Bernard G, Salsano E, Mercimek-Andrews S, Waldman A, Vanderver A. Brainstem Chipmunk Sign: A Diagnostic Imaging Clue across All Subtypes of Alexander Disease. AJNR Am J Neuroradiol. 2024 Jun 7;45(6):769-772. doi: 10.3174/ajnr.A8220.

Posern C, Dreyer B, Maier SL, Eichler F, Gelb MH, Santer R, Bley A, Murko S. Quantification of N-acetyl-l-aspartate in dried blood spots: A simple and fast LC-MS/MS neonatal screening method for the diagnosis of Canavan disease. Mol Genet Metab. 2024 Jun;142(2):108489. doi: 10.1016/j.ymgme.2024.108489. Epub 2024 May 3.

Berger JA, Simpao AF, Dubow SR, McClung HA, Liu GW, Waldman AT, Drum ET. A retrospective observational cohort study of the anesthetic management and outcomes of pediatric patients with Alexander disease undergoing lumbar puncture or magnetic resonance imaging. Paediatr Anaesth. 2024 Aug;34(8):810-817. doi: 10.1111/pan.14937. Epub 2024 May 31. PMID: 38818870; PMCID: PMC11223980.

Alexander disease is a rare disorder of the nervous system characterized by leukodystrophy, or the destruction of myelin (the fatty coating surrounding nerve fibers). Patients with Alexander disease can experience developmental delay, seizures, difficulty swallowing, vomiting, and sleep apnea. These symptoms can also lead to complications under general anesthesia. However, not much is known about outcomes related to anesthesia for patients with Alexander disease.

In this study, researchers describe anesthetic outcomes of pediatric patients with Alexander disease undergoing magnetic resonance imaging or lumbar puncture. Among 40 patients undergoing 64 procedures, the team reviewed data on patient characteristics, anesthetic techniques, medications, and complications under anesthesia as well as in the following 24 hours.

Results show that participants did not experience significant complications while undergoing general anesthesia or monitored anesthesia care, demonstrating that patients with Alexander disease can safely be anesthetized for low-risk procedures. Authors note that further study is needed to understand the long-term safety outcomes of repeat anesthetic exposures in patients with Alexander disease.

Yska HAF, Turk BR, Fatemi A, Goodman J, Voermans M, Amos D, Amanat M, van de Stadt S, Engelen M, Smith-Fine A, Keller J. International validation of meaningfulness of postural sway and gait to assess myeloneuropathy in adults with adrenoleukodystrophy. J Inherit Metab Dis. 2024 May 25. doi: 10.1002/jimd.12753. Epub ahead of print. PMID: 38795020.

Adrenoleukodystrophy (ALD) is an X-linked disorder (on the X chromosome) characterized by the disruption in fat metabolism (break down) which leads to the accumulation of long-chain fatty acids throughout the nervous system, adrenal glands, and testes. Individuals with ALD experience a slowly progressive myeloneuropathy, which causes problems with balance and gait. Evaluating this progression can often be complicated due to the inconsistency of symptom patterns. However, wearable sensors could make it easier to collect more frequent information about balance and gait.

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In this study, researchers assessed balance and gait in adults with ALD using wearable sensors. The team measured postural body sway and gait in 120 participants using a type of wearable device called an accelerometer. Researchers also measured disease severity, as well as falling frequency and quality of life in men.

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Results show clinically meaningful relationships for sway and gait with use of an assistive device, falling frequency, and quality of life. Authors note that wearable accelerometers are a valid means to measure sway and gait in ALD, which could help improve clinical trial designs to assess myeloneuropathy and monitor disease progression.

Adang LA, Sevagamoorthy A, Sherbini O, Fraser JL, Bonkowsky JL, Gavazzi F, D'Aiello R, Modesti NB, Yu E, Mutua S, Kotes E, Shults J, Vincent A, Emrick LT, Keller S, Van Haren KP, Woidill S, Barcelos I, Pizzino A, Schmidt JL, Eichler F, Fatemi A, Vanderver A. Longitudinal natural history studies based on real-world data in rare diseases: Opportunity and a novel approach. Mol Genet Metab. 2024 May;142(1):108453. doi: 10.1016/j.ymgme.2024.108453. Epub 2024 Mar 18. PMID: 38522179.

In rare diseases, natural history studies are essential to understanding disease progression over time. Prospective studies are limited by fewer available patients at a given time, impacting the timely collection of natural history data. These studies are also unlikely to capture pre-diagnostic clinical trajectories in conditions where diagnostic delays are common. 

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In this study, researchers shared a new approach to creating real-world data-based longitudinal natural history studies for rare diseases. The team outlined various strategies developed by the Global Leukodystrophy Initiative Clinical Trials Network. Strategies include use of standard operating procedures and rigorous processes for staff training, data extraction, source documentation, and data management.

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Authors note that these strategies will complement prospective studies by enabling the use of existing medical records to collect natural history data on large numbers of patients in a short time and map complete disease trajectory, including the time period before diagnosis.

de Barcelos IP, Woidill S, Gavazzi F, Modesti NB, Sevagamoorthy A, Vanderver A, Adang L. Systematic analysis of genotype-phenotype variability in siblings with Aicardi Goutières Syndrome (AGS). Mol Genet Metab. 2024 May;142(1):108346. doi: 10.1016/j.ymgme.2024.108346. Epub 2024 Feb 13.

Kiefer M, Simione M, Eichler FS, Townsend EL4. Development of an Infantile GM2 Clinical Rating Scale: Remote Assessment of Clinically Meaningful Health-Related Function. J Child Neurol. 2024 May;39(5-6):161-170. doi: 10.1177/08830738241246703. Epub 2024 Apr 25.

Fortin O, Christoffel K, Shoaib A, Venkatesan C, Cilli K, Schroeder JW, Alves C, Ganetzky RD, Fraser JL. Characteristic Fetal Brain MRI Abnormalities in Pyruvate Dehydrogenase Complex Deficiency. medRxiv. 2024 Apr 10:2024.04.08.24303574. doi: 10.1101/2024.04.08.24303574.

Chen Y, Dawes R, Kim HC, Stenton SL, Walker S, Ljungdahl A, Lord J, Ganesh VS, Ma J, Martin-Geary AC, Lemire G, D'Souza EN, Dong S, Ellingford JM, Adams DR, Allan K, Bakshi M, Baldwin EE, Berger SI, Bernstein JA, Brown NJ, Burrage LC, Chapman K, Compton AG, Cunningham CA, D'Souza P, Délot EC, Dias KR, Elias ER, Evans CA, Ewans L, Ezell K, Fraser JL, Gallacher L, Genetti CA, Grant CL, Haack T, Kuechler A, Lalani SR, Leitão E, Fevre AL, Leventer RJ, Liebelt JE, Lockhart PJ, Ma AS, Macnamara EF, Maurer TM, Mendez HR, Montgomery SB, Nassogne MC, Neumann S, O'Leary M, Palmer EE, Phillips J, Pitsava G, Pysar R, Rehm HL, Reuter CM, Revencu N, Riess A, Rius R, Rodan L, Roscioli T, Rosenfeld JA, Sachdev R, Simons C, Sisodiya SM, Snell P, Clair L, Stark Z, Tan TY, Tan NB, Temple SE, Thorburn DR, Tifft CJ, Uebergang E, VanNoy GE, Vilain E, Viskochil DH, Wedd L, Wheeler MT, White SM, Wojcik M, Wolfe LA, Wolfenson Z, Xiao C, Zocche D, Rubenstein JL, Markenscoff-Papadimitriou E, Fica SM, Baralle D, Depienne C, MacArthur DG, Howson JM, Sanders SJ, O'Donnell-Luria A, Whiffin N. De novo variants in the non-coding spliceosomal snRNA gene RNU4-2 are a frequent cause of syndromic neurodevelopmental disorders. medRxiv. 2024 Apr 9:2024.04.07.24305438. doi: 10.1101/2024.04.07.24305438.

Gold JI, Stefanatos AK, Fraser JL, Vanderver A, Cuddapah S. Enasidenib-induced hepatitis in an individual with Type II D2-hydroxyglutaric aciduria. JIMD Rep. 2024 Apr 16;65(3):156-162. doi: 10.1002/jmd2.12421. eCollection 2024 May.

Ashton NJ, Di Molfetta G, Tan K, Blennow K, Zetterberg H, Messing A. Plasma concentrations of glial fibrillary acidic protein, neurofilament light, and tau in Alexander disease. Neurol Sci. 2024 Apr 1. doi: 10.1007/s10072-024-07495-8. Epub ahead of print. PMID: 38558318.

Alexander disease is a rare disorder of the nervous system characterized by leukodystrophy, or the destruction of myelin (the fatty coating surrounding nerve fibers). Biomarkers are needed to help researchers monitor the progression of the disease and response to treatments. Elevated levels of the GFAP protein in the blood of patients with Alexander disease could serve as a possible biomarker. However, therapies currently in development involve targeting GFAP for treatment, highlighting a critical need for additional biomarkers.

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In this study, researchers explored the potential of biomarkers used in other neurodegenerative diseases for Alexander disease. The team measured concentrations of GFAP, neurofilament light, and tau in blood samples from individuals with Alexander disease and healthy controls.

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Results show significant changes in these levels in individuals with Alexander disease, especially those with infantile onset. 

Cusack SV, Gavazzi F, de Barcelos IP, Modesti NB, Woidill S, Formanowski B, DeMauro SB, Lorch S, Vincent A, Jawad AF, Estilow T, Glanzman AM, Vanderver A, Adang LA. Characterization of Fine Motor and Visual Motor Skills in Aicardi-Goutières Syndrome. J Child Neurol. 2024 Mar;39(3-4):147-154. doi: 10.1177/08830738241241786. Epub 2024 Mar 27.

Gavazzi F, Gonzalez CD, Arnold K, Swantkowski M, Charlton L, Modesti N, Dar AA, Vanderver A, Bennett M, Adang LA. Nucleotide metabolism, leukodystrophies, and CNS pathology. J Inherit Metab Dis. 2024 Feb 29:10.1002/jimd.12721. doi: 10.1002/jimd.12721. Online ahead of print.

Nagy A, Molay F, Hargadon S, Brito Pires C, Grant N, De La Rosa Abreu L, Chen JY, D'Souza P, Macnamara E, Tifft C, Becker C, Melo De Gusmao C, Khurana V, Neumeyer AM, Eichler FS. The spectrum of neurological presentation in individuals affected by TBL1XR1 gene defects. Orphanet J Rare Dis. 2024 Feb 20;19(1):79. doi: 10.1186/s13023-024-03083-3. PMID: 38378692; PMCID: PMC10880200.

TBL1XR1-related disorder is a group of neurodevelopmental disorders caused by variants in the TBL1XR1 gene. As these disorders are rare with a wide range of characteristics, not much is known about the developmental trajectory and progression of neurological symptoms over time.

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In this study, researchers describe the largest group of patients to date with TBL1XR1-related disorder. The team surveyed caregivers of 41 patients with TBL1XR1-related disorder, focusing on the pregnancy and perinatal course, caregiver-reported developmental trajectory, associated symptoms and diagnoses, neurological progression over time, and genetic information.

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Results reflect the spectrum of diverse traits in TBL1XR1-related disorder, including developmental delay and regression ranging in severity. Seizures were common, which could be related to language regression. Authors note that further study is needed to determine whether functional differences caused by different variants in the TBL1XR1 gene explain the range of characteristics in this disorder.

Ahmed F, Do N, Vanderver AL, Treat JR. Dyschromatosis symmetrica hereditaria: A clue to early diagnosis of Aicardi-Goutières syndrome. Pediatr Dermatol. 2024 Jan-Feb;41(1):156-157. doi: 10.1111/pde.15437. Epub 2023 Sep 28.

Goldberg G, Coelho L, Mo G, Adang LA, Patne M, Chen Z, Garcia-Bassets I, Mesci P, Muotri AR. TREX1 is required for microglial cholesterol homeostasis and oligodendrocyte terminal differentiation in human neural assembloids. Mol Psychiatry. 2023 Dec 21. doi: 10.1038/s41380-023-02348-w. Online ahead of print.

Gong Y, Laheji F, Berenson A, Li Y, Moser A, Qian A, Frosch M, Sadjadi R, Hahn R, Maguire CA, Eichler F. Role of Basal Forebrain Neurons in Adrenomyeloneuropathy in Mice and Humans. Ann Neurol. 2023 Dec 7. doi: 10.1002/ana.26849. Online ahead of print.

Joung J, Gallison K, Sollee JJ, Vigilante N, Cooper H, Liu GW, Ballester L, Faig W, Waldman AT. Acquisition and Loss of Developmental Milestones and Time to Disease-Related Outcomes in Cerebral Alexander Disease. J Child Neurol. 2023 Dec;38(13-14):672-678. doi: 10.1177/08830738231210040. Epub 2023 Nov 3.

Adang LA, Mowafy S, Herbst ZM, Zhou Z, Schlotawa L, Radhakrishnan K, Bentley B, Pham V, Yu E, Pillai NR, Orchard PJ, De Castro M, Vanderver A, Pasquali M, Gelb MH, Ahrens-Nicklas RC. Biochemical signatures of disease severity in multiple sulfatase deficiency. J Inherit Metab Dis. 2023 Oct 23. doi: 10.1002/jimd.12688. Online ahead of print.

Ramirez Alcantara J, Grant NR, Sethuram S, Nagy A, Becker C, Sahai I, Stanley T, Halper A, Eichler FS. Early Detection of Adrenal Insufficiency: The Impact of Newborn Screening for Adrenoleukodystrophy. J Clin Endocrinol Metab. 2023 Oct 18;108(11):e1306-e1315.

Adrenoleukodystrophy (ALD) is an X-linked disorder (on the X chromosome) characterized by accumulation of very long-chain fatty acids throughout the nervous system, adrenal glands, and testes. Males with ALD have a high risk of developing adrenal insufficiency, which can be life-threatening when undetected. Although newborn screening for ALD is becoming more common, its impact on clinical management has not yet been reported.

In this study, researchers investigated the impact of newborn screening on time to diagnosis of adrenal insufficiency in children with ALD. The team conducted a medical chart review of 116 patients with ALD, extracting information about diagnosis in all patients and adrenal insufficiency surveillance, diagnosis, and treatment in boys with ALD.

Results suggest that implementing newborn screening for ALD leads to significantly earlier detection of adrenal insufficiency, as well as earlier initiation of glucocorticoid supplementation in boys affected by ALD.

Weinhofer I, Rommer P, Gleiss A, Ponleitner M, Zierfuss B, Waidhofer-Söllner P, Fourcade S, Grabmeier-Pfistershammer K, Reinert MC, Göpfert J, Heine A, Yska HAF, Casasnovas C, Cantarín V, Bergner CG, Mallack E, Forss-Petter S, Aubourg P, Bley A, Engelen M, Eichler F, Lund TC, Pujol A, Köhler W, Kühl JS, Berger J. Biomarker-based risk prediction for the onset of neuroinflammation in X-linked adrenoleukodystrophy. EBioMedicine. 2023 Oct;96:104781. doi: 10.1016/j.ebiom.2023.104781. Epub 2023 Sep 7.

Mirchi A, Guay SP, Tran LT, Wolf NI, Vanderver A, Brais B, Sylvain M, Pohl D, Rossignol E, Saito M, Moutton S, González-Gutiérrez-Solana L, Thiffault I, Kruer MC, Moron DG, Kauffman M, Goizet C, Sztriha L, Glamuzina E, Melançon SB, Naidu S, Retrouvey JM, Lacombe S, Bernardino-Cuesta B, De Bie I, Bernard G. Craniofacial features of POLR3-related leukodystrophy caused by biallelic variants in POLR3A, POLR3B and POLR1C. J Med Genet. 2023 Oct;60(10):1026-1034. doi: 10.1136/jmg-2023-109223. Epub 2023 May 16. PMID: 37197783

RNA polymerase III-related or 4H leukodystrophy (POLR3-HLD) is a rare genetic disorder characterized by hypomyelination (inability to produce sufficient myelin, the fatty coating surrounding nerve fibers, at normal levels during development), neurological dysfunction, hypodontia (missing teeth), and hypogonadotropic hypogonadism (delayed puberty). Description of craniofacial features in individuals with POLR3-HLD is currently very limited.

In this study, researchers assessed the craniofacial features of 31 patients with POLR3-HLD. The team also proposed genotype-phenotype correlations based on patients’ facial features.

Results demonstrate that craniofacial abnormalities are common in patients with POLR3-HLD. Authors note that these findings will assist clinicians in diagnosing POLR3-HLD, help to provide care directed to this patient population’s specific needs, and allow future studies characterizing the underlying pathophysiology. 

Wong KN, Botto LD, He M, Baker PR 2nd, Vanderver AL, Bonkowsky JL. Novel SLC13A3 Variants and Cases of Acute Reversible Leukoencephalopathy and α-Ketoglutarate Accumulation and Literature Review. Neurol Genet. 2023 Sep 26;9(6):e200101. doi: 10.1212/NXG.0000000000200101. eCollection 2023 Dec.

Schoenmakers DH, Leferink PS, Vanderver A, Bonkowsky JL, Krägeloh-Mann I, Bernard G, Bertini E, Fatemi A, Fogel BL, Wolf NI, Skwirut D, Buck A, Holberg B, Saunier-Vivar EF, Rauner R, Dekker H, van Bokhoven P, Stellingwerff MD, Berkhof J, van der Knaap MS. Core protocol development for phase 2/3 clinical trials in the leukodystrophy vanishing white matter: a consensus statement by the VWM consortium and patient advocates. BMC Neurol. 2023 Aug 17;23(1):305. doi: 10.1186/s12883-023-03354-9.

Gavazzi F, Patel V, Charsar B, Glanzman A, Erler J, Sevagamoorthy A, McKenzie E, Kornafel T, Ballance E, Pierce SR, Teng M, Formanowski B, Woidill S, Shults J, Wassmer E, Tonduti D, Magrinelli F, Bernard G, Van Der Knaap M, Wolf N, Adang L, Vanderver A. Gross Motor Function in Pediatric Onset TUBB4A-Related Leukodystrophy: GMFM-88 Performance and Validation of GMFC-MLD in TUBB4A. J Child Neurol. 2023 Aug;38(8-9):498-504. doi: 10.1177/08830738231188159. Epub 2023 Jul 17.

Gavazzi F, Glanzman AM, Woidill S, Formanowski B, Dixit A, Isaacs D, Kornafel T, Ballance E, Pierce SR, Modesti N, Barcelos I, Cusack SV, Jan AK, Flores Z, Sherbini O, Vincent A, D'Aiello R, Lorch SA, DeMauro SB, Jawad A, Vanderver A, Adang L. Exploration of Gross Motor Function in Aicardi-Goutières Syndrome. J Child Neurol. 2023 Jul 27:8830738231188753. doi: 10.1177/08830738231188753. Epub ahead of print. PMID: 37499181

Aicardi-Goutières syndrome (AGS) is a rare genetic disorder characterized by a spectrum of motor abilities. The AGS Severity Scale is used to measure outcomes in individuals with AGS. However, because of the relatively limited granularity of this tool, there is a need to define tools that can measure function across the AGS spectrum. 

In this study, researchers explored gross motor function as an outcome measure of AGS. The team administered the Gross Motor Function Measure–88 (GMFM-88) and AGS Severity Scale in 71 individuals affected by AGS, characterizing performance variability by genotype. 

Results support the GMFM-88 as a potential clinical outcome assessment in subsets of the AGS population. Authors note the need for additional validation of outcome measures that can reflect the diverse gross motor function observed in individuals with AGS, including low motor function.

Al-Saady M, Beerepoot S, Plug BC, Breur M, Galabova H, Pouwels PJW, Boelens JJ, Lindemans C, van Hasselt PM, Matzner U, Vanderver A, Bugiani M, van der Knaap MS, Wolf NI. Neurodegenerative disease after hematopoietic stem cell transplantation in metachromatic leukodystrophy. Ann Clin Transl Neurol. 2023 Jul;10(7):1146-1159. doi: 10.1002/acn3.51796. Epub 2023 May 22.

Köhler W, Engelen M, Eichler F, Lachmann R, Fatemi A, Sampson J, Salsano E, Gamez J, Molnar MJ, Pascual S, Rovira M, Vilà A, Pina G, Martín-Ugarte I, Mantilla A, Pizcueta P, Rodríguez-Pascau L, Traver E, Vilalta A, Pascual M, Martinell M, Meya U, Mochel F; ADVANCE Study Group. Safety and efficacy of leriglitazone for preventing disease progression in men with adrenomyeloneuropathy (ADVANCE): a randomised, double-blind, multi-centre, placebo-controlled phase 2-3 trial. Lancet Neurol. 2023 Feb;22(2):127-136. doi: 10.1016/S1474-4422(22)00495-1.

Srivastava S, Shaked HM, Gable K, Gupta SD, Pan X, Somashekarappa N, Han G, Mohassel P, Gotkine M, Doney E, Goldenberg P, Tan QKG, Gong Y, Kleinstiver B, Wishart B, Cope H, Pires CB, Stutzman H, Spillmann RC; Undiagnosed Disease Network; Sadjadi R, Elpeleg O, Lee CH, Bellen HJ, Edvardson S, Eichler F, Dunn TM. SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia. Brain. 2023 Jan 30:awac460. doi: 10.1093/brain/awac460. Epub ahead of print. PMID: 36718090.

Hereditary spastic paraplegia (HSP) is a group of neurodegenerative disorders that primarily affect the upper motor neurons. In the nervous system, a diverse family of lipids called sphingolipids play a critical role in structural and signaling functions. The synthesis of sphingolipids is regulated by the protein SPTSSA.

In this study, researchers identified three children with a complex form of HSP. The team used exome sequencing to discover two different disease-causing variants in the SPTSSA gene. Next, they investigated the effects of these variants on sphingolipid synthesis.

Findings showed that the variants in SPTSSA caused excessive sphingolipid synthesis, leading to HSP. Authors note that these findings provide a better understanding of the elevated sphingolipid synthesis involved in progressive neurodegenerative diseases.

Modesti NB, Evans SH, Jaffe N, Vanderver A, Gavazzi F. Early recognition of patients with leukodystrophies. Curr Probl Pediatr Adolesc Health Care. 2022 Dec;52(12):101311. doi: 10.1016/j.cppeds.2022.101311. Epub 2022 Dec 2.

Perez G, Young L, Kravitz R, Sheehan D, Adang L, Van Haren K, Lin JL, Jaffe NN, Kuo D, Ball L, Keller J, Sank J, DiVito D, Naime S. Pulmonological issues. Curr Probl Pediatr Adolesc Health Care. 2022 Dec;52(12):101313. doi: 10.1016/j.cppeds.2022.101313. Epub 2022 Dec 5.

Engelen M, van Ballegoij WJC, Mallack EJ, Van Haren KP, Köhler W, Salsano E, van Trotsenburg ASP, Mochel F, Sevin C, Regelmann MO, Tritos NA, Halper A, Lachmann RH, Davison J, Raymond GV, Lund TC, Orchard PJ, Kuehl JS, Lindemans CA, Caruso P, Turk BR, Moser AB, Vaz FM, Ferdinandusse S, Kemp S, Fatemi A, Eichler FS, Huffnagel IC. International Recommendations for the Diagnosis and Management of Patients With Adrenoleukodystrophy: A Consensus-Based Approach. Neurology. 2022 Nov 22;99(21):940-951. doi: 10.1212/WNL.0000000000201374. Epub 2022 Sep 29.

Harting I, Garbade SF, Rosendaal SD, Mohr A, Sherbini O, Vanderver A, Wolf NI. Identification of PMD subgroups using a myelination score for PMD. Eur J Paediatr Neurol. 2022 Nov;41:71-79. doi: 10.1016/j.ejpn.2022.10.003. Epub 2022 Nov 4.

Eichler F, Sevin C, Barth M, Pang F, Howie K, Walz M, Wilds A, Calcagni C, Chanson C, Campbell L. Understanding caregiver descriptions of initial signs and symptoms to improve diagnosis of metachromatic leukodystrophy. Orphanet J Rare Dis. 2022 Oct 4;17(1):370. doi: 10.1186/s13023-022-02518-z.

Gavazzi F, Pierce SR, Vithayathil J, Cunningham K, Anderson K, McCann J, Moll A, Muirhead K, Sherbini O, Prange E, Dubbs H, Tochen L, Fraser J, Helbig I, Lewin N, Thakur N, Adang LA. Psychometric outcome measures in beta-propeller protein-associated neurodegeneration (BPAN). Mol Genet Metab. 2022 Sep-Oct;137(1-2):26-32. doi: 10.1016/j.ymgme.2022.07.009. Epub 2022 Jul 20.

Helman G, Takanohashi A, Hagemann TL, Perng MD, Walkiewicz M, Woidill S, Sase S, Cross Z, Du Y, Zhao L, Waldman A, Haake BC, Fatemi A, Brenner M, Sherbini O, Messing A, Vanderver A, Simons C. Type II Alexander disease caused by splicing errors and aberrant overexpression of an uncharacterized GFAP isoform. Hum Mutat. 2022 Sep;43(9):1344. doi: 10.1002/humu.24400.

Stutterd CA, Vanderver A, Lockhart PJ, Helman G, Pope K, Uebergang E, Love C, Delatycki MB, Thorburn D, Mackay MT, Peters H, Kornberg AJ, Patel C, Rodriguez-Casero V, Waak M, Silberstein J, Sinclair A, Nolan M, Field M, Davis MR, Fahey M, Scheffer IE, Freeman JL, Wolf NI, Taft RJ, van der Knaap MS, Simons C, Leventer RJ. Unclassified white matter disorders: A diagnostic journey requiring close collaboration between clinical and laboratory services. Eur J Med Genet. 2022 Sep;65(9):104551. doi: 10.1016/j.ejmg.2022.104551. Epub 2022 Jul 5.

Adang L. Leukodystrophies. Continuum (Minneap Minn). 2022 Aug 1;28(4):1194-1216. doi: 10.1212/CON.0000000000001130.

Wongkittichote P, Magistrati M, Shimony JS, Smyser CD, Fatemi SA, Fine AS, Bellacchio E, Dallabona C, Shinawi M. Functional analysis of missense DARS2 variants in siblings with leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. Mol Genet Metab. 2022 Aug;136(4):260-267. doi: 10.1016/j.ymgme.2022.07.002. Epub 2022 Jul 5.

Alves CAPF, Sherbini O, D'Arco F, Steel D, Kurian MA, Radio FC, Ferrero GB, Carli D, Tartaglia M, Balci TB, Powell-Hamilton NN, Schrier Vergano SA, Reutter H, Hoefele J, Günthner R, Roeder ER, Littlejohn RO, Lessel D, Lüttgen S, Kentros C, Anyane-Yeboa K, Catarino CB, Mercimek-Andrews S, Denecke J, Lyons MJ, Klopstock T, Bhoj EJ, Bryant L, Vanderver A. Brain Abnormalities in Patients with Germline Variants in H3F3: Novel Imaging Findings and Neurologic Symptoms Beyond Somatic Variants and Brain Tumors. AJNR Am J Neuroradiol. 2022 Jul;43(7):1048-1053. doi: 10.3174/ajnr.A7555. Epub 2022 Jun 30.

Adang LA, Gavazzi F, D'Aiello R, Isaacs D, Bronner N, Arici ZS, Flores Z, Jan A, Scher C, Sherbini O, Behrens EM, Goldbach-Mansky R, Olson TS, Lambert MP, Sullivan KE, Teachey DT, Witmer C, Vanderver A, Shults J. Hematologic abnormalities in Aicardi Goutières Syndrome. Mol Genet Metab.. 2022 Jun 16:S1096-7192(22)00339-0. doi: 10.1016/j.ymgme.2022.06.003. Epub ahead of print. PMID: 35786528.

Aicardi Goutières syndrome (AGS) is an inherited disease that is associated with early onset neurologic disability and systemic inflammation. Cytopenias—conditions in which there are lower-than-normal numbers of blood cells—are a potentially serious, but poorly understood, complication of AGS. As new treatment options are developed, it is important to understand the roles of the disease versus the treatment in hematologic abnormalities, allowing for better management of cytopenia. In this study, researchers identified novel patterns of hematologic abnormalities in AGS. The team collected laboratory data throughout the lifespan from 142 individuals with AGS. Results showed that AGS results in multilineage cytopenias not limited to the neonatal period. Neutropenia, anemia, and thrombocytopenia were common. For patients on the treatment baricitinib, moderate to severe graded events of neutropenia, anemia, and leukopenia were more common, but rarely of clinical consequence. Based on these results, authors recommend careful monitoring of hematologic parameters in children with AGS throughout the lifespan, especially while on therapy. Authors also note that AGS should be considered in children with neurologic impairment of unclear cause and hematologic abnormalities.

Mallack EJ, Van Haren KP, Torrey A, van de Stadt S, Engelen M, Raymond GV, Fatemi A, Eichler FS. Presymptomatic Lesion in Childhood Cerebral Adrenoleukodystrophy: Timing and Treatment. Neurology. 2022 May 24:10.1212/WNL.0000000000200571. doi: 10.1212/WNL.0000000000200571. Online ahead of print.

Cetin Gedik K, Lamot L, Romano M, Demirkaya E, Piskin D, Torreggiani S, Adang LA, Armangue T, Barchus K, Cordova DR, Crow YJ, Dale RC, Durrant KL, Eleftheriou D, Fazzi EM, Gattorno M, Gavazzi F, Hanson EP, Lee-Kirsch MA, Montealegre Sanchez GA, Neven B, Orcesi S, Ozen S, Poli MC, Schumacher E, Tonduti D, Uss K, Aletaha D, Feldman BM, Vanderver A, Brogan PA, Goldbach-Mansky R. The 2021 European Alliance of Associations for Rheumatology/American College of Rheumatology points to consider for diagnosis and management of autoinflammatory type I interferonopathies: CANDLE/PRAAS, SAVI and AGS. Ann Rheum Dis. 2022 May;81(5):601-613. doi: 10.1136/annrheumdis-2021-221814. Epub 2022 Jan 27.

Casas-Alba D, Darling A, Caballero E, Mensa-Vilaró A, Bartrons J, Antón J, García-Cazorla À, Vanderver A, Armangué T. Efficacy of baricitinib on chronic pericardial effusion in a patient with Aicardi-Goutières syndrome. Rheumatology (Oxford). 2022 Apr 11;61(4):e87-e89. doi: 10.1093/rheumatology/keab860.

Stellingwerff MD, Nulton C, Helman G, Roosendaal SD, Benko WS, Pizzino A, Bugiani M, Vanderver A, Simons C, van der Knaap MS. Early-Onset Vascular Leukoencephalopathy Caused by Bi-Allelic NOTCH3 Variants. Neuropediatrics. 2022 Apr;53(2):115-121. doi: 10.1055/a-1739-2722. Epub 2022 Jan 13. PMID: 35026854.

Cerebral autosomal dominant arteriopathy with sub-cortical infarcts and leukoencephalopathy (CADASIL) is an inherited disease of the blood vessels that occurs when the thickening of blood vessel walls blocks the flow of blood to the brain. Heterozygous variants of the NOTCH3 gene are known to cause CADASIL, with patients typically presenting in adulthood. In this study, researchers describe three patients from two unrelated families presenting at an early age with a vascular leukoencephalopathy. The team reviewed clinical records, MRI, and CT scans of the patients. Genome sequencing revealed bi-allelic variants in the NOTCH3 gene. These results indicate that bi-allelic loss-of-function NOTCH3 variants may cause a vascular leukoencephalopathy, distinct from CADASIL.

Macintosh J, Derksen A, Poulin C, Braverman N, Vanderver A, Thiffault I, Albrecht S, Bernard G. Novel biallelic variants in NRROS associated with a lethal microgliopathy, brain calcifications, and neurodegeneration. Neurogenetics. 2022 Apr;23(2):151-156. doi: 10.1007/s10048-022-00683-8. Epub 2022 Jan 31. PMID: 35099671.

The protein NRROS (negative regulator of reactive oxygen species) is expressed by microglia (immune cells of the central nervous system) and perivascular macrophages (brain macrophages, or immune cells, characterized by a close association with the cerebral vasculature). To date, 9 individuals have been reported with biallelic (affecting both alleles of a gene) NRROS variants. In this study, researchers used exome sequencing to identify 2 novel NRROS variants—a missense variant and a premature stop codon—in an individual with a severe neurodegenerative phenotype. Through pathological examination, they found both extensive grey and white matter involvement, dystrophic calcifications, and infiltration of foamy macrophages. Authors state that this is the first reported case of NRROS variants with a mitochondrial ultrastructure abnormality noted on electron microscopy analysis of post-mortem tissue.

Bonkowsky JL, Wilkes J. Time to Transplant in X-Linked Adrenoleukodystrophy. J Child Neurol.. 2022 Apr;37(5):397-400. doi: 10.1177/08830738221081141. Epub 2022 Mar 3.

Cerebral X-linked adrenoleukodystrophy (cALD) is a disorder characterized by the destruction of myelin (the insulation surrounding nerve fibers) in the brain. Survival and improved outcomes for cALD are associated with hematopoietic stem cell transplantation (HSCT) at earliest evidence of disease on magnetic resonance imaging (MRI). In this study, researchers aimed to determine average duration between diagnosis of cALD and HSCT. Among 27 patients with cALD in the hospitals they evaluated, the team found that time to HSCT was greater than 3 months. They also noted differences in average time by race/ethnicity and by hospital. Authors state that these findings suggest an opportunity to reduce time to transplant in cALD.

Smith Fine A, Kaufman M, Goodman J, Turk B, Bastian A, Lin D, Fatemi A, Keller J. Wearable sensors detect impaired gait and coordination in LBSL during remote assessments. Ann Clin Transl Neurol. 2022 Apr;9(4):468-477. doi: 10.1002/acn3.51509. Epub 2022 Mar 8.

Winkelman JW, Grant NR, Molay F, Stephen CD, Sadjadi R, Eichler FS. Restless Legs Syndrome in X-linked adrenoleukodystrophy. Sleep Med. 2022 Mar;91:31-34. doi: 10.1016/j.sleep.2022.02.008. Epub 2022 Feb 16. PMID: 35245789; PMCID: PMC9035065.

X-linked adrenoleukodystrophy (ALD) is a neurodegenerative disease that causes progressive gait and balance problems. Leg discomfort, sleep disturbances, and pain contribute to daily disability. In this study, researchers investigated the prevalence and severity of restless legs syndrome (RLS) in 32 adults with ALD. The team gathered data from questionnaires, telephone interviews, neurological examinations, functional gait measures, and laboratory assessments. Results suggest a high prevalence of RLS in adults with ALD. Researchers also found that ALD patients with RLS have more neurological signs and symptoms, and RLS is more common in females with ALD than in males. Authors note that increased awareness of RLS in patients with ALD would allow for more effective treatment.

Keller JL, Eloyan A, Raymond GV, Fatemi A, Zackowski KM. Sensorimotor outcomes in adrenomyeloneuropathy show significant disease progression. J Inherit Metab Dis. 2022 Mar;45(2):308-317. doi: 10.1002/jimd.12457. Epub 2021 Dec 9. PMID: 34796974; PMCID: PMC8987487.

Adrenomyeloneuropathy is an X-linked disorder (on the X chromosome) characterized by the disruption in fat metabolism (break down) which leads to the accumulation of very long-chain fatty acids throughout the nervous system, adrenal glands, and testes. As current outcomes used to evaluate the disorder are limited, quantitative outcomes are needed. In this prospective study, researchers aimed to track sensorimotor outcomes in adults with adrenomyeloneuropathy and evaluate differences in progression between men and women. The team analyzed data to detect changes in outcomes over 2 years. Outcomes included postural sway in four static standing conditions, great-toe vibration, hip strength, walking velocity, timed up-and-go, and 6-minute walk distance. They found that participants showed significant worsening in all standing conditions, sensation, and strength. However, they showed more stability in walking, with only velocity significantly declining. For each sex, postural sway declined significantly in all conditions except for eyes closed feet together for women. Strength declined significantly by sex for hip flexion. Sex-specific significant decline was seen in walking for men only. Authors note that quantitative measures of postural sway, sensation strength, and walking are effective measures of adrenomyeloneuropathy progression in 2 years.

Papapetropoulos S, Pontius A, Finger E, Karrenbauer V, Lynch DS, Brennan M, Zappia S, Koehler W, Schoels L, Hayer SN, Konno T, Ikeuchi T, Lund T, Orthmann-Murphy J, Eichler F, Wszolek ZK. Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia: Review of Clinical Manifestations as Foundations for Therapeutic Development. Front Neurol. 2022 Feb 3;12:788168. doi: 10.3389/fneur.2021.788168. eCollection 2021.

van der Knaap MS, Bonkowsky JL, Vanderver A, Schiffmann R, Krägeloh-Mann I, Bertini E, Bernard G, Fatemi SA, Wolf NI, Saunier-Vivar E, Rauner R, Dekker H, van Bokhoven P, van de Ven P, Leferink PS. Therapy Trial Design in Vanishing White Matter: An Expert Consortium Opinion. Neurol Genet. 2022 Feb 2;8(2):e657. doi: 10.1212/NXG.0000000000000657. eCollection 2022 Apr.

Gavazzi F, Fraser JL, Bloom M, Tochen L, Rhee J, Kwan M, Victoria T, Teachey DT, Ho CY, Vanderver A, Linn RL. Hodgkin lymphoma in an individual with TREX1-mediated Aicardi Goutières syndrome. Pediatr Blood Cancer. 2022 Jan;69(1):e29322. doi: 10.1002/pbc.29322. Epub 2021 Sep 7.

Ghabash G, Wilkes J, Barney BJ, Bonkowsky JL. Hospitalization Burden and Incidence of Krabbe Disease. J Child Neurol. 2022 Jan;37(1):12-19. doi: 10.1177/08830738211027717. Epub 2021 Oct 20.

Muirhead KJ, Clause AR, Schlachetzki Z, Dubbs H, Perry DL, Hagelstrom RT, Taft RJ, Vanderver A. Genome sequencing identifies three molecular diagnoses including a mosaic variant in the COL2A1 gene in an individual with Pol III-related leukodystrophy and Feingold syndrome. Cold Spring Harb Mol Case Stud. 2021 Dec 9;7(6):a006143. doi: 10.1101/mcs.a006143. Print 2021 Dec.

Waldman AT, Benson L, Sollee JR, Lavery AM, Liu GW, Green AJ, Waubant E, Heidary G, Conger D, Graves J, Greenberg B. Interocular Difference in Retinal Nerve Fiber Layer Thickness Predicts Optic Neuritis in Pediatric-Onset Multiple Sclerosis. J Neuroophthalmol. 2021 Dec 1;41(4):469-475. doi: 10.1097/WNO.0000000000001070.

Gavazzi F, Cross ZM, Woidill S, McMann JM, Rand EB, Takanohashi A, Ulrick N, Shults J, Vanderver AL, Adang L. Hepatic Involvement in Aicardi-Goutières Syndrome. Neuropediatrics. 2021 Dec;52(6):441-447. doi: 10.1055/s-0040-1722673. Epub 2021 Jan 14.

Gavazzi F, Adang L, Waldman A, Jan AK, Liu G, Lorch SA, DeMauro SB, Shults J, Pierce SR, Ballance E, Kornafel T, Harrington A, Glanzman AM, Vanderver A. Reliability of the Telemedicine Application of the Gross Motor Function Measure-88 in Patients With Leukodystrophy. Pediatr Neurol. 2021 Dec;125:34-39. doi: 10.1016/j.pediatrneurol.2021.09.012. Epub 2021 Sep 24. PMID: 34624609; PMCID: PMC8629609.

Leukodystrophies are a group of rare neurological disorders affecting the white matter of the brain that are characterized by severe neuromotor disability. Research on the functional status of people with leukodystrophy is limited by the need for in-person mobility assessments. The Gross Motor Function Measure-88 (GMFM-88) is an assessment tool used to measure change in gross motor function over time. In this study, researchers assessed the reliability of the GMFM-88 using telemedicine compared with standard in-person assessments in patients with leukodystrophy. They found that remote application of the GMFM-88 is a feasible and reliable approach. The authors note that this approach may be of particular value in rare diseases and those with severe neurologic disability that impacts travel ability.

Ghabash G, Wilkes J, Bonkowsky JL. National U.S. Patient and Transplant Data for Krabbe Disease. Front Pediatr. 2021 Nov 11;9:764626. doi: 10.3389/fped.2021.764626. eCollection 2021.

Mallack EJ, Askin G, van de Stadt S, Caruso PA, Musolino PL, Engelen M, Niogi SN, Eichler FS. A Longitudinal Analysis of Early Lesion Growth in Presymptomatic Patients with Cerebral Adrenoleukodystrophy. AJNR Am J Neuroradiol. 2021 Oct;42(10):1904-1911. doi: 10.3174/ajnr.A7250. Epub 2021 Sep 9.

Malhotra A, Ziegler A, Shu L, Perrier R, Amlie-Wolf L, Wohler E, Lygia de Macena Sobreira N, Colin E, Vanderver A, Sherbini O, Stouffs K, Scalais E, Serretti A, Barth M, Navet B, Rollier P, Xi H, Wang H, Zhang H, Perry DL, Ferrarini A, Colombo R, Pepler A, Schneider A, Tomiwa K, Okamoto N, Matsumoto N, Miyake N, Taft R, Mao X, Bonneau D. De novo missense variants in LMBRD2 are associated with developmental and motor delays, brain structure abnormalities and dysmorphic features. J Med Genet. 2021 Oct;58(10):712-716. doi: 10.1136/jmedgenet-2020-107137. Epub 2020 Aug 20.

Barczykowski AL, Langan TJ, Vanderver A, Jalal K, Carter RL. Death rates in the U.S. due to Leukodystrophies with pediatric forms. Am J Med Genet A. 2021 Aug;185(8):2361-2373. doi: 10.1002/ajmg.a.62248. Epub 2021 May 7.

Helman G, Zerem A, Almad A, Hacker JL, Woidill S, Sase S, LeFevre AN, Ekstein J, Johansson MM, Stutterd CA, Taft RJ, Simons C, Grinspan JB, Pizzino A, Schmidt JL, Harding B, Hirsch Y, Viaene AN, Fattal-Valevski A, Vanderver A. Further Delineation of the Clinical and Pathologic Features of HIKESHI-Related Hypomyelinating Leukodystrophy. Pediatr Neurol. 2021 Aug;121:11-19. doi: 10.1016/j.pediatrneurol.2021.04.014. Epub 2021 May 14.

Roosendaal SD, van de Brug T, Alves CAPF, Blaser S, Vanderver A, Wolf NI, van der Knaap MS. Imaging Patterns Characterizing Mitochondrial Leukodystrophies. AJNR Am J Neuroradiol. 2021 Jul;42(7):1334-1340. doi: 10.3174/ajnr.A7097. Epub 2021 Apr 1.

Bley A, Denecke J, Kohlschütter A, Schön G, Hischke S, Guder P, Bierhals T, Lau H, Hempel M, Eichler FS. The natural history of Canavan disease: 23 new cases and comparison with patients from literature. Orphanet J Rare Dis. 2021 May 19;16(1):227. doi: 10.1186/s13023-020-01659-3.

Mallack EJ, Turk BR, Yan H, Price C, Demetres M, Moser AB, Becker C, Hollandsworth K, Adang L, Vanderver A, Van Haren K, Ruzhnikov M, Kurtzberg J, Maegawa G, Orchard PJ, Lund TC, Raymond GV, Regelmann M, Orsini JJ, Seeger E, Kemp S, Eichler F, Fatemi A. MRI surveillance of boys with X-linked adrenoleukodystrophy identified by newborn screening: Meta-analysis and consensus guidelines. J Inherit Metab Dis. 2021 May;44(3):728-739. doi: 10.1002/jimd.12356. Epub 2021 Jan 9.

Gavazzi F, Charsar BA, Williams C, Shults J, Alves CA, Adang L, Vanderver A. Acquisition of Developmental Milestones in Hypomyelination With Atrophy of the Basal Ganglia and Cerebellum and Other TUBB4A-Related Leukoencephalopathy. J Child Neurol. 2021 Apr 12:883073821000977. doi: 10.1177/0883073821000977. Online ahead of print.

Weinhofer I, Rommer P, Zierfuss B, Altmann P, Foiani M, Heslegrave A, Zetterberg H, Gleiss A, Musolino PL, Gong Y, Forss-Petter S, Berger T, Eichler F, Aubourg P, Köhler W, Berger J. Neurofilament light chain as a potential biomarker for monitoring neurodegeneration in X-linked adrenoleukodystrophy. Nat Commun. 2021 Mar 22;12(1):1816. doi: 10.1038/s41467-021-22114-2.

Ramirez Alcantara J, Halper A. Adrenal insufficiency updates in children. Curr Opin Endocrinol Diabetes Obes. 2021 Feb 1;28(1):75-81. doi: 10.1097/MED.0000000000000591.

Piccoli C, Bronner N, Gavazzi F, Dubbs H, De Simone M, De Giorgis V, Orcesi S, Fazzi E, Galli J, Masnada S, Tonduti D, Varesio C, Vanderver A, Vossough A, Adang L. Late-Onset Aicardi-Goutières Syndrome: A Characterization of Presenting Clinical Features. Pediatr Neurol. 2021 Feb;115:1-6. doi: 10.1016/j.pediatrneurol.2020.10.012. Epub 2020 Nov 2.

Pelletier F, Perrier S, Cayami FK, Mirchi A, Saikali S, Tran LT, Ulrick N, Guerrero K, Rampakakis E, van Spaendonk RML, Naidu S, Pohl D, Gibson WT, Demos M, Goizet C, Tejera-Martin I, Potic A, Fogel BL, Brais B, Sylvain M, Sébire G, Lourenço CM, Bonkowsky JL, Catsman-Berrevoets C, Pinto PS, Tirupathi S, Strømme P, de Grauw T, Gieruszczak-Bialek D, Krägeloh-Mann I, Mierzewska H, Philippi H, Rankin J, Atik T, Banwell B, Benko WS, Blaschek A, Bley A, Boltshauser E, Bratkovic D, Brozova K, Cimas I, Clough C, Corenblum B, Dinopoulos A, Dolan G, Faletra F, Fernandez R, Fletcher J, Garcia Garcia ME, Gasparini P, Gburek-Augustat J, Gonzalez Moron D, Hamati A, Harting I, Hertzberg C, Hill A, Hobson GM, Innes AM, Kauffman M, Kirwin SM, Kluger G, Kolditz P, Kotzaeridou U, La Piana R, Liston E, McClintock W, McEntagart M, McKenzie F, Melançon S, Misbahuddin A, Suri M, Monton FI, Moutton S, Murphy RPJ, Nickel M, Onay H, Orcesi S, Özkınay F, Patzer S, Pedro H, Pekic S, Pineda Marfa M, Pizzino A, Plecko B, Poll-The BT, Popovic V, Rating D, Rioux MF, Rodriguez Espinosa N, Ronan A, Ostergaard JR, Rossignol E, Sanchez-Carpintero R, Schossig A, Senbil N, Sønderberg Roos LK, Stevens CA, Synofzik M, Sztriha L, et al. Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C. J Clin Endocrinol Metab. 2021 Jan 23;106(2):e660-e674. doi: 10.1210/clinem/dgaa700.

Engelen M, Kemp S, Eichler F. Endocrine dysfunction in adrenoleukodystrophy. Handb Clin Neurol. 2021;182:257-267. doi: 10.1016/B978-0-12-819973-2.00018-6.

Adang L, Goldbach-Mansky R, Vanderver A. JAK Inhibition in the Aicardi-Goutières Syndrome. Reply. N Engl J Med. 2020 Nov 26;383(22):2191-2193. doi: 10.1056/NEJMc2031081.

Lewis H, Samanta D, Örsell JL, Bosanko KA, Rowell A, Jones M, Dale RC, Taravath S, Hahn CD, Krishnakumar D, Chagnon S, Keller S, Hagebeuk E, Pathak S, Bebin EM, Arndt DH, Alexander JJ, Mainali G, Coppola G, Maclean J, Sparagana S, McNamara N, Smith DM, Raggio V, Cruz M, Fernández-Jaén A, Kava MP, Emrick L, Fish JL, Vanderver A, Helman G, Pierson TM, Zarate YA. Epilepsy and Electroencephalographic Abnormalities in SATB2-Associated Syndrome. Pediatr Neurol. 2020 Nov;112:94-100. doi: 10.1016/j.pediatrneurol.2020.04.006. Epub 2020 Apr 13.

Grineski SE, Morales DX, Collins T, Wilkes J, Bonkowsky JL. Racial/Ethnic and Insurance Status Disparities in Distance Traveled to Access Children's Hospital Care for Severe Illness: the Case of Children with Leukodystrophies. J Racial Ethn Health Disparities. 2020 Oct;7(5):975-986. doi: 10.1007/s40615-020-00722-w. Epub 2020 Feb 24.

Vanderver A, Adang L, Gavazzi F, McDonald K, Helman G, Frank DB, Jaffe N, Yum SW, Collins A, Keller SR, Lebon P, Meritet JF, Rhee J, Takanohashi A, Armangue T, Ulrick N, Sherbini O, Koh J, Peer K, Besnier C, Scher C, Boyle K, Dubbs H, Kramer-Golinkoff J, Pizzino A, Woidill S, Shults J. Janus Kinase Inhibition in the Aicardi-Goutières Syndrome. N Engl J Med. 2020 Sep 3;383(10):986-989. doi: 10.1056/NEJMc2001362.

Schmidt JL, Pizzino A, Nicholl J, Foley A, Wang Y, Rosenfeld JA, Mighion L, Bean L, da Silva C, Cho MT, Truty R, Garcia J, Speare V, Blanco K, Powis Z, Hobson GM, Kirwin S, Krock B, Lee H, Deignan JL, Westemeyer MA, Subaran RL, Thiffault I, Tsai EA, Fang T, Helman G, Vanderver A. Estimating the relative frequency of leukodystrophies and recommendations for carrier screening in the era of next-generation sequencing. Am J Med Genet A. 2020 Aug;182(8):1906-1912. doi: 10.1002/ajmg.a.61641. Epub 2020 Jun 23.

Vanderver A, Bernard G, Helman G, Sherbini O, Boeck R, Cohn J, Collins A, Demarest S, Dobbins K, Emrick L, Fraser JL, Masser-Frye D, Hayward J, Karmarkar S, Keller S, Mirrop S, Mitchell W, Pathak S, Sherr E, van Haren K, Waters E, Wilson JL, Zhorne L, Schiffmann R, van der Knaap MS, Pizzino A, Dubbs H, Shults J, Simons C, Taft RJ; LeukoSEQ Workgroup. Randomized Clinical Trial of First-Line Genome Sequencing in Pediatric White Matter Disorders. Ann Neurol. 2020 Aug;88(2):264-273. doi: 10.1002/ana.25757. Epub 2020 Jun 9.

Adang LA, Gavazzi F, Jawad AF, Cusack SV, Kopin K, Peer K, Besnier C, De Simone M, De Giorgis V, Orcesi S, Fazzi E, Galli J, Shults J, Vanderver A. Development of a neurologic severity scale for Aicardi Goutières Syndrome. Mol Genet Metab. 2020 Jun;130(2):153-160. doi: 10.1016/j.ymgme.2020.03.008. Epub 2020 Apr 2.

Helman G, Takanohashi A, Hagemann TL, Perng MD, Walkiewicz M, Woidill S, Sase S, Cross Z, Du Y, Zhao L, Waldman A, Haake BC, Fatemi A, Brenner M, Sherbini O, Messing A, Vanderver A, Simons C. Type II Alexander disease caused by splicing errors and aberrant overexpression of an uncharacterized GFAP isoform. Hum Mutat. 2020 Jun;41(6):1131-1137. doi: 10.1002/humu.24008. Epub 2020 Mar 11.

Wolf NI, Breur M, Plug B, Beerepoot S, Westerveld ASR, van Rappard DF, de Vries SI, Kole MHP, Vanderver A, van der Knaap MS, Lindemans CA, van Hasselt PM, Boelens JJ, Matzner U, Gieselmann V, Bugiani M. Metachromatic leukodystrophy and transplantation: remyelination, no cross-correction. Ann Clin Transl Neurol. 2020 Feb;7(2):169-180. doi: 10.1002/acn3.50975. Epub 2020 Jan 22.

Helman G, Lajoie BR, Crawford J, Takanohashi A, Walkiewicz M, Dolzhenko E, Gross AM, Gainullin VG, Bent SJ, Jenkinson EM, Ferdinandusse S, Waterham HR, Dorboz I, Bertini E, Miyake N, Wolf NI, Abbink TEM, Kirwin SM, Tan CM, Hobson GM, Guo L, Ikegawa S, Pizzino A, Schmidt JL, Bernard G, Schiffmann R, van der Knaap MS, Simons C, Taft RJ, Vanderver A. Genome sequencing in persistently unsolved white matter disorders. Ann Clin Transl Neurol. 2020 Jan;7(1):144-152. doi: 10.1002/acn3.50957. Epub 2020 Jan 7.

Mendes MI, Green LMC, Bertini E, Tonduti D, Aiello C, Smith D, Salsano E, Beerepoot S, Hertecant J, von Spiczak S, Livingston JH, Emrick L, Fraser J, Russell L, Bernard G, Magri S, Di Bella D, Taroni F, Koenig MK, Moroni I, Cappuccio G, Brunetti-Pierri N, Rhee J, Mendelsohn BA, Helbig I, Helbig K, Muhle H, Ismayl O, Vanderver AL, Salomons GS, van der Knaap MS, Wolf NI. RARS1-related hypomyelinating leukodystrophy: Expanding the spectrum. Ann Clin Transl Neurol. 2020 Jan;7(1):83-93. doi: 10.1002/acn3.50960. Epub 2019 Dec 8.

Bursle C, Yiu EM, Yeung A, Freeman JL, Stutterd C, Leventer RJ, Vanderver A, Yaplito-Lee J. Hyperinsulinaemic hypoglycaemia: A rare association of vanishing white matter disease. JIMD Rep. 2019 Nov 12;51(1):11-16. doi: 10.1002/jmd2.12081. eCollection 2020 Jan.

Gauquelin L, Cayami FK, Sztriha L, Yoon G, Tran LT, Guerrero K, Hocke F, van Spaendonk RML, Fung EL, D'Arrigo S, Vasco G, Thiffault I, Niyazov DM, Person R, Lewis KS, Wassmer E, Prescott T, Fallon P, McEntagart M, Rankin J, Webster R, Philippi H, van de Warrenburg B, Timmann D, Dixit A, Searle C; DDD Study,; Thakur N, Kruer MC, Sharma S, Vanderver A, Tonduti D, van der Knaap MS, Bertini E, Goizet C, Fribourg S, Wolf NI, Bernard G. Clinical spectrum of POLR3-related leukodystrophy caused by biallelic POLR1C pathogenic variants. Neurol Genet. 2019 Oct 30;5(6):e369. doi: 10.1212/NXG.0000000000000369. eCollection 2019 Dec.

Zarate YA, Bosanko KA, Caffrey AR, Bernstein JA, Martin DM, Williams MS, Berry-Kravis EM, Mark PR, Manning MA, Bhambhani V, Vargas M, Seeley AH, Estrada-Veras JI, van Dooren MF, Schwab M, Vanderver A, Melis D, Alsadah A, Sadler L, Van Esch H, Callewaert B, Oostra A, Maclean J, Dentici ML, Orlando V, Lipson M, Sparagana SP, Maarup TJ, Alsters SI, Brautbar A, Kovitch E, Naidu S, Lees M, Smith DM, Turner L, Raggio V, Spangenberg L, Garcia-Miñaúr S, Roeder ER, Littlejohn RO, Grange D, Pfotenhauer J, Jones MC, Balasubramanian M, Martinez-Monseny A, Blok LS, Gavrilova R, Fish JL. Mutation update for the SATB2 gene. Hum Mutat. 2019 Aug;40(8):1013-1029. doi: 10.1002/humu.23771. Epub 2019 Jun 18.

Guo L, Bertola DR, Takanohashi A, Saito A, Segawa Y, Yokota T, Ishibashi S, Nishida Y, Yamamoto GL, Franco JFDS, Honjo RS, Kim CA, Musso CM, Timmons M, Pizzino A, Taft RJ, Lajoie B, Knight MA, Fischbeck KH, Singleton AB, Ferreira CR, Wang Z, Yan L, Garbern JY, Simsek-Kiper PO, Ohashi H, Robey PG, Boyde A, Matsumoto N, Miyake N, Spranger J, Schiffmann R, Vanderver A, Nishimura G, Passos-Bueno MRDS, Simons C, Ishikawa K, Ikegawa S. Bi-allelic CSF1R Mutations Cause Skeletal Dysplasia of Dysosteosclerosis-Pyle Disease Spectrum and Degenerative Encephalopathy with Brain Malformation. Am J Hum Genet. 2019 May 2;104(5):925-935. doi: 10.1016/j.ajhg.2019.03.004. Epub 2019 Apr 11.

Al Yazidi G, Tran LT, Guerrero K, Vanderver A, Schiffmann R, Wolf NI, Chouinard S, Bernard G. Dystonia in RNA Polymerase III-Related Leukodystrophy. Mov Disord Clin Pract. 2019 Jan 9;6(2):155-159. doi: 10.1002/mdc3.12715. eCollection 2019 Feb.

Stutterd CA, Lake NJ, Peters H, Lockhart PJ, Taft RJ, van der Knaap MS, Vanderver A, Thorburn DR, Simons C, Leventer RJ. Severe Leukoencephalopathy with Clinical Recovery Caused by Recessive BOLA3 Mutations. JIMD Rep. 2019;43:63-70. doi: 10.1007/8904_2018_100. Epub 2018 Apr 14.

Köhler W, Curiel J, Vanderver A. Adulthood leukodystrophies. Nat Rev Neurol. 2018 Feb;14(2):94-105. doi: 10.1038/nrneurol.2017.175. Epub 2018 Jan 5.

Jenkinson EM, Rodero MP, Kasher PR, Uggenti C, Oojageer A, Goosey LC, Rose Y, Kershaw CJ, Urquhart JE, Williams SG, Bhaskar SS, O'Sullivan J, Baerlocher GM, Haubitz M, Aubert G, Barañano KW, Barnicoat AJ, Battini R, Berger A, Blair EM, Brunstrom-Hernandez JE, Buckard JA, Cassiman DM, Caumes R, Cordelli DM, De Waele LM, Fay AJ, Ferreira P, Fletcher NA, Fryer AE, Goel H, Hemingway CA, Henneke M, Hughes I, Jefferson RJ, Kumar R, Lagae L, Landrieu PG, Lourenço CM, Malpas TJ, Mehta SG, Metz I, Naidu S, Õunap K, Panzer A, Prabhakar P, Quaghebeur G, Schiffmann R, Sherr EH, Sinnathuray KR, Soh C, Stewart HS, Stone J, Van Esch H, Van Mol CE, Vanderver A, Wakeling EL, Whitney A, Pavitt GD, Griffiths-Jones S, Rice GI, Revy P, van der Knaap MS, Livingston JH, O'Keefe RT, Crow YJ. Corrigendum: Mutations in SNORD118 cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts. Nat Genet. 2017 Jan 31;49(2):317. doi: 10.1038/ng0217-317b.

Beijer D, Dohrn MF, Rebelo A, Danzi MC, Grosz BR, Ellis M, Kumar KR, Vucic S, Vais H, Weissenrieder JS, Lunko O, Paudel U, Simpson LC, Camarena V, Raposo J, Saporta M, Arcia Y, Xu I, Feely S, Record CJ, Blake J, Reilly MM, Scherer SS, Kennerson M, Lee YC, Foskett JK, Shy ME, Zuchner S. A recurrent missense variant in ITPR3 causes demyelinating Charcot-Marie-Tooth with variable severity. Brain. 2025 Jan 7;148(1):227-237. doi: 10.1093/brain/awae206. PMID: 38938188; PMCID: PMC11706300.

Charcot-Marie-Tooth disease (CMT) is a group of neuromuscular disorders that affect the peripheral nerves of the feet and hands, leading to neuropathy. Most cases of CMT type 1 (CMT1)—a form of CMT which causes demyelination, or problems with myelin (the fatty coating) around extremity nerves—are diagnosed via duplications in the PMP22 gene. However, CMT1 can also be caused by other genetic mutations.

In this study, researchers used whole exome and whole genome sequencing data to investigate new causal genes and mutations in CMT. The team analyzed data from 2,670 individuals with CMT neuropathy included in the GENESIS genomic research platform.

Results reveal that a recurrent missense variant in the gene ITPR3 causes CMT1. The variant was found in 33 individuals from nine unrelated families of multiple populations. Patients with the variant also showed differences in age at onset and severity, even within families. Authors note that these findings strengthen the gene-disease relationship in CMT1.

Record CJ, O'Connor A, Verbeek NE, van Rheenen W, Zamba Papanicolaou E, Peric S, Ligthart PC, Skorupinska M, van Binsbergen E, Campeau PM, Ivanovic V, Hennigan B, McHugh JC, Blake JC, Murakami Y, Laura M, Murphy SM, Reilly MM. Recessive Variants in PIGG Cause a Motor Neuropathy with Variable Conduction Block, Childhood Tremor, and Febrile Seizures: Expanding the Phenotype. Ann Neurol. 2025 Feb;97(2):388-396. doi: 10.1002/ana.27113. Epub 2024 Oct 23. PMID: 39444079; PMCID: PMC11740278.

Neuropathy is characterized by nerve damage resulting in muscle weakness, muscle atrophy, and abnormal sensations such as numbness, tingling, pins and needles, and pain in affected regions. While variants in the PIGG gene have been suspected to cause motor neuropathy—along with hypotonia, intellectual disability, seizures, and cerebellar involvement—these findings have not been confirmed.

In this study, researchers identified the first known patients with a distinct motor neuropathy caused by variants in the PIGG gene. The team used whole exome sequencing and whole genome sequencing to classify genetic variants.

Results revealed eight patients from six families with PIGG variants and a motor neuropathy associated with childhood-onset tremor, febrile seizures, and cerebellar involvement. Authors note that the PIGG gene should be considered in all unsolved cases of inherited motor neuropathy.

Reynolds EL, Koenig F, Watanabe M, Kwiatek A, Elafros MA, Stino A, Henderson D, Herrmann DN, Feldman EL, Callaghan BC. Comparison of intraepidermal nerve fiber density and confocal corneal microscopy for neuropathy. Ann Clin Transl Neurol. 2024 Dec;11(12):3115-3124. doi: 10.1002/acn3.52218. Epub 2024 Oct 12. PMID: 39394845; PMCID: PMC11651211.

Distal symmetric polyneuropathy (DSP) is a condition characterized by damage to the peripheral nerves of the feet and hands. Small fiber neuropathy (SFN), which is characterized by damage to small unmyelinated nerve fibers in the feet and hands, is an early sign in the development of DSP. Not much is known about how two diagnostic tools for neuropathy—intraepidermal nerve fiber density (IENFD) and confocal corneal microscopy (CCM)—compare, particularly in a population with obesity.

In this study, researchers compared the use of IENFD and CCM to diagnose DSP and SFN. In 140 individuals with obesity recruited from bariatric surgery clinics, researchers used both IENFD and CCM techniques to test for DSP and SFN prior to surgery. The team also compared these more invasive tests to the Michigan Neuropathy Screening Instrument questionnaire (MNSIq).

Results show that distal leg IENFD was the best quantitative measure of DSP and SFN. CCM showed poor diagnostic characteristics and lower preference among patients compared to IENFD. However, the MNSIq showed similar diagnostic characteristics to distal leg IENFD, demonstrating its potential as an easy-to-perform diagnostic tool for DSP and SFN.

Rehbein T, Purks J, Dilek N, Behrens-Spraggins S, Sowden JE, Eichinger KJ; ACT‐CMT Study Group; Burns J, Pareyson D, Scherer SS, Reilly MM, Shy ME, McDermott MP, Heatwole CR, Herrmann DN. Patient-reported disease burden in the Accelerate Clinical Trials in Charcot–Marie–Tooth Disease Study. J Peripher Nerv Syst. 2024 Dec;29(4):487-493. doi: 10.1111/jns.12662. Epub 2024 Oct 10. PMID: 39390667; PMCID: PMC11631656.

Charcot-Marie-Tooth disease (CMT) is a group of disorders that affect the peripheral nerves of the feet and hands, leading to neuropathy. Symptoms may include weakness, sensory loss, muscle atrophy, balance problems, and foot deformities.

In this study, researchers investigated patient perspectives on disease burden over time in CMT. As part of an international clinical trial readiness study, 215 individuals with CMT type 1A participated in clinical outcome assessments (including the CMT Health Index) to capture changes in patient-reported disease burden over 12 months.

Results show that patient-reported disease burden in CMT type 1A as measured by the CMT Health Index is associated with measures of neurologic impairment and physical functioning. Women reported a higher disease burden than men. Authors note that these data will inform the design of clinical trials in CMT type 1A.

Rossor AM, Haddad S, Reilly MM. The evolving spectrum of complex inherited neuropathies. Curr Opin Neurol. 2024 Oct 1;37(5):427-444. doi: 10.1097/WCO.0000000000001307. Epub 2024 Jul 31.

Fennessy JR, Cornett KMD, Donlevy GA, Mckay MJ, Burns J, Menezes MP. Long-term outcomes in children with riboflavin transporter deficiency and surveillance recommendations. Dev Med Child Neurol. 2024 Sep 9. doi: 10.1111/dmcn.16083. Epub ahead of print. PMID: 39252496.

Riboflavin transporter deficiency (RTD) is a progressive neurodegenerative disease characterized by paralysis of the cranial nerves, sensorineural deafness, and signs of damage to other nerves. Without treatment, children with RTD can experience life-threatening respiratory failure. The only known effective treatment is high-dose oral riboflavin. To provide accurate prognosis information to newly diagnosed families and learn if additional treatments are required, more data is needed about the long-term effects of oral riboflavin supplementation.

In this study, researchers explored the long-term outcomes of children with RTD who were supplemented with high-dose oral riboflavin. The team assessed disease progression in 11 children with RTD, following up each year until they transitioned to adult services.

Results show that children with RTD who were treated early after symptom onset had better long-term outcomes. However, although treatment with riboflavin slowed disease progression, patients were left with residual disability. To track disease progression and treatment response over time, authors recommend regular surveillance using the RTD Pediatric Scale, as well as the provided list of clinical measures.

Record CJ, Pipis M, Skorupinska M, Blake J, Poh R, Polke JM, Eggleton K, Nanji T, Zuchner S, Cortese A, Houlden H, Rossor AM, Laura M, Reilly MM. Whole genome sequencing increases the diagnostic rate in Charcot-Marie-Tooth disease. Brain. 2024 Sep 3;147(9):3144-3156. doi: 10.1093/brain/awae064. PMID: 38481354; PMCID: PMC11370804.

Charcot-Marie-Tooth disease (CMT) is one of the most common inherited neurological diseases, with more than 130 disease-causing genes. Although whole-genome sequencing has improved diagnosis across genetic diseases, the impact in CMT has not yet been explored.  

In this study, researchers investigated the impact of whole-genome sequencing on the diagnostic rate of CMT. The team reviewed diagnostic results from 1,515 patients with a clinical diagnosis of CMT and related disorders at a single specialist inherited neuropathy center.

Results show a 3.5% increase in the diagnostic rate of participants due to whole-genome sequencing. Although the center’s diagnostic rate is the highest reported, almost one-quarter of all cases are still unsolved. Authors note that a new reference genome and technologies will help to improve diagnosis.

Henning F, Naidu K, Record CJ, Dominik N, Vandrovcova J, Lubbe F, Dercksen M; ICGNMD Consortium; Wilson LA, Van Der Westhuizen F, Reilly MM, Houlden H, Hanna MG, Carr J. Extended Phenotype of PEX11B Pathogenic Variants: Ataxia, Tremor, and Dystonia Due to a Novel C.2T > G Variant. Mov Disord Clin Pract. 2024 Aug 2. doi: 10.1002/mdc3.14178. Epub ahead of print. PMID: 39092477.

Peroxisome biogenesis disorders (PBDs), also known as Zellweger spectrum, are a group of genetic conditions that affect many parts of the body. PBDs are characterized by failure of the body to produce properly functioning peroxisomes, which are membrane-bound organelles involved in a variety of metabolic reactions. These disorders are usually caused by variants in peroxin (PEX) genes.

In this report, researchers expand the phenotype of peroxisome biogenesis disorders by uncovering a new genetic variant. The team performed whole exome sequencing in two patients presenting with late-onset PBD, including movement disorders noticed at age 34 and 41, respectively.

Results revealed a new PEX11B variant in these patients. Symptoms included dystonia, ataxia, and tremor, which had not been previously described in PBDs. Authors note that movement disorders may only manifest at a later age in patients with PBD.

Yanick C, Maciel R, Jacobs E, Schatzman J, Shy M, Zuchner S, Saporta M. Generation of 3 patient induced Pluripotent stem cell lines containing SORD mutations linked to a recessive neuropathy. Stem Cell Res. 2024 Aug;78:103449. doi: 10.1016/j.scr.2024.103449. Epub 2024 May 22.

Maroofian R, Sarraf P, O'Brien TJ, Kamel M, Cakar A, Elkhateeb N, Lau T, Patil SJ, Record CJ, Horga A, Essid M, Selim L, Benrhouma H, Ben Younes T, Zifarelli G, Pagnamenta AT, Bauer P, Khundadze M, Mirecki A, Kamel SM, Elmonem MA, Ghayoor Karimiani E, Jamshidi Y, Offiah AC, Rossor AM, Youssef-Turki IB, Hübner CA, Munot P, Reilly MM, Brown AEX, Nagy S, Houlden H. RTN2 deficiency results in an autosomal recessive distal motor neuropathy with lower limb spasticity. Brain. 2024 Jul 5;147(7):2334-2343. doi: 10.1093/brain/awae091. PMID: 38527963; PMCID: PMC11224604.

Distal hereditary motor neuropathies (dHMNs) are a diverse group of rare neuromuscular disorders characterized by muscle weakness and atrophy. Clinical and genetic overlap among hereditary neurological disorders highlights the potential of a shared molecular cause.

In this study, researchers describe a new subtype of recessive dHMN caused by deficiency of the RTN2 protein. The team used exome, genome, and Sanger sequencing techniques coupled with deep-phenotyping to identify and validate seven new or ultra-rare variants in the RTN2 gene in 14 individuals with dHMN.

Findings reveal that this new subtype shares similarities with two other subtypes of dHMN—SIGMAR1-related disorder and Silver-like syndromes. Authors note that this study provides valuable insights on the clinical spectrum and potential therapeutic strategies for RTN2-related dHMN.

Xu IRL, Danzi MC, Ruiz A, Raposo J, De Jesus YA, Reilly MM, Cortese A, Shy ME, Scherer SS, Herrmann DN, Fridman V, Baets J, Saporta M, Seyedsadjadi R, Stojkovic T, Claeys KG, Patel P, Feely S, Rebelo AP. A study concept of expeditious clinical enrollment for genetic modifier studies in Charcot-Marie-Tooth neuropathy 1A. J Peripher Nerv Syst. 2024 Jun;29(2):202-212. doi: 10.1111/jns.12621. Epub 2024 Apr 5. PMID: 38581130; PMCID: PMC11209807.

Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common form of hereditary neuropathy. Although all cases of CMT1A are caused by duplications of the PMP22 gene, each case can have significant differences in severity, which may result from genetic modifiers.

In this study, researchers analyzed genetic modifiers to characterize severity in patients with CMT1A. The team reviewed clinical examination results from 1,564 patients in a natural history study conducted by the Inherited Neuropathy Consortium (INC). Next, the team identified extreme cases (mild and severe) among these patients.

Results reveal insights on genetic modifiers that have significant effects on the severity and course of CMT1A. Authors note that the metrics used in this study can also improve patient enrollment strategies for future studies.

Murray GC, Hines TJ, Tadenev ALD, Xu I, Zuchner S, Burgess RW. Testing SIPA1L2 as a modifier of CMT1A using mouse models. J Neuropathol Exp Neurol. 2024 Mar 12:nlae020. doi: 10.1093/jnen/nlae020. Online ahead of print.

Tomaselli PJ, Blake J, Polke JM, do Nascimento OJM, Reilly MM, Marques Júnior W, Laurá M. Intermediate conduction velocity in two cases of Charcot-Marie-Tooth disease type 1A. Eur J Neurol. 2024 Feb 26:e16199. doi: 10.1111/ene.16199. Epub ahead of print. PMID: 38409938.

Charcot-Marie-Tooth disease type 1A (CMT1A), the most common form of inherited peripheral neuropathy, is caused by duplication of the PMP22 gene. Individuals with CMT1A experience slow nerve conduction velocity (the speed of electrical impulses moving through nerves). Because most patients have nerve conduction rates below 38 meters per second, genetic testing for PMP22 duplication is not usually recommended for those with higher rates. 

In this study, researchers report cases of intermediate nerve conduction velocity in two patients with CMT1A. Both individuals had upper limb motor nerve conduction velocities above 38 meters per second. These patients also presented with very mild forms of CMT1A.

Authors note that although these cases are very rare, they highlight the importance of testing PMP22 duplication in patients with intermediate conduction velocities.

Ptak CP, Peterson TA, Hopkins JB, Ahern CA, Shy ME, Piper RC. Homomeric interactions of the MPZ Ig domain and their relation to Charcot-Marie-Tooth disease. Brain. 2023 Dec 1;146(12):5110-5123. doi: 10.1093/brain/awad258.

Rebelo AP, Tomaselli PJ, Medina J, Wang Y, Dohrn MF, Nyvltova E, Danzi MC, Garrett M, Smith SE, Pestronk A, Li C, Ruiz A, Jacobs E, Feely SME, França MC, Gomes MV, Santos DF, Kumar S, Lombard DB, Saporta M, Hekimi S, Barrientos A, Weihl C, Shy ME, Marques W, Zuchner S. Biallelic variants in COQ7 cause distal hereditary motor neuropathy with upper motor neuron signs. Brain. 2023 Oct 3;146(10):4191-4199. doi: 10.1093/brain/awad158.

Pipis M, Won S, Poh R, Efthymiou S, Polke JM, Skorupinska M, Blake J, Rossor AM, Moran JJ, Munot P, Muntoni F, Laura M, Svaren J, Reilly MM. Post-transcriptional microRNA repression of PMP22 dose in severe Charcot-Marie-Tooth disease type 1. Brain. 2023 Oct 3;146(10):4025-4032. doi: 10.1093/brain/awad203. PMID: 37337674; PMCID: PMC10545524

Charcot-Marie-Tooth disease type 1A (CMT1A), the most common form of inherited peripheral neuropathy, is caused by a copy number variation (CNV) in the PMP22 gene. In rodent models of CMT1A, overexpression of miR-29a, a type of microRNA, has been shown to reduce the PMP22 transcript and protein level.

In this study, researchers demonstrate for the first time how imbalance in the microRNA-mediated regulation of gene expression can mimic a CNV-associated disease in humans. Study participants included a family of CMT1A patients enrolled in a natural history study.

Authors state that these findings show the importance of miR-29a in regulating PMP22 expression and could lead to development of new therapeutic drugs.

Cortese A, Currò R, Ronco R, Blake J, Rossor AM, Bugiardini E, Laurà M, Warner T, Yousry T, Poh R, Polke J, Rebelo A, Dohrn MF, Saporta M, Houlden H, Zuchner S, Reilly MM. Mutations in alpha-B-crystallin cause autosomal dominant axonal Charcot-Marie-Tooth disease with congenital cataracts. Eur J Neurol. 2023 Sep 29. doi: 10.1111/ene.16063. Epub ahead of print. PMID: 37772343

Charcot–Marie–Tooth disease type 2 (CMT2), also known as hereditary motor and sensory neuropathy, is a disorder affecting nerve axons (ends of the nerves) which carry signals from the brain to the extremities. While mutations in the alpha-B-crystallin (CRYAB) gene have been associated with myofibrillar myopathy, dilated cardiomyopathy, and cataracts, they have not previously included peripheral neuropathy.

In this study, researchers expand the phenotype (observable characteristics) of CRYAB-related disease to include CMT2. The team performed whole-exome sequencing in two unrelated families with genetically unsolved axonal CMT2, assessing clinical, neurophysiological, and radiological features.

Results identify CRYAB mutations as a cause of CMT2 in these patients. Authors note that CRYAB mutations should be suspected in cases with late-onset CMT2, especially in the presence of congenital cataracts.

Rehbein T, Wu TT, Treidler S, Pareyson D, Lewis R, Yum SW, McCray BA, Ramchandren S, Burns J, Li J, Finkel RS, Scherer SS, Zuchner S, Shy ME, Reilly MM, Herrmann DN. Neuropathy due to bi-allelic SH3TC2 variants: genotype-phenotype correlation and natural history. Brain. 2023 Sep 1;146(9):3826-3835. doi: 10.1093/brain/awad095. PMID: 36947133; PMCID: PMC10473553

Charcot-Marie-Tooth disease type 4C (CMT4C) is an inherited, degenerative disorder affecting the nerves that travel to the feet and hands. CMT4C is caused by recessive variants in the SH3TC2 gene and characterized by early onset spinal deformities, as well as a wide spectrum of symptoms and severity. Currently, not much is known about the relationship between pathogenic (disease-causing) variants and disease manifestations.

In this study, researchers explored the natural history of CMT4C by gathering genetic and clinical data from the Inherited Neuropathy Consortium (INC). The team examined symptoms, neurological examinations, and neurophysiological characteristics over time in 56 individuals with CMT4C.

The resulting analysis marks the largest cross-sectional and only longitudinal study to date of the clinical phenotype of both adults and children with CMT4C. Authors note that by further defining the natural history of CMT4C, these data will help inform study design of future clinical trials for genetic treatments.

Wu TT, Finkel RS, Siskind CE, Feely SME, Burns J, Reilly MM, Muntoni F, Milev E, Estilow T, Shy ME, Ramchandren S; Childhood CMT Study Group of the Inherited Neuropathy Consortium. Validation of the parent-proxy version of the pediatric Charcot-Marie-Tooth disease quality of life instrument for children aged 0-7 years. J Peripher Nerv Syst. 2023 Sep;28(3):382-389. doi: 10.1111/jns.12557. Epub 2023 May 18.

Donlevy GA, Cornett KMD, Garnett SP, Shy R, Estilow T, Yum SW, Anderson K, Pareyson D, Moroni I, Muntoni F, Reilly MM, Finkel RS, Herrmann DN, Eichinger KJ, Shy ME, Burns J, Menezes MP. Association of Body Mass Index With Disease Progression in Children With Charcot-Marie-Tooth Disease. Neurology. 2023 Aug 15;101(7):e717-e727. doi: 10.1212/WNL.0000000000207488. Epub 2023 Jun 28. PMID: 37380432; PMCID: PMC10437011

Charcot-Marie-Tooth disease (CMT) is a group of disorders that affect the peripheral nerves, which connect the brain and spinal cord to muscles and sensory cells. Symptoms include weakness, sensory loss, muscle atrophy (wasting), and foot deformities.

In this study, researchers evaluated the impact of body mass index (BMI) on disease progression over two years in children with CMT. Among 242 participants aged 3–20 years with CMT, the team categorized groups by BMI and assessed disease severity using the CMT Pediatric Scale (CMTPedS).

Results show that children with CMT who were severely underweight, underweight, or obese exhibited greater disability at baseline. Over the two-year period in those whose BMI remained stable, severely underweight children deteriorated at the fastest rate. For children who changed BMI categories over the two years, CMTPedS scores deteriorated faster in those who became overweight or obese. Authors note that interventions to maintain or improve BMI toward healthy weight may reduce disability in children with CMT.

Ajjarapu A, Feely SME, Shy ME, Trout C, Zuchner S, Moore SA, Mathews KD. Thirty-Year Follow-Up of Early Onset Amyotrophic Lateral Sclerosis with a Pathogenic Variant in SPTLC1. Case Rep Neurol. 2023 Jun 12;15(1):146-152. doi: 10.1159/000530974. eCollection 2023 Jan-Dec.

Record CJ, Skorupinska M, Laura M, Rossor AM, Pareyson D, Pisciotta C, Feely SME, Lloyd TE, Horvath R, Sadjadi R, Herrmann DN, Li J, Walk D, Yum SW, Lewis RA, Day J, Burns J, Finkel RS, Saporta MA, Ramchandren S, Weiss MD, Acsadi G, Fridman V, Muntoni F, Poh R, Polke JM, Zuchner S, Shy ME, Scherer SS, Reilly MM; Inherited Neuropathies Consortium - Rare Disease Clinical Research Network. Genetic analysis and natural history of Charcot-Marie-Tooth disease CMTX1 due to GJB1 variants. Brain. 2023 Jun 7:awad187. doi: 10.1093/brain/awad187. Online ahead of print.

Zhu Y, Lobato AG, Rebelo AP, Canic T, Ortiz-Vega N, Tao X, Syed S, Yanick C, Saporta M, Shy M, Perfetti R, Shendelman S, Zuchner S, Zhai RG. Sorbitol reduction via govorestat ameliorates synaptic dysfunction and neurodegeneration in sorbitol dehydrogenase deficiency. JCI Insight. 2023 May 22;8(10):e164954. doi: 10.1172/jci.insight.164954.

Reilly MM, Herrmann DN, Pareyson D, Scherer SS, Finkel RS, Zuchner S, Burns J, Shy ME. Trials for Slowly Progressive Neurogenetic Diseases Need Surrogate Endpoints. Ann Neurol. 2023 May;93(5):906-910. doi: 10.1002/ana.26633. Epub 2023 Mar 21.

Record CJ, Pipis M, Poh R, Polke JM, Reilly MM. Beware next-generation sequencing gene panels as the first-line genetic test in Charcot-Marie-Tooth disease. J Neurol Neurosurg Psychiatry. 2023 Apr;94(4):327-328. doi: 10.1136/jnnp-2022-330223. Epub 2022 Nov 14.

Silsby M, Feldman EL, Dortch RD, Roth A, Haroutounian S, Rajabally YA, Vucic S, Shy ME, Oaklander AL, Simon NG. Advances in diagnosis and management of distal sensory polyneuropathies. J Neurol Neurosurg Psychiatry. 2023 Mar 30:jnnp-2021-328489. doi: 10.1136/jnnp-2021-328489. Online ahead of print.

Fridman V, Sillau S, Bockhorst J, Smith K, Moroni I, Pagliano E, Pisciotta C, Piscosquito G, Laurá M, Muntoni F, Bacon C, Feely S, Grider T, Gutmann L, Shy R, Wilcox J, Herrmann DN, Li J, Ramchandren S, Sumner CJ, Lloyd TE, Day J, Siskind CE, Yum SW, Sadjadi R, Finkel RS, Scherer SS, Pareyson D, Reilly MM, Shy ME; Inherited Neuropathies Consortium-Rare Diseases Clinical Research Network. Disease Progression in Charcot-Marie-Tooth Disease Related to MPZ Mutations: A Longitudinal Study. Ann Neurol. 2023 Mar;93(3):563-576. doi: 10.1002/ana.26518. Epub 2022 Oct 28.

Leone E, Davenport S, Robertson C, Laurà M, Skorupinska M, Reilly MM, Ramdharry G. Incidence and risk factors for patellofemoral dislocation in adults with Charcot-Marie-Tooth disease: An observational study. Physiother Res Int. 2023 Feb 19;28(3):e1996. doi: 10.1002/pri.1996. Online ahead of print.

Wu TT, Finkel RS, Siskind CE, Feely SME, Burns J, Reilly MM, Muntoni F, Estilow T, Shy ME, Ramchandren S; Childhood CMT Study Group of the Inherited Neuropathy Consortium. Validation of the parent-proxy pediatric Charcot-Marie-Tooth disease quality of life outcome measure. J Peripher Nerv Syst. 2023 Feb 7. doi: 10.1111/jns.12538. Epub ahead of print. PMID: 36748295.

Charcot-Marie-Tooth disease (CMT) is a group of genetic disorders that affect the peripheral nerves, which connect the brain and spinal cord to muscles and sensory endings. With symptoms including weakness, sensory loss, muscle atrophy (wasting), balance problems, and foot deformities, CMT is known to reduce health-related quality of life (QOL) in children as well as adults. However, there is currently no parent-proxy CMT QOL outcome measure for use in children for either natural history studies or clinical trials. 

In this study, researchers describe the validation of the parent-proxy pediatric CMT-QOL outcome measure for children aged 8 to 18 years. After developing a working version of the outcome measure, the team administered this version to 358 parents of children with CMT seen at the participating study sites of the Inherited Neuropathy Consortium from 2010 to 2016. Results from the parent-proxy version were compared with previously published results completed by the children themselves. To develop the final version, researchers performed rigorous tests of the data, including psychometric analysis, factor analysis, test-retest reliability, internal consistency, convergent validity, IRT analysis, and longitudinal analysis.

Results show that the parent-proxy version of the pediatric CMT-QOL outcome measure is a reliable, valid, and sensitive proxy measure of health-related QOL for children aged 8 to 18 with CMT.

Kapoor M, Carr A, Foiani M, Heslegrave A, Zetterberg H, Malaspina A, Compton L, Hutton E, Rossor A, Reilly MM, Lunn MP. Association of plasma neurofilament light chain with disease activity in chronic inflammatory demyelinating polyradiculoneuropathy. Eur J Neurol. 2022 Nov;29(11):3347-3357. doi: 10.1111/ene.15496. Epub 2022 Jul 25.

Malcorps M, Amor-Barris S, Burnyte B, Vilimiene R, Armirola-Ricaurte C, Grigalioniene K, Ekshteyn A, Morkuniene A, Vaitkevicius A, De Vriendt E, Baets J, Scherer SS, Ambrozaityte L, Utkus A, Jordanova A, Peeters K. HINT1 neuropathy in Lithuania: clinical, genetic, and functional profiling. Orphanet J Rare Dis. 2022 Oct 14;17(1):374. doi: 10.1186/s13023-022-02541-0. PMID: 36242072; PMCID: PMC9569031.

Neuromyotonia and axonal neuropathy (NMAN) is a rare peripheral neuropathy and subtype of Charcot-Marie-Tooth disease. NMAN is characterized by damage to nerve axons (nerve ends) and overactivation of peripheral nerves. The disease is caused by mutations in the HINT1 gene, which are among the most common causes of recessive neuropathy. Most patients with NMAN are found to have an HINT1 variant that has spread throughout Eurasia and America. In this study, researchers performed the first analysis of NMAN in Lithuania. The team identified eight patients from 46 families with variations in the HINT1 gene, including a new variant. Study participants showed typical symptoms associated with NMAN (such as motor impairment in lower limbs), but also some atypical features (such as developmental delay and mood problems). In addition to expanding the understanding of NMAN, these findings may help diagnose inherited neuropathies in the Baltic region and beyond. Authors note that study results could also impact future therapeutic strategies, as a patient’s specific genetic mutation will determine their treatment options.

Record CJ, Alsukhni RA, Curro R, Kaski D, Rubin JS, Morris HR, Cortese A, Iodice V, Reilly MM. Severe distinct dysautonomia in RFC1-related disease associated with Parkinsonism. J Peripher Nerv Syst. 2022 Sep 30. doi: 10.1111/jns.12515. Epub ahead of print. PMID: 36177974.

Recently, biallelic (both alleles of a single gene) expansions in the RFC1 gene have been found to cause several neurological disorders in addition to a form of inherited neuropathy known as CANVAS (cerebellar ataxia, neuropathy, and vestibular areflexia syndrome). There are also descriptions of Parkinsonism and a multiple system atrophy (MSA)-like syndrome. However, the profile of the autonomic nervous system in a patient with CANVAS/MSA-like overlap syndrome had not yet been fully characterized. In this study, researchers present the first detailed description of autonomic characteristics in a patient with multisystem RFC1-related disease. Initially presenting with CANVAS, the patient developed Parkinsonism, cardiovascular failure, and severe autonomic failure similar to classical MSA. Results suggest that patients with an MSA-like syndrome, plus signs of vestibular (balance) failure or sensory neuropathy, should be tested for the RFC1 expansion. Authors also note that the link between MSA and CANVAS should be further explored.

Eichinger K, Sowden JE, Burns J, McDermott MP, Krischer J, Thornton J, Pareyson D, Scherer SS, Shy ME, Reilly MM, Herrmann DN. Accelerate Clinical Trials in Charcot-Marie-Tooth Disease (ACT-CMT): A Protocol to Address Clinical Trial Readiness in CMT1A. Front Neurol. 2022 Jun 27;13:930435. doi: 10.3389/fneur.2022.930435. eCollection 2022.

Yiu EM, Bray P, Baets J, Baker SK, Barisic N, de Valle K, Estilow T, Farrar MA, Finkel RS, Haberlová J, Kennedy RA, Moroni I, Nicholson GA, Ramchandren S, Reilly MM, Rose K, Shy ME, Siskind CE, Yum SW, Menezes MP, Ryan MM, Burns J. Clinical practice guideline for the management of paediatric Charcot-Marie-Tooth disease. J Neurol Neurosurg Psychiatry. 2022 May;93(5):530-538. doi: 10.1136/jnnp-2021-328483. Epub 2022 Feb 9.

Record CJ, Pipis M, Blake J, Curro R, Lunn MP, Rossor AM, Laura M, Cortese A, Reilly MM. Unusual upper limb features in SORD neuropathy. J Peripher Nerv Syst. 2022 Apr 13. doi: 10.1111/jns.12492. Online ahead of print.

Morikawa M, Jerath NU, Ogawa T, Morikawa M, Tanaka Y, Shy ME, Zuchner S, Hirokawa N. A neuropathy-associated kinesin KIF1A mutation hyper-stabilizes the motor-neck interaction during the ATPase cycle. EMBO J. 2022 Mar 1;41(5):e108899. doi: 10.15252/embj.2021108899. Epub 2022 Feb 8. PMID: 35132656.

Charcot-Marie-Tooth (CMT) is a group of inherited, degenerative disorders affecting the nerves that travel to the feet and hands, causing muscle weakness, problems with balance and sensation as well as other symptoms. Axonal transport (a process essential for nerve development, function, and survival) mediated by the KIF1A gene is driven by interaction cycles between the kinesin (motor protein)’s motor and neck domains. In this study, researchers characterized a KIF1A mutant identified in a family with axonal-type CMT and other cases of human neuropathies. This characterization reveals that dynamic dissociation of the motor-neck interaction via the β7 (integrin protein) domain is essential for neuronal function.

Pipis M, Cortese A, Polke JM, Poh R, Vandrovcova J, Laura M, Skorupinska M, Jacquier A, Juntas-Morales R, Latour P, Petiot P, Sole G, Fromes Y, Shah S, Blake J, Choi BO, Chung KW, Stojkovic T, Rossor AM, Reilly MM. Charcot-Marie-Tooth disease type 2CC due to NEFH variants causes a progressive, non-length-dependent, motor-predominant phenotype. J Neurol Neurosurg Psychiatry. 2022 Jan;93(1):48-56. doi: 10.1136/jnnp-2021-327186. Epub 2021 Sep 13. PMID: 34518334; PMCID: PMC8685631.

Researchers seeking to better understand axonal Charcot-Marie-Tooth disease type 2CC (CMT2CC) conducted an observational study of 30 affected and 3 asymptomatic mutation carriers from 8 families, examining phenotype-genotype correlations. Study subjects had variants in the gene NEFH, which is thought to cause CMT2CC. Researchers found that most patients developed lower-limb predominant symptoms in adulthood. The disease progressed more rapidly than is typically seen in other CMT subtypes, and half of patients needed to use a wheelchair an average of 24.1 years after symptoms began. They found that that the unusual phenotype of CMT2CC is more similar to spinal muscular atrophy than classic CMT. Study authors said that these findings should allow a better understanding of the natural history of the disease and aid in variant interpretation.

Rossor AM, Kapoor M, Wellington H, Spaulding E, Sleigh JN, Burgess RW, Laura M, Zetterberg H, Bacha A, Wu X, Heslegrave A, Shy ME, Reilly MM. A longitudinal and cross-sectional study of plasma neurofilament light chain concentration in Charcot-Marie-Tooth disease. J Peripher Nerv Syst. 2021 Dec 1. doi: 10.1111/jns.12477. Online ahead of print.

Kapoor M, Compton L, Rossor A, Hutton E, Manji H, Lunn M, Reilly M, Carr A. An approach to assessing immunoglobulin dependence in chronic inflammatory demyelinating inflammatory polyneuropathy. J Peripher Nerv Syst. 2021 Dec;26(4):461-468. doi: 10.1111/jns.12470. Epub 2021 Oct 20.

Ramdharry GM, Wallace A, Hennis P, Dewar E, Dudziec M, Jones K, Pietrusz A, Reilly MM, Hanna MG. Cardiopulmonary exercise performance and factors associated with aerobic capacity in neuromuscular diseases. Muscle Nerve. 2021 Dec;64(6):683-690. doi: 10.1002/mus.27423. Epub 2021 Oct 6.

Gilley J, Jackson O, Pipis M, Estiar MA, Al-Chalabi A, Danzi MC, van Eijk KR, Goutman SA, Harms MB, Houlden H, Iacoangeli A, Kaye J, Lima L; Queen Square Genomics; Ravits J, Rouleau GA, Schüle R, Xu J, Züchner S, Cooper-Knock J, Gan-Or Z, Reilly MM, Coleman MP. Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders. Elife. 2021 Nov 19;10:e70905. doi: 10.7554/eLife.70905. PMID: 34796871; PMCID: PMC8735862.

SARM1 is a protein with critical NAD-glycohydrolase (NADase) activity. This protein drives axon (nerve fiber) degeneration, a characteristic of many neurodegenerative diseases. In this study, researchers screened patient data for mutations associated with amyotrophic lateral sclerosis (ALS). They discovered disease-associated variant alleles that alter SARM1 function, hyperactivating the NADase activity that drives degeneration. The authors conclude that these may represent risk alleles for ALS and other motor nerve diseases. These findings highlight the role of axonal degeneration in motor neuron diseases. The study also provides a rationale for SARM1-directed therapeutic intervention.

Baty K, Farrugia ME, Hopton S, Falkous G, Schaefer AM, Stewart W, Willison HJ, Reilly MM, Blakely EL, Taylor RW, Ng YS. A novel MT-CO2 variant causing cerebellar ataxia and neuropathy: The role of muscle biopsy in diagnosis and defining pathogenicity. Neuromuscul Disord. 2021 Nov;31(11):1186-1193. doi: 10.1016/j.nmd.2021.05.014. Epub 2021 Jun 4.

McCray BA, Scherer SS. Axonal Charcot-Marie-Tooth Disease: from Common Pathogenic Mechanisms to Emerging Treatment Opportunities. Neurotherapeutics. 2021 Oct 4. doi: 10.1007/s13311-021-01099-2. Online ahead of print.

In this review paper, two researchers associated with the Inherited Neuropathies Consortium offer an overview of Charcot-Marie-Tooth disease type 2 (CMT2), a group of genetic neuropathies that primarily cause axonal degeneration (damage to the portion of the nerve that carries nerve impulses away from the cell body) rather than demyelination (damage to the protective covering that surrounds nerve fibers). They review gene identification efforts over the past three decades and emerging treatment strategies. Promising strategies include specific approaches for single forms of neuropathy as well as more general approaches that have the potential to treat multiple types of neuropathy. The INC is particularly pleased because coauthor Brett Andrew McCray, MD, PhD, of Johns Hopkins is a recent INC scholar who was supported by a Career Enhancement Award.

Spaulding EL, Hines TJ, Bais P, Tadenev ALD, Schneider R, Jewett D, Pattavina B, Pratt SL, Morelli KH, Stum MG, Hill DP, Gobet C, Pipis M, Reilly MM, Jennings MJ, Horvath R, Bai Y, Shy ME, Alvarez-Castelao B, Schuman EM, Bogdanik LP, Storkebaum E, Burgess RW. The integrated stress response contributes to tRNA synthetase-associated peripheral neuropathy. Science. 2021 Sep 3;373(6559):1156-1161. doi: 10.1126/science.abb3414. Epub 2021 Sep 1.

Researchers have identified a pathway common to several types of axonal peripheral neuropathies (APNs), including multiple forms of Charcot-Marie-Tooth (CMT) disease, and have identified a possible drug target that could help treat the disorder. The research was led by Robert W. Burgess, PhD, Emily Spaulding, and their team at The Jackson Laboratory in Maine. Researchers with the RDCRN’s Inherited Neuropathies Consortium (INC) contributed by providing patient material to add a human disease component to the team’s efforts. “The serum samples provide by the INC were a way for us to test whether the same mechanisms we found in our mouse models were also involved in patients,” says Burgess, senior author on the study. “As an unexpected bonus, it led to the identification of GDF15 as a possible biomarker, which is being investigated further.” The study, which was published in Science, was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health, and featured in a recent NIH media advisory. APNs cause the body’s peripheral nerves to wither and degenerate, which makes them unable to send messages to the muscles or to transmit sensory signals back to the spinal cord. While usually not life-threatening, APNs typically result in some measure of disability. Genetic studies have shown that many APNs are caused by mutations that affect how proteins are built within cells. Proteins are made by first transcribing the DNA code into messenger RNA (mRNA). The mRNA is then transcribed by transfer RNA (tRNA) molecules that string together amino acids in the proper sequence, like building a train track. The mutations underlying APNs affect the enzymes responsible for adding amino acid blocks to tRNA. Previous work in flies showed that these mutations inhibit cells’ ability to make proteins. This causes stress within the motor neurons affected by APNs, particularly through a mechanism called the integrated stress response (ISR), ultimately leading to degeneration of nerve structures. Of the proteins previously implicated in the activation of the ISR, one of them, GCN2, had also been connected to defects in protein translation. Using a mouse model, the researchers looked at APN mice that were also missing GCN2. These mice began to develop symptoms of the disease around two weeks of age, but the disease did not progress much beyond the initial stages. When the APN mice were instead treated with a drug to stop GCN2 from working, they showed improvements in many symptoms.

Cintra VP, Dohrn MF, Tomaselli PJ, Figueiredo FB, Marques SE, Camargos ST, Barbosa LSM, P Rebelo A, Abreu L, Danzi M, Marques W Jr, Zuchner S. Rare mutations in ATL3, SPTLC2 and SCN9A explaining hereditary sensory neuropathy and congenital insensitivity to pain in a Brazilian cohort. J Neurol Sci. 2021 Aug 15;427:117498. doi: 10.1016/j.jns.2021.117498. Epub 2021 May 18.

Heredity sensory neuropathies (HSNs) are rare neurological disorders where peripheral neurons and axons are affected, leading to delayed sensations of pain, delayed healing, infections, osteomyelitis, and infections. Researchers performed a whole genome sequencing (WGS) study of 23 unrelated Brazilian families diagnosed with hereditary sensory neuropathies. They detected pathogenic variants in 21.7% of families that caused symptoms such as congenital insensitivity to pain, sensory deficits, neuropathic pain, and recurrent ulcerations. Authors suggest that most of the cases could be explained by yet to be discovered genes or unusual alleles. They say that first mutational screen in a Brazilian HSN cohort offers insights for genotype-phenotype correlations, reducing misdiagnoses, and providing early treatment considerations.

Wang H, Davison M, Wang K, Xia TH, Call KM, Luo J, Wu X, Zuccarino R, Bacha A, Bai Y, Gutmann L, Feely SME, Grider T, Rossor AM, Reilly MM, Shy ME, Svaren J. MicroRNAs as Biomarkers of Charcot-Marie-Tooth Disease Type 1A. Neurology. 2021 Aug 3;97(5):e489-e500. doi: 10.1212/WNL.0000000000012266. Epub 2021 May 24.

Charcot-Marie-Tooth disease type 1A (CMT1A) is an inherited neurological disorder that affects the peripheral nerves of patients, causing weakness and wasting of the muscles of the lower legs, hand weakness, and sensory loss. To identify candidate biomarkers for clinical trials in CMT1A, researchers performed microRNA (miR) profiling on control and CMT1A plasma with the goal of determining whether microRNAs are elevated in affected individuals. Results confirmed elevated levels of several muscle-associated miRNAs (miR1, -133a, -133b, and -206, known as myomiRs) along with a set of miRs that are highly expressed in Schwann cells of peripheral nerves. Authors say the study provides Class III evidence that a set of plasma mIRs are elevated in patients with CMT1A.

Clark AJ, Kugathasan U, Baskozos G, Priestman DA, Fugger N, Lone MA, Othman A, Chu KH, Blesneac I, Wilson ER, Laura M, Kalmar B, Greensmith L, Hornemann T, Platt FM, Reilly MM, Bennett DL. An iPSC model of hereditary sensory neuropathy-1 reveals L-serine-responsive deficits in neuronal ganglioside composition and axoglial interactions. Cell Rep Med. 2021 Jul 21;2(7):100345. doi: 10.1016/j.xcrm.2021.100345. eCollection 2021 Jul 20.

Hamedani AG, Wilson JA, Avery RA, Scherer SS. Optic Neuropathy in Charcot-Marie-Tooth Disease. J Neuro Ophthalmol. 2021 Jun 1;41(2):233-238. doi: 10.1097/WNO.0000000000000965.

Ramdharry G, Singh D, Gray J, Kozyra D, Skorupinska M, Reilly MM, Laura M. A prospective study on surgical management of foot deformities in Charcot Marie tooth disease. J Peripher Nerv Syst. 2021 Jun;26(2):187-192. doi: 10.1111/jns.12437. Epub 2021 Mar 13.

Rebelo AP, Cortese A, Abraham A, Eshed-Eisenbach Y, Shner G, Vainshtein A, Buglo E, Camarena V, Gaidosh G, Shiekhattar R, Abreu L, Courel S, Burns DK, Bai Y, Bacon C, Feely SME, Castro D, Peles E, Reilly MM, Shy ME, Zuchner S. A CADM3 variant causes Charcot-Marie-Tooth disease with marked upper limb involvement. Brain. 2021 May 7;144(4):1197-1213. doi: 10.1093/brain/awab019.

Researchers used whole exome sequencing in three unrelated families with axonal Charcot-Marie-Tooth disease (CMT2) to identify a unique pathogenic variant causing CMT with marked upper limb involvement. CMT2 is a group of genetic neuropathies that primarily cause axonal degeneration (damage to the portion of the nerve that carries nerve impulses away from the cell body). The variant identified is in the CADM family of proteins, which mediate the contact and interaction between axons and the glia (non-neuronal cells that form myelin in the peripheral nervous system and support and protect neurons). The families studied all shared the same private variant in CADM3, Tyr172Cys. Findings were also confirmed in mouse studies. Researchers conclude that this abnormal axon-glia interaction is a disease-causing mechanism in CMT patients with CADM3 mutations. This is the first example that directly disrupting the interactions between glia and axons is sufficient to cause neuropathy.

Howard P, Feely SME, Grider T, Bacha A, Scarlato M, Fazio R, Quattrini A, Shy ME, Previtali SC. Loss of function MPZ mutation causes milder CMT1B neuropathy. J Peripher Nerv Syst. 2021 May 7. doi: 10.1111/jns.12452. Online ahead of print.

Jurkute N, Shanmugarajah PD, Hadjivassiliou M, Higgs J, Vojcic M, Horrocks I, Nadjar Y, Touitou V, Lenaers G, Poh R, Acheson J, Robson AG, Raymond FL, Reilly MM, Yu-Wai-Man P, Moore AT, Webster AR, Arno G; Genomics England Research Consortium. Expanding the FDXR-Associated Disease Phenotype: Retinal Dystrophy Is a Recurrent Ocular Feature. Invest Ophthalmol Vis Sci. 2021 May 3;62(6):2. doi: 10.1167/iovs.62.6.2.

Vujovic D, Cornblath DR, Scherer SS. A recurrent MORC2 mutation causes Charcot-Marie-Tooth disease type 2Z. J Peripher Nerv Syst. 2021 Apr 12. doi: 10.1111/jns.12443. Online ahead of print.

Sullivan R, Yau WY, Chelban V, Rossi S, Dominik N, O'Connor E, Hardy J, Wood N, Cortese A, Houlden H. RFC1-related ataxia is a mimic of early multiple system atrophy. J Neurol Neurosurg Psychiatry. 2021 Feb 9;92(4):444-6. doi: 10.1136/jnnp-2020-325092. Online ahead of print.

Ramchandren S, Wu TT, Finkel RS, Siskind CE, Feely SME, Burns J, Reilly MM, Estilow T, Shy ME; Childhood CMT Study Group. Development and Validation of the Pediatric Charcot-Marie-Tooth Disease Quality of Life Outcome Measure. Ann Neurol. 2021 Feb;89(2):369-379. doi: 10.1002/ana.25966. Epub 2020 Dec 7.

Zuccarino R, Anderson KM, Shy ME, Wilken JM. Satisfaction with ankle foot orthoses in individuals with Charcot-Marie-Tooth disease. Muscle Nerve. 2021 Jan;63(1):40-45. doi: 10.1002/mus.27027. Epub 2020 Aug 26.

Senderek J, Lassuthova P, Kabzińska D, Abreu L, Baets J, Beetz C, Braathen GJ, Brenner D, Dalton J, Dankwa L, Deconinck T, De Jonghe P, Dräger B, Eggermann K, Ellis M, Fischer C, Stojkovic T, Herrmann DN, Horvath R, Høyer H, Iglseder S, Kennerson M, Kinslechner K, Kohler JN, Kurth I, Laing NG, Lamont PJ, Wolfgang N L, Ludolph A, Marques W Jr, Nicholson G, Ong R, Petri S, Ravenscroft G, Rebelo A, Ricci G, Rudnik-Schöneborn S, Schirmacher A, Schlotter-Weigel B, Schoels L, Schüle R, Synofzik M, Francou B, Strom TM, Wagner J, Walk D, Wanschitz J, Weinmann D, Weishaupt J, Wiessner M, Windhager R, Young P, Züchner S, Toegel S, Seeman P, Kochański A, Auer-Grumbach M. The genetic landscape of axonal neuropathies in the middle-aged and elderly: Focus on MME. Neurology. 2020 Dec 15;95(24):e3163-e3179. doi: 10.1212/WNL.0000000000011132. Epub 2020 Nov 3.

Pipis M, Feely SME, Polke JM, Skorupinska M, Perez L, Shy RR, Laura M, Morrow JM, Moroni I, Pisciotta C, Taroni F, Vujovic D, Lloyd TE, Acsadi G, Yum SW, Lewis RA, Finkel RS, Herrmann DN, Day JW, Li J, Saporta M, Sadjadi R, Walk D, Burns J, Muntoni F, Ramchandren S, Horvath R, Johnson NE, Züchner S, Pareyson D, Scherer SS, Rossor AM, Shy ME, Reilly MM; Inherited Neuropathies Consortium - Rare Disease Clinical Research Network (INC-RDCRN). Natural history of Charcot-Marie-Tooth disease type 2A: a large international multicentre study. Brain. 2020 Dec 1;143(12):3589-3602. doi: 10.1093/brain/awaa323.

Bis-Brewer DM, Gan-Or Z, Sleiman P; Inherited Neuropathy Consortium; Hakonarson H, Fazal S, Courel S, Cintra V, Tao F, Estiar MA, Tarnopolsky M, Boycott KM, Yoon G, Suchowersky O, Dupré N, Cheng A, Lloyd TE, Rouleau G, Schüle R, Züchner S. Assessing non-Mendelian inheritance in inherited axonopathies. Genet Med. 2020 Dec;22(12):2114-2119. doi: 10.1038/s41436-020-0924-0. Epub 2020 Aug 3.

Reilly MM, Rossor AM. Humans: the ultimate animal models. J Neurol Neurosurg Psychiatry. 2020 Nov;91(11):1132-1136. doi: 10.1136/jnnp-2020-323016. Epub 2020 Aug 7.

Cortese A, Callegari I, Currò R, Vegezzi E, Colnaghi S, Versino M, Alfonsi E, Cosentino G, Valente E, Gana S, Tassorelli C, Pichiecchio A, Rossor AM, Bugiardini E, Biroli A, Di Capua D, Houlden H, Reilly MM. Mutation in RNF170 causes sensory ataxic neuropathy with vestibular areflexia: a CANVAS mimic. J Neurol Neurosurg Psychiatry. 2020 Nov;91(11):1237-1238. doi: 10.1136/jnnp-2020-323719. Epub 2020 Sep 17.

Franco A, Dang X, Walton EK, Ho JN, Zablocka B, Ly C, Miller TM, Baloh RH, Shy ME, Yoo AS, Dorn GW 2nd. Burst mitofusin activation reverses neuromuscular dysfunction in murine CMT2A. Elife. 2020 Oct 19;9:e61119. doi: 10.7554/eLife.61119.

Edgar JR, Ho AK, Laurá M, Horvath R, Reilly MM, Luzio JP, Roberts RC. A dysfunctional endolysosomal pathway common to two sub-types of demyelinating Charcot-Marie-Tooth disease. Acta Neuropathol Commun. 2020 Oct 15;8(1):165. doi: 10.1186/s40478-020-01043-z.

Scriba CK, Beecroft SJ, Clayton JS, Cortese A, Sullivan R, Yau WY, Dominik N, Rodrigues M, Walker E, Dyer Z, Wu TY, Davis MR, Chandler DC, Weisburd B, Houlden H, Reilly MM, Laing NG, Lamont PJ, Roxburgh RH, Ravenscroft G. A novel RFC1 repeat motif (ACAGG) in two Asia-Pacific CANVAS families. Brain. 2020 Oct 1;143(10):2904-2910. doi: 10.1093/brain/awaa263.

Beecroft SJ, Cortese A, Sullivan R, Yau WY, Dyer Z, Wu TY, Mulroy E, Pelosi L, Rodrigues M, Taylor R, Mossman S, Leadbetter R, Cleland J, Anderson T, Ravenscroft G, Laing NG, Houlden H, Reilly MM, Roxburgh RH. A Māori specific RFC1 pathogenic repeat configuration in CANVAS, likely due to a founder allele. Brain. 2020 Sep 1;143(9):2673-2680. doi: 10.1093/brain/awaa203.

Bray P, Cornett KMD, Estilow T, Pareyson D, Zuccarino R, Skorupinska M, Pipis M, Sowden JE, Scherer S, Reilly MM, Shy ME, Herrmann DN, Burns J, Eichinger KJ. Reliability of the Charcot-Marie-Tooth functional outcome measure. J Peripher Nerv Syst. 2020 Sep;25(3):288-291. doi: 10.1111/jns.12406. Epub 2020 Aug 26.

Charcot-Marie-Tooth (CMT) is a group of inherited, degenerative disorders affecting the nerves that travel to the feet and hands, causing pain, muscle weakness, and other symptoms. In order to assess disease severity and changes over time, researchers have developed a functional outcome measure called the CMT-FOM. This 13-item clinical outcome assessment tool measures physical ability in adults with Charcot-Marie-Tooth (CMT) disease. To assess inter-rater reliability of the tool, or the degree to which independent observers using the CMT-FOM agree, researchers trained six evaluators in its use. The evaluators then each used the CMT-FOM separately to evaluate 10 patient participants with genetically diagnosed CMT1A (the most common form of CMT) and their assessments were compared. Results indicated excellent inter-rater reliability. Researchers conclude that the CMT-FOM is a reliable clinical outcome assessment tool. CMT-FOM is important for natural history and clinical trial studies as it provides an evaluation based on functions that the patient performs in their hands and feet. It also allows a transition from the CMT Pediatric Scale (CMTPedS), a similar instrument for children with CMT.

Pisciotta C, Ciafaloni E, Zuccarino R, Calabrese D, Saveri P, Fenu S, Tramacere I, Genovese F, Dilek N, Johnson NE, Heatwole C, Herrmann DN, Pareyson D; ACT-CMT Study Group. Validation of the Italian version of the Charcot-Marie-Tooth Health Index. J Peripher Nerv Syst. 2020 Sep;25(3):292-296. doi: 10.1111/jns.12397. Epub 2020 Jun 24.

Sullivan R, Yau WY, Chelban V, Rossi S, O'Connor E, Wood NW, Cortese A, Houlden H. RFC1 Intronic Repeat Expansions Absent in Pathologically Confirmed Multiple Systems Atrophy. Mov Disord. 2020 Jul;35(7):1277-1279. doi: 10.1002/mds.28074. Epub 2020 Apr 24.

Zuccarino R, Prada V, Moroni I, Pagliano E, Foscan M, Robbiano G, Pisciotta C, Cornett K, Shy R, Schenone A, Pareyson D, Shy M, Burns J. Validation of the Italian version of the Charcot-Marie-Tooth disease Pediatric Scale. J Peripher Nerv Syst. 2020 Jun;25(2):138-142. doi: 10.1111/jns.12383. Epub 2020 May 26.

Cortese A, Zhu Y, Rebelo AP, Negri S, Courel S, Abreu L, Bacon CJ, Bai Y, Bis-Brewer DM, Bugiardini E, Buglo E, Danzi MC, Feely SME, Athanasiou-Fragkouli A, Haridy NA; Inherited Neuropathy Consortium, Isasi R, Khan A, Laurà M, Magri S, Pipis M, Pisciotta C, Powell E, Rossor AM, Saveri P, Sowden JE, Tozza S, Vandrovcova J, Dallman J, Grignani E, Marchioni E, Scherer SS, Tang B, Lin Z, Al-Ajmi A, Schüle R, Synofzik M, Maisonobe T, Stojkovic T, Auer-Grumbach M, Abdelhamed MA, Hamed SA, Zhang R, Manganelli F, Santoro L, Taroni F, Pareyson D, Houlden H, Herrmann DN, Reilly MM, Shy ME, Zhai RG, Zuchner S. Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes. Nat Genet. 2020 May;52(5):473-481. doi: 10.1038/s41588-020-0615-4. Epub 2020 May 4.

Saveri P, De Luca M, Nisi V, Pisciotta C, Romano R, Piscosquito G, Reilly MM, Polke JM, Cavallaro T, Fabrizi GM, Fossa P, Cichero E, Lombardi R, Lauria G, Magri S, Taroni F, Pareyson D, Bucci C. Charcot-Marie-Tooth Type 2B: A New Phenotype Associated with a Novel RAB7A Mutation and Inhibited EGFR Degradation. Cells. 2020 Apr 21;9(4):1028. doi: 10.3390/cells9041028.

Fridman V, Sillau S, Acsadi G, Bacon C, Dooley K, Burns J, Day J, Feely S, Finkel RS, Grider T, Gutmann L, Herrmann DN, Kirk CA, Knause SA, Laurá M, Lewis RA, Li J, Lloyd TE, Moroni I, Muntoni F, Pagliano E, Pisciotta C, Piscosquito G, Ramchandren S, Saporta M, Sadjadi R, Shy RR, Siskind CE, Sumner CJ, Walk D, Wilcox J, Yum SW, Züchner S, Scherer SS, Pareyson D, Reilly MM, Shy ME; Inherited Neuropathies Consortium—Rare Diseases Clinical Research Network (INC-RDCRN). A longitudinal study of CMT1A using Rasch analysis based CMT neuropathy and examination scores. Neurology. 2020 Mar 3;94(9):e884-e896. doi: 10.1212/WNL.0000000000009035. Epub 2020 Feb 11.

Deng S, Feely SME, Shi Y, Zhai H, Zhan L, Siddique T, Deng HX, Shy ME. Incidence and Clinical Features of TRPV4-Linked Axonal Neuropathies in a USA Cohort of Charcot-Marie-Tooth Disease Type 2. Neuromolecular Med. 2020 Mar;22(1):68-72. doi: 10.1007/s12017-019-08564-4. Epub 2019 Aug 29.

Rossor AM, Shy ME, Reilly MM. Are we prepared for clinical trials in Charcot-Marie-Tooth disease?. Brain Res. 2020 Feb 15;1729:146625. doi: 10.1016/j.brainres.2019.146625. Epub 2019 Dec 30.

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Wang H, Davison M, Wang K, Xia TH, Kramer M, Call K, Luo J, Wu X, Zuccarino R, Bacon C, Bai Y, Moran JJ, Gutmann L, Feely SME, Grider T, Rossor AM, Reilly MM, Svaren J, Shy ME. Transmembrane protease serine 5: a novel Schwann cell plasma marker for CMT1A. Ann Clin Transl Neurol. 2020 Jan;7(1):69-82. doi: 10.1002/acn3.50965. Epub 2019 Dec 12.

Lee DC, Meyer-Schuman R, Bacon C, Shy ME, Antonellis A, Scherer SS. A recurrent GARS mutation causes distal hereditary motor neuropathy. J Peripher Nerv Syst. 2019 Dec;24(4):320-323. doi: 10.1111/jns.12353. Epub 2019 Nov 22.

Kapoor M, Foiani M, Heslegrave A, Zetterberg H, Lunn MP, Malaspina A, Gillmore JD, Rossor AM, Reilly MM. Plasma neurofilament light chain concentration is increased and correlates with the severity of neuropathy in hereditary transthyretin amyloidosis. J Peripher Nerv Syst. 2019 Dec;24(4):314-319. doi: 10.1111/jns.12350. Epub 2019 Oct 14.

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Laurá M, Pipis M, Rossor AM, Reilly MM. Charcot-Marie-Tooth disease and related disorders: an evolving landscape. Curr Opin Neurol. 2019 Oct;32(5):641-650. doi: 10.1097/WCO.0000000000000735.

Estilow T, Glanzman AM, Burns J, Harrington A, Cornett K, Menezes MP, Shy R, Moroni I, Pagliano E, Pareyson D, Bhandari T, Muntoni F, Laurá M, Reilly MM, Finkel RS, Eichinger KJ, Herrmann DN, Troutman G, Bray P, Halaki M, Shy ME, Yum SW; CMTPedS STUDY GROUP. Balance impairment in pediatric charcot-marie-tooth disease. Muscle Nerve. 2019 Sep;60(3):242-249. doi: 10.1002/mus.26500. Epub 2019 May 15.

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Smith GA, Lin TH, Sheehan AE, Van der Goes van Naters W, Neukomm LJ, Graves HK, Bis-Brewer DM, Züchner S, Freeman MR. Glutathione S-Transferase Regulates Mitochondrial Populations in Axons through Increased Glutathione Oxidation. Neuron. 2019 Jul 3;103(1):52-65.e6. doi: 10.1016/j.neuron.2019.04.017. Epub 2019 May 14.

Pareyson D, Stojkovic T, Reilly MM, Leonard-Louis S, Laurà M, Blake J, Parman Y, Battaloglu E, Tazir M, Bellatache M, Bonello-Palot N, Lévy N, Sacconi S, Guimarães-Costa R, Attarian S, Latour P, Solé G, Megarbane A, Horvath R, Ricci G, Choi BO, Schenone A, Gemelli C, Geroldi A, Sabatelli M, Luigetti M, Santoro L, Manganelli F, Quattrone A, Valentino P, Murakami T, Scherer SS, Dankwa L, Shy ME, Bacon CJ, Herrmann DN, Zambon A, Tramacere I, Pisciotta C, Magri S, Previtali SC, Bolino A. A multicenter retrospective study of charcot-marie-tooth disease type 4B (CMT4B) associated with mutations in myotubularin-related proteins (MTMRs). Ann Neurol. 2019 Jul;86(1):55-67. doi: 10.1002/ana.25500. Epub 2019 May 27.

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Phillips J, Courel S, Rebelo AP, Bis-Brewer DM, Bardakjian T, Dankwa L, Hamedani AG, Zuchner S, Scherer SS. POLG mutations presenting as Charcot-Marie-Tooth disease. J Peripher Nerv Syst. 2019 Jun;24(2):213-218. doi: 10.1111/jns.12313. Epub 2019 Apr 10.

Svaren J, Moran JJ, Wu X, Zuccarino R, Bacon C, Bai Y, Ramesh R, Gutmann L, Anderson DM, Pavelec D, Shy ME. Schwann cell transcript biomarkers for hereditary neuropathy skin biopsies. Ann Neurol. 2019 Jun;85(6):887-898. doi: 10.1002/ana.25480. Epub 2019 Apr 22.

Cortese A, Simone R, Sullivan R, Vandrovcova J, Tariq H, Yau WY, Humphrey J, Jaunmuktane Z, Sivakumar P, Polke J, Ilyas M, Tribollet E, Tomaselli PJ, Devigili G, Callegari I, Versino M, Salpietro V, Efthymiou S, Kaski D, Wood NW, Andrade NS, Buglo E, Rebelo A, Rossor AM, Bronstein A, Fratta P, Marques WJ, Züchner S, Reilly MM, Houlden H. Author Correction: Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia. Nat Genet. 2019 May;51(5):920. doi: 10.1038/s41588-019-0422-y.

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Cortese A, Simone R, Sullivan R, Vandrovcova J, Tariq H, Yau WY, Humphrey J, Jaunmuktane Z, Sivakumar P, Polke J, Ilyas M, Tribollet E, Tomaselli PJ, Devigili G, Callegari I, Versino M, Salpietro V, Efthymiou S, Kaski D, Wood NW, Andrade NS, Buglo E, Rebelo A, Rossor AM, Bronstein A, Fratta P, Marques WJ, Züchner S, Reilly MM, Houlden H. Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia. Nat Genet. 2019 Apr;51(4):649-658. doi: 10.1038/s41588-019-0372-4. Epub 2019 Mar 29.

Tao F, Beecham GW, Rebelo AP, Svaren J, Blanton SH, Moran JJ, Lopez-Anido C, Morrow JM, Abreu L, Rizzo D, Kirk CA, Wu X, Feely S, Verhamme C, Saporta MA, Herrmann DN, Day JW, Sumner CJ, Lloyd TE, Li J, Yum SW, Taroni F, Baas F, Choi BO, Pareyson D, Scherer SS, Reilly MM, Shy ME, Züchner S; Inherited Neuropathy Consortium. Variation in SIPA1L2 is correlated with phenotype modification in Charcot- Marie- Tooth disease type 1A. Ann Neurol. 2019 Mar;85(3):316-330. doi: 10.1002/ana.25426.

Bis-Brewer DM, Danzi MC, Wuchty S, Züchner S. A network biology approach to unraveling inherited axonopathies. Sci Rep. 2019 Feb 8;9(1):1692. doi: 10.1038/s41598-018-37119-z.

Dankwa L, Richardson J, Motley WW, Scavina M, Courel S, Bardakjian T, Züchner S, Scherer SS. A novel MFN2 mutation causes variable clinical severity in a multi-generational CMT2 family. Neuromuscul Disord. 2019 Feb;29(2):134-137. doi: 10.1016/j.nmd.2018.12.008. Epub 2018 Dec 21.

Bardakjian T, Scherer SS. A MT-ATP6 Mutation Causes a Slowly Progressive Myeloneuropathy. J Neuromuscul Dis. 2019;6(3):385-387. doi: 10.3233/JND-190400.

Kapoor M, Rossor AM, Laura M, Reilly MM. Clinical Presentation, Diagnosis and Treatment of TTR Amyloidosis. J Neuromuscul Dis. 2019;6(2):189-199. doi: 10.3233/JND-180371.

Tao F, Beecham GW, Rebelo AP, Blanton SH, Moran JJ, Lopez-Anido C, Svaren J, Abreu L, Rizzo D, Kirk CA, Wu X, Feely S, Verhamme C, Saporta MA, Herrmann DN, Day JW, Sumner CJ, Lloyd TE, Li J, Yum SW, Taroni F, Baas F, Choi BO, Pareyson D, Scherer SS, Reilly MM, Shy ME, Züchner S; Inherited Neuropathy Consortium. Modifier Gene Candidates in Charcot-Marie-Tooth Disease Type 1A: A Case-Only Genome-Wide Association Study. J Neuromuscul Dis. 2019;6(2):201-211. doi: 10.3233/JND-190377.

Mandarakas MR, Menezes MP, Rose KJ, Shy R, Eichinger K, Foscan M, Estilow T, Kennedy R, Herbert K, Bray P, Refshauge K, Ryan MM, Yiu EM, Farrar M, Sampaio H, Moroni I, Pagliano E, Pareyson D, Yum SW, Herrmann DN, Acsadi G, Shy ME, Burns J, Sanmaneechai O. Development and validation of the Charcot-Marie-Tooth Disease Infant Scale. Brain. 2018 Dec 1;141(12):3319-3330. doi: 10.1093/brain/awy280.

Tomaselli PJ, Horga A, Rossor AM, Jaunmuktane Z, Cortese A, Blake JC, Zarate-Lopez N, Houlden H, Reilly MM. IGHMBP2 mutation associated with organ-specific autonomic dysfunction. Neuromuscul Disord. 2018 Dec;28(12):1012-1015. doi: 10.1016/j.nmd.2018.08.010. Epub 2018 Aug 29.

Abrams AJ, Fontanesi F, Tan NBL, Buglo E, Campeanu IJ, Rebelo AP, Kornberg AJ, Phelan DG, Stark Z, Zuchner S. Insights into the genotype-phenotype correlation and molecular function of SLC25A46. Hum Mutat. 2018 Dec;39(12):1995-2007. doi: 10.1002/humu.23639. Epub 2018 Sep 17.

Synofzik M, Helbig KL, Harmuth F, Deconinck T, Tanpaiboon P, Sun B, Guo W, Wang R, Palmaer E, Tang S, Schaefer GB, Gburek-Augustat J, Züchner S, Krägeloh-Mann I, Baets J, de Jonghe P, Bauer P, Chen SRW, Schöls L, Schüle R. De novo ITPR1 variants are a recurrent cause of early-onset ataxia, acting via loss of channel function. Eur J Hum Genet. 2018 Nov;26(11):1623-1634. doi: 10.1038/s41431-018-0206-3. Epub 2018 Jun 20.

Eichinger K, Burns J, Cornett K, Bacon C, Shepherd ML, Mountain J, Sowden J, Shy R, Shy ME, Herrmann DN. The Charcot-Marie-Tooth Functional Outcome Measure (CMT-FOM). Neurology. 2018 Oct 9;91(15):e1381-e1384. doi: 10.1212/WNL.0000000000006323. Epub 2018 Sep 19.

Davies JL, Engelstad JK Sr, E Gove L, Linbo LK, Carter RE, Lynch C, Staff NP, Klein CJ, Dyck PJB, Herrmann DN, Dyck PJ. Somatotopic heat pain thresholds and intraepidermal nerve fibers in health. Muscle Nerve. 2018 Oct;58(4):509-516. doi: 10.1002/mus.26128. Epub 2018 Apr 20.

Morrow JM, Evans MRB, Grider T, Sinclair CDJ, Thedens D, Shah S, Yousry TA, Hanna MG, Nopoulos P, Thornton JS, Shy ME, Reilly MM. Validation of MRC Centre MRI calf muscle fat fraction protocol as an outcome measure in CMT1A. Neurology. 2018 Sep 18;91(12):e1125-e1129. doi: 10.1212/WNL.0000000000006214. Epub 2018 Aug 17.

Silwal A, Pitt M, Phadke R, Mankad K, Davison JE, Rossor A, DeVile C, Reilly MM, Manzur AY, Muntoni F, Munot P. Clinical spectrum, treatment and outcome of children with suspected diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy. Neuromuscul Disord. 2018 Sep;28(9):757-765. doi: 10.1016/j.nmd.2018.06.001. Epub 2018 Jun 12.

Johnson NE, Heatwole C, Creigh P, McDermott MP, Dilek N, Hung M, Bounsanga J, Tang W, Shy ME, Herrmann DN. The Charcot-Marie-Tooth Health Index: Evaluation of a Patient-Reported Outcome. Ann Neurol. 2018 Aug;84(2):225-233. doi: 10.1002/ana.25282. Epub 2018 Aug 29.

Kanhangad M, Cornett K, Brewer MH, Nicholson GA, Ryan MM, Smith RL, Subramanian GM, Young HK, Zuchner S, Kennerson ML, Burns J, Menezes MP. Unique clinical and neurophysiologic profile of a cohort of children with CMTX3. Neurology. 2018 May 8;90(19):e1706-e1710. doi: 10.1212/WNL.0000000000005479. Epub 2018 Apr 6.

Jerath NU, Mankodi A, Crawford TO, Grunseich C, Baloui H, Nnamdi-Emeratom C, Schindler AB, Heiman-Patterson T, Chrast R, Shy ME. Charcot-Marie-Tooth Disease type 4C: Novel mutations, clinical presentations, and diagnostic challenges. Muscle Nerve. 2018 May;57(5):749-755. doi: 10.1002/mus.25981. Epub 2017 Oct 24.

Saghira C, Bis DM, Stanek D, Strickland A, Herrmann DN, Reilly MM, Scherer SS, Shy ME; Inherited Neuropathy Consortium, Zuchner S. Variant pathogenicity evaluation in the community-driven Inherited Neuropathy Variant Browser. Hum Mutat. 2018 May;39(5):635-642. doi: 10.1002/humu.23412. Epub 2018 Mar 14.

Hu B, McCollum M, Ravi V, Arpag S, Moiseev D, Castoro R, Mobley B, Burnette B, Siskind C, Day J, Yawn R, Feely S, Li Y, Yan Q, Shy M, Li J. Myelin abnormality in Charcot-Marie-Tooth type 4J recapitulates features of acquired demyelination. Ann Neurol. 2018 Apr;83(4):756-770. doi: 10.1002/ana.25198. Epub 2018 Mar 30.

Bai Y, Wu X, Brennan KM, Wang DS, D'Antonio M, Moran J, Svaren J, Shy ME. Myelin protein zero mutations and the unfolded protein response in Charcot Marie Tooth disease type 1B. Ann Clin Transl Neurol. 2018 Mar 10;5(4):445-455. doi: 10.1002/acn3.543. eCollection 2018 Apr.

Lassuthova P, Rebelo AP, Ravenscroft G, Lamont PJ, Davis MR, Manganelli F, Feely SM, Bacon C, Brožková DŠ, Haberlova J, Mazanec R, Tao F, Saghira C, Abreu L, Courel S, Powell E, Buglo E, Bis DM, Baxter MF, Ong RW, Marns L, Lee YC, Bai Y, Isom DG, Barro-Soria R, Chung KW, Scherer SS, Larsson HP, Laing NG, Choi BO, Seeman P, Shy ME, Santoro L, Zuchner S. Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2. Am J Hum Genet. 2018 Mar 1;102(3):505-514. doi: 10.1016/j.ajhg.2018.01.023. PMID: 29499166; PMCID: PMC5985288.

Rebelo AP, Saade D, Pereira CV, Farooq A, Huff TC, Abreu L, Moraes CT, Mnatsakanova D, Mathews K, Yang H, Schon EA, Zuchner S, Shy ME. SCO2 mutations cause early-onset axonal Charcot-Marie-Tooth disease associated with cellular copper deficiency. Brain. 2018 Mar 1;141(3):662-672. doi: 10.1093/brain/awx369.

Dankwa L, Richardson J, Motley WW, Züchner S, Scherer SS. A mutation in the heptad repeat 2 domain of MFN2 in a large CMT2A family. J Peripher Nerv Syst. 2018 Mar;23(1):36-39. doi: 10.1111/jns.12248. Epub 2018 Feb 6.

Panosyan FB, Kirk CA, Marking D, Reilly MM, Scherer SS, Shy ME, Herrmann DN. Carpal tunnel syndrome in inherited neuropathies: A retrospective survey. Muscle Nerve. 2018 Mar;57(3):388-394. doi: 10.1002/mus.25742. Epub 2017 Jul 21.

Shy M, Rebelo AP, Feely SM, Abreu LA, Tao F, Swenson A, Bacon C, Zuchner S. Mutations in BAG3 cause adult-onset Charcot-Marie-Tooth disease. J Neurol Neurosurg Psychiatry. 2018 Mar;89(3):313-315. doi: 10.1136/jnnp-2017-315929. Epub 2017 Jul 28.

Abbott JA, Meyer-Schuman R, Lupo V, Feely S, Mademan I, Oprescu SN, Griffin LB, Alberti MA, Casasnovas C, Aharoni S, Basel-Vanagaite L, Züchner S, De Jonghe P, Baets J, Shy ME, Espinós C, Demeler B, Antonellis A, Francklyn C. Substrate interaction defects in histidyl-tRNA synthetase linked to dominant axonal peripheral neuropathy. Hum Mutat. 2018 Mar;39(3):415-432. doi: 10.1002/humu.23380. Epub 2017 Dec 26.

Pareyson D, Shy ME. Neurofilament light, biomarkers, and Charcot-Marie-Tooth disease. Neurology. 2018 Feb 6;90(6):257-259. doi: 10.1212/WNL.0000000000004936. Epub 2018 Jan 10.

Sandelius Å, Zetterberg H, Blennow K, Adiutori R, Malaspina A, Laura M, Reilly MM, Rossor AM. Plasma neurofilament light chain concentration in the inherited peripheral neuropathies. Neurology. 2018 Feb 6;90(6):e518-e524. doi: 10.1212/WNL.0000000000004932. Epub 2018 Jan 10.

Laura M, Singh D, Ramdharry G, Morrow J, Skorupinska M, Pareyson D, Burns J, Lewis RA, Scherer SS, Herrmann DN, Cullen N, Bradish C, Gaiani L, Martinelli N, Gibbons P, Pfeffer G, Phisitkul P, Wapner K, Sanders J, Flemister S, Shy ME, Reilly MM; Inherited Neuropathies Consortium. Prevalence and orthopedic management of foot and ankle deformities in Charcot-Marie-Tooth disease. Muscle Nerve. 2018 Feb;57(2):255-259. doi: 10.1002/mus.25724. Epub 2017 Jul 7.

Orengo JP, Khemani P, Day JW, Li J, Siskind CE. Charcot Marie Tooth disease type 4J with complex central nervous system features. Ann Clin Transl Neurol. 2018 Jan 22;5(2):222-225. doi: 10.1002/acn3.525. eCollection 2018 Feb.

Shy ME. Antisense oligonucleotides offer hope to patients with Charcot-Marie-Tooth disease type 1A. J Clin Invest. 2018 Jan 2;128(1):110-112. doi: 10.1172/JCI98617. Epub 2017 Dec 4.

Burnor E, Yang L, Zhou H, Patterson KR, Quinn C, Reilly MM, Rossor AM, Scherer SS, Lancaster E. Neurofascin antibodies in autoimmune, genetic, and idiopathic neuropathies. Neurology. 2018 Jan 2;90(1):e31-e38. doi: 10.1212/WNL.0000000000004773. Epub 2017 Nov 29.

Schöls L, Rattay TW, Martus P, Meisner C, Baets J, Fischer I, Jägle C, Fraidakis MJ, Martinuzzi A, Saute JA, Scarlato M, Antenora A, Stendel C, Höflinger P, Lourenco CM, Abreu L, Smets K, Paucar M, Deconinck T, Bis DM, Wiethoff S, Bauer P, Arnoldi A, Marques W, Jardim LB, Hauser S, Criscuolo C, Filla A, Züchner S, Bassi MT, Klopstock T, De Jonghe P, Björkhem I, Schüle R. Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial. Brain. 2017 Dec 1;140(12):3112-3127. doi: 10.1093/brain/awx273. PMID: 29126212; PMCID: PMC5841036.

Tomaselli PJ, Rossor AM, Horga A, Laura M, Blake JC, Houlden H, Reilly MM. A de novo dominant mutation in KIF1A associated with axonal neuropathy, spasticity and autism spectrum disorder. J Peripher Nerv Syst. 2017 Dec;22(4):460-463. doi: 10.1111/jns.12235. Epub 2017 Sep 11.

Jerath NU, Shy ME. Charcot-Marie-Tooth disease type 1C: Clinical and electrophysiological findings for the c.334G>a (p.Gly112Ser) Litaf/Simple mutation. Muscle Nerve. 2017 Dec;56(6):1092-1095. doi: 10.1002/mus.25600. Epub 2017 Apr 29.

Fledrich R, Mannil M, Leha A, Ehbrecht C, Solari A, Pelayo-Negro AL, Berciano J, Schlotter-Weigel B, Schnizer TJ, Prukop T, Garcia-Angarita N, Czesnik D, Haberlová J, Mazanec R, Paulus W, Beissbarth T, Walter MC, Triaal C, Hogrel JY, Dubourg O, Schenone A, Baets J, De Jonghe P, Shy ME, Horvath R, Pareyson D, Seeman P, Young P, Sereda MW. Biomarkers predict outcome in Charcot-Marie-Tooth disease 1A. J Neurol Neurosurg Psychiatry. 2017 Nov;88(11):941-952. doi: 10.1136/jnnp-2017-315721. Epub 2017 Aug 31.

Jerath NU, Shy ME. Charcot-Marie-Tooth Disease Type 1A: Influence of Body Mass Index on Nerve Conduction Studies and on the Charcot-Marie-Tooth Examination Score. J Clin Neurophysiol. 2017 Nov;34(6):508-511. doi: 10.1097/WNP.0000000000000415.

Ozes B, Karagoz N, Schüle R, Rebelo A, Sobrido MJ, Harmuth F, Synofzik M, Pascual SIP, Colak M, Ciftci-Kavaklioglu B, Kara B, Ordóñez-Ugalde A, Quintáns B, Gonzalez MA, Soysal A, Zuchner S, Battaloglu E. PLA2G6 mutations associated with a continuous clinical spectrum from neuroaxonal dystrophy to hereditary spastic paraplegia. Clin Genet. 2017 Nov;92(5):534-539. doi: 10.1111/cge.13008. Epub 2017 Apr 19.

Kalmar B, Innes A, Wanisch K, Kolaszynska AK, Pandraud A, Kelly G, Abramov AY, Reilly MM, Schiavo G, Greensmith L. Mitochondrial deficits and abnormal mitochondrial retrograde axonal transport play a role in the pathogenesis of mutant Hsp27-induced Charcot Marie Tooth Disease. Hum Mol Genet. 2017 Sep 1;26(17):3313-3326. doi: 10.1093/hmg/ddx216.

Zis P, Reilly MM, Rao DG, Tomaselli P, Rossor AM, Hadjivassiliou M. A novel mutation in the FGD4 gene causing Charcot-Marie-Tooth disease. J Peripher Nerv Syst. 2017 Sep;22(3):224-225. doi: 10.1111/jns.12222.

Cornett KMD, Menezes MP, Shy RR, Moroni I, Pagliano E, Pareyson D, Estilow T, Yum SW, Bhandari T, Muntoni F, Laura M, Reilly MM, Finkel RS, Eichinger KJ, Herrmann DN, Bray P, Halaki M, Shy ME, Burns J; CMTPedS Study Group. Natural history of Charcot-Marie-Tooth disease during childhood. Ann Neurol. 2017 Sep;82(3):353-359. doi: 10.1002/ana.25009.

Panosyan FB, Laura M, Rossor AM, Pisciotta C, Piscosquito G, Burns J, Li J, Yum SW, Lewis RA, Day J, Horvath R, Herrmann DN, Shy ME, Pareyson D, Reilly MM, Scherer SS; Inherited Neuropathies Consortium—Rare Diseases Clinical Research Network (INC-RDCRN). Cross-sectional analysis of a large cohort with X-linked Charcot-Marie-Tooth disease (CMTX1). Neurology. 2017 Aug 29;89(9):927-935. doi: 10.1212/WNL.0000000000004296. Epub 2017 Aug 2.

Ramdharry GM, Pollard AJ, Grant R, Dewar EL, Laurá M, Moore SA, Hallsworth K, Ploetz T, Trenell MI, Reilly MM. A study of physical activity comparing people with Charcot-Marie-Tooth disease to normal control subjects. Disabil Rehabil. 2017 Aug;39(17):1753-1758. doi: 10.1080/09638288.2016.1211180. Epub 2016 Aug 16.

Jacquier A, Delorme C, Belotti E, Juntas-Morales R, Solé G, Dubourg O, Giroux M, Maurage CA, Castellani V, Rebelo A, Abrams A, Züchner S, Stojkovic T, Schaeffer L, Latour P. Cryptic amyloidogenic elements in mutant NEFH causing Charcot-Marie-Tooth 2 trigger aggresome formation and neuronal death. Acta Neuropathol Commun. 2017 Jul 14;5(1):55. doi: 10.1186/s40478-017-0457-1. PMID: 28709447; PMCID: PMC5513089.

Hainline C, Rizzo D, Shy ME, Inherited Neuropathies Consortium, Rare Diseases Clinical Research Network Data Management and Coordinating Center. Enhancements to the RDCRN Contact Registry for the Inherited Neuropathies Consortium. Poster presented at Peripheral Nerve Society Annual Meeting. Jul. 8-12, 2017; Sitges, Spain.

Horga A, Laurà M, Jaunmuktane Z, Jerath NU, Gonzalez MA, Polke JM, Poh R, Blake JC, Liu YT, Wiethoff S, Bettencourt C, Lunn MP, Manji H, Hanna MG, Houlden H, Brandner S, Züchner S, Shy M, Reilly MM. Genetic and clinical characteristics of NEFL-related Charcot-Marie-Tooth disease. J Neurol Neurosurg Psychiatry. 2017 Jul;88(7):575-585. doi: 10.1136/jnnp-2016-315077. Epub 2017 May 13.

Manganelli F, Parisi S, Nolano M, Tao F, Paladino S, Pisciotta C, Tozza S, Nesti C, Rebelo AP, Provitera V, Santorelli FM, Shy ME, Russo T, Zuchner S, Santoro L. Novel mutations in dystonin provide clues to the pathomechanisms of HSAN-VI. Neurology. 2017 May 30;88(22):2132-2140. doi: 10.1212/WNL.0000000000003992. Epub 2017 May 3.

Tsai PC, Soong BW, Mademan I, Huang YH, Liu CR, Hsiao CT, Wu HT, Liu TT, Liu YT, Tseng YT, Lin KP, Yang UC, Chung KW, Choi BO, Nicholson GA, Kennerson ML, Chan CC, De Jonghe P, Cheng TH, Liao YC, Züchner S, Baets J, Lee YC. A recurrent WARS mutation is a novel cause of autosomal dominant distal hereditary motor neuropathy. Brain. 2017 May 1;140(5):1252-1266. doi: 10.1093/brain/awx058.

Rocha N, Bulger DA, Frontini A, Titheradge H, Gribsholt SB, Knox R, Page M, Harris J, Payne F, Adams C, Sleigh A, Crawford J, Gjesing AP, Bork-Jensen J, Pedersen O, Barroso I, Hansen T, Cox H, Reilly M, Rossor A, Brown RJ, Taylor SI, McHale D, Armstrong M, Oral EA, Saudek V, O'Rahilly S, Maher ER, Richelsen B, Savage DB, Semple RK. Human biallelic MFN2 mutations induce mitochondrial dysfunction, upper body adipose hyperplasia, and suppression of leptin expression. Elife. 2017 Apr 19;6:e23813. doi: 10.7554/eLife.23813.

Tomaselli PJ, Rossor AM, Horga A, Jaunmuktane Z, Carr A, Saveri P, Piscosquito G, Pareyson D, Laura M, Blake JC, Poh R, Polke J, Houlden H, Reilly MM. Mutations in noncoding regions of GJB1 are a major cause of X-linked CMT. Neurology. 2017 Apr 11;88(15):1445-1453. doi: 10.1212/WNL.0000000000003819. Epub 2017 Mar 10.

Bis DM, Schüle R, Reichbauer J, Synofzik M, Rattay TW, Soehn A, de Jonghe P, Schöls L, Züchner S. Uniparental disomy determined by whole-exome sequencing in a spectrum of rare motoneuron diseases and ataxias. Mol Genet Genomic Med. 2017 Apr 5;5(3):280-286. doi: 10.1002/mgg3.285. eCollection 2017 May.

Saporta MA, Shy ME. A human cellular model to study peripheral myelination and demyelinating neuropathies. Brain. 2017 Apr 1;140(4):856-859. doi: 10.1093/brain/awx048.

Hengel H, Magee A, Mahanjah M, Vallat JM, Ouvrier R, Abu-Rashid M, Mahamid J, Schüle R, Schulze M, Krägeloh-Mann I, Bauer P, Züchner S, Sharkia R, Schöls L. CNTNAP1 mutations cause CNS hypomyelination and neuropathy with or without arthrogryposis. Neurol Genet. 2017 Mar 22;3(2):e144. doi: 10.1212/NXG.0000000000000144. eCollection 2017 Apr.

Wang DS, Wu X, Bai Y, Zaidman C, Grider T, Kamholz J, Lupski JR, Connolly AM, Shy ME. PMP22 exon 4 deletion causes ER retention of PMP22 and a gain-of-function allele in CMT1E. Ann Clin Transl Neurol. 2017 Mar 12;4(4):236-245. doi: 10.1002/acn3.395. eCollection 2017 Apr.

Liao C, Ashley N, Diot A, Morten K, Phadwal K, Williams A, Fearnley I, Rosser L, Lowndes J, Fratter C, Ferguson DJ, Vay L, Quaghebeur G, Moroni I, Bianchi S, Lamperti C, Downes SM, Sitarz KS, Flannery PJ, Carver J, Dombi E, East D, Laura M, Reilly MM, Mortiboys H, Prevo R, Campanella M, Daniels MJ, Zeviani M, Yu-Wai-Man P, Simon AK, Votruba M, Poulton J. Dysregulated mitophagy and mitochondrial organization in optic atrophy due to OPA1 mutations. Neurology. 2017 Jan 10;88(2):131-142. doi: 10.1212/WNL.0000000000003491. Epub 2016 Dec 14.

Rossor AM, Morrow JM, Polke JM, Murphy SM, Houlden H; INC-RDCRC, Laura M, Manji H, Blake J, Reilly MM. Pilot phenotype and natural history study of hereditary neuropathies caused by mutations in the HSPB1 gene. Neuromuscul Disord. 2017 Jan;27(1):50-56. doi: 10.1016/j.nmd.2016.10.001. Epub 2016 Oct 8.

Vallat JM, Nizon M, Magee A, Isidor B, Magy L, Péréon Y, Richard L, Ouvrier R, Cogné B, Devaux J, Zuchner S, Mathis S. Contactin-Associated Protein 1 (CNTNAP1) Mutations Induce Characteristic Lesions of the Paranodal Region. J Neuropathol Exp Neurol. 2016 Dec 1;75(12):1155-1159. doi: 10.1093/jnen/nlw093.

Hu B, Arpag S, Zuchner S, Li J. A novel missense mutation of CMT2P alters transcription machinery. Ann Neurol. 2016 Dec;80(6):834-845. doi: 10.1002/ana.24776. Epub 2016 Sep 27.

Shy M. LRSAM1 lessons. Ann Neurol. 2016 Dec;80(6):821-822. doi: 10.1002/ana.24817.

Manole A, Chelban V, Haridy NA, Hamed SA, Berardo A, Reilly MM, Houlden H. Severe axonal neuropathy is a late manifestation of SPG11. J Neurol. 2016 Nov;263(11):2278-2286. doi: 10.1007/s00415-016-8254-5. Epub 2016 Aug 20.

Horga A, Tomaselli PJ, Gonzalez MA, Laura M, Muntoni F, Manzur AY, Hanna MG, Blake JC, Houlden H, Zuchner S, Reilly MM. SIGMAR1 mutation associated with autosomal recessive Silver-like syndrome. Neurology. 2016 Oct 11;87(15):1607-1612. doi: 10.1212/WNL.0000000000003212. Epub 2016 Sep 14.

Jerath NU, Gutmann L, Reddy CG, Shy ME. Charcot-marie-tooth disease type 1X in women: Electrodiagnostic findings. Muscle Nerve. 2016 Oct;54(4):728-32. doi: 10.1002/mus.25077. Epub 2016 Jul 4.

Manganelli F, Pisciotta C, Reilly MM, Tozza S, Schenone A, Fabrizi GM, Cavallaro T, Vita G, Padua L, Gemignani F, Laurà M, Hughes RA, Solari A, Pareyson D, Santoro L; CMT-TRIAAL and CMT-TRAUK Group. Nerve conduction velocity in CMT1A: what else can we tell?. Eur J Neurol. 2016 Oct;23(10):1566-71. doi: 10.1111/ene.13079. Epub 2016 Jul 14.

Rossor AM, Tomaselli PJ, Reilly MM. Recent advances in the genetic neuropathies. Curr Opin Neurol. 2016 Oct;29(5):537-48. doi: 10.1097/WCO.0000000000000373.

Perez-Siles G, Grant A, Ellis M, Ly C, Kidambi A, Khalil M, Llanos RM, Fontaine SL, Strickland AV, Züchner S, Bermeo S, Neist E, Brennan-Speranza TC, Takata RI, Speck-Martins CE, Mercer JF, Nicholson GA, Kennerson ML. Characterizing the molecular phenotype of an Atp7a(T985I) conditional knock in mouse model for X-linked distal hereditary motor neuropathy (dHMNX). Metallomics. 2016 Sep 1;8(9):981-92. doi: 10.1039/c6mt00082g. Epub 2016 Jun 13.

Auer-Grumbach M, Toegel S, Schabhüttl M, Weinmann D, Chiari C, Bennett DLH, Beetz C, Klein D, Andersen PM, Böhme I, Fink-Puches R, Gonzalez M, Harms MB, Motley W, Reilly MM, Renner W, Rudnik-Schöneborn S, Schlotter-Weigel B, Themistocleous AC, Weishaupt JH, Ludolph AC, Wieland T, Tao F, Abreu L, Windhager R, Zitzelsberger M, Strom TM, Walther T, Scherer SS, Züchner S, Martini R, Senderek J. Rare Variants in MME, Encoding Metalloprotease Neprilysin, Are Linked to Late-Onset Autosomal-Dominant Axonal Polyneuropathies. Am J Hum Genet. 2016 Sep 1;99(3):607-623. doi: 10.1016/j.ajhg.2016.07.008.

Piscosquito G, Saveri P, Magri S, Ciano C, Gandioli C, Morbin M, Bella DD, Moroni I, Taroni F, Pareyson D. Screening for SH3TC2 gene mutations in a series of demyelinating recessive Charcot-Marie-Tooth disease (CMT4). J Peripher Nerv Syst. 2016 Sep;21(3):142-9. doi: 10.1111/jns.12175.

Panosyan FB, Mountain JM, Reilly MM, Shy ME, Herrmann DN. Rydel-Seiffer fork revisited: Beyond a simple case of black and white. Neurology. 2016 Aug 16;87(7):738-40. doi: 10.1212/WNL.0000000000002991. Epub 2016 Jul 13.

Mademan I, Harmuth F, Giordano I, Timmann D, Magri S, Deconinck T, Claaßen J, Jokisch D, Genc G, Di Bella D, Romito S, Schüle R, Züchner S, Taroni F, Klockgether T, Schöls L, De Jonghe P, Bauer P, Consortium E, Baets J, Synofzik M. Multisystemic SYNE1 ataxia: confirming the high frequency and extending the mutational and phenotypic spectrum. Brain. 2016 Aug;139(Pt 8):e46. doi: 10.1093/brain/aww115. Epub 2016 May 19.

Brewer MH, Chaudhry R, Qi J, Kidambi A, Drew AP, Menezes MP, Ryan MM, Farrar MA, Mowat D, Subramanian GM, Young HK, Zuchner S, Reddel SW, Nicholson GA, Kennerson ML. Whole Genome Sequencing Identifies a 78 kb Insertion from Chromosome 8 as the Cause of Charcot-Marie-Tooth Neuropathy CMTX3. PLoS Genet. 2016 Jul 20;12(7):e1006177. doi: 10.1371/journal.pgen.1006177. eCollection 2016 Jul.

Cornett KM, Menezes MP, Bray P, Halaki M, Shy RR, Yum SW, Estilow T, Moroni I, Foscan M, Pagliano E, Pareyson D, Laura M, Bhandari T, Muntoni F, Reilly MM, Finkel RS, Sowden J, Eichinger KJ, Herrmann DN, Shy ME, Burns J; Inherited Neuropathies Consortium. Phenotypic Variability of Childhood Charcot-Marie-Tooth Disease. JAMA Neurol. 2016 Jun 1;73(6):645-51. doi: 10.1001/jamaneurol.2016.0171.

Motley WW, Palaima P, Yum SW, Gonzalez MA, Tao F, Wanschitz JV, Strickland AV, Löscher WN, De Vriendt E, Koppi S, Medne L, Janecke AR, Jordanova A, Zuchner S, Scherer SS. De novo PMP2 mutations in families with type 1 Charcot-Marie-Tooth disease. Brain. 2016 Jun;139(Pt 6):1649-56. doi: 10.1093/brain/aww055. Epub 2016 Mar 23.

Rossor AM, Lu CH, Petzold A, Malaspina A, Laura M, Greensmith L, Reilly MM. Plasma neurofilament heavy chain is not a useful biomarker in Charcot-Marie-Tooth disease. Muscle Nerve. 2016 Jun;53(6):972-5. doi: 10.1002/mus.25124. Epub 2016 Apr 27.

Merkel PA, Manion M, Gopal-Srivastava R, Groft S, Jinnah HA, Robertson D, Krischer JP; Rare Diseases Clinical Research Network. The partnership of patient advocacy groups and clinical investigators in the rare diseases clinical research network. Orphanet J Rare Dis. 2016 May 18;11(1):66. doi: 10.1186/s13023-016-0445-8.

Synofzik M, Smets K, Mallaret M, Di Bella D, Gallenmüller C, Baets J, Schulze M, Magri S, Sarto E, Mustafa M, Deconinck T, Haack T, Züchner S, Gonzalez M, Timmann D, Stendel C, Klopstock T, Durr A, Tranchant C, Sturm M, Hamza W, Nanetti L, Mariotti C, Koenig M, Schöls L, Schüle R, de Jonghe P, Anheim M, Taroni F, Bauer P. SYNE1 ataxia is a common recessive ataxia with major non-cerebellar features: a large multi-centre study. Brain. 2016 May;139(Pt 5):1378-93. doi: 10.1093/brain/aww079. Epub 2016 Apr 17.

Shy ME. Gene therapy, CMT1X, and the inherited neuropathies. Proc Natl Acad Sci U S A. 2016 Apr 26;113(17):4552-4. doi: 10.1073/pnas.1604005113. Epub 2016 Apr 14.

Rebelo AP, Abrams AJ, Cottenie E, Horga A, Gonzalez M, Bis DM, Sanchez-Mejias A, Pinto M, Buglo E, Markel K, Prince J, Laura M, Houlden H, Blake J, Woodward C, Sweeney MG, Holton JL, Hanna M, Dallman JE, Auer-Grumbach M, Reilly MM, Zuchner S. Cryptic Amyloidogenic Elements in the 3' UTRs of Neurofilament Genes Trigger Axonal Neuropathy. Am J Hum Genet. 2016 Apr 7;98(4):597-614. doi: 10.1016/j.ajhg.2016.02.022. Epub 2016 Mar 31. PMID: 27040688; PMCID: PMC4833435.

Laššuthová P, Šafka Brožková D, Krůtová M, Mazanec R, Züchner S, Gonzalez MA, Seeman P. Severe axonal Charcot-Marie-Tooth disease with proximal weakness caused by de novo mutation in the MORC2 gene. Brain. 2016 Apr;139(Pt 4):e26. doi: 10.1093/brain/awv411. Epub 2016 Feb 11.

Lunn MP, Ellis L, Hadden RD, Rajabally YA, Winer JB, Reilly MM. A proposed dosing algorithm for the individualized dosing of human immunoglobulin in chronic inflammatory neuropathies. J Peripher Nerv Syst. 2016 Mar;21(1):33-7. doi: 10.1111/jns.12158.

Albulym OM, Kennerson ML, Harms MB, Drew AP, Siddell AH, Auer-Grumbach M, Pestronk A, Connolly A, Baloh RH, Zuchner S, Reddel SW, Nicholson GA. MORC2 mutations cause axonal Charcot-Marie-Tooth disease with pyramidal signs. Ann Neurol. 2016 Mar;79(3):419-27. doi: 10.1002/ana.24575. Epub 2016 Jan 13.

Begg L, McLaughlin P, Vicaretti M, Fletcher J, Burns J. Total contact cast wall load in patients with a plantar forefoot ulcer and diabetes. J Foot Ankle Res. 2016 Jan 7;9:2. doi: 10.1186/s13047-015-0119-0. eCollection 2016.

Morrow JM, Sinclair CD, Fischmann A, Machado PM, Reilly MM, Yousry TA, Thornton JS, Hanna MG. MRI biomarker assessment of neuromuscular disease progression: a prospective observational cohort study. Lancet Neurol. 2016 Jan;15(1):65-77. doi: 10.1016/S1474-4422(15)00242-2. Epub 2015 Nov 6.

Schmidt WM, Rutledge SL, Schüle R, Mayerhofer B, Züchner S, Boltshauser E, Bittner RE. Disruptive SCYL1 Mutations Underlie a Syndrome Characterized by Recurrent Episodes of Liver Failure, Peripheral Neuropathy, Cerebellar Atrophy, and Ataxia. Am J Hum Genet. 2015 Dec 3;97(6):855-61. doi: 10.1016/j.ajhg.2015.10.011. Epub 2015 Nov 12.

Whittaker RG, Herrmann DN, Bansagi B, Hasan BA, Lofra RM, Logigian EL, Sowden JE, Almodovar JL, Littleton JT, Zuchner S, Horvath R, Lochmüller H. Electrophysiologic features of SYT2 mutations causing a treatable neuromuscular syndrome. Neurology. 2015 Dec 1;85(22):1964-71. doi: 10.1212/WNL.0000000000002185. Epub 2015 Oct 30.

Rose KJ, Hiller CE, Mandarakas M, Raymond J, Refshauge K, Burns J. Correlates of functional ankle instability in children and adolescents with Charcot-Marie-Tooth disease. J Foot Ankle Res. 2015 Nov 5;8:61. doi: 10.1186/s13047-015-0118-1. eCollection 2015.

Jerath NU, Kamholz J, Grider T, Harper A, Swenson A, Shy ME. Coexistence of a T118M PMP22 missense mutation and chromosome 17 (17p11.2-p12) deletion. Muscle Nerve. 2015 Nov;52(5):905-8. doi: 10.1002/mus.24713. Epub 2015 Jun 19.

Sanmaneechai O, Feely S, Scherer SS, Herrmann DN, Burns J, Muntoni F, Li J, Siskind CE, Day JW, Laura M, Sumner CJ, Lloyd TE, Ramchandren S, Shy RR, Grider T, Bacon C, Finkel RS, Yum SW, Moroni I, Piscosquito G, Pareyson D, Reilly MM, Shy ME; Inherited Neuropathies Consortium - Rare Disease Clinical Research Consortium (INC-RDCRC). Genotype-phenotype characteristics and baseline natural history of heritable neuropathies caused by mutations in the MPZ gene. Brain. 2015 Nov;138(Pt 11):3180-92. doi: 10.1093/brain/awv241. Epub 2015 Aug 25.

Thal DR, Züchner S, Gierer S, Schulte C, Schöls L, Schüle R, Synofzik M. Abnormal Paraplegin Expression in Swollen Neurites, τ- and α-Synuclein Pathology in a Case of Hereditary Spastic Paraplegia SPG7 with an Ala510Val Mutation. Int J Mol Sci. 2015 Oct 21;16(10):25050-66. doi: 10.3390/ijms161025050.

Jerath NU, Grider T, Shy ME. Progressive Lower Extremity Weakness and Axonal Sensorimotor Polyneuropathy from a Mutation in KIF5A (c.611G>A;p.Arg204Gln). Case Rep Genet. 2015;2015:496053. doi: 10.1155/2015/496053. Epub 2015 Oct 12.

Brennan KM, Bai Y, Pisciotta C, Wang S, Feely SM, Hoegger M, Gutmann L, Moore SA, Gonzalez M, Sherman DL, Brophy PJ, Züchner S, Shy ME. Absence of Dystrophin Related Protein-2 disrupts Cajal bands in a patient with Charcot-Marie-Tooth disease. Neuromuscul Disord. 2015 Oct;25(10):786-93. doi: 10.1016/j.nmd.2015.07.001. Epub 2015 Jul 7.

Gonzalez M, Falk MJ, Gai X, Postrel R, Schüle R, Zuchner S. Innovative genomic collaboration using the GENESIS (GEM.app) platform. Hum Mutat. 2015 Oct;36(10):950-6. doi: 10.1002/humu.22836. Epub 2015 Aug 12.

Philippakis AA, Azzariti DR, Beltran S, Brookes AJ, Brownstein CA, Brudno M, Brunner HG, Buske OJ, Carey K, Doll C, Dumitriu S, Dyke SO, den Dunnen JT, Firth HV, Gibbs RA, Girdea M, Gonzalez M, Haendel MA, Hamosh A, Holm IA, Huang L, Hurles ME, Hutton B, Krier JB, Misyura A, Mungall CJ, Paschall J, Paten B, Robinson PN, Schiettecatte F, Sobreira NL, Swaminathan GJ, Taschner PE, Terry SF, Washington NL, Züchner S, Boycott KM, Rehm HL. Hum Mutat. The Matchmaker Exchange: a platform for rare disease gene discovery. Hum Mutat. 2015 Oct;36(10):915-21. doi: 10.1002/humu.22858.

Gutmann L, Shy M. Update on Charcot-Marie-Tooth disease. Curr Opin Neurol. 2015 Oct;28(5):462-7. doi: 10.1097/WCO.0000000000000237.

Strickland AV, Schabhüttl M, Offenbacher H, Synofzik M, Hauser NS, Brunner-Krainz M, Gruber-Sedlmayr U, Moore SA, Windhager R, Bender B, Harms M, Klebe S, Young P, Kennerson M, Garcia AS, Gonzalez MA, Züchner S, Schule R, Shy ME, Auer-Grumbach M. Mutation screen reveals novel variants and expands the phenotypes associated with DYNC1H1. J Neurol. 2015 Sep;262(9):2124-34. doi: 10.1007/s00415-015-7727-2. Epub 2015 Jun 24.

Saifee TA, Pareés I, Kassavetis P, Kaski D, Bronstein AM, Rothwell JC, Sadnicka A, Lunn MP, Manji H, Teo JT, Bhatia KP, Reilly MM, Edwards MJ. Tremor in Charcot-Marie-Tooth disease: No evidence of cerebellar dysfunction. Clin Neurophysiol. Sep 2015;126(9):1817-1824. PMID: 25641441.

Gonzaga-Jauregui C, Harel T, Gambin T, Kousi M, Griffin LB, Francescatto L, Ozes B, Karaca E, Jhangiani SN, Bainbridge MN, Lawson KS, Pehlivan D, Okamoto Y, Withers M, Mancias P, Slavotinek A, Reitnauer PJ, Goksungur MT, Shy M, Crawford TO, Koenig M, Willer J, Flores BN, Pediaditrakis I, Us O, Wiszniewski W, Parman Y, Antonellis A, Muzny DM; Baylor-Hopkins Center for Mendelian Genomics, Katsanis N, Battaloglu E, Boerwinkle E, Gibbs RA, Lupski JR. Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy. Cell Rep. 2015 Aug 18;12(7):1169-83. doi: 10.1016/j.celrep.2015.07.023. Epub 2015 Aug 6.

Coutelier M, Goizet C, Durr A, Habarou F, Morais S, Dionne-Laporte A, Tao F, Konop J, Stoll M, Charles P, Jacoupy M, Matusiak R, Alonso I, Tallaksen C, Mairey M, Kennerson M, Gaussen M, Schule R, Janin M, Morice-Picard F, Durand CM, Depienne C, Calvas P, Coutinho P, Saudubray JM, Rouleau G, Brice A, Nicholson G, Darios F, Loureiro JL, Zuchner S, Ottolenghi C, Mochel F, Stevanin G. Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia. Brain. 2015 Aug;138(Pt 8):2191-205. doi: 10.1093/brain/awv143. Epub 2015 May 29.

Fridman V, Bundy B, Reilly MM, Pareyson D, Bacon C, Burns J, Day J, Feely S, Finkel RS, Grider T, Kirk CA, Herrmann DN, Laurá M, Li J, Lloyd T, Sumner CJ, Muntoni F, Piscosquito G, Ramchandren S, Shy R, Siskind CE, Yum SW, Moroni I, Pagliano E, Zuchner S, Scherer SS, Shy ME; Inherited Neuropathies Consortium. CMT subtypes and disease burden in patients enrolled in the Inherited Neuropathies Consortium natural history study: a cross-sectional analysis. J Neurol Neurosurg Psychiatry. 2015 Aug;86(8):873-8. doi: 10.1136/jnnp-2014-308826. Epub 2014 Nov 27.

Safka Brozkova D, Deconinck T, Griffin LB, Ferbert A, Haberlova J, Mazanec R, Lassuthova P, Roth C, Pilunthanakul T, Rautenstrauss B, Janecke AR, Zavadakova P, Chrast R, Rivolta C, Zuchner S, Antonellis A, Beg AA, De Jonghe P, Senderek J, Seeman P, Baets J. Loss of function mutations in HARS cause a spectrum of inherited peripheral neuropathies. Brain. 2015 Aug;138(Pt 8):2161-72. doi: 10.1093/brain/awv158. Epub 2015 Jun 13.

Abrams AJ, Hufnagel RB, Rebelo A, Zanna C, Patel N, Gonzalez MA, Campeanu IJ, Griffin LB, Groenewald S, Strickland AV, Tao F, Speziani F, Abreu L, Schüle R, Caporali L, La Morgia C, Maresca A, Liguori R, Lodi R, Ahmed ZM, Sund KL, Wang X, Krueger LA, Peng Y, Prada CE, Prows CA, Schorry EK, Antonellis A, Zimmerman HH, Abdul-Rahman OA, Yang Y, Downes SM, Prince J, Fontanesi F, Barrientos A, Németh AH, Carelli V, Huang T, Zuchner S, Dallman JE. Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder. Nat Genet. 2015 Aug;47(8):926-32. doi: 10.1038/ng.3354. Epub 2015 Jul 13.

Pisciotta C, Bai Y, Brennan KM, Wu X, Grider T, Feely S, Wang S, Moore S, Siskind C, Gonzalez M, Zuchner S, Shy ME. Reduced neurofilament expression in cutaneous nerve fibers of patients with CMT2E. Neurology. 2015 Jul 21;85(3):228-34. doi: 10.1212/WNL.0000000000001773. Epub 2015 Jun 24.

Brennan KM, Bai Y, Shy ME. Demyelinating CMT--what's known, what's new and what's in store?. Neurosci Lett. 2015 Jun 2;596:14-26. doi: 10.1016/j.neulet.2015.01.059. Epub 2015 Jan 24.

Tétreault M, Gonzalez M, Dicaire MJ, Allard P, Gehring K, Leblanc D, Leclerc N, Schondorf R, Mathieu J, Zuchner S, Brais B. Adult-onset painful axonal polyneuropathy caused by a dominant NAGLU mutation. Brain. 2015 Jun;138(Pt 6):1477-83. doi: 10.1093/brain/awv074. Epub 2015 Mar 28.

Rossor AM, Evans MR, Reilly MM. A practical approach to the genetic neuropathies. Pract Neurol. 2015 Jun;15(3):187-98. doi: 10.1136/practneurol-2015-001095. Epub 2015 Apr 21.

Ramchandren S, Shy M, Feldman E, Carlos R, Siskind C. Defining disability: development and validation of a mobility-Disability Severity Index (mDSI) in Charcot-Marie-tooth disease. J Neurol Neurosurg Psychiatry. 2015 Jun;86(6):635-9. doi: 10.1136/jnnp-2013-307390. Epub 2014 Aug 25.

Carr AS, Polke JM, Wilson J, Pelayo-Negro AL, Laura M, Nanji T, Holt J, Vaughan J, Rankin J, Sweeney MG, Blake J, Houlden H, Reilly MM. MFN2 deletion of exons 7 and 8: founder mutation in the UK population. J Peripher Nerv Syst. 2015 Jun;20(2):67-71. doi: 10.1111/jns.12117.

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Burns J, Menezes M, Finkel RS, Estilow T, Moroni I, Pagliano E, Laurá M, Muntoni F, Herrmann DN, Eichinger K, Shy R, Pareyson D, Reilly MM, Shy ME. Transitioning outcome measures: relationship between the CMTPedS and CMTNSv2 in children, adolescents, and young adults with Charcot-Marie-Tooth disease. J Peripher Nerv Syst. 2013 Jun;18(2):177-80. doi: 10.1111/jns5.12024.

Saporta MA, Shy ME. Inherited peripheral neuropathies. Neurol Clin. 2013 May;31(2):597-619. doi: 10.1016/j.ncl.2013.01.009. Epub 2013 Mar 5.

Cottenie E, Menezes MP, Rossor AM, Morrow JM, Yousry TA, Dick DJ, Anderson JR, Jaunmuktane Z, Brandner S, Blake JC, Houlden H, Reilly MM. Rapidly progressive asymmetrical weakness in Charcot-Marie-Tooth disease type 4J resembles chronic inflammatory demyelinating polyneuropathy. Neuromuscul Disord. 2013 May;23(5):399-403. doi: 10.1016/j.nmd.2013.01.010. Epub 2013 Mar 13.

Kennerson ML, Yiu EM, Chuang DT, Kidambi A, Tso SC, Ly C, Chaudhry R, Drew AP, Rance G, Delatycki MB, Züchner S, Ryan MM, Nicholson GA. A new locus for X-linked dominant Charcot-Marie-Tooth disease (CMTX6) is caused by mutations in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene. Hum Mol Genet. 2013 Apr 1;22(7):1404-16. doi: 10.1093/hmg/dds557. Epub 2013 Jan 7.

Komyathy K, Neal S, Feely S, Miller LJ, Lewis RA, Trigge G, Siskind CE, Shy ME, Ramchandren S. Anterior tibialis CMAP amplitude correlations with impairment in CMT1A. Muscle Nerve. 2013 Apr;47(4):493-6. doi: 10.1002/mus.23614. Epub 2013 Mar 3.

Martin E, Schule R, Smets K, et al. Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia. Am J Hum Genet. Feb 7 2013;92(2):238- 244. PMID: 23332916, PMCID: PMC3567271.

Vester A, Velez-Ruiz G, McLaughlin HM; NISC Comparative Sequencing Program, Lupski JR, Talbot K, Vance JM, Zuchner S, Roda RH, Fischbeck KH, Biesecker LG, Nicholson G, Beg AA, Antonellis A. A loss-of-function variant in the human histidyl-tRNA synthetase (HARS) gene is neurotoxic in vivo. Hum Mutat. 2013 Jan;34(1):191-9. doi: 10.1002/humu.22210. Epub 2012 Oct 11.

Stevens JC, Murphy SM, Davagnanam I, Phadke R, Anderson G, Nethisinghe S, Bremner F, Giunti P, Reilly MM. The ARSACS phenotype can include supranuclear gaze palsy and skin lipofuscin deposits. J Neurol Neurosurg Psychiatry. 2013 Jan;84(1):114-6. doi: 10.1136/jnnp-2012-303634. Epub 2012 Nov 3.

Murphy SM, Laurá M, Reilly MM. DNA testing in hereditary neuropathies. Handb Clin Neurol. 2013;115:213-32. doi: 10.1016/B978-0-444-52902-2.00012-6.

Begg L, McLaughlin P, Manning L, Vicaretti M, Fletcher J, Burns J. A novel approach to mapping load transfer from the plantar surface of the foot to the walls of the total contact cast: a proof of concept study. J Foot Ankle Res. 2012 Dec 13;5(1):32. doi: 10.1186/1757-1146-5-32.

Tesson C, Nawara M, Salih MA, et al. Alteration of fatty-acid-metabolizing enzymes affects mitochondrial form and function in hereditary spastic paraplegia. Am J Hum Genet. Dec 7 2012;91(6):1051-1064. PMID: 23176821, PMCID: PMC3516610.

Kleopa KA, Abrams CK, Scherer SS. How do mutations in GJB1 cause X-linked Charcot-Marie-Tooth disease?. Brain Res. 2012 Dec 3;1487:198-205. doi: 10.1016/j.brainres.2012.03.068. Epub 2012 Jul 6.

Fawcett KA, Murphy SM, Polke JM, Wray S, Burchell VS, Manji H, Quinlivan RM, Zdebik AA, Reilly MM, Houlden H. Comprehensive analysis of the TRPV4 gene in a large series of inherited neuropathies and controls. J Neurol Neurosurg Psychiatry. 2012 Dec;83(12):1204-9. doi: 10.1136/jnnp-2012-303055. Epub 2012 Jul 31.

Patzkó A, Bai Y, Saporta MA, Katona I, Wu X, Vizzuso D, Feltri ML, Wang S, Dillon LM, Kamholz J, Kirschner D, Sarkar FH, Wrabetz L, Shy ME. Curcumin derivatives promote Schwann cell differentiation and improve neuropathy in R98C CMT1B mice. Brain. 2012 Dec;135(Pt 12):3551-66. doi: 10.1093/brain/aws299.

Ramdharry GM, Thornhill A, Mein G, Reilly MM, Marsden JF. Exploring the experience of fatigue in people with Charcot-Marie-Tooth disease. Neuromuscul Disord. Dec 2012;22 Suppl 3:S208- 213. PMID: 23182641.

Estilow T, Kozin SH, Glanzman AM, Burns J, Finkel RS. Flexor digitorum superficialis opposition tendon transfer improves hand function in children with Charcot-Marie-Tooth disease: case series. Neuromuscul Disord. 2012 Dec;22(12):1090-5. doi: 10.1016/j.nmd.2012.07.011. Epub 2012 Sep 1.

Scherer SS, Kleopa KA. X-linked Charcot-Marie-Tooth disease. J Peripher Nerv Syst. 2012 Dec;17 Suppl 3(0 3):9-13. doi: 10.1111/j.1529-8027.2012.00424.x.

Ramdharry GM, Day BL, Reilly MM, Marsden JF. Foot drop splints improve proximal as well as distal leg control during gait in Charcot-Marie-Tooth disease. Muscle Nerve. Oct 2012;46(4):512- 519. PMID: 22987691.

Zimoń M, Baets J, Almeida-Souza L, De Vriendt E, Nikodinovic J, Parman Y, Battaloğlu E, Matur Z, Guergueltcheva V, Tournev I, Auer-Grumbach M, De Rijk P, Petersen BS, Müller T, Fransen E, Van Damme P, Löscher WN, Barišić N, Mitrovic Z, Previtali SC, Topaloğlu H, Bernert G, Beleza-Meireles A, Todorovic S, Savic-Pavicevic D, Ishpekova B, Lechner S, Peeters K, Ooms T, Hahn AF, Züchner S, Timmerman V, Van Dijck P, Rasic VM, Janecke AR, De Jonghe P, Jordanova A. Loss-of-function mutations in HINT1 cause axonal neuropathy with neuromyotonia. Nat Genet. 2012 Oct;44(10):1080-3. doi: 10.1038/ng.2406. Epub 2012 Sep 9.

Murphy SM, Puwanant A, Griggs RC; Consortium for Clinical Investigations of Neurological Channelopathies (CINCH) and Inherited Neuropathies Consortium (INC) Consortia of the Rare Disease Clinical Research Network. Unintended effects of orphan product designation for rare neurological diseases. Ann Neurol. 2012 Oct;72(4):481-90. doi: 10.1002/ana.23672.

Pitceathly RD, Murphy SM, Cottenie E, Chalasani A, Sweeney MG, Woodward C, Mudanohwo EE, Hargreaves I, Heales S, Land J, Holton JL, Houlden H, Blake J, Champion M, Flinter F, Robb SA, Page R, Rose M, Palace J, Crowe C, Longman C, Lunn MP, Rahman S, Reilly MM, Hanna MG. Genetic dysfunction of MT-ATP6 causes axonal Charcot-Marie-Tooth disease. Neurology. 2012 Sep 11;79(11):1145-54. doi: 10.1212/WNL.0b013e3182698d8d. Epub 2012 Aug 29.

Davidson G, Murphy S, Polke J, Laura M, Salih M, Muntoni F, Blake J, Brandner S, Davies N, Horvath R, Price S, Donaghy M, Roberts M, Foulds N, Ramdharry G, Soler D, Lunn M, Manji H, Davis M, Houlden H, Reilly M. Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort. J Neurol. 2012 Aug;259(8):1673-85. doi: 10.1007/s00415-011-6397-y.

Abrams CK, Scherer SS. Gap junctions in inherited human disorders of the central nervous system. Biochim Biophys Acta. Aug 2012;1818(8):2030-2047. PMID: 21871435, PMCID: PMC3771870.

Michell AW, Gaitatzis A, Burge J, Reilly MM, Kapoor R, Koltzenburg M. Isolated motor conduction block associated with infliximab. J Neurol. 2012 Aug;259(8):1758-60. doi: 10.1007/s00415-012-6452-3. Epub 2012 Feb 18.

Shy ME. Lessons from London. J Neurol Neurosurg Psychiatry. 2012 Aug;83(8):767-8. doi: 10.1136/jnnp-2012-302858. Epub 2012 Jun 13.

Burns J, Ouvrier R, Estilow T, Shy R, Laurá M, Eichinger K, Muntoni F, Reilly MM, Pareyson D, Acsadi G, Shy ME, Finkel RS. Symmetry of foot alignment and ankle flexibility in paediatric Charcot-Marie-Tooth disease. Clin Biomech (Bristol, Avon). 2012 Aug;27(7):744-7. doi: 10.1016/j.clinbiomech.2012.02.006. Epub 2012 Mar 16.

Osterloh JM, Yang J, Rooney TM, Fox AN, Adalbert R, Powell EH, Sheehan AE, Avery MA, Hackett R, Logan MA, MacDonald JM, Ziegenfuss JS, Milde S, Hou YJ, Nathan C, Ding A, Brown RH Jr, Conforti L, Coleman M, Tessier-Lavigne M, Züchner S, Freeman MR. dSarm/Sarm1 is required for activation of an injury-induced axon death pathway. Science. 2012 Jul 27;337(6093):481-4. doi: 10.1126/science.1223899. Epub 2012 Jun 7.

Murphy SM, Laura M, Fawcett K, Pandraud A, Liu YT, Davidson GL, Rossor AM, Polke JM, Castleman V, Manji H, Lunn MP, Bull K, Ramdharry G, Davis M, Blake JC, Houlden H, Reilly MM. Charcot-Marie-Tooth disease: frequency of genetic subtypes and guidelines for genetic testing. J Neurol Neurosurg Psychiatry. 2012 Jul;83(7):706-10. doi: 10.1136/jnnp-2012-302451. Epub 2012 May 10.

Arthur-Farraj PJ, Murphy SM, Laura M, Lunn MP, Manji H, Blake J, Ramdharry G, Fox Z, Reilly MM. Hand weakness in Charcot-Marie-Tooth disease 1X. Neuromuscul Disord. 2012 Jul;22(7):622-6. doi: 10.1016/j.nmd.2012.02.008. Epub 2012 Mar 28.

Saporta MA, Shy BR, Patzko A, Bai Y, Pennuto M, Ferri C, Tinelli E, Saveri P, Kirschner D, Crowther M, Southwood C, Wu X, Gow A, Feltri ML, Wrabetz L, Shy ME. MpzR98C arrests Schwann cell development in a mouse model of early-onset Charcot-Marie-Tooth disease type 1B. Brain. 2012 Jul;135(Pt 7):2032-47. doi: 10.1093/brain/aws140. Epub 2012 Jun 10.

Murphy SM, Ovens R, Polke J, Siskind CE, Laura M, Bull K, Ramdharry G, Houlden H, Murphy RP, Shy ME, Reilly MM. X inactivation in females with X-linked Charcot-Marie-Tooth disease. Neuromuscul Disord. 2012 Jul;22(7):617-21. doi: 10.1016/j.nmd.2012.02.009. Epub 2012 Apr 6.

Scanlon C, Park K, Mapletoft D, Begg L, Burns J.. Interrater and intrarater reliability of photoplethysmography for measuring toe blood pressure and toe-brachial index in people with diabetes mellitus. J Foot Ankle Res. 2012 Jun 7;5:13. doi: 10.1186/1757-1146-5-13.

Rossor AM, Davidson GL, Blake J, Polke JM, Murphy SM, Houlden H, Innes A, Kalmar B, Greensmith L, Reilly MM. A novel p.Gln175X [corrected] premature stop mutation in the C-terminal end of HSP27 is a cause of CMT2. J Peripher Nerv Syst. 2012 Jun;17(2):201-5. doi: 10.1111/j.1529-8027.2012.00400.x.

Jaffer F, Murphy SM, Scoto M, Healy E, Rossor AM, Brandner S, Phadke R, Selcen D, Jungbluth H, Muntoni F, Reilly MM. BAG3 mutations: another cause of giant axonal neuropathy. J Peripher Nerv Syst. 2012 Jun;17(2):210-6. doi: 10.1111/j.1529-8027.2012.00409.x.

Rossor AM, Murphy S, Reilly MM. Knee bobbing in Charcot-Marie-Tooth disease. Pract Neurol. 2012 Jun;12(3):182-3. doi: 10.1136/practneurol-2011-000167.

Miller LJ, Patzko A, Lewis RA, Shy ME. Phenotypic presentation of the Ser63Del MPZ mutation. J Peripher Nerv Syst. 2012 Jun;17(2):197-200. doi: 10.1111/j.1529-8027.2012.00398.x.

Voermans NC, Kleefstra T, Gabreels-Festen AA, et al. Severe Dejerine-Sottas disease with respiratory failure and dysmorphic features in association with a PMP22 point mutation and a 3q23 microdeletion. J Peripher Nerv Syst. Jun 2012;17(2):223-225. PMID: 22734911.

Harms MB, Ori-McKenney KM, Scoto M, Tuck EP, Bell S, Ma D, Masi S, Allred P, Al-Lozi M, Reilly MM, Miller LJ, Jani-Acsadi A, Pestronk A, Shy ME, Muntoni F, Vallee RB, Baloh RH. Mutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy. Neurology. 2012 May 29;78(22):1714-20. doi: 10.1212/WNL.0b013e3182556c05. Epub 2012 Mar 28.

Burns J, Ouvrier R, Estilow T, Shy R, Laura M, Pallant JF, Lek M, Muntoni F, Reilly MM, Pareyson D, Acsadi G, Shy ME, Finkel RS. Validation of the Charcot-Marie-Tooth disease pediatric scale as an outcome measure of disability. Ann Neurol. 2012 May;71(5):642-52. doi: 10.1002/ana.23572.

Lloyd TE, Machamer J, O'Hara K, Kim JH, Collins SE, Wong MY, Sahin B, Imlach W, Yang Y, Levitan ES, McCabe BD, Kolodkin AL. The p150(Glued) CAP-Gly domain regulates initiation of retrograde transport at synaptic termini. Neuron. Apr 26 2012;74(2):344-360. PMID: 22542187, PMCID: PMC3353876.

Norton N, Robertson PD, Rieder MJ, Züchner S, Rampersaud E, Martin E, Li D, Nickerson DA, Hershberger RE; National Heart, Lung and Blood Institute GO Exome Sequencing Project. Evaluating pathogenicity of rare variants from dilated cardiomyopathy in the exome era. Circ Cardiovasc Genet. 2012 Apr 1;5(2):167-74. doi: 10.1161/CIRCGENETICS.111.961805. Epub 2012 Feb 15.

Blyton F, Chuter V, Burns J. Unknotting night-time muscle cramp: a survey of patient experience, help-seeking behaviour and perceived treatment effectiveness. J Foot Ankle Res. 2012 Mar 15;5:7. doi: 10.1186/1757-1146-5-7.

Morrow JM, D'Sa S, Page RA, Hilali MA, Lunn MP, Reilly MM. Rituximab responsive multiple radiculopathies and cranial nerve palsies in association with chronic lymphocytic leukaemia. J Neurol. Mar 2012;259(3):571-573. PMID: 21887515.

Montenegro G, Rebelo AP, Connell J, et al. Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12. J Clin Invest. Feb 1 2012;122(2):538-544. PMID: 22232211, PMCID: PMC3266795.

Murphy SM, Khan U, Alifrangis C, Hazell S, Hrouda D, Blake J, Ball J, Gabriel C, Markarian P, Rees J, Karim A, Seckl MJ, Lunn MP, Reilly MM. Anti Ma2-associated myeloradiculopathy: expanding the phenotype of anti-Ma2 associated paraneoplastic syndromes. J Neurol Neurosurg Psychiatry. 2012 Feb;83(2):232-3. doi: 10.1136/jnnp.2010.223271. Epub 2011 Jan 4.

Patzko A, Shy ME. Charcot-Marie-Tooth disease and related genetic neuropathies. Continuum (Minneapolis, Minn). Feb 2012;18(1):39-59. PMID: 22810069.

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Murphy SM, Davidson GL, Brandner S, Houlden H, Reilly MM. Mutation in FAM134B causing severe hereditary sensory neuropathy. J Neurol Neurosurg Psychiatry. 2012 Jan;83(1):119-20. doi: 10.1136/jnnp.2010.228965. Epub 2010 Nov 28.

Sinclair CD, Morrow JM, Miranda MA, Davagnanam I, Cowley PC, Mehta H, Hanna MG, Koltzenburg M, Yousry TA, Reilly MM, Thornton JS. Skeletal muscle MRI magnetisation transfer ratio reflects clinical severity in peripheral neuropathies. J Neurol Neurosurg Psychiatry. Jan 2012;83(1):29-32. PMID: 21613652.

Rossor AM, Kalmar B, Greensmith L, Reilly MM. The distal hereditary motor neuropathies. J Neurol Neurosurg Psychiatry. 2012 Jan;83(1):6-14. doi: 10.1136/jnnp-2011-300952. Epub 2011 Oct 25.

Scherer SS, Feltri ML, Wrabetz L. Genetic Mutations Affecting Myelin Formation. In: Kettenmann H, Ransom BR, eds. Neuroglia. New York, NY: Oxford University Press. 2012:798-808.

Murphy SM, Reilly M. Hereditary amyloid neuropathy. Autonomic Failure: a textbook of clinical disorders of the autonomic nervous system. New York: Oxford University Press; 2012.

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Holzbaur EL, Scherer SS. Microtubules, axonal transport, and neuropathy. N Engl J Med. 2011 Dec 15;365(24):2330-2. doi: 10.1056/NEJMcibr1112481.

Hutton EJ, Carty L, Laurá M, Houlden H, Lunn MP, Brandner S, Mirsky R, Jessen K, Reilly MM. c-Jun expression in human neuropathies: a pilot study. J Peripher Nerv Syst. 2011 Dec;16(4):295-303. doi: 10.1111/j.1529-8027.2011.00360.x.

Scherer SS. The debut of a rational treatment for an inherited neuropathy. J Clin Invest. Dec 2011;121(12):4624-4627. PMID: 22045569, PMCID: PMC3226011.

Siskind CE, Shy ME. Genetics of neuropathies. Semin Neurol. Nov 2011;31(5):494-505. PMID: 22266887.

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Miller LJ, Saporta AS, Sottile SL, Siskind CE, Feely SM, Shy ME. Strategy for genetic testing in Charcot-Marie-disease. Acta Myol. 2011 Oct;30(2):109-16.

Saporta MA, Grskovic M, Dimos JT. Induced pluripotent stem cells in the study of neurological diseases. Stem cell research & therapy. 2011 Sep 21;2(5):37. doi: 10.1186/scrt78. PMID: 21936964; PMCID: PMC3308034.

Almodovar JL, Ferguson M, McDermott MP, Lewis RA, Shy ME, Herrmann DN. In vivo confocal microscopy of Meissner corpuscles as a novel sensory measure in CMT1A. J Peripher Nerv Syst. 2011 Sep;16(3):169-74. doi: 10.1111/j.1529-8027.2011.00342.x.

Murphy SM, Herrmann DN, McDermott MP, Scherer SS, Shy ME, Reilly MM, Pareyson D. Reliability of the CMT neuropathy score (second version) in Charcot-Marie-Tooth disease. J Peripher Nerv Syst. 2011 Sep;16(3):191-8. doi: 10.1111/j.1529-8027.2011.00350.x.

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Saporta MA, Katona I, Zhang X, Roper HP, McClelland L, Macdonald F, Brueton L, Blake J, Suter U, Reilly MM, Shy ME, Li J. Neuropathy in a human without the PMP22 gene. Arch Neurol. Jun 2011;68(6):814-821. PMID: 21670407, PMCID: PMC3711535.

Siskind CE, Murphy SM, Ovens R, Polke J, Reilly MM, Shy ME. Phenotype expression in women with CMT1X. J Peripher Nerv Syst. 2011 Jun;16(2):102-7. doi: 10.1111/j.1529-8027.2011.00332.x.

Scherer SS. CMT2A: the name doesn't tell the whole story. Neurology. May 17 2011;76(20):1686-1687. PMID: 21508332.

Feely SM, Laura M, Siskind CE, Sottile S, Davis M, Gibbons VS, Reilly MM, Shy ME. MFN2 mutations cause severe phenotypes in most patients with CMT2A. Neurology. 2011 May 17;76(20):1690-6. doi: 10.1212/WNL.0b013e31821a441e. Epub 2011 Apr 20.

Pareyson D, Reilly MM, Schenone A, et al. Ascorbic acid in Charcot-Marie-Tooth disease type 1A (CMT-TRIAAL and CMT-TRAUK): a double-blind randomised trial. Lancet Neurol. Apr 2011;10(4):320-328. PMID: 21393063, PMCID: PMC3154498.

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Shy ME. Inherited peripheral neuropathies. Continuum (Minneapolis, Minn). Apr 2011;17(2 Neurogenetics):294-315. PMID: 22810821.

Smith LJ, Murphy SM, Holmes P, Reilly MM, Reiniger L, Thom M, Lunn MP. A painful right leg. BMJ. 2011 Mar 16;342:d1009. doi: 10.1136/bmj.d1009. PMID: 21411806.

Murphy SM, Polke J, Manji H, Blake J, Reiniger L, Sweeney M, Houlden H, Brandner S, Reilly MM. A novel mutation in the nerve-specific 5'UTR of the GJB1 gene causes X-linked Charcot-Marie-Tooth disease. J Peripher Nerv Syst. 2011 Mar;16(1):65-70. doi: 10.1111/j.1529-8027.2011.00321.x.

Reilly MM, Murphy SM, Laurá M. Charcot-Marie-Tooth disease. J Peripher Nerv Syst. 2011 Mar;16(1):1-14. doi: 10.1111/j.1529-8027.2011.00324.x.

Murphy SM, Laurá M, Blake J, Polke J, Bremner F, Reilly MM. Conduction block and tonic pupils in Charcot-Marie-Tooth disease caused by a myelin protein zero p.Ile112Thr mutation. Neuromuscul Disord. 2011 Mar;21(3):223-6. doi: 10.1016/j.nmd.2010.12.010. Epub 2011 Jan 21.

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Züchner S, Dallman J, Wen R, Beecham G, Naj A, Farooq A, Kohli MA, Whitehead PL, Hulme W, Konidari I, Edwards YJ, Cai G, Peter I, Seo D, Buxbaum JD, Haines JL, Blanton S, Young J, Alfonso E, Vance JM, Lam BL, Peričak-Vance MA. Whole-exome sequencing links a variant in DHDDS to retinitis pigmentosa. Am J Hum Genet. 2011 Feb 11;88(2):201-6. doi: 10.1016/j.ajhg.2011.01.001. Epub 2011 Feb 3.

Patzkó A, Shy ME. Update on Charcot-Marie-Tooth disease. Curr Neurol Neurosci Rep. 2011 Feb;11(1):78-88. doi: 10.1007/s11910-010-0158-7.

Russo M, Laurá M, Polke JM, Davis MB, Blake J, Brandner S, Hughes RA, Houlden H, Bennett DL, Lunn MP, Reilly MM. Variable phenotypes are associated with PMP22 missense mutations. Neuromuscul Disord. Feb 2011;21(2):106-114. PMID: 21194947.

Saporta AS, Sottile SL, Miller LJ, Feely SM, Siskind CE, Shy ME. Charcot-Marie-Tooth disease subtypes and genetic testing strategies. Ann Neurol. 2011 Jan;69(1):22-33. doi: 10.1002/ana.22166.

Amato AA, Reilly MM. The death panel for Charcot-Marie-Tooth panels. Ann Neurol. Jan 2011;69(1):1-4. PMID: 21280068.

Reilly MM, Shy ME, Muntoni F, Pareyson D. 168th ENMC International Workshop: outcome measures and clinical trials in Charcot-Marie-Tooth disease (CMT). Neuromuscul Disord. Dec 2010;20(12):839-846. PMID: 20850975.

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Scherer SS. Genes and Inherited Neuropathies. Companion to Peripheral Neuropathy. Philadelphia, PA: Saunders Elsevier. 2010:335-342.

Hedges DJ, Burges D, Powell E, Almonte C, Huang J, Young S, Boese B, Schmidt M, Pericak-Vance MA, Martin E, Zhang X, Harkins TT, Züchner S. Exome sequencing of a multigenerational human pedigree. PLoS One. 2009 Dec 14;4(12):e8232. doi: 10.1371/journal.pone.0008232.

Reilly MM, Shy ME. Diagnosis and new treatments in genetic neuropathies. J Neurol Neurosurg Psychiatry. 2009 Dec;80(12):1304-14. doi: 10.1136/jnnp.2008.158295. PMID: 19917815.

Ramchandren S, Shy ME, Finkel RS. Quality of life in children with CMT type 1A. Lancet Neurol. Oct 2009;8(10):880-881; author reply 881. PMID: 19747650.

Ramdharry GM, Day BL, Reilly MM, Marsden JF. Hip flexor fatigue limits walking in Charcot-Marie-Tooth disease. Muscle Nerve. 2009 Jul;40(1):103-11. doi: 10.1002/mus.21264.

Katona I, Wu X, Feely SM, et al. PMP22 expression in dermal nerve myelin from patients with CMT1A. Brain. Jul 2009;132(Pt 7):1734-1740. PMID: 19447823, PMCID: PMC2724915.

Shy M. Ascorbic acid for treatment of CMT1A: the jury is still out. Lancet Neurol. Jun 2009;8(6):505-507. PMID: 19427270.

Siskind C, Feely SM, Bernes S, Shy ME, Garbern JY. Persistent CNS dysfunction in a boy with CMT1X. J Neurol Sci. Apr 15 2009;279(1-2):109-113. PMID: 19193385.

Houlden H, Laura M, Ginsberg L, Jungbluth H, Robb SA, Blake J, Robinson S, King RH, Reilly MM. The phenotype of Charcot-Marie-Tooth disease type 4C due to SH3TC2 mutations and possible predisposition to an inflammatory neuropathy. Neuromuscul Disord. Apr 2009;19(4):264-269. PMID: 19272779.

Dimos JT, Rodolfa KT, Niakan KK, Weisenthal LM, Mitsumoto H, Chung W, Croft GF, Saphier G, Leibel R, Goland R, Wichterle H, Henderson CE, Eggan K. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science. Aug 29 2008;321(5893):1218-1221. PMID: 18669821.

Svatkova A, Pasternak O, Eisengart JB, Rudser KD, Bednařík P, Mueller BA, Delaney KA, Shapiro EG, Whitley CB, Nestrašil I. Diffusion tensor imaging with free-water correction reveals distinctions between severe and attenuated subtypes in Mucopolysaccharidosis type I. J Inherit Metab Dis. 2025 Jan;48(1):e12830. doi: 10.1002/jimd.12830. PMID: 39761695; PMCID: PMC11703597.

Mucopolysaccharidosis type I (MPS I, with clinical subtypes Hurler syndrome, Hurler-Scheie syndrome, and Scheie syndrome) are inherited lysosomal disorders that cause severe damage to multiple organs, including the white matter of the brain. Whole-brain diffusion tensor imaging (DTI) analysis has not been feasible in patients with MPS diseases due to structural MPS-related brain abnormalities. However, the effects of these abnormalities on DTI measurements could be lessened with a method called free-water correction (FWC).

In this study, investigators analyzed DTI with FWC to explore distinctions between subtypes of MPS I. The team studied DTI data from 44 patients with a range of subtypes of MPS I as well as 27 healthy controls.

Results reveal distinct spatial patterns of white matter damage in severe and attenuated MPS I subtypes. Findings also highlight a relationship between attention, age at hematopoietic stem cell transplantation, and white matter microstructure. The investigators concluded that free-water fraction is a unique measure for longitudinal MPS studies to monitor disease progression and response to treatment.

Ankit K Desai, Garima Shrivastava, Christina L Grant, Raymond Y Wang, Trevor D Burt, Priya S Kishnani. An updated management approach of Pompe disease patients with high-sustained anti-rhGAA IgG antibody titers: experience with bortezomib-based immunomodulation. Front Immunol. 2024 Mar 8;15:1360369. doi: 10.3389/fimmu.2024.1360369. PMID: 38524130; PMCID: PMC10959098.

Pompe disease is an inherited lysosomal disorder caused by an abnormal enzyme that cannot break down glycogen. Patients with infantile-onset Pompe disease often experience high-sustained anti-rhGAA IgG antibody titers (HSAT), which can lower the efficacy of enzyme replacement therapy and lead to health complications.

In this study, researchers explored management approaches for HSAT in patients with Pompe disease. The team compared the disease course of eight patients with infantile-onset Pompe who were treated with the drug bortezomib. Researchers tracked differences in timing, dosage, and outcomes among these patients.

Results suggest that bortezomib should be initiated at the earliest sign of HSAT with a minimum of two consecutive treatment cycles to achieve optimal outcomes. Authors recommend close monitoring of HSAT and early intervention as soon as significantly elevated levels are noted.

Brima T, Freedman EG, Prinsloo KD, Augustine EF, Adams HR, Wang KH, Mink JW, Shaw LH, Mantel EP, Foxe JJ. Assessing the integrity of auditory sensory memory processing in CLN3 disease (Juvenile Neuronal Ceroid Lipofuscinosis (Batten disease)): an auditory evoked potential study of the duration-evoked mismatch negativity (MMN). J Neurodev Disord. 2024 Jan 6;16(1):3. doi: 10.1186/s11689-023-09515-8. PMID: 38183037; PMCID: PMC10770910.

CLN3 disease, also known as juvenile neuronal ceroid lipofuscinosis or Batten disease, is a type of lysosomal disorder that affects the nervous system beginning in childhood. Throughout adolescence and early adulthood, patients often experience progressive vision loss, motor dysfunction, and cognitive decline. This combination of symptoms can make it challenging to assess neurocognitive decline, highlighting the need for quantitative measures of brain function.

In this study, researchers assessed auditory sensory memory capabilities in individuals with CLN3 disease as a potential biomarker for neurocognitive decline. The team used a type of assessment called duration-evoked mismatch negativity (MMN)—which does not require participant engagement—to study early auditory processing, discrimination, and sensory memory in 21 individuals with CLN3 disease and 41 neurotypical controls.

Results reveal a decline in auditory sensory memory for duration as CLN3 disease progresses. Authors note that duration-evoked MMN may also serve as a sensitive measure of disease severity in other neurodevelopmental disorders.

Wu TT, Finkel RS, Siskind CE, Feely SME, Burns J, Reilly MM, Muntoni F, Milev E, Estilow T, Shy ME, Ramchandren S; Childhood CMT Study Group of the Inherited Neuropathy Consortium. Validation of the parent-proxy version of the pediatric Charcot-Marie-Tooth disease quality of life instrument for children aged 0-7 years. J Peripher Nerv Syst. 2023 Sep;28(3):382-389. doi: 10.1111/jns.12557. Epub 2023 May 18.

Miller BS, Fung EB, White KK, Lund TC, Harmatz P, Orchard PJ, Whitley CB, Polgreen LE. Persistent bone and joint disease despite current treatments for mucopolysaccharidosis types I, II, and VI: Data from a 10-year prospective study. J Inherit Metab Dis. 2023 Feb 25. doi: 10.1002/jimd.12598. Epub ahead of print. PMID: 36840680.

Mucopolysaccharidosis (MPS) disorders are a group of nine rare, inherited, lysosomal storage disorders caused by genetic mutations which produce 11 dysfunctional enzymes that cannot break down glycosaminoglycans (complex sugar molecules with amino groups that are critical components of connective tissues). MPS disorders have many potential new therapies on the horizon. However, historic control data on disease progression and variability are needed to understand the long-term benefits and limitations of these treatments.

In this study, researchers conducted a 10-year prospective observational study of 55 children with multiple types of MPS. The team used several techniques, including annual measurements and mixed effects modeling, to systematically evaluate bone and joint disease over time.

Results show that despite current treatments, patients with MPS I, II, and VI still experience short stature, joint contractures, and elevation in average BMI. Authors note that data from this study could be used to expedite testing of therapies directed to bones and joints, as well as highlight the need for weight management in routine clinical care for patients with MPS.

Sahasrabudhe SA, Terluk MR, Rudser KD, Cloyd JC, Kartha RV. Biological Variation in Peripheral Inflammation and Oxidative Stress Biomarkers in Individuals with Gaucher Disease. Int J Mol Sci. 2022 Aug 16;23(16):9189. doi: 10.3390/ijms23169189. PMID: 36012454; PMCID: PMC9409136.

Gaucher disease type 1 (GD1) is a rare lysosomal storage disorder in which harmful amounts of fatty materials (lipids) accumulate in various cells and tissues in the body. Currently, there is a lack of reliable biomarkers for GD1, which could help predict treatment success or disease progression. In this study, researchers aimed to validate measures of oxidative stress and inflammation as biomarkers for GD1. For three months, the team investigated and compared variation in various blood-based oxidative stress and inflammation biomarkers in participants with GD1. Results show that specific biomarkers are consistently altered in GD1, regardless of therapy status. These findings highlight the need for additional therapies that can target and modulate these biomarkers. Authors note that this information can help guide the selection of candidate biomarkers for future intervention-based studies in patients with GD1.

Silvestroni A, Sokolovskiy A, Tøndel C, Svarstad E, Obrisca B, Ismail G, Holida MD, Mauer M. A novel unbiased method reveals progressive podocyte globotriaosylceramide accumulation and loss with age in females with Fabry disease. Kidney Int.. 2022 Jul;102(1):173-182. doi: 10.1016/j.kint.2022.03.023. Epub 2022 Apr 26. PMID: 35483528; PMCID: PMC9233139.

Fabry disease is a lysosomal storage disorder caused by an abnormal enzyme that cannot break down some of the glycosphingolipids (cell membrane components containing fats with sugar molecules attached). The increase in one of these glycosphingolipids, called globotriasylceramide (GL3), is the hallmark of the disease and associated with cellular injury. The Fabry disease gene is located on the X chromosome. In contrast to males, females have two X chromosomes in their cells, one of which is randomly inactivated. Although female patients can experience serious complications of Fabry disease, most studies focus on male patients in order to avoid confusion resulting from mosaicism caused by X chromosome inactivation. In this study, researchers developed a new, unbiased method for GL3 estimation in podocytes (kidney cells that wrap around capillaries in the kidney filters called glomeruli) independent of mosaicism in female patients with Fabry disease. Researchers used this method to make age-matched comparisons between female and male patients and controls. Results showed that GL3 accumulation in podocytes that carry the gene defect in female patients with Fabry disease increases with age—and to the same levels as podocytes in males, all of which carry this defect. This accumulation is also associated with podocyte loss and leaking protein in the urine, predictors of kidney failure. These studies indicate that Fabry-affected podocytes in female patients do not benefit from the circulating normal enzyme from their normal cells or from normal neighbor podocytes. Authors note that these novel findings help us better understand the mechanisms involved in Fabry disease complications and have important clinical implications.

Ahmed A, Rudser K, King KE, Eisengart JB, Orchard PJ, Shapiro E, Whitley CB. Quantifying medical manifestations in Hurler syndrome with the infant physical symptom score: associations with long-term physical and adaptive outcomes. Mol Genet Metab. 2022 May;136(1):22-27. doi: 10.1016/j.ymgme.2022.03.003. Epub 2022 Mar 10. PMID: 35304037.

Mucopolysaccharidosis (MPS) is a group of inherited conditions in which the body is unable to properly break down mucopolysaccharides (long chains of sugar molecules that are found throughout the body). As a result, these sugars build up in cells, blood, and connective tissue, leading to a variety of health problems. A physical symptom score (PSS) has been developed to characterize physical symptoms of MPS in older children. With the onset of newborn screening, there is an increased need to characterize these symptoms in infants and toddlers. In this study, researchers aimed to create a measure to quantify somatic (physical) burden in patients with MPS under 36 months of age. They established the Infant Physical Symptom Score (IPSS) using data from 39 patients with Hurler syndrome (MPS IH) enrolled in a Lysosomal Disease Network (LDN) study. To validate the new scale, researchers compared the IPSS with the PSS. Results show that the IPSS is a useful approach to quantifying the somatic disease burden of MPS IH patients under 36 months of age. Authors note that the IPSS may also provide a predictor of later outcomes, especially adaptive function.

Masten MC, Corre C, Paciorkowski AR, Vierhile A, Adams HR, Vermilion J, Zimmerman GA, Augustine EF, Mink JW. A diagnostic confidence scheme for CLN3 disease. J Inherit Metab Dis. J Inherit Metab Dis. 2021 Aug 28. doi: 10.1002/jimd.12429. Online ahead of print.

CLN3 disease is an inherited disorder that primarily affects the nervous system. After 4 to 6 years of normal development, children with this condition develop vision impairment, intellectual disability, movement problems, speech difficulties, and seizures, which worsen over time. Researchers seeking to improve diagnostic methods for CLN3 disease used genotype and phenotype data from an ongoing natural history study to develop a hierarchical diagnostic confidence scheme with three major classes: Definite, Probable, or Possible CLN3 disease. An additional level, CLN3 Disease PLUS, includes individuals with CLN3 disease plus an additional disorder that substantially affects the phenotype. They used the scheme to classify individuals and then performed a blinded reclassification to assess the reliability of this scheme. Test-retest reliability showed 96% agreement. Authors conclude that their diagnostic confidence scheme for CLN3 disease appears to be effective and has implications for clinical research in CLN3 and other rare genetic neurodegenerative disorders.

Kovacs KD, Orlin A, Sondhi D, Kaminsky SM, D'Amico DJ, Crystal RG, Kiss S. Automated Retinal Layer Segmentation in CLN2-Associated Disease: Commercially Available Software Characterizing a Progressive Maculopathy. Transl Vis Sci Technol. 2021 Jul 1;10(8):23. doi: 10.1167/tvst.10.8.23.

CLN2-associated disease is an inherited, fatal lysosomal storage disorder characterized by progressive brain and retinal deterioration. In this study, researchers evaluated the eyes of 14 patients using the automated segmentation software in optical coherence tomography scans to characterize inner and outer retinal degeneration. Their goal was to identify sensitive, quantitative biomarkers for assessing retinal degeneration in anticipation of future clinical trials. They identified a significant, progressive difference in the thickness of the outer nuclear layers (ONL) of the parafovea, a region in the retina, in patients from 39 to 45 months versus 46 to 52 months. They conclude that parafoveal ONL thickness is a sensitive, early age indicator of CLN2-associated retinal degeneration.

Flanagan M, Pathak I, Gan Q, Winter L, Emnet R, Akel S, Montaño AM. Umbilical mesenchymal stem cell-derived extracellular vesicles as enzyme delivery vehicle to treat Morquio A fibroblasts. Stem Cell Res Ther. 2021 May 6;12(1):276. doi: 10.1186/s13287-021-02355-0.

Li C, Desai AK, Gupta P, Dempsey K, Bhambhani V, Hopkin RJ, Ficicioglu C, Tanpaiboon P, Craigen WJ, Rosenberg AS, Kishnani PS. Transforming the clinical outcome in CRIM-negative infantile Pompe disease identified via newborn screening: the benefits of early treatment with enzyme replacement therapy and immune tolerance induction. Genet Med. 2021 May;23(5):845-855. doi: 10.1038/s41436-020-01080-y. Epub 2021 Jan 25.

This study of 41 patients with cross-reactive immunological material (CRIM)-negative infantile Pompe disease (IPD) showed that early treatment with enzyme replacement therapy and prophylactic immune tolerance induction can transform the long-term CRIM-negative phenotype, which represents the most severe end of the Pompe disease spectrum.

Lund TC, Doherty TM, Eisengart JB, Freese RL, Rudser KD, Fung EB, Miller BS, White KK, Orchard PJ, Whitley CB, Polgreen LE. Biomarkers for prediction of skeletal disease progression in mucopolysaccharidosis type I. JIMD Rep. 2020 Dec 8;58(1):89-99. doi: 10.1002/jmd2.12190. eCollection 2021 Mar.

Sondhi D, Kaminsky SM, Hackett NR, Pagovich OE, Rosenberg JB, De BP, Chen A, Van de Graaf B, Mezey JG, Mammen GW, Mancenido D, Xu F, Kosofsky B, Yohay K, Worgall S, Kaner RJ, Souwedaine M, Greenwald BM, Kaplitt M, Dyke JP, Ballon DJ, Heier LA, Kiss S, Crystal RG. Slowing late infantile Batten disease by direct brain parenchymal administration of a rh.10 adeno-associated virus expressing CLN2. Sci Transl Med. 2020 Dec 2;12(572):eabb5413. doi: 10.1126/scitranslmed.abb5413.

Elmerskog B, Tøssebro AG, Atkinson R, Rokne S, Cole B, Ockelford A, Adams HR. Overview of advances in educational and social supports for young persons with NCL disorders. Biochim Biophys Acta Mol Basis Dis. 2020 Sep 1;1866(9):165480. doi: 10.1016/j.bbadis.2019.05.016. Epub 2019 May 30.

Korlimarla A, Spiridigliozzi GA, Crisp K, Herbert M, Chen S, Malinzak M, Stefanescu M, Austin SL, Cope H, Zimmerman K, Jones H, Provenzale JM, Kishnani PS. Novel approaches to quantify CNS involvement in children with Pompe disease. Neurology. 2020 Aug 11;95(6):e718-e732. doi: 10.1212/WNL.0000000000009979. Epub 2020 Jun 9.

Desai AK, Baloh CH, Sleasman JW, Rosenberg AS, Kishnani PS. Benefits of Prophylactic Short-Course Immune Tolerance Induction in Patients With Infantile Pompe Disease: Demonstration of Long-Term Safety and Efficacy in an Expanded Cohort. Front Immunol. 2020 Aug 6;11:1727. doi: 10.3389/fimmu.2020.01727. eCollection 2020.

Korlimarla A, Spiridigliozzi GA, Stefanescu M, Austin SL, Kishnani PS. Behavioral, social and school functioning in children with Pompe disease. Mol Genet Metab Rep. 2020 Aug 5;25:100635. doi: 10.1016/j.ymgmr.2020.100635. eCollection 2020 Dec.

Kovacs KD, Patel S, Orlin A, Kim K, Van Everen S, Conner T, Sondhi D, Kaminsky SM, D'Amico DJ, Crystal RG, Kiss S. Symmetric Age Association of Retinal Degeneration in Patients with CLN2-Associated Batten Disease. Ophthalmol Retina. 2020 Jul;4(7):728-736. doi: 10.1016/j.oret.2020.01.011. Epub 2020 Jan 22.

Masten MC, Williams JD, Vermilion J, Adams HR, Vierhile A, Collins A, Marshall FJ, Augustine EF, Mink JW. The CLN3 Disease Staging System: A new tool for clinical research in Batten disease. Neurology. 2020 Jun 9;94(23):e2436-e2440. doi: 10.1212/WNL.0000000000009454. Epub 2020 Apr 16.

Ou L, Przybilla MJ, Tăbăran AF, Overn P, O'Sullivan MG, Jiang X, Sidhu R, Kell PJ, Ory DS, Whitley CB. A novel gene editing system to treat both Tay-Sachs and Sandhoff diseases. Gene Ther. 2020 May;27(5):226-236. doi: 10.1038/s41434-019-0120-5. Epub 2020 Jan 2.

Kartha RV, Joers J, Terluk MR, Travis A, Rudser K, Tuite PJ, Weinreb NJ, Jarnes JR, Cloyd JC, Öz G. Neurochemical abnormalities in patients with type 1 Gaucher disease on standard of care therapy. J Inherit Metab Dis. 2020 May;43(3):564-573. doi: 10.1002/jimd.12182. Epub 2019 Dec 17.

Najafian B, Tøndel C, Svarstad E, Gubler MC, Oliveira JP, Mauer M. Accumulation of Globotriaosylceramide in Podocytes in Fabry Nephropathy Is Associated with Progressive Podocyte Loss. J Am Soc Nephrol. 2020 Apr;31(4):865-875. doi: 10.1681/ASN.2019050497. Epub 2020 Mar 3.

ElMallah MK, Desai AK, Nading EB, DeArmey S, Kravitz RM, Kishnani PS. Pulmonary outcome measures in long-term survivors of infantile Pompe disease on enzyme replacement therapy: A case series. Pediatr Pulmonol. 2020 Mar;55(3):674-681. doi: 10.1002/ppul.24621. Epub 2020 Jan 3.

Vera MU, Le SQ, Victoroff A, Passage MB, Brown JR, Crawford BE, Polgreen LE, Chen AH, Dickson PI. Evaluation of non-reducing end pathologic glycosaminoglycan detection method for monitoring therapeutic response to enzyme replacement therapy in human mucopolysaccharidosis I. Mol Genet Metab. 2020 Feb;129(2):91-97. doi: 10.1016/j.ymgme.2019.09.001. Epub 2019 Sep 11.

Johnson PH, Weinreb NJ, Cloyd JC, Tuite PJ, Kartha RV. GBA1 mutations: Prospects for exosomal biomarkers in α-synuclein pathologies. Mol Genet Metab. 2020 Feb;129(2):35-46. doi: 10.1016/j.ymgme.2019.10.006. Epub 2019 Oct 23.

Chen AH, Harmatz P, Nestrasil I, Eisengart JB, King KE, Rudser K, Kaizer AM, Svatkova A, Wakumoto A, Le SQ, Madden J, Young S, Zhang H, Polgreen LE, Dickson PI. Intrathecal enzyme replacement for cognitive decline in mucopolysaccharidosis type I, a randomized, open-label, controlled pilot study. Mol Genet Metab. 2020 Feb;129(2):80-90. doi: 10.1016/j.ymgme.2019.11.007. Epub 2019 Nov 30.

Polgreen LE, Lund TC, Braunlin E, Tolar J, Miller BS, Fung E, Whitley CB, Eisengart JB, Northrop E, Rudser K, Miller WP, Orchard PJ. Clinical trial of laronidase in Hurler syndrome after hematopoietic cell transplantation. Pediatr Res. 2020 Jan;87(1):104-111. doi: 10.1038/s41390-019-0541-2. Epub 2019 Aug 21.

Eisengart JB, Pierpont EI, Kaizer AM, Rudser KD, King KE, Pasquali M, Polgreen LE, Dickson PI, Le SQ, Miller WP, Tolar J, Orchard PJ, Lund TC. Intrathecal enzyme replacement for Hurler syndrome: biomarker association with neurocognitive outcomes. Genet Med. 2019 Nov;21(11):2552-2560. doi: 10.1038/s41436-019-0522-1. Epub 2019 Apr 25.

Cathey SS, Sarasua SM, Simensen R, Pietris K, Kimbrell G, Sillence D, Wilson C, Horowitz L. Intellectual functioning in alpha-mannosidosis. JIMD Rep. 2019 Sep 21;50(1):44-49. doi: 10.1002/jmd2.12073. eCollection 2019 Nov.

Ou L, Kim S, Whitley CB, Jarnes-Utz JR. Genotype-phenotype correlation of gangliosidosis mutations using in silico tools and homology modeling. Mol Genet Metab Rep. 2019 Jul 17;20:100495. doi: 10.1016/j.ymgmr.2019.100495. eCollection 2019 Sep.

Ahmed A, Ou L, Rudser K, Shapiro E, Eisengart JB, King K, Chen A, Dickson P, Whitley CB. A longitudinal study of neurocognition and behavior in patients with Hurler-Scheie syndrome heterozygous for the L238Q mutation. Mol Genet Metab Rep. 2019 Jun 27;20:100484. doi: 10.1016/j.ymgmr.2019.100484. eCollection 2019 Sep.

Langan TJ, Barczykowski A, Jalal K, Sherwood L, Allewelt H, Kurtzberg J, Carter RL. Survey of quality of life, phenotypic expression, and response to treatment in Krabbe leukodystrophy. JIMD Rep. 2019 Apr 11;47(1):47-54. doi: 10.1002/jmd2.12033. eCollection 2019 May.

Kazi ZB, Desai AK, Troxler RB, Kronn D, Packman S, Sabbadini M, Rizzo WB, Scherer K, Abdul-Rahman O, Tanpaiboon P, Nampoothiri S, Gupta N, Feigenbaum A, Niyazov DM, Sherry L, Segel R, McVie-Wylie A, Sung C, Joseph AM, Richards S, Kishnani PS. An immune tolerance approach using transient low-dose methotrexate in the ERT-naïve setting of patients treated with a therapeutic protein: experience in infantile-onset Pompe disease. Genet Med. 2019 Apr;21(4):887-895. doi: 10.1038/s41436-018-0270-7. Epub 2018 Sep 14.

Pant DC, Dorboz I, Schluter A, Fourcade S, Launay N, Joya J, Aguilera-Albesa S, Yoldi ME, Casasnovas C, Willis MJ, Ruiz M, Ville D, Lesca G, Siquier-Pernet K, Desguerre I, Yan H, Wang J, Burmeister M, Brady L, Tarnopolsky M, Cornet C, Rubbini D, Terriente J, James KN, Musaev D, Zaki MS, Patterson MC, Lanpher BC, Klee EW, Pinto E Vairo F, Wohler E, Sobreira NLM, Cohen JS, Maroofian R, Galehdari H, Mazaheri N, Shariati G, Colleaux L, Rodriguez D, Gleeson JG, Pujades C, Fatemi A, Boespflug-Tanguy O, Pujol A. Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy. J Clin Invest. 2019 Mar 1;129(3):1240-1256. doi: 10.1172/JCI123959. Epub 2019 Feb 11.

Herbert M, Case LE, Rairikar M, Cope H, Bailey L, Austin SL, Kishnani PS. Early-onset of symptoms and clinical course of Pompe disease associated with the c.-32-13 T > G variant. Mol Genet Metab. 2019 Feb;126(2):106-116. doi: 10.1016/j.ymgme.2018.08.009. Epub 2018 Aug 23.

Ou L, Przybilla MJ, Whitley CB. Metabolomics profiling reveals profound metabolic impairments in mice and patients with Sandhoff disease. Mol Genet Metab. 2019 Feb;126(2):151-156. doi: 10.1016/j.ymgme.2018.09.005. Epub 2018 Sep 14.

Adang LA, Frank DB, Gilani A, Takanohashi A, Ulrick N, Collins A, Cross Z, Galambos C, Helman G, Kanaan U, Keller S, Simon D, Sherbini O, Hanna BD, Vanderver AL. Aicardi goutières syndrome is associated with pulmonary hypertension. Mol Genet Metab. 2018 Dec;125(4):351-358. doi: 10.1016/j.ymgme.2018.09.004. Epub 2018 Sep 7.

Eisengart JB, Rudser KD, Xue Y, Orchard P, Miller W, Lund T, Van der Ploeg A, Mercer J, Jones S, Mengel KE, Gökce S, Guffon N, Giugliani R, de Souza CFM, Shapiro EG, Whitley CB. Long-term outcomes of systemic therapies for Hurler syndrome: an international multicenter comparison. Genet Med. 2018 Nov;20(11):1423-1429. doi: 10.1038/gim.2018.29. Epub 2018 Mar 8.

Sindelar M, Dyke JP, Deeb RS, Sondhi D, Kaminsky SM, Kosofsky BE, Ballon DJ, Crystal RG, Gross SS. Untargeted Metabolite Profiling of Cerebrospinal Fluid Uncovers Biomarkers for Severity of Late Infantile Neuronal Ceroid Lipofuscinosis (CLN2, Batten Disease). Sci Rep. 2018 Oct 15;8(1):15229. doi: 10.1038/s41598-018-33449-0.

Nickel M, Simonati A, Jacoby D, Lezius S, Kilian D, Van de Graaf B, Pagovich OE, Kosofsky B, Yohay K, Downs M, Slasor P, Ajayi T, Crystal RG, Kohlschütter A, Sondhi D, Schulz A. Disease characteristics and progression in patients with late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease: an observational cohort study. Lancet Child Adolesc Health. 2018 Aug;2(8):582-590. doi: 10.1016/S2352-4642(18)30179-2. Epub 2018 Jul 2.

Schiffmann R, Swift C, McNeill N, Benjamin ER, Castelli JP, Barth J, Sweetman L, Wang X, Wu X. Low frequency of Fabry disease in patients with common heart disease. Genet Med. 2018 Jul;20(7):754-759. doi: 10.1038/gim.2017.175. Epub 2017 Oct 26.

Pizzino A, Whitehead M, Sabet Rasekh P, Murphy J, Helman G, Bloom M, Evans SH, Murnick JG, Conry J, Taft RJ, Simons C, Vanderver A, Adang LA. Mutations in SZT2 result in early-onset epileptic encephalopathy and leukoencephalopathy. Am J Med Genet A. 2018 Jun;176(6):1443-1448. doi: 10.1002/ajmg.a.38717. Epub 2018 Apr 25.

Shapiro EG, Whitley CB, Eisengart JB. Beneath the floor: re-analysis of neurodevelopmental outcomes in untreated Hurler syndrome. Orphanet J Rare Dis. 2018 May 11;13(1):76. doi: 10.1186/s13023-018-0817-3.

Ou L, Przybilla MJ, Whitley CB. SAAMP 2.0: An algorithm to predict genotype-phenotype correlation of lysosomal storage diseases. Clin Genet. 2018 May;93(5):1008-1014. doi: 10.1111/cge.13226. Epub 2018 Mar 5.

Ahrens-Nicklas R, Schlotawa L, Ballabio A, Brunetti-Pierri N, De Castro M, Dierks T, Eichler F, Ficicioglu C, Finglas A, Gaertner J, Kirmse B, Klepper J, Lee M, Olsen A, Parenti G, Vossough A, Vanderver A, Adang LA. Complex care of individuals with multiple sulfatase deficiency: Clinical cases and consensus statement. Mol Genet Metab. 2018 Mar;123(3):337-346. doi: 10.1016/j.ymgme.2018.01.005. Epub 2018 Jan 31.

Nestrasil I, Ahmed A, Utz JM, Rudser K, Whitley CB, Jarnes-Utz JR. Distinct progression patterns of brain disease in infantile and juvenile gangliosidoses: Volumetric quantitative MRI study. Mol Genet Metab. 2018 Feb;123(2):97-104. doi: 10.1016/j.ymgme.2017.12.432. Epub 2017 Dec 20.

Desai AK, Walters CK, Cope HL, Kazi ZB, DeArmey SM, Kishnani PS. Enzyme replacement therapy with alglucosidase alfa in Pompe disease: Clinical experience with rate escalation. Mol Genet Metab. 2018 Feb;123(2):92-96. doi: 10.1016/j.ymgme.2017.12.435. Epub 2017 Dec 23.

McIntosh PT, Hobson-Webb LD, Kazi ZB, Prater SN, Banugaria SG, Austin S, Wang R, Enterline DS, Frush DP, Kishnani PS. Neuroimaging findings in infantile Pompe patients treated with enzyme replacement therapy. Mol Genet Metab. 2018 Feb;123(2):85-91. doi: 10.1016/j.ymgme.2017.10.005. Epub 2017 Oct 13.

Shapiro E, Ahmed A, Whitley C, Delaney K. Observing the advanced disease course in mucopolysaccharidosis, type IIIA; a case series. Mol Genet Metab. 2018 Feb;123(2):123-126. doi: 10.1016/j.ymgme.2017.11.014. Epub 2017 Nov 28.

Ou L, Przybilla MJ, Koniar B, Whitley CB. RTB lectin-mediated delivery of lysosomal α-l-iduronidase mitigates disease manifestations systemically including the central nervous system. Mol Genet Metab. 2018 Feb;123(2):105-111. doi: 10.1016/j.ymgme.2017.11.013. Epub 2017 Nov 28.

Kim J, Sinha S, Solomon M, Perez-Herrero E, Hsu J, Tsinas Z, Muro S. Co-coating of receptor-targeted drug nanocarriers with anti-phagocytic moieties enhances specific tissue uptake versus non-specific phagocytic clearance. Biomaterials. 2017 Dec;147:14-25. doi: 10.1016/j.biomaterials.2017.08.045. Epub 2017 Sep 6.

Mori M, Haskell G, Kazi Z, Zhu X, DeArmey SM, Goldstein JL, Bali D, Rehder C, Cirulli ET, Kishnani PS. Sensitivity of whole exome sequencing in detecting infantile- and late-onset Pompe disease. Mol Genet Metab. 2017 Dec;122(4):189-197. doi: 10.1016/j.ymgme.2017.10.008. Epub 2017 Oct 17.

Rairikar MV, Case LE, Bailey LA, Kazi ZB, Desai AK, Berrier KL, Coats J, Gandy R, Quinones R, Kishnani PS. Insight into the phenotype of infants with Pompe disease identified by newborn screening with the common c.-32-13T>G "late-onset" GAA variant. Mol Genet Metab. 2017 Nov;122(3):99-107. doi: 10.1016/j.ymgme.2017.09.008. Epub 2017 Sep 19.

Mauer M, Sokolovskiy A, Barth JA, Castelli JP, Williams HN, Benjamin ER, Najafian B. Reduction of podocyte globotriaosylceramide content in adult male patients with Fabry disease with amenable GLA mutations following 6 months of migalastat treatment. J Med Genet. 2017 Nov;54(11):781-786. doi: 10.1136/jmedgenet-2017-104826. Epub 2017 Jul 29.

Eisengart JB, Jarnes J, Ahmed A, Nestrasil I, Ziegler R, Delaney K, Shapiro E, Whitley C. Long-term cognitive and somatic outcomes of enzyme replacement therapy in untransplanted Hurler syndrome. Mol Genet Metab Rep. 2017 Sep 27;13:64-68. doi: 10.1016/j.ymgmr.2017.07.012. eCollection 2017 Dec.

Solomon M, Muro S. Lysosomal enzyme replacement therapies: Historical development, clinical outcomes, and future perspectives. Adv Drug Deliv Rev. 2017 Sep 1;118:109-134. doi: 10.1016/j.addr.2017.05.004. Epub 2017 May 11.

Kim S, Whitley CB, Jarnes Utz JR. Correlation between urinary GAG and anti-idursulfase ERT neutralizing antibodies during treatment with NICIT immune tolerance regimen: A case report. Mol Genet Metab. 2017 Sep;122(1-2):92-99. doi: 10.1016/j.ymgme.2017.06.001. Epub 2017 Jun 3.

Rairikar M, Kazi ZB, Desai A, Walters C, Rosenberg A, Kishnani PS. High dose IVIG successfully reduces high rhGAA IgG antibody titers in a CRIM-negative infantile Pompe disease patient. Mol Genet Metab. 2017 Sep;122(1-2):76-79. doi: 10.1016/j.ymgme.2017.05.006. Epub 2017 May 18.

Kazi ZB, Desai AK, Berrier KL, Troxler RB, Wang RY, Abdul-Rahman OA, Tanpaiboon P, Mendelsohn NJ, Herskovitz E, Kronn D, Inbar-Feigenberg M, Ward-Melver C, Polan M, Gupta P, Rosenberg AS, Kishnani PS. Sustained immune tolerance induction in enzyme replacement therapy-treated CRIM-negative patients with infantile Pompe disease. JCI Insight. 2017 Aug 17;2(16):e94328. doi: 10.1172/jci.insight.94328. eCollection 2017 Aug 17.

Spiridigliozzi GA, Keeling LA, Stefanescu M, Li C, Austin S, Kishnani PS. Cognitive and academic outcomes in long-term survivors of infantile-onset Pompe disease: A longitudinal follow-up. Mol Genet Metab. 2017 Jun;121(2):127-137. doi: 10.1016/j.ymgme.2017.04.014. Epub 2017 May 1.

Jarnes Utz JR, Kim S, King K, Ziegler R, Schema L, Redtree ES, Whitley CB. Infantile gangliosidoses: Mapping a timeline of clinical changes. Mol Genet Metab. 2017 Jun;121(2):170-179. doi: 10.1016/j.ymgme.2017.04.011. Epub 2017 Apr 29.

Wang RY, Rudser KD, Dengel DR, Braunlin EA, Steinberger J, Jacobs DR, Sinaiko AR, Kelly AS. The Carotid Intima-Media Thickness and Arterial Stiffness of Pediatric Mucopolysaccharidosis Patients Are Increased Compared to Both Pediatric and Adult Controls. Int J Mol Sci. 2017 Mar 15;18(3):637. doi: 10.3390/ijms18030637.

Nestrasil I, Shapiro E, Svatkova A, Dickson P, Chen A, Wakumoto A, Ahmed A, Stehel E, McNeil S, Gravance C, Maher E. Intrathecal enzyme replacement therapy reverses cognitive decline in mucopolysaccharidosis type I. Am J Med Genet A. 2017 Mar;173(3):780-783. doi: 10.1002/ajmg.a.38073.

Ou L, Przybilla MJ, Whitley CB. Proteomic analysis of mucopolysaccharidosis I mouse brain with two-dimensional polyacrylamide gel electrophoresis. Mol Genet Metab. 2017 Jan-Feb;120(1-2):101-110. doi: 10.1016/j.ymgme.2016.10.001. Epub 2016 Oct 11.

Karimian Z, Whitley CB, Rudser KD, Utz JRJ. Delayed Infusion Reactions to Enzyme Replacement Therapies. JIMD Rep. 2017;34:63-70. doi: 10.1007/8904_2016_8. Epub 2016 Aug 25.

Langan TJ, Barcykowski AL, Dare J, Pannullo EC, Muscarella L, Carter RL. Evidence for improved survival in postsymptomatic stem cell-transplanted patients with Krabbe's disease. J Neurosci Res. 2016 Nov;94(11):1189-94. doi: 10.1002/jnr.23787.

Ou L, Przybilla MJ, Koniar BL, Whitley CB. Elements of lentiviral vector design toward gene therapy for treating mucopolysaccharidosis I. Mol Genet Metab Rep. 2016 Aug 13;8:87-93. doi: 10.1016/j.ymgmr.2015.11.004. eCollection 2016 Sep.

Kazi ZB, Prater SN, Kobori JA, Viskochil D, Bailey C, Gera R, Stockton DW, McIntosh P, Rosenberg AS, Kishnani PS. Durable and sustained immune tolerance to ERT in Pompe disease with entrenched immune responses. JCI Insight. 2016 Jul 21;1(11):e86821. doi: 10.1172/jci.insight.86821.

Schneider J, Burmeister LA, Rudser K, Whitley CB, Jarnes Utz J. Hypothyroidism in late-onset Pompe disease. Mol Genet Metab Rep. 2016 Jul 1;8:24-7. doi: 10.1016/j.ymgmr.2016.06.002. eCollection 2016 Sep.

Dyke JP, Sondhi D, Voss HU, Yohay K, Hollmann C, Mancenido D, Kaminsky SM, Heier LA, Rudser KD, Kosofsky B, Casey BJ, Crystal RG, Ballon D. Brain Region-Specific Degeneration with Disease Progression in Late Infantile Neuronal Ceroid Lipofuscinosis (CLN2 Disease). AJNR Am J Neuroradiol. 2016 Jun;37(6):1160-9. doi: 10.3174/ajnr.A4669. Epub 2016 Jan 28.

Merkel PA, Manion M, Gopal-Srivastava R, Groft S, Jinnah HA, Robertson D, Krischer JP; Rare Diseases Clinical Research Network. The partnership of patient advocacy groups and clinical investigators in the rare diseases clinical research network. Orphanet J Rare Dis. 2016 May 18;11(1):66. doi: 10.1186/s13023-016-0445-8.

Najafian B, Tøndel C, Svarstad E, Sokolovkiy A, Smith K, Mauer M. One Year of Enzyme Replacement Therapy Reduces Globotriaosylceramide Inclusions in Podocytes in Male Adult Patients with Fabry Disease. PLoS One. 2016 Apr 15;11(4):e0152812. doi: 10.1371/journal.pone.0152812. eCollection 2016.

Shapiro EG, Rudser K, Ahmed A, Steiner RD, Delaney KA, Yund B, King K, Kunin-Batson A, Eisengart J, Whitley CB. A longitudinal study of emotional adjustment, quality of life and adaptive function in attenuated MPS II. Mol Genet Metab Rep. 2016 Apr 1;7:32-9. doi: 10.1016/j.ymgmr.2016.03.005. eCollection 2016 Jun.

Ahmed A, Shapiro E, Rudser K, Kunin-Batson A, King K, Whitley CB. Association of somatic burden of disease with age and neuropsychological measures in attenuated mucopolysaccharidosis types I, II and VI. Mol Genet Metab Rep. 2016 Apr 1;7:27-31. doi: 10.1016/j.ymgmr.2016.03.006. eCollection 2016 Jun.

Polgreen LE, Vehe RK, Rudser K, Kunin-Batson A, Utz JJ, Dickson P, Shapiro E, Whitley CB. Elevated TNF-α is associated with pain and physical disability in mucopolysaccharidosis types I, II, and VI. Mol Genet Metab. 2016 Apr;117(4):427-30. doi: 10.1016/j.ymgme.2016.01.012. Epub 2016 Jan 28.

Khalid O, Vera MU, Gordts PL, Ellinwood NM, Schwartz PH, Dickson PI, Esko JD, Wang RY. Immune-Mediated Inflammation May Contribute to the Pathogenesis of Cardiovascular Disease in Mucopolysaccharidosis Type I. PLoS One. 2016 Mar 17;11(3):e0150850. doi: 10.1371/journal.pone.0150850. eCollection 2016.

Shapiro E, King K, Ahmed A, Rudser K, Rumsey R, Yund B, Delaney K, Nestrasil I, Whitley C, Potegal M. The Neurobehavioral Phenotype in Mucopolysaccharidosis Type IIIB: an Exploratory Study. Mol Genet Metab Rep. 2016 Mar 1;6:41-47. doi: 10.1016/j.ymgmr.2016.01.003.

Rappaport J, Manthe RL, Solomon M, Garnacho C, Muro S. A Comparative Study on the Alterations of Endocytic Pathways in Multiple Lysosomal Storage Disorders. Mol Pharm. 2016 Feb 1;13(2):357-368. doi: 10.1021/acs.molpharmaceut.5b00542. Epub 2016 Jan 11.

Ahmed A, Rudser K, Kunin-Batson A, Delaney K, Whitley C, Shapiro E. Mucopolysaccharidosis (MPS) Physical Symptom Score: Development, Reliability, and Validity. JIMD Rep. 2016;26:61-8. doi: 10.1007/8904_2015_485. Epub 2015 Aug 25.

Bali DS, Goldstein JL, Rehder C, Kazi ZB, Berrier KL, Dai J, Kishnani PS. Clinical Laboratory Experience of Blood CRIM Testing in Infantile Pompe Disease. Mol Genet Metab Rep. 2015 Dec 1;5:76-79. doi: 10.1016/j.ymgmr.2015.10.012.

Berrier KL, Kazi ZB, Prater SN, Bali DS, Goldstein J, Stefanescu MC, Rehder CW, Botha EG, Ellaway C, Bhattacharya K, Tylki-Szymanska A, Karabul N, Rosenberg AS, Kishnani PS. CRIM-negative infantile Pompe disease: characterization of immune responses in patients treated with ERT monotherapy. Genet Med. 2015 Nov;17(11):912-8. doi: 10.1038/gim.2015.6. Epub 2015 Mar 5.

Stenger EO, Kazi Z, Lisi E, Gambello MJ, Kishnani P. Immune Tolerance Strategies in Siblings with Infantile Pompe Disease-Advantages for a Preemptive Approach to High-Sustained Antibody Titers. Mol Genet Metab Rep. 2015 Sep 1;4:30-34. doi: 10.1016/j.ymgmr.2015.05.004.

Shapiro EG, Nestrasil I, Rudser K, Delaney K, Kovac V, Ahmed A, Yund B, Orchard PJ, Eisengart J, Niklason GR, Raiman J, Mamak E, Cowan MJ, Bailey-Olson M, Harmatz P, Shankar SP, Cagle S, Ali N, Steiner RD, Wozniak J, Lim KO, Whitley CB. Neurocognition across the spectrum of mucopolysaccharidosis type I: Age, severity, and treatment. Mol Genet Metab. 2015 Sep-Oct;116(1-2):61-8. doi: 10.1016/j.ymgme.2015.06.002. Epub 2015 Jun 17.

Freeze HH, Eklund EA, Ng BG, Patterson MC. Neurological aspects of human glycosylation disorders. Annu Rev Neurosci. 2015 Jul 8;38:105-25. doi: 10.1146/annurev-neuro-071714-034019. Epub 2015 Apr 2.

Patterson MC, Mengel E, Vanier MT, Schwierin B, Muller A, Cornelisse P, Pineda M; NPC Registry investigators. Stable or improved neurological manifestations during miglustat therapy in patients from the international disease registry for Niemann-Pick disease type C: an observational cohort study. Orphanet J Rare Dis. 2015 May 28;10:65. doi: 10.1186/s13023-015-0284-z.

Parikh S, Bernard G, Leventer RJ, van der Knaap MS, van Hove J, Pizzino A, McNeill NH, Helman G, Simons C, Schmidt JL, Rizzo WB, Patterson MC, Taft RJ, Vanderver A; GLIA Consortium. A clinical approach to the diagnosis of patients with leukodystrophies and genetic leukoencephelopathies. Mol Genet Metab. 2015 Apr;114(4):501-515. doi: 10.1016/j.ymgme.2014.12.434. Epub 2014 Dec 29.

Vanderver A, Prust M, Tonduti D, Mochel F, Hussey HM, Helman G, Garbern J, Eichler F, Labauge P, Aubourg P, Rodriguez D, Patterson MC, Van Hove JL, Schmidt J, Wolf NI, Boespflug-Tanguy O, Schiffmann R, van der Knaap MS; GLIA Consortium. Case definition and classification of leukodystrophies and leukoencephalopathies. Mol Genet Metab. 2015 Apr;114(4):494-500. doi: 10.1016/j.ymgme.2015.01.006. Epub 2015 Jan 29.

Van Haren K, Bonkowsky JL, Bernard G, Murphy JL, Pizzino A, Helman G, Suhr D, Waggoner J, Hobson D, Vanderver A, Patterson MC; GLIA Consortium. Consensus statement on preventive and symptomatic care of leukodystrophy patients. Mol Genet Metab. 2015 Apr;114(4):516-26. doi: 10.1016/j.ymgme.2014.12.433. Epub 2014 Dec 27.

Helman G, Van Haren K, Bonkowsky JL, Bernard G, Pizzino A, Braverman N, Suhr D, Patterson MC, Ali Fatemi S, Leonard J, van der Knaap MS, Back SA, Damiani S, Goldman SA, Takanohashi A, Petryniak M, Rowitch D, Messing A, Wrabetz L, Schiffmann R, Eichler F, Escolar ML, Vanderver A; GLIA Consortium. Disease specific therapies in leukodystrophies and leukoencephalopathies. Mol Genet Metab. 2015 Apr;114(4):527-36. doi: 10.1016/j.ymgme.2015.01.014. Epub 2015 Feb 7.

Tan QK, Stockton DW, Pivnick E, Choudhri AF, Hines-Dowell S, Pena LD, Deimling MA, Freemark MS, Kishnani PS. Premature pubarche in children with Pompe disease. J Pediatr. 2015 Apr;166(4):1075-8.e1. doi: 10.1016/j.jpeds.2014.12.074. Epub 2015 Feb 14.

Shapiro EG, Nestrasil I, Ahmed A, Wey A, Rudser KR, Delaney KA, Rumsey RK, Haslett PA, Whitley CB, Potegal M. Quantifying behaviors of children with Sanfilippo syndrome: the Sanfilippo Behavior Rating Scale. Mol Genet Metab. 2015 Apr;114(4):594-8. doi: 10.1016/j.ymgme.2015.02.008. Epub 2015 Mar 5.

Utz JR, Crutcher T, Schneider J, Sorgen P, Whitley CB. Biomarkers of central nervous system inflammation in infantile and juvenile gangliosidoses. Mol Genet Metab. 2015 Feb;114(2):274-80. doi: 10.1016/j.ymgme.2014.11.015. Epub 2014 Dec 6.

Yund B, Rudser K, Ahmed A, Kovac V, Nestrasil I, Raiman J, Mamak E, Harmatz P, Steiner R, Lau H, Vekaria P, Wozniak JR, Lim KO, Delaney K, Whitley C, Shapiro EG. Cognitive, medical, and neuroimaging characteristics of attenuated mucopolysaccharidosis type II. Mol Genet Metab. 2015 Feb;114(2):170-7. doi: 10.1016/j.ymgme.2014.12.299. Epub 2014 Dec 9.

Wolf DA, Banerjee S, Hackett PB, Whitley CB, McIvor RS, Low WC. Gene therapy for neurologic manifestations of mucopolysaccharidoses. Expert Opin Drug Deliv. 2015 Feb;12(2):283-96. doi: 10.1517/17425247.2015.966682. Epub 2014 Dec 16.

Mauer M, Glynn E, Svarstad E, Tøndel C, Gubler MC, West M, Sokolovskiy A, Whitley C, Najafian B. Mosaicism of podocyte involvement is related to podocyte injury in females with Fabry disease. PLoS One. 2014 Nov 11;9(11):e112188. doi: 10.1371/journal.pone.0112188. eCollection 2014.

Patterson MC. Brave New World. Child Neurol Open. 2014 Aug 26;1(1):2329048X14542399. doi: 10.1177/2329048X14542399. eCollection 2014 Jul-Sep.

Rumsey RK, Rudser K, Delaney K, Potegal M, Whitley CB, Shapiro E. Acquired autistic behaviors in children with mucopolysaccharidosis type IIIA. J Pediatr. 2014 May;164(5):1147-1151.e1. doi: 10.1016/j.jpeds.2014.01.007. Epub 2014 Feb 25.

Leroy JG, Sillence D, Wood T, Barnes J, Lebel RR, Friez MJ, Stevenson RE, Steet R, Cathey SS. A novel intermediate mucolipidosis II/IIIαβ caused by GNPTAB mutation in the cytosolic N-terminal domain. Eur J Hum Genet. 2014 May;22(5):594-601. doi: 10.1038/ejhg.2013.207. Epub 2013 Sep 18.

Schiffmann R, Forni S, Swift C, Brignol N, Wu X, Lockhart DJ, Blankenship D, Wang X, Grayburn PA, Taylor MR, Lowes BD, Fuller M, Benjamin ER, Sweetman L. Risk of death in heart disease is associated with elevated urinary globotriaosylceramide. J Am Heart Assoc. 2014 Feb 4;3(1):e000394. doi: 10.1161/JAHA.113.000394.

Wang RY, Braunlin EA, Rudser KD, Dengel DR, Metzig AM, Covault KK, Polgreen LE, Shapiro E, Steinberger J, Kelly AS. Carotid intima-media thickness is increased in patients with treated mucopolysaccharidosis types I and II, and correlates with arterial stiffness. Mol Genet Metab. 2014 Feb;111(2):128-32. doi: 10.1016/j.ymgme.2013.11.001. Epub 2013 Nov 12.

Polgreen LE, Thomas W, Orchard PJ, Whitley CB, Miller BS. Effect of recombinant human growth hormone on changes in height, bone mineral density, and body composition over 1-2 years in children with Hurler or Hunter syndrome. Mol Genet Metab. 2014 Feb;111(2):101-6. doi: 10.1016/j.ymgme.2013.11.013. Epub 2013 Dec 11.

None listed. Lysosomal Disease Network's WORLD Symposium™ 2014. Mol Genet Metab. 2014 Feb;111(2):S2-6. doi: 10.1016/j.ymgme.2014.01.003. Epub 2014 Jan 9.

Ahmed A, Whitley CB, Cooksley R, Rudser K, Cagle S, Ali N, Delaney K, Yund B, Shapiro E. Neurocognitive and neuropsychiatric phenotypes associated with the mutation L238Q of the α-L-iduronidase gene in Hurler-Scheie syndrome. Mol Genet Metab. 2014 Feb;111(2):123-7. doi: 10.1016/j.ymgme.2013.11.014. Epub 2013 Dec 12.

Schiffmann R, Mayfield J, Swift C, Nestrasil I. Quantitative neuroimaging in mucolipidosis type IV. Mol Genet Metab. 2014 Feb;111(2):147-51. doi: 10.1016/j.ymgme.2013.11.007. Epub 2013 Nov 21.

Prater SN, Banugaria SG, Morgan C, Sung CC, Rosenberg AS, Kishnani PS. Letter to the Editors: Concerning "CRIM-negative Pompe disease patients with satisfactory clinical outcomes on enzyme replacement therapy" by Al Khallaf et al. J Inherit Metab Dis. 2014 Jan;37(1):141-3. doi: 10.1007/s10545-013-9637-8. Epub 2013 Jul 26.

Polgreen LE, Thomas W, Fung E, Viskochil D, Stevenson DA, Steinberger J, Orchard P, Whitley CB, Ensrud KE. Low bone mineral content and challenges in interpretation of dual-energy X-ray absorptiometry in children with mucopolysaccharidosis types I, II, and VI. J Clin Densitom. 2014 Jan-Mar;17(1):200-6. doi: 10.1016/j.jocd.2013.03.004. Epub 2013 Apr 2.

Stevenson DA, Rudser K, Kunin-Batson A, Fung EB, Viskochil D, Shapiro E, Orchard PJ, Whitley CB, Polgreen LE. Biomarkers of bone remodeling in children with mucopolysaccharidosis types I, II, and VI. J Pediatr Rehabil Med. 2014;7(2):159-65. doi: 10.3233/PRM-140285.

Taylor NE, Dengel DR, Lund TC, Rudser KD, Orchard PJ, Steinberger J, Whitley CB, Polgreen LE. Isokinetic muscle strength differences in patients with mucopolysaccharidosis I, II, and VI. J Pediatr Rehabil Med. 2014;7(4):353-60. doi: 10.3233/PRM-140305.

Delaney KA, Rudser KR, Yund BD, Whitley CB, Haslett PA, Shapiro EG. Methods of neurodevelopmental assessment in children with neurodegenerative disease: Sanfilippo syndrome. JIMD Rep. 2014;13:129-37. doi: 10.1007/8904_2013_269. Epub 2013 Nov 5.

Vera M, Le S, Kan SH, Garban H, Naylor D, Mlikotic A, Kaitila I, Harmatz P, Chen A, Dickson P. Immune response to intrathecal enzyme replacement therapy in mucopolysaccharidosis I patients. Pediatr Res. 2013 Dec;74(6):712-20. doi: 10.1038/pr.2013.158. Epub 2013 Sep 3.

Schulz A, Kohlschütter A, Mink J, Simonati A, Williams R. NCL diseases - clinical perspectives. Biochim Biophys Acta. 2013 Nov;1832(11):1801-6. doi: 10.1016/j.bbadis.2013.04.008. Epub 2013 Apr 17.

Dolisca SB, Mehta M, Pearce DA, Mink JW, Maria BL. Batten disease: clinical aspects, molecular mechanisms, translational science, and future directions. J Child Neurol. 2013 Sep;28(9):1074-100. doi: 10.1177/0883073813493665. Epub 2013 Jul 9.

Mink JW, Augustine EF, Adams HR, Marshall FJ, Kwon JM. Classification and natural history of the neuronal ceroid lipofuscinoses. J Child Neurol. 2013 Sep;28(9):1101-5. doi: 10.1177/0883073813494268. Epub 2013 Jul 9.

Augustine EF, Adams HR, Mink JW. Clinical trials in rare disease: challenges and opportunities. J Child Neurol. 2013 Sep;28(9):1142-50. doi: 10.1177/0883073813495959.

Adams HR, Mink JW; University of Rochester Batten Center Study Group. Neurobehavioral features and natural history of juvenile neuronal ceroid lipofuscinosis (Batten disease). J Child Neurol. 2013 Sep;28(9):1128-36. doi: 10.1177/0883073813494813.

de Blieck EA, Augustine EF, Marshall FJ, Adams H, Cialone J, Dure L, Kwon JM, Newhouse N, Rose K, Rothberg PG, Vierhile A, Mink JW; Batten Study Group. Methodology of clinical research in rare diseases: development of a research program in juvenile neuronal ceroid lipofuscinosis (JNCL) via creation of a patient registry and collaboration with patient advocates. Contemp Clin Trials. 2013 Jul;35(2):48-54. doi: 10.1016/j.cct.2013.04.004. Epub 2013 Apr 26.

Holmay MJ, Terpstra M, Coles LD, Mishra U, Ahlskog M, Öz G, Cloyd JC, Tuite PJ. N-Acetylcysteine boosts brain and blood glutathione in Gaucher and Parkinson diseases. Clin Neuropharmacol. 2013 Jul-Aug;36(4):103-6. doi: 10.1097/WNF.0b013e31829ae713.

Banugaria SG, Prater SN, Patel TT, Dearmey SM, Milleson C, Sheets KB, Bali DS, Rehder CW, Raiman JA, Wang RA, Labarthe F, Charrow J, Harmatz P, Chakraborty P, Rosenberg AS, Kishnani PS. Algorithm for the early diagnosis and treatment of patients with cross reactive immunologic material-negative classic infantile pompe disease: a step towards improving the efficacy of ERT. PLoS One. 2013 Jun 25;8(6):e67052. doi: 10.1371/journal.pone.0067052. Print 2013.

Najafian B, Mauer M, Hopkin RJ, Svarstad E. Renal complications of Fabry disease in children. Pediatr Nephrol. 2013 May;28(5):679-87. doi: 10.1007/s00467-012-2222-9. Epub 2012 Aug 17.

Dyke JP, Sondhi D, Voss HU, Shungu DC, Mao X, Yohay K, Worgall S, Hackett NR, Hollmann C, Yeotsas ME, Jeong AL, Van de Graaf B, Cao I, Kaminsky SM, Heier LA, Rudser KD, Souweidane MM, Kaplitt MG, Kosofsky B, Crystal RG, Ballon D. Assessment of disease severity in late infantile neuronal ceroid lipofuscinosis using multiparametric MR imaging. AJNR Am J Neuroradiol. 2013 Apr;34(4):884-9. doi: 10.3174/ajnr.A3297. Epub 2012 Oct 4.

Patel TT, Banugaria SG, Frush DP, Enterline DS, Tanpaiboon P, Kishnani PS. Basilar artery aneurysm: a new finding in classic infantile Pompe disease. Muscle Nerve. 2013 Apr;47(4):613-5. doi: 10.1002/mus.23659. Epub 2013 Feb 10.

Banugaria SG, Prater SN, McGann JK, Feldman JD, Tannenbaum JA, Bailey C, Gera R, Conway RL, Viskochil D, Kobori JA, Rosenberg AS, Kishnani PS. Bortezomib in the rapid reduction of high sustained antibody titers in disorders treated with therapeutic protein: lessons learned from Pompe disease. Genet Med. 2013 Feb;15(2):123-31. doi: 10.1038/gim.2012.110. Epub 2012 Oct 11.

Eisengart JB, Rudser KD, Tolar J, Orchard PJ, Kivisto T, Ziegler RS, Whitley CB, Shapiro EG. Enzyme replacement is associated with better cognitive outcomes after transplant in Hurler syndrome. J Pediatr. 2013 Feb;162(2):375-80.e1. doi: 10.1016/j.jpeds.2012.07.052. Epub 2012 Sep 10.

Whitley C. Lysosomal Disease Network's WORLD Symposium™ 2013. Mol Genet Metab. 2013 Feb;108(2):S2-7. doi: 10.1016/j.ymgme.2012.12.003. Epub 2012 Dec 25.

Potegal M, Yund B, Rudser K, Ahmed A, Delaney K, Nestrasil I, Whitley CB, Shapiro EG. Mucopolysaccharidosis Type IIIA presents as a variant of Klüver-Bucy syndrome. J Clin Exp Neuropsychol. 2013;35(6):608-16. doi: 10.1080/13803395.2013.804035. Epub 2013 Jun 8.

Shapiro E, Guler OE, Rudser K, Delaney K, Bjoraker K, Whitley C, Tolar J, Orchard P, Provenzale J, Thomas KM. An exploratory study of brain function and structure in mucopolysaccharidosis type I: long term observations following hematopoietic cell transplantation (HCT). Mol Genet Metab. 2012 Sep;107(1-2):116-21. doi: 10.1016/j.ymgme.2012.07.016. Epub 2012 Jul 20.

Prater SN, Banugaria SG, DeArmey SM, Botha EG, Stege EM, Case LE, Jones HN, Phornphutkul C, Wang RY, Young SP, Kishnani PS. The emerging phenotype of long-term survivors with infantile Pompe disease. Genet Med. 2012 Sep;14(9):800-10. doi: 10.1038/gim.2012.44. Epub 2012 Apr 26.

Lo SM, Choi M, Liu J, Jain D, Boot RG, Kallemeijn WW, Aerts JM, Pashankar F, Kupfer GM, Mane S, Lifton RP, Mistry PK. Phenotype diversity in type 1 Gaucher disease: discovering the genetic basis of Gaucher disease/hematologic malignancy phenotype by individual genome analysis. Blood. 2012 May 17;119(20):4731-40. doi: 10.1182/blood-2011-10-386862. Epub 2012 Apr 4.

Cialone J, Adams H, Augustine EF, Marshall FJ, Kwon JM, Newhouse N, Vierhile A, Levy E, Dure LS, Rose KR, Ramirez-Montealegre D, de Blieck EA, Mink JW. Females experience a more severe disease course in Batten disease. J Inherit Metab Dis. 2012 May;35(3):549-55. doi: 10.1007/s10545-011-9421-6. Epub 2011 Dec 14.

Freeze HH, Eklund EA, Ng BG, Patterson MC. Neurology of inherited glycosylation disorders. Lancet Neurol. 2012 May;11(5):453-66. doi: 10.1016/S1474-4422(12)70040-6.

Banugaria SG, Patel TT, Mackey J, Das S, Amalfitano A, Rosenberg AS, Charrow J, Chen YT, Kishnani PS. Persistence of high sustained antibodies to enzyme replacement therapy despite extensive immunomodulatory therapy in an infant with Pompe disease: need for agents to target antibody-secreting plasma cells. Mol Genet Metab. 2012 Apr;105(4):677-80. doi: 10.1016/j.ymgme.2012.01.019. Epub 2012 Jan 28.

Bali DS, Goldstein JL, Banugaria S, Dai J, Mackey J, Rehder C, Kishnani PS. Predicting cross-reactive immunological material (CRIM) status in Pompe disease using GAA mutations: lessons learned from 10 years of clinical laboratory testing experience. Am J Med Genet C Semin Med Genet. 2012 Feb 15;160C(1):40-9. doi: 10.1002/ajmg.c.31319. Epub 2012 Jan 17.

Whitley CB. Lysosomal Disease Network's WORLD Symposium™ 2012. Mol Genet Metab. 2012 Feb;105(2):S3-6. doi: 10.1016/j.ymgme.2011.12.001. Epub 2011 Dec 7.

Messinger YH, Mendelsohn NJ, Rhead W, Dimmock D, Hershkovitz E, Champion M, Jones SA, Olson R, White A, Wells C, Bali D, Case LE, Young SP, Rosenberg AS, Kishnani PS. Successful immune tolerance induction to enzyme replacement therapy in CRIM-negative infantile Pompe disease. Genet Med. 2012 Jan;14(1):135-42. doi: 10.1038/gim.2011.4.

Abbott MA, Prater SN, Banugaria SG, Richards SM, Young SP, Rosenberg AS, Kishnani PS. Atypical immunologic response in a patient with CRIM-negative Pompe disease. Mol Genet Metab. 2011 Dec;104(4):583-6. doi: 10.1016/j.ymgme.2011.08.003. Epub 2011 Aug 11.

Kwon JM, Adams H, Rothberg PG, Augustine EF, Marshall FJ, Deblieck EA, Vierhile A, Beck CA, Newhouse NJ, Cialone J, Levy E, Ramirez-Montealegre D, Dure LS, Rose KR, Mink JW. Quantifying physical decline in juvenile neuronal ceroid lipofuscinosis (Batten disease). Neurology. 2011 Nov 15;77(20):1801-7. doi: 10.1212/WNL.0b013e318237f649. Epub 2011 Oct 19.

Cialone J, Augustine EF, Newhouse N, Vierhile A, Marshall FJ, Mink JW. Quantitative telemedicine ratings in Batten disease: implications for rare disease research. Neurology. 2011 Nov 15;77(20):1808-11. doi: 10.1212/WNL.0b013e3182377e29. Epub 2011 Oct 19.

Bley AE, Giannikopoulos OA, Hayden D, Kubilus K, Tifft CJ, Eichler FS. Natural history of infantile G(M2) gangliosidosis. Pediatrics. 2011 Nov;128(5):e1233-41. doi: 10.1542/peds.2011-0078. Epub 2011 Oct 24.

Cialone J, Augustine EF, Newhouse N, Adams H, Vierhile A, Marshall FJ, de Blieck EA, Kwon J, Rothberg PG, Mink JW. Parent-reported benefits of flupirtine in juvenile neuronal ceroid lipofuscinosis (Batten disease; CLN3) are not supported by quantitative data. J Inherit Metab Dis. 2011 Oct;34(5):1075-81. doi: 10.1007/s10545-011-9346-0. Epub 2011 May 10.

El-Gharbawy AH, Mackey J, DeArmey S, Westby G, Grinnell SG, Malovrh P, Conway R, Kishnani PS. An individually, modified approach to desensitize infants and young children with Pompe disease, and significant reactions to alglucosidase alfa infusions. Mol Genet Metab. 2011 Sep-Oct;104(1-2):118-22. doi: 10.1016/j.ymgme.2011.07.004. Epub 2011 Jul 13.

Banugaria SG, Prater SN, Ng YK, Kobori JA, Finkel RS, Ladda RL, Chen YT, Rosenberg AS, Kishnani PS. The impact of antibodies on clinical outcomes in diseases treated with therapeutic protein: lessons learned from infantile Pompe disease. Genet Med. 2011 Aug;13(8):729-36. doi: 10.1097/GIM.0b013e3182174703.

Dickson PI, Chen AH. Intrathecal enzyme replacement therapy for mucopolysaccharidosis I: translating success in animal models to patients. Curr Pharm Biotechnol. 2011 Jun;12(6):946-55. doi: 10.2174/138920111795542642.

Kerr DA, Memoli VA, Cathey SS, Harris BT. Mucolipidosis type III α/β: the first characterization of this rare disease by autopsy. Arch Pathol Lab Med. 2011 Apr;135(4):503-10. doi: 10.5858/2010-0236-CR.1.

Najafian B, Svarstad E, Bostad L, Gubler MC, Tøndel C, Whitley C, Mauer M. Progressive podocyte injury and globotriaosylceramide (GL-3) accumulation in young patients with Fabry disease. Kidney Int. 2011 Mar;79(6):663-670. doi: 10.1038/ki.2010.484. Epub 2010 Dec 15.

Dickson PI, Pariser AR, Groft SC, Ishihara RW, McNeil DE, Tagle D, Griebel DJ, Kaler SG, Mink JW, Shapiro EG, Bjoraker KJ, Krivitzky L, Provenzale JM, Gropman A, Orchard P, Raymond G, Cohen BH, Steiner RD, Goldkind SF, Nelson RM, Kakkis E, Patterson MC. Research challenges in central nervous system manifestations of inborn errors of metabolism. Mol Genet Metab. 2011 Mar;102(3):326-38. doi: 10.1016/j.ymgme.2010.11.164. Epub 2010 Dec 2.

Sowell J, Wood T. Towards a selected reaction monitoring mass spectrometry fingerprint approach for the screening of oligosaccharidoses. Anal Chim Acta. 2011 Feb 7;686(1-2):102-6. doi: 10.1016/j.aca.2010.11.047. Epub 2010 Dec 7.

Najafian B, Mauer M. Quantitating glomerular endothelial fenestration: an unbiased stereological approach. Am J Nephrol. 2011;33 Suppl 1(Suppl 1):34-9. doi: 10.1159/000327075. Epub 2011 Jun 10.

Patterson MC. Movers and shakers: diagnosing neurotransmitter diseases with CSF. Neurology. 2010 Jul 6;75(1):15-7. doi: 10.1212/WNL.0b013e3181e9aeea. Epub 2010 Jun 9.

David-Vizcarra G, Briody J, Ault J, Fietz M, Fletcher J, Savarirayan R, Wilson M, McGill J, Edwards M, Munns C, Alcausin M, Cathey S, Sillence D. The natural history and osteodystrophy of mucolipidosis types II and III. J Paediatr Child Health. 2010 Jun;46(6):316-22. doi: 10.1111/j.1440-1754.2010.01715.x. Epub 2010 Mar 29.

Ramaswami U, Najafian B, Schieppati A, Mauer M, Bichet DG. Assessment of renal pathology and dysfunction in children with Fabry disease. Clin J Am Soc Nephrol. 2010 Feb;5(2):365-70. doi: 10.2215/CJN.08091109. Epub 2010 Jan 7.

Kishnani PS, Goldenberg PC, DeArmey SL, Heller J, Benjamin D, Young S, Bali D, Smith SA, Li JS, Mandel H, Koeberl D, Rosenberg A, Chen YT. Cross-reactive immunologic material status affects treatment outcomes in Pompe disease infants. Mol Genet Metab. 2010 Jan;99(1):26-33. doi: 10.1016/j.ymgme.2009.08.003.

Cathey SS, Leroy JG, Wood T, Eaves K, Simensen RJ, Kudo M, Stevenson RE, Friez MJ. Phenotype and genotype in mucolipidoses II and III alpha/beta: a study of 61 probands. J Med Genet. 2010 Jan;47(1):38-48. doi: 10.1136/jmg.2009.067736. Epub 2009 Jul 16.

Polgreen LE, Miller BS. Growth patterns and the use of growth hormone in the mucopolysaccharidoses. J Pediatr Rehabil Med. 2010;3(1):25-38. doi: 10.3233/PRM-2010-0106.

Garbey M, Lesport Q, Girma H, Öztosun G, Abu-Rub M, Guidon AC, Juel V, Nowak RJ, Soliven B, Aban I, Kaminski HJ. Application of digital tools and artificial intelligence in the Myasthenia Gravis Core Examination. Front Neurol. 2024 Dec 4;15:1474884. doi: 10.3389/fneur.2024.1474884. eCollection 2024.

Falso S, Marini S, Carrozza C, Sabatelli E, Mascagna G, Marini M, Morroni J, Evoli A, Iorio R. Concordance between radioimmunoassay and fixed cell-based assay in subjects without myasthenia gravis: optimizing the diagnostic approach. Eur J Neurol. 2024 Dec;31(12):e16435. doi: 10.1111/ene.16435. Epub 2024 Aug 8. PMID: 39118440; PMCID: PMC11554847.

Myasthenia gravis (MG) is a neuromuscular disorder caused by an autoimmune response which blocks or damages acetylcholine receptors in muscles, causing disabling weakness. Acetylcholine receptor antibody detection is crucial for MG diagnosis. Currently, radioimmunoassay is the gold-standard test used to measure the concentration of acetylcholine receptor antibodies. However, this test may detect false positives for nonpathogenic antibodies.

In this study, researchers compared the accuracy of radioimmunoassay and fixed cell-based assay for MG diagnosis. First, the team reviewed medical records of 605 patients who tested positive for acetylcholine receptor antibodies via radioimmunoassay and confirmed these results. Next, the team retested asymptomatic patients via fixed cell-based assay to determine whether this method would show higher accuracy in detecting pathogenic antibodies.

Results show that, in rare cases, fixed cell-based assay may be more specific than radioimmunoassay in detecting pathogenic antibodies. Authors note that fixed cell-based assay may be performed as an additional tool to increase diagnostic accuracy when clinical presentation and electrodiagnostic studies are found to be atypical for MG.

Spagni G, Vincent A, Sun B, Falso S, Jacobson LW, Devenish S, Evoli A, Damato V. Serological Markers of Clinical Improvement in MuSK Myasthenia Gravis. Neurol Neuroimmunol Neuroinflamm. 2024 Nov;11(6):e200313. doi: 10.1212/NXI.0000000000200313. Epub 2024 Sep 9.

Lesport Q, Palmie D, Öztosun G, Kaminski HJ, Garbey M. AI-Powered Telemedicine for Automatic Scoring of Neuromuscular Examinations. Bioengineering (Basel). 2024 Sep 20;11(9):942. doi: 10.3390/bioengineering11090942.

Falso S, Gessi M, Marini S, Benvenuto R, Sabatelli E, D'Amati A, Marini M, Evoli A, Iorio R. Cancer Frequency in MuSK Myasthenia Gravis and Histological Evidence of Paraneoplastic Etiology. Ann Neurol. 2024 Jul 15. doi: 10.1002/ana.27033. Epub ahead of print. PMID: 39007444.

Muscle-specific kinase myasthenia gravis (MuSK-MG) is an autoimmune disorder caused by antibodies targeting the muscle-specific kinase (MuSK), causing muscle weakness. Although neurological autoimmunity can potentially increase the risk of cancer, not much is known about cancer rates among patients with MuSK-MG.

In this study, researchers explored the frequency and timing of cancer in patients with MuSK-MG. The team reviewed records of 94 patients, recording information about diagnosis and treatment of associated cancers. In two patients with MuSK-MG onset after cancer diagnosis, researchers performed immunohistochemistry to assess MuSK expression in cancer cells of tumor specimens.

Assessment of tumor specimens revealed strong nuclear expression of the MuSK protein in cancer cells. These findings suggest a new pathway in the formation of tumors as well as a potential therapeutic target. Authors note that this preliminary study needs to be replicated in a much larger cohort of patients to determine if cancers could be a trigger for MuSK MG.

Kaminski HJ, Sikorski P, Coronel SI, Kusner LL. Myasthenia gravis: the future is here. J Clin Invest. 2024 Jun 17;134(12):e179742. doi: 10.1172/JCI179742. PMCID: PMC11178544.

Myasthenia gravis (MG) is a rare neuromuscular disorder that occurs when the body’s immune system attacks the nerve-muscle communication point, causing disabling weakness. Over the past few decades, understanding of MG has progressed significantly, leading to the development of new therapies.

In this review paper, researchers discuss the current understanding of pathophysiology and new therapies in MG. The team covers the various subgroups of MG as well as emerging therapeutic strategies. Authors note that these insights shed light on the evolving landscape of MG treatment and exciting prospects for further research.

Li Y, Yi JS, Guptill JT, Juel VC, Hobson-Webb L, Raja SM, Karatz T, Gable KL. Immune dysregulation in chronic inflammatory demyelinating polyneuropathy. J Neuroimmunol. 2024 Jun 15;391:578360. doi: 10.1016/j.jneuroim.2024.578360. Epub 2024 May 5.

Bodansky A, Yu DJ, Rallistan A, Kalaycioglu M, Boonyaratanakornkit J, Green DJ, Gauthier J, Turtle CJ, Zorn K, O'Donovan B, Mandel-Brehm C, Asaki J, Kortbawi H, Kung AF, Rackaityte E, Wang CY, Saxena A, de Dios K, Masi G, Nowak RJ, O'Connor KC, Li H, Diaz VE, Saloner R, Casaletto KB, Gontrum EQ, Chan B, Kramer JH, Wilson MR, Utz PJ, Hill JA, Jackson SW, Anderson MS, DeRisi JL. Unveiling the proteome-wide autoreactome enables enhanced evaluation of emerging CAR T cell therapies in autoimmunity. J Clin Invest. 2024 May 16;134(13):e180012. doi: 10.1172/JCI180012. PMID: 38753445; PMCID: PMC11213466.

Autoimmune diseases are a group of conditions caused by a dysregulated immune system that attacks and damages the body. As autoimmune diseases have become increasingly more common, new therapies have emerged. However, how they specifically alter the immune system is not well understood. 

In this study, researchers studied the circulating autoantibody repertoire to further understand the effect of therapies used for autoimmune diseases. Leveraging a custom set of over 730,000 human-derived peptides (short chains of amino acids), the team explored variations in autoantibody profiles across individuals who were treated with different immune-modulating therapies. 

Results show that each individual—regardless of disease state—has a distinct and complex set of autoantibodies, which creates a unique immunological footprint researchers call the “autoreactome” that remains surprisingly stable over many years. The team found that therapies targeting B cell maturation antigen (BCMA) greatly altered an individual’s autoreactome, while anti-CD19 and anti-CD20 therapies, which deplete B cells, had minimal effects. Authors note that these findings suggest the potential for BCMA therapy in treating autoantibody diseases that are resistant to current therapies.

Yandamuri SS, Filipek B, Lele N, Cohen I, Bennett JL, Nowak RJ, Sotirchos ES, Longbrake EE, Mace EM, O'Connor KC. A Noncanonical CD56dimCD16dim/− NK Cell Subset Indicative of Prior Cytotoxic Activity Is Elevated in Patients with Autoantibody-Mediated Neurologic Diseases. J Immunol. 2024 Mar 1;212(5):785-800. doi: 10.4049/jimmunol.2300015. PMID: 38251887; PMCID: PMC10932911.

Neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein Ab disease, and autoimmune myasthenia gravis (MG) are autoantibody-mediated autoimmune diseases. Autoantibodies can cause a type of immune reaction called Ab-dependent cellular cytotoxicity (ADCC) involving natural killer (NK) cells. However, it is not known whether ADCC contributes to disease development in patients with these conditions.

In this study, researchers investigated the characteristics of circulating NK cells in patients with NMOSD, myelin oligodendrocyte glycoprotein Ab disease, and MG. The team used functional assays, phenotyping, and transcriptomics to explore the role of NK cells in these diseases.

Results show elevated subsets of NK cells in patients with NMOSD and MG. Authors note that this elevation suggests prior ADCC activity occurring in the affected tissues.

Macaluso M, Rothenberg ME, Ferkol T, Kuhnell P, Kaminski HJ, Kimberlin DW, Benatar M, Chehade M; Principal Investigators of the Rare Diseases Clinical Research Network – Cycle 4. Impact of the COVID-19 Pandemic on People Living With Rare Diseases and Their Families: Results of a National Survey. JMIR Public Health Surveill. 2024 Feb 14;10:e48430. doi: 10.2196/48430.

Vega Prado I, Shymansky J, Apte A, Mortman K, Kaminski HJ, Barak S. A Rare Case of Metaplastic Thymoma Presenting With Myasthenia Gravis. Int J Surg Pathol. 2024 Feb;32(1):155-159. doi: 10.1177/10668969231168344. Epub 2023 Apr 24.

Iorio R. Myasthenia gravis: the changing treatment landscape in the era of molecular therapies. Nat Rev Neurol. 2024 Feb;20(2):84-98. doi: 10.1038/s41582-023-00916-w. Epub 2024 Jan 8. PMID: 38191918.

Myasthenia gravis (MG) is a rare neuromuscular disorder caused by an autoimmune response which blocks or damages acetylcholine receptors (AChRs) or muscle-specific kinase (MuSK) on muscles. To date, the standard therapy for MG has relied on acetylcholinesterase inhibitors, corticosteroids, and immunosuppressants. These therapies have shown good efficacy in improving MG-related symptoms in most individuals. However, they can also cause long-term adverse effects, and up to 15% of individuals with MG show limited or no response.

This review paper provides a comprehensive overview of emerging molecular therapies for MG. The author discusses progress in therapies associated with AChR antibodies and MuSK antibodies, including both challenges and opportunities.

The author notes that molecular therapies have the potential to revolutionize the MG treatment landscape, unlocking new potential for personalized medicine approaches.

Farina A, Villagrán-García M, Vogrig A, Zekeridou A, Muñiz-Castrillo S, Velasco R, Guidon AC, Joubert B, Honnorat J. Neurological adverse events of immune checkpoint inhibitors and the development of paraneoplastic neurological syndromes. Lancet Neurol. 2024 Jan;23(1):81-94. doi: 10.1016/S1474-4422(23)00369-1.

Bodansky A, Yu DJ, Rallistan A, Kalaycioglu M, Boonyaratanakornkit J, Green DJ, Gauthier J, Turtle CJ, Zorn K, O'Donovan B, Mandel-Brehm C, Asaki J, Kortbawi H, Kung AF, Rackaityte E, Wang CY, Saxena A, de Dios K, Masi G, Nowak RJ, O'Connor KC, Li H, Diaz VE, Casaletto KB, Gontrum EQ, Chan B, Kramer JH, Wilson MR, Utz PJ, Hill JA, Jackson SW, Anderson MS, DeRisi JL. Unveiling the autoreactome: Proteome-wide immunological fingerprints reveal the promise of plasma cell depleting therapy. medRxiv. 2023 Dec 20:2023.12.19.23300188. doi: 10.1101/2023.12.19.23300188.

Spagni G, Gastaldi M, Businaro P, Chemkhi Z, Carrozza C, Mascagna G, Falso S, Scaranzin S, Franciotta D, Evoli A, Damato V. Comparison of Fixed and Live Cell-Based Assay for the Detection of AChR and MuSK Antibodies in Myasthenia Gravis. Neurol Neuroimmunol Neuroinflamm. 2022 Oct 21;10(1):e200038. doi: 10.1212/NXI.0000000000200038. PMID: 36270951; PMCID: PMC9621337.

Myasthenia gravis (MG) is a neuromuscular disorder caused by an autoimmune response which blocks or damages acetylcholine receptors (AChRs) in muscles. Double seronegative myasthenia gravis (dSN-MG) is a type of MG where patients do not have detectable AChRs or muscle-specific tyrosine kinase (MuSK) antibodies, which are two of the most common antibody markers for MG. In some patients with dSN-MG, a technique called cell-based assay (CBA) can be used to detect these antibodies. However, research comparing fixed and live CBA is lacking.

In this study, the research group of MGNet Pilot Awardee Valentina Damato, MD, PhD, compared the performance of fixed and live CBAs in serum samples from 192 patients with radioimmunoassay (RIA)-dSN-MG and 100 control subjects. The team also assessed the sensitivity and specificity of these techniques in RIA-positive MG samples.

Results show that fixed CBA represents a valuable alternative to RIA for AChR and MuSK antibody detection in patients with MG. Authors note that fixed CBA could be considered as a first-step diagnostic test, while live CBA can be useful in serologic testing of RIA- and fixed CBA-negative samples.

Sikorski P, Li Y, Cheema M, Wolfe GI, Kusner LL, Aban I, Kaminski HJ. Serum metabolomics of treatment response in myasthenia gravis. PLoS One. 2023 Oct 10;18(10):e0287654. doi: 10.1371/journal.pone.0287654. PMID: 37816000; PMCID: PMC10564178

Myasthenia gravis (MG) is a neuromuscular disorder caused by an autoimmune response which blocks or damages acetylcholine receptors in muscles. The primary initial therapy for MG is high-dose prednisone use. However, more than a third of patients do not respond to this treatment. Currently, there are no biomarkers to predict clinical responsiveness to corticosteroid treatment.

In this study, researchers defined a treatment-responsive biomarker for MG patients undergoing corticosteroid therapy. The team used serum from MG patients collected for a clinical trial of thymectomy (removal of the thymus gland) and prednisone to create metabolomic and lipidomic profiles. Next, researchers correlated these profiles with treatment response.

Results show that metabolomic and lipidomic profiles could be used to predict treatment response. Authors note that variation in prednisone metabolism may determine how well patients respond to treatment.

Regnault A, Morel T, de la Loge C, Mazerolle F, Kaminski HJ, Habib AA. Measuring Overall Severity of Myasthenia Gravis (MG): Evidence for the Added Value of the MG Symptoms PRO. Neurol Ther. 2023 Oct;12(5):1573-1590. doi: 10.1007/s40120-023-00464-x. Epub 2023 May 11.

Schlatter MI, Yandamuri SS, O'Connor KC, Nowak RJ, Pham MC, Obaid AH, Redman C, Provost M, McSweeney PA, Pearlman ML, Tees MT, Bowen JD, Nash RA, Georges GE. Remission of severe myasthenia gravis after autologous stem cell transplantation. Ann Clin Transl Neurol. 2023 Sep 19. doi: 10.1002/acn3.51898. Epub ahead of print. PMID: 37726935

Myasthenia gravis (MG) is a rare neuromuscular disorder caused by an autoimmune response which blocks or damages acetylcholine receptors (AChRs) on muscles. High-dose chemotherapy (HDIT) and autologous hematopoietic cell transplantation (HCT), also known as bone marrow transplant, are potential treatments for MG.

In this study, researchers investigated the safety and efficacy of HDIT and HCT in a patient with severe, treatment-resistant MG. Results show that HDIT and HCT induced remission of MG. The team also assessed the effect of treatment on the underlying immunopathology. Intriguingly, the AChR autoantibodies—the known pathogenic mediators of MG—did not appreciably lower after the treatment.

Authors state that these findings suggest a cell-based disease mechanism, which responds to high-dose therapy, may play a role in the pathology in addition to AChR autoantibodies. Further studies are needed to establish whether HDIT and HCT can be an effective therapy for severe MG.

Lesport Q, Joerger G, Kaminski HJ, Girma H, McNett S, Abu-Rub M, Garbey M. Eye Segmentation Method for Telehealth: Application to the Myasthenia Gravis Physical Examination. Sensors (Basel). 2023 Sep 7;23(18):7744. doi: 10.3390/s23187744. PMID: 37765800; PMCID: PMC10536520

Myasthenia gravis (MG) is a neuromuscular disorder which produces muscle weakness that can worsen over the course of a minute during an examination. Use of telemedicine has recently increased for monitoring MG, although these evaluations rely entirely on subjective evaluations of an examiner.

In this study, researchers developed a new telehealth platform to assist with telemedicine evaluations of ocular manifestations of patients with MG. The team created a hybrid algorithm that combines deep learning with computer vision, giving quantitative metrics of ptosis (eyelid droop) and ocular muscle fatigue leading to symptoms like double vision.

The method, which works on both a fixed image and frame by frame of the video in real-time, is able to operate in standard telehealth conditions. Authors note that this approach is general and can be applied to many disorders of ocular motility and ptosis.

Oh S, Mao X, Manfredo-Vieira S, Lee J, Patel D, Choi EJ, Alvarado A, Cottman-Thomas E, Maseda D, Tsao PY, Ellebrecht CT, Khella SL, Richman DP, O'Connor KC, Herzberg U, Binder GK, Milone MC, Basu S, Payne AS. Precision targeting of autoantigen-specific B cells in muscle-specific tyrosine kinase myasthenia gravis with chimeric autoantibody receptor T cells. Nat Biotechnol. 2023 Sep;41(9):1229-1238. doi: 10.1038/s41587-022-01637-z. Epub 2023 Jan 19.

Pham MC, Masi G, Patzina R, Obaid AH, Oxendine SR, Oh S, Payne AS, Nowak RJ, O'Connor KC. Individual myasthenia gravis autoantibody clones can efficiently mediate multiple mechanisms of pathology. Acta Neuropathol. 2023 Aug;146(2):319-336. doi: 10.1007/s00401-023-02603-y. Epub 2023 Jun 21. PMID: 37344701

In patients with myasthenia gravis (MG), an autoimmune response blocks or damages acetylcholine receptors in muscles. Autoantibody clones drive three different pathogenic (disease-causing) mechanisms of MG, including complement activation, receptor blockade, and antigenic modulation. However, it is unclear whether these mechanisms are driven by single or multiple antibody clones.

In this study, researchers investigated the ability of individual autoantibody clones to drive multiple pathogenic mechanisms of MG. First, the team produced monoclonal autoantibodies (mAbs) from patients with MG. Next, researchers assessed the binding properties and pathogenic capacities of the mAbs.

Results show that these mAbs can drive pathology through blocking the acetylcholine binding site, internalizing the AChR through crosslinking (modulation), and activating complement. While some mAbs can drive one or two of these mechanisms, several mAbs were able to drive all three simultaneously. Authors note that these new insights on the immunopathology of MG could help inform therapeutic approaches.

Kusner LL, Misra RS, Lucas R. Editorial: Global excellence in inflammatory diseases: North America 2021. Front Immunol. 2023 Jul 6;14:1245827. doi: 10.3389/fimmu.2023.1245827. eCollection 2023.

Yandamuri SS, Filipek B, Obaid AH, Lele N, Thurman JM, Makhani N, Nowak RJ, Guo Y, Lucchinetti CF, Flanagan EP, Longbrake EE, O'Connor KC. MOGAD patient autoantibodies induce complement, phagocytosis, and cellular cytotoxicity. JCI Insight. 2023 Jun 8;8(11):e165373. doi: 10.1172/jci.insight.165373.

Masi G, Pham MC, Karatz T, Oh S, Payne AS, Nowak RJ, Howard JF Jr, Guptill JT, Juel VC, O'Connor KC. Clinicoserological insights into patients with immune checkpoint inhibitor-induced myasthenia gravis. Ann Clin Transl Neurol. 2023 May;10(5):825-831. doi: 10.1002/acn3.51761. Epub 2023 Mar 16.

Guptill JT, Benatar M, Granit V, Habib AA, Howard JF, Barnett-Tapia C, Nowak RJ, Lee I, Ruzhansky K, Dimachkie MM, Cutter GR, Kaminski HJ. Addressing Outcome Measure Variability in Myasthenia Gravis Clinical Trials. Neurology. 2023 Apr 19;10.1212/WNL.0000000000207278. doi: 10.1212/WNL.0000000000207278. Online ahead of print.

Garbey M, Joerger G, Lesport Q, Girma H, McNett S, Abu-Rub M, Kaminski H. A Digital Telehealth System to Compute Myasthenia Gravis Core Examination Metrics: Exploratory Cohort Study. JMIR Neurotech. 2023;2:e43387. doi: 10.2196/43387. Epub 2023 Apr 19. PMID: 37435094; PMCID: PMC10334459

Myasthenia gravis (MG) is a neuromuscular disorder caused by an autoimmune response which blocks or damages acetylcholine receptors in muscles. Recently, telemedicine practices have grown for neurological diseases, including MG. Telemedicine evaluation of patients with MG has been recommended via the Myasthenia Gravis Core Examination (MG-CE).

In this study, researchers developed a new telehealth system to automate data acquisition and analytics during the MG-CE. Using Zoom videos of patients with MG undergoing the MG-CE, the team created an algorithm toolbox—including computer vision and signal processing methods—to analyze eye motions, body motions, and vocalizations.  

Results show that this new system can objectively quantitate metrics from the MG-CE, allowing the medical examiner to concentrate on the patient instead of managing logistics. Authors note that the system could also be applied to many other neurological disorders, potentially improving clinical care.

Benatar M, Cutter G, Kaminski HJ. The best and worst of times in therapy development for myasthenia gravis. Muscle Nerve. 2022 Nov 2. doi: 10.1002/mus.27742. Epub ahead of print. PMID: 36321730.

Myasthenia gravis (MG) is a neuromuscular disorder caused by an autoimmune response which blocks or damages acetylcholine receptors in muscles. The US Federal Drug Administration (FDA) has approved complement and neonatal Fc receptor (FcRN)-inhibitors, a type of therapy for autoimmune diseases, for treatment of MG. Several other therapies are also in late stage clinical trials or under regulatory review. However, questions remain about which patients are most likely to benefit from which therapies and how effective the treatments will be. In this review article, researchers discuss therapy development for MG, including the most critical needs for clinical trial readiness and biomarker development. Authors provide a summary of Myasthenia Gravis Rare Disease Network (MGNet) meetings held during the MG Foundation of America International Conference, where these topics were discussed. Authors conclude with a series of recommendations to guide focused research in the most critical areas of therapy development for MG, welcoming ongoing discussion.

Fichtner ML, Hoehn KB, Ford EE, Mane-Damas M, Oh S, Waters P, Payne AS, Smith ML, Watson CT, Losen M, Martinez-Martinez P, Nowak RJ, Kleinstein SH, O'Connor KC. Reemergence of pathogenic, autoantibody-producing B cell clones in myasthenia gravis following B cell depletion therapy. Acta Neuropathol Commun. 2022 Oct 28;10(1):154. doi: 10.1186/s40478-022-01454-0. PMID: 36307868; PMCID: PMC9617453.

Myasthenia gravis (MG) is a neuromuscular disorder caused by an autoimmune response which blocks or damages acetylcholine receptors in muscles. A small number of individuals with MG have autoantibodies that target muscle-specific tyrosine kinase (MuSK), which is an enzyme that is crucial to the development and maintenance of the neuromuscular junction. Most patients with MuSK MG can experience remission with CD20-mediated B cell depletion therapy (BCDT). However, relapse is common. In this study, researchers explored the factors that lead to relapse after BCDT in patients with MuSK MG. The team studied autoantibody-producing B cells over the course of BCDT, identifying MuSK-specific B cells from nine patients. Researchers isolated two MuSK-specific B cells from two patients who were experiencing relapse after BCDT. Next, the team explored the molecular properties of these B cells and collected longitudinal samples from the patients. Findings showed that a reservoir of pathogenic, autoantibody-producing B cell clones survived BCDT and reemerged several months before relapse. Authors state that this study provides a better understanding of MuSK MG relapse, as well as a possible biomarker for relapse prediction.

Damato V, Spagni G, Monte G, Woodhall M, Jacobson L, Falso S, Smith T, Iorio R, Waters P, Irani SR, Vincent A, Evoli A. Clinical value of cell-based assays in the characterisation of seronegative myasthenia gravis. J Neurol Neurosurg Psychiatry. 2022 Sep;93(9):995-1000. doi: 10.1136/jnnp-2022-329284. Epub 2022 Jul 14.

Masi G, O'Connor KC. Novel pathophysiological insights in autoimmune myasthenia gravis. Curr Opin Neurol. 2022 Aug 5. doi: 10.1097/WCO.0000000000001088. Epub ahead of print. PMID: 35942663.

Myasthenia gravis (MG) is a neuromuscular disorder caused by an autoimmune response which blocks or damages acetylcholine receptors in muscles. Affected receptors cannot properly receive nerve signals, impacting voluntary muscle contractions. Generalized muscle weakness and fatigue with prolonged activity are characteristic symptoms, which improve with rest. In this review article, authors summarize recent insights into the development of MG relating to the immune system, including the mechanisms of various MG disease subtypes. They also describe the wide range of treatment options now available to patients with MG, which have uncovered significant differences in clinical responses between subtypes. These differences could help clinicians choose specific therapeutic strategies. Authors conclude that improved understanding of autoantibodies is revealing the mechanisms that guide the development of MG. In the future, authors note that studies on the differences in immunology among MG patients will be key to developing effective, individualized therapies.

Masi G, Li Y, Karatz T, Pham MC, Oxendine SR, Nowak RJ, Guptill JT, O'Connor KC. The clinical need for clustered AChR cell-based assay testing of seronegative MG. J Neuroimmunol. 2022 Jun 15;367:577850. doi: 10.1016/j.jneuroim.2022.577850. Epub 2022 Mar 25.

Guidon AC, Guptill JT, Aban I, Cutter G, Soliven B, Benatar M, Kaminski HJ, Nowak RJ, on behalf of MGNet. Adapting Disease Specific Outcome Measures Pilot Trial for Telehealth in Myasthenia Gravis (ADAPT-teleMG): An Innovation in Rare Disesae Study Design During the COVID-19 Pandemic. Muscle Nerve. 2022 May. [Presented as poster at the 14th MGFA International Conference on Myasthenia and Related Disorders in Miami, Florida in May 2022, Presented at the EveryLife Foundation for Rare Diseases 2020 Scientific Workshop.]

Guptill JT, Nowak RJ, Guidon AC, Howard JF, Soliven B, Hammett A, Munro Sheldon B, Li Y, Meece T, Aban I, Cutter G, Kaminski HJ, and the EXPLORE-MG2 Study Team. A prospective natural history study and biorepository for patients with myasthenia gravis (EXPLORE-MG2). Muscle Nerve. 2022 May; 65:S1;S7-S8. [Presented as poster at the 14th MGFA International Conference on Myasthenia and Related Disorders in Miami, Florida in May 2022.]

Obaid AH, Zografou C, Vadysirisack DD, Munro-Sheldon B, Fichtner ML, Roy B, Philbrick WM, Bennett JL, Nowak RJ, O'Connor KC. Heterogeneity of Acetylcholine Receptor Autoantibody-Mediated Complement Activity in Patients With Myasthenia Gravis. Neurol Neuroimmunol Neuroinflamm.. 2022 Apr 26;9(4):e1169. doi: 10.1212/NXI.0000000000001169. PMID: 35473886.

Myasthenia gravis (MG) is a neuromuscular disorder caused by an autoimmune response which blocks or damages acetylcholine receptors in muscles. Clinical assays—laboratory tests used to diagnose and monitor patients—only measure autoantibody binding. Therefore, these tests often provide limited insight on disease burden and therapeutic response. To address these limitations, Dr. Kevin C. O’Connor and colleagues at Yale University developed a new assay for evaluating acetylcholine receptor autoantibody–mediated complement activity. Results suggested that a subset of patients lacks association between membrane attack complex formation and autoantibody binding or disease burden. Authors note that this assay provides a better understanding of autoantibody mechanisms and may improve predictions for treatment response. Ultimately, these measurements could help assess disease progression and provide more individualized treatment plans.

Kaminski HJ, Denk J. Corticosteroid Treatment-Resistance in Myasthenia Gravis. Front Neurol. 2022 Apr 25;13:886625. doi: 10.3389/fneur.2022.886625. eCollection 2022.

Guptill JT, Nowak RJ, Guidon AC, Howard JF, Soliven B, Hammett A, Munro Sheldon B, Li Y, Meece T, Aban I, Cutter G, Kaminski HJ, and the EXPLORE-MG2 Study Team. A prospective natural history study and biorepository for patients with myasthenia gravis (EXPLORE-MG2). Neurology. 2022 April P.6005. [Presented as poster at the 2022 American Academy of Neurology (AAN) Annual Meeting in Seattle, WA  April 2022.]

Fichtner ML, Hoarty MD, Vadysirisack DD, Munro-Sheldon B, Nowak RJ, O'Connor KC. Myasthenia gravis complement activity is independent of autoantibody titer and disease severity. PLoS One. 2022 Mar 15;17(3):e0264489. doi: 10.1371/journal.pone.0264489. eCollection 2022.

Chia R, Saez-Atienzar S, Murphy N, Chiò A, Blauwendraat C; International Myasthenia Gravis Genomics Consortium, Roda RH, Tienari PJ, Kaminski HJ, Ricciardi R, Guida M, De Rosa A, Petrucci L, Evoli A, Provenzano C, Drachman DB, Traynor BJ. Identification of genetic risk loci and prioritization of genes and pathways for myasthenia gravis: a genome-wide association study. Proc Natl Acad Sci U S A. 2022 Feb 1;119(5):e2108672119. doi: 10.1073/pnas.2108672119.

Verschuuren JJ, Palace J, Murai H, Tannemaat MR, Kaminski HJ, Bril V. Advances and ongoing research in the treatment of autoimmune neuromuscular junction disorders. Erratum in: Lancet Neurol. 2022 Feb;21(2):189-202. doi: 10.1016/S1474-4422(21)00463-4. Erratum in: Lancet Neurol. 2022 Mar;21(3):e3. PMID: 35065041.

Henry Kaminski, MD, principal investigator of the Myasthenia Gravis Rare Disease Network (MGNet), and his colleagues have published a review of the present-day therapy for the autoimmune disease myasthenia gravis (MG). Despite there being only 120,000 patients with MG in the US, the well-understood pathophysiology provides a testing ground for drug development to reduce pathogenic antibody in circulation and for B cell depletion to target autoreactive cells. This review paper discusses a new class of agent, FcRn inhibitors, as well as complement inhibitors, which have recently been approved by the US Food and Drug Administration for use in MG. Challenges remain as a cure remains an elusive goal.

Cleanthous S, Mork AC, Regnault A, Cano S, Kaminski HJ, Morel T. Development of the Myasthenia Gravis (MG) Symptoms PRO: a case study of a patient-centred outcome measure in rare disease. Orphanet J Rare Dis. 2021 Oct 30;16(1):457. doi: 10.1186/s13023-021-02064-0.

Mandel-Brehm C, Fichtner ML, Jiang R, Winton VJ, Vazquez SE, Pham MC, Hoehn KB, Kelleher NL, Nowak RJ, Kleinstein SH, Wilson MR, DeRisi JL, O'Connor KC. Elevated N-Linked Glycosylation of IgG V Regions in Myasthenia Gravis Disease Subtypes. J Immunol. 2021 Oct 15;207(8):2005-2014. doi: 10.4049/jimmunol.2100225. Epub 2021 Sep 20.

Myasthenia gravis (MG) is a B cell mediated autoimmune disorder that affects neuromuscular transmission. Patients with MG experience severe muscle weakness and increased fatigability. MG pathology is directly facilitated by IgG isotype autoantibodies. Diversity of immunoglobin G V regions (IgG-Vs) is critical for immunity. Recently, the presence of N-linked glycosylation of IgG-Vs (IgG-VN-Glyc) has been shown to contribute to diversity. In autoimmune disorders, researchers have observed higher frequencies of IgG-VN-Glyc when compared to healthy individuals. To test the boarder specificity of elevated IgG-VN-Glyc, MGNet investigators studied patients with distinct subtypes of MG: AChR and MuSK. The investigators focused on examining the B cell repertoire and total IgG, applying complementary sequencing and proteomic-based approaches. When compared with healthy donors, MGNet investigators found that the frequency of IgG-VN-Glyc motifs was increased in the total B cell receptor (BCR) repertoire of patients with MG. The investigators also found that the fraction of total IgG-VN-Glyc in MG serum is elevated, and the presence of IgG-VN-Glyc did not alter binding of several MG patient-derived monoclonal antibodies (mAbs). These findings contribute to efforts to understand the basic biology of IgG-VN-Glyc and its association with disease.

Guidon AC, Muppidi S, Nowak RJ, Guptill JT, Hehir MK, Ruzhansky K, Burton LB, Post D, Cutter G, Conwit R, Mejia NI, Kaminski HJ, Howard JF Jr. Telemedicine visits in myasthenia gravis: Expert guidance and the Myasthenia Gravis Core Exam (MG-CE). Muscle Nerve. 2021 Sep;64(3):270-276. doi: 10.1002/mus.27260. Epub 2021 Jul 7.

Fichtner ML, Vieni C, Redler RL, Kolich L, Jiang R, Takata K, Stathopoulos P, Suarez PA, Nowak RJ, Burden SJ, Ekiert DC, O'Connor KC. Affinity maturation is required for pathogenic monovalent IgG4 autoantibody development in myasthenia gravis. J Exp Med. 2020 Dec 7;217(12):e20200513. doi: 10.1084/jem.20200513.

Alabbad S, AlGaeed M, Sikorski P, Kaminski HJ. Monoclonal Antibody-Based Therapies for Myasthenia Gravis. BioDrugs. 2020 Oct;34(5):557-566. doi: 10.1007/s40259-020-00443-w.

Green JD, Barohn RJ, Bartoccion E, Benatar M, Blackmore D, Chaudhry V, Chopra M, Corse A, Dimachkie MM, Evoli A, Florence J, Freimer M, Howard JF, Jiwa T, Kaminski HJ, Kissel JT, Koopman WJ, Lipscomb B, Maestri M, Marino M, Massey JM, McVey A, Mezei MM, Muppidi S, Nicolle MW, Oger J, Pascuzzi RM, Pasnoor M, Pestronk A, Provenzano C, Ricciardi R, Richman DP, Rowin J, Sanders DB, Siddiqi Z, Soloway A, Wolfe GI, Wulf C, Drachman DB, Traynor BJ. Epidemiological evidence for a hereditary contribution to myasthenia gravis: a retrospective cohort study of patients from North America. BMJ Open. 2020 Sep 18;10(9):e037909. doi: 10.1136/bmjopen-2020-037909.

Jiang R, Fichtner ML, Hoehn KB, Pham MC, Stathopoulos P, Nowak RJ, Kleinstein SH, O'Connor KC. Single-cell repertoire tracing identifies rituximab refractory B cells during myasthenia gravis relapses. JCI Insight. 2020 Jul 23;5(14):e136471. doi: 10.1172/jci.insight.136471. PMID: 32573488; PMCID: PMC7453893.

Albazli K, Kaminski HJ, Howard JF Jr. Complement Inhibitor Therapy for Myasthenia Gravis. Front Immunol. 2020 Jun 3;11:917. doi: 10.3389/fimmu.2020.00917. eCollection 2020.

Fichtner ML, Jiang R, Bourke A, Nowak RJ, O'Connor KC. Autoimmune Pathology in Myasthenia Gravis Disease Subtypes Is Governed by Divergent Mechanisms of Immunopathology. Front Immunol. 2020 May 27;11:776. doi: 10.3389/fimmu.2020.00776. eCollection 2020.

Meffre E, O'Connor KC. Impaired B-cell tolerance checkpoints promote the development of autoimmune diseases and pathogenic autoantibodies. Immunol Rev. 2019 Nov;292(1):90-101. doi: 10.1111/imr.12821. Epub 2019 Nov 12.

Walker C, Talawalla T, Toth R, Ambekar A, Rea K, Chamian O, Fan F, Berezowska S, Rottenberg S, Madabhushi A, Maillard M, Barisoni L, Horlings HM, Janowczyk A. PatchSorter: a high throughput deep learning digital pathology tool for object labeling. NPJ Digit Med. 2024 Jun 20;7(1):164. doi: 10.1038/s41746-024-01150-4. PMID: 38902336; PMCID: PMC11190251.

Histology slides are used to study tissues and organs under a microscope. Increasingly, slides are being digitized into whole slide images, which are sequential images stitched together to create a single high-resolution file. These images can help us discover patterns associated with diagnosis, prognosis, and therapy response. However, in order to reveal these patterns, a large number of objects in the images must be labeled—for example, a single image may contain over 1 million cells.

In this study, researchers used an artificial intelligence tool to improve digital pathology labeling. The team tested the tool in four use cases with objects containing various numbers of cells and cell types. These use cases included renal tubules (small tubes in the kidneys) and glomeruli (small balls of capillaries in the kidneys).

Results show that the tool, PatchSorter, improves label efficiency, allowing the user to leverage deep learning to quickly review and apply labels at a group level. Authors note that these labels are also highly accurate. 

Troost JP, D'Souza J, Buxton M, Kshirsagar AV, Engel LS, O'Lenick CR, Smoyer WE, Klein J, Ju W, Eddy S, Helmuth M, Mariani LH, Kretzler M, Trachtman H. : Elevated Exposure to Air Pollutants Accelerates Primary Glomerular Disease Progression. Kidney Int Rep. 2024 May 18;9(8):2527-2536. doi: 10.1016/j.ekir.2024.05.013. PMID: 39156153; PMCID: PMC11328569.

Primary glomerular diseases are a group of conditions that affect kidney function by attacking the glomeruli, which are kidney structures responsible for filtering the blood and removing waste in urine. Not much is known about how environmental factors contribute to the progression of primary glomerular diseases.

In this study, researchers explored how residential air pollution affects disease progression in patients with primary glomerular diseases. Among 228 patients from the Nephrotic Syndrome Study Network (NEPTUNE) and 697 patients from CureGlomerulonephropathy (CureGN), the team studied residential census data and two years or more of follow-up. Researchers examined the associations between air pollution—including particulate matter, black carbon, and sulfates—and molecular markers of disease progression. 

Results show that elevated exposure to particulate matter and black carbon is associated with an increased risk of disease progression in patients with primary glomerular diseases. Authors note that by identifying air pollution as a potentially modifiable external risk factor for kidney disease progression, health outcomes could be improved for patients with primary glomerulopathies.

Trachtman H, Desmond H, Williams AL, Mariani LH, Eddy S, Ju W, Barisoni L, Ascani HK, Uhlmann WR, Spino C, Holzman LB, Sedor JR, Gadegbeku C, Subramanian L, Lienczewski CC, Manieri T, Roberts SJ, Gipson DS, Kretzler M; NEPTUNE investigators. Rationale and design of the Nephrotic Syndrome Study Network (NEPTUNE) Match in glomerular diseases: designing the right trial for the right patient, today. Kidney Int. 2024 Feb;105(2):218-230. doi: 10.1016/j.kint.2023.11.018. PMID: 38245210

Glomerular diseases are a group of rare conditions that affect kidney function by attacking the glomeruli, causing problems with the kidney’s filtering system. These diseases include focal segmental glomerular sclerosis (FSGS), minimal change disease, and membranous nephropathy. Glomerular diseases are associated with debilitating symptoms like swelling, protein leakage in urine, and loss of kidney function, sometimes leading to kidney failure. Despite the same diagnosis, response to treatment and disease progression can vary considerably, suggesting differences in disease biology. Few treatments are available, and the efficacy of approved treatments and potential drugs in clinical trials are diminished when patients with differing disease biology are grouped together. 

In this paper, researchers describe the design and implementation of the NEPTUNE Match study. This study is designed to effectively communicate individualized reports to participants and their physicians about the molecular features of their disease state, informing decisions about the suitability of available clinical trials and treatment options. This also paves the way for patients with different rare diseases who share a common disease pathway to be treated using existing, approved drugs.

Authors note that NEPTUNE Match represents the first application of precision medicine in nephrology with the aim of developing targeted therapies and providing the right medication for each patient with primary glomerular disease.

Modi ZJ, Zhai Y, Yee J, Desmond H, Hao W, Sampson MG, Sethna CB, Wang CS, Gipson DS, Trachtman H, Kretzler M; NEPTUNE investigators. Pediatric contributions and lessons learned from the NEPTUNE cohort study. Pediatr Nephrol. 2024 Jan 18. doi: 10.1007/s00467-023-06256-7. Epub ahead of print. PMID: 38233720

Primary glomerular diseases are a group of conditions that affect kidney function by attacking the glomeruli, which are kidney structures responsible for filtering the blood and removing waste in urine. NEPTUNE is a rare disease network that focuses on patients with minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy. The NEPTUNE longitudinal cohort study collects detailed demographic, clinical, histopathologic, genomic, transcriptomic, and metabolomic data from patients of all ages to develop a molecular classification for these disorders.

In this review, researchers provide a snapshot of pediatric patients and lessons learned from the NEPTUNE cohort study. The team summarizes key observations and describes the development of the NEPTUNE Match program, which provides individualized guidance about potential clinical trial participation based on the molecular characterization and non-invasive biomarker profile of each patient.

Authors note that NEPTUNE has proven to be an invaluable asset in the study of glomerular diseases in patients of all ages, including children and adolescents.

Gupta Y, Friedman DJ, McNulty MT, Khan A, Lane B, Wang C, Ke J, Jin G, Wooden B, Knob AL, Lim TY, Appel GB, Huggins K, Liu L, Mitrotti A, Stangl MC, Bomback A, Westland R, Bodria M, Marasa M, Shang N, Cohen DJ, Crew RJ, Morello W, Canetta P, Radhakrishnan J, Martino J, Liu Q, Chung WK, Espinoza A, Luo Y, Wei WQ, Feng Q, Weng C, Fang Y, Kullo IJ, Naderian M, Limdi N, Irvin MR, Tiwari H, Mohan S, Rao M, Dube GK, Chaudhary NS, Gutiérrez OM, Judd SE, Cushman M, Lange LA, Lange EM, Bivona DL, Verbitsky M, Winkler CA, Kopp JB, Santoriello D, Batal I, Pinheiro SVB, Oliveira EA, Simoes E Silva AC, Pisani I, Fiaccadori E, Lin F, Gesualdo L, Amoroso A, Ghiggeri GM, D'Agati VD, Magistroni R, Kenny EE, Loos RJF, Montini G, Hildebrandt F, Paul DS, Petrovski S, Goldstein DB, Kretzler M, Gbadegesin R, Gharavi AG, Kiryluk K, Sampson MG, Pollak MR, Sanna-Cherchi S. Strong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease. Nat Commun. 2023 Nov 30;14(1):7836. doi: 10.1038/s41467-023-43020-9. PMID: 38036523; PMCID: PMC10689833

Focal segmental glomerulosclerosis (FSGS) is a kidney disorder characterized by scarring of a limited number of glomeruli (kidney structures responsible for filtering the blood and removing waste in urine). African Americans have a significantly higher risk of developing chronic kidney disease, especially FSGS, than European Americans. Two coding variants (G1 and G2) in the APOL1 gene play a major role in this disparity.

In this study, researchers investigated the role of the APOL1 p.N264K variant in G2-associated FSGS and chronic kidney disease. The team compared the frequency of this variant in patients with FSGS and those without kidney disease, conducting a comprehensive analysis to explore its impact.

Results show a strong protective effect of the variant against APOL1-related FSGS and chronic kidney disease, countering the toxic effect of the G2 allele. Authors note that this allows APOL1 high-risk individuals to be reclassified as non-high-risk if they carry the variant.

Marchel D, Trachtman H, Larkina M, Helmuth M, Lai Yee JY, Fermin D, Bomback AS, Canetta PA, Gipson DS, Mottl AK, Parekh RS, Saha MK, Sampson MG, Lafayette RA, Mariani LH; Nephrotic Syndrome Study Network (NEPTUNE); Cure Glomerulonephropathy (CureGN). The Significance of Hematuria in Podocytopathies. Clin J Am Soc Nephrol. 2023 Sep 21. doi: 10.2215/CJN.0000000000000309. Epub ahead of print. PMID: 37733352

Podocytopathies are kidney diseases in which injury to podocytes (cells that form the last barrier of the kidney filtration unit) cause nephrotic syndrome. Hematuria (blood in urine) is common in podocytopathies. However, the significance and predictive value of hematuria in these diseases is not well understood.

In this study, researchers describe the prevalence and association between hematuria and kidney-related outcomes in podocytopathies. The team assessed hematuria in urine samples from 1,516 adults and children with podocytopathies.

Results show that hematuria was prevalent among participants and associated with worse kidney-related outcomes, including progressive loss of kidney function and lower rates of proteinuria remission.

Lassé M, El Saghir J, Berthier CC, Eddy S, Fischer M, Laufer SD, Kylies D, Hutzfeldt A, Bonin LL, Dumoulin B, Menon R, Vega-Warner V, Eichinger F, Alakwaa F, Fermin D, Billing AM, Minakawa A, McCown PJ, Rose MP, Godfrey B, Meister E, Wiech T, Noriega M, Chrysopoulou M, Brandts P, Ju W, Reinhard L, Hoxha E, Grahammer F, Lindenmeyer MT, Huber TB, Schlüter H, Thiel S, Mariani LH, Puelles VG, Braun F, Kretzler M, Demir F, Harder JL, Rinschen MM. An integrated organoid omics map extends modeling potential of kidney disease. Nat Commun. 2023 Aug 14;14(1):4903. doi: 10.1038/s41467-023-39740-7. PMID: 37580326; PMCID: PMC10425428

Kidney diseases are characterized by damage and loss of function in the kidneys. Kidney organoids are a promising model to study kidney disease. However, a better understanding of these models and their relevance to disease is critical to advance their use. 

In this study, researchers created an integrated kidney organoid omics map, capturing the complexity of human kidney disease. The team combined omics data from organoid disease models and other preclinical models with data from humans with disease, showing that both inflammation and fibrosis can be rapidly triggered in organoids even in the absence of immune cells.

The new map will enable modeling of more complex kidney disease, driving better outcomes for patients. Authors suggest that other kidney disease researchers can integrate these datasets with their own to improve and refine the creation of organoids relevant to kidney disease.

Lake BB, Menon R, Winfree S, Hu Q, Ferreira RM, Kalhor K, Barwinska D, Otto EA, Ferkowicz M, Diep D, Plongthongkum N, Knoten A, Urata S, Mariani LH, Naik AS, Eddy S, Zhang B, Wu Y, Salamon D, Williams JC, Wang X, Balderrama KS, Hoover PJ, Murray E, Marshall JL, Noel T, Vijayan A, Hartman A, Chen F, Waikar SS, Rosas SE, Wilson FP, Palevsky PM, Kiryluk K, Sedor JR, Toto RD, Parikh CR, Kim EH, Satija R, Greka A, Macosko EZ, Kharchenko PV, Gaut JP, Hodgin JB; KPMP Consortium; Eadon MT, Dagher PC, El-Achkar TM, Zhang K, Kretzler M, Jain S. An atlas of healthy and injured cell states and niches in the human kidney. Nature. 2023 Jul;619(7970):585-594. doi: 10.1038/s41586-023-05769-3. Epub 2023 Jul 19. PMID: 37468583; PMCID: PMC10356613

Kidney diseases are characterized by damage and loss of function in the kidneys. Due to the complexity of the kidney, models that accurately represent human kidney structures and function have been difficult to develop. Without these models, the development of new drugs to treat or prevent kidney disease has been limited.

In this study, a nationwide research team aimed to create the most comprehensive atlas of the human kidney. The team used multiple techniques—including single-cell assays, single-nucleus assays, and spatial imaging technologies—to analyze both healthy reference kidneys and diseased kidneys.

The resulting Kidney Tissue Atlas includes maps of 51 main kidney cell types from rare and novel cell populations, 28 kidney cellular states representing injury or disease, a repository of raw gene data, and interactive 3D models of cells and microenvironment relationships. By allowing the comparison of healthy kidney cells to those injured by kidney disease, data from the new atlas will help investigators understand the factors that contribute to the progression of kidney disease and kidney failure or recovery from injury.

Mariani LH, Eddy S, AlAkwaa FM, McCown PJ, Harder JL, Nair V, Eichinger F, Martini S, Ademola AD, Boima V, Reich HN, El Saghir J, Godfrey B, Ju W, Tanner EC, Vega-Warner V, Wys NL, Adler SG, Appel GB, Athavale A, Atkinson MA, Bagnasco SM, Barisoni L, Brown E, Cattran DC, Coppock GM, Dell KM, Derebail VK, Fervenza FC, Fornoni A, Gadegbeku CA, Gibson KL, Greenbaum LA, Hingorani SR, Hladunewich MA, Hodgin JB, Hogan MC, Holzman LB, Jefferson JA, Kaskel FJ, Kopp JB, Lafayette RA, Lemley KV, Lieske JC, Lin JJ, Menon R, Meyers KE, Nachman PH, Nast CC, O'Shaughnessy MM, Otto EA, Reidy KJ, Sambandam KK, Sedor JR, Sethna CB, Singer P, Srivastava T, Tran CL, Tuttle KR, Vento SM, Wang CS, Ojo AO, Adu D, Gipson DS, Trachtman H, Kretzler M. Precision nephrology identified tumor necrosis factor activation variability in minimal change disease and focal segmental glomerulosclerosis. Kidney Int.. 2023 Mar;103(3):565-579. doi: 10.1016/j.kint.2022.10.023. Epub 2022 Nov 25. PMID: 36442540

Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are kidney disorders characterized by damaged glomeruli, which are kidney structures responsible for filtering the blood and removing waste in urine. Although these disorders have similar clinical presentations and treatment approaches, response to therapies and risk of progression to kidney failure varies widely among patients. Personalized treatments are currently unavailable due to limited understanding of disease mechanisms and lack of tools to identify biologically relevant subgroups.

In this study, researchers investigated the molecular pathways that are shared by subgroups of patients with MCD and FSGS. First, the team identified groups of patients with shared molecular signatures from kidney biopsy tissue. Next, they identified the pathways from these signatures that could be evaluated in individual patients using noninvasive markers measured in the urine.

Authors note that these markers of disease mechanisms may enable targeted therapeutic interventions for subgroups of patients with MCD and FSGS.

Pfaff M, Denburg MR, Meyers KE, Brady TM, Leonard MB, Hoofnagle AN, Sethna CB.. Association of Fibroblast Growth Factor 23 with Blood Pressure in Primary Proteinuric Glomerulopathies. Am J Nephrol. 2024;55(2):187-195. doi: 10.1159/000535092. Epub 2023 Dec 21. PMID: 38128487; PMCID: PMC10987260.

Primary proteinuric glomerulopathies are a group of kidney disorders characterized by dysfunction of the glomeruli (kidney structures responsible for filtering the blood and removing waste in urine), leading to elevated protein in the urine. Elevated levels of fibroblast growth factor 23 (FGF23), a hormone that helps regulate kidney function, are a risk factor for cardiovascular disease. However, not much is known about how FGF23 impacts cardiovascular health in proteinuric glomerulopathies.

In this study, researchers investigated the association of FGF23 levels with resting blood pressure and lipids over time in patients with proteinuric glomerulopathies. The team analyzed data from 204 adults and 93 children using generalized estimating equation regression techniques.

Results showed that higher baseline FGF23 levels were significantly associated with hypertensive blood pressure over time. Authors note that FGF23 should be investigated further as a potential therapeutic target for reducing cardiovascular disease in proteinuric glomerulopathies.

Denicolò S, Nair V, Leierer J, Rudnicki M, Kretzler M, Mayer G, Ju W, Perco P. Assessment of Fibrinogen-like 2 (FGL2) in Human Chronic Kidney Disease through Transcriptomics Data Analysis. Biomolecules. 2022 Dec 31;13(1):89. doi: 10.3390/biom13010089. PMID: 36671474; PMCID: PMC9855364

Chronic kidney disease (CKD) is a condition characterized by a loss of kidney function over time. Although there can be many causes of CKD, most involve fibrosis, where tissue in the kidneys becomes hardened and scarred. Methods to treat fibrosis in CKD remain limited. However, fibrinogen-like 2 (FGL2)—a protein involved in immune and T-cell function—was recently found to be associated with fibrosis in a mouse model of kidney damage, making it a potential therapeutic target in CKD. In this study, researchers investigated the association of FGL2 gene expression with kidney function and disease outcomes in patients with CKD and healthy controls. The team also assessed the localization of FGL2 in kidney biopsies of CKD patients and identified regulators of FGL2 gene expression in renal tissue. Results show that renal FGL2 mRNA expression was elevated in patients with CKD. Higher FGL2 levels were also associated with fibrosis and worse outcomes. Authors note that these findings suggest an important role of FGL2 in human CKD and fibrosis.

Mitrofanova A, Fontanella A, Tolerico M, Mallela S, Molina David J, Zuo Y, Boulina M, Kim JJ, Santos J, Ge M, Sloan A, Issa W, Gurumani M, Pressly J, Ito M, Kretzler M, Eddy S, Nelson R, Merscher S, Burke G, Fornoni A. Activation of Stimulator of IFN Genes (STING) Causes Proteinuria and Contributes to Glomerular Diseases. J Am Soc Nephrol. 2022 Dec;33(12):2153-2173. doi: 10.1681/ASN.2021101286. Epub 2022 Oct 5. PMID: 36198430; PMCID: PMC9731637

Glomerular diseases are a group of conditions that affect kidney function by attacking the glomeruli, which are kidney structures responsible for filtering the blood and removing waste in urine. Diabetic kidney disease (DKD) and Alport syndrome are two types of glomerular diseases. Stimulator of IFN genes (STING)—a signaling molecule—is a crucial regulator of the cyclic GMP-AMP synthase (cGAS)-STING pathway. Under conditions of obesity, kidney fibrosis, and acute kidney injury, this signaling pathway regulates inflammation and energy homeostasis. However, the role of the STING pathway in glomerular diseases is unclear. In this study, researchers investigated whether STING activation contributes to the development and progression of glomerular diseases such as DKD and Alport syndrome. The team used several mouse models, including diabetic and Alport, to assess the role of the STING signaling pathway in kidney failure. Results suggest that activation of the STING pathway acts as a mediator of disease progression in DKD and Alport syndrome. Authors state that targeting STING may offer a therapeutic option to treat glomerular diseases and prevent their development or progression.

Riella CV, McNulty M, Ribas GT, Tattersfield CF, Perez-Gill C, Eichinger F, Kelly J, Chun J, Subramanian B, Guizelini D; Nephrotic Syndrome Study Network (NEPTUNE), Alper SL, Pollak MR, Sampson MG, Friedman DJ. ADAR regulates APOL1 via A-to-I RNA editing by inhibition of MDA5 activation in a paradoxical biological circuit. Proc Natl Acad Sci U S A. 2022 Nov;119(44):e2210150119. doi: 10.1073/pnas.2210150119. Epub 2022 Oct 25. PMID: 36282916; PMCID: PMC9636950.

APOL1-associated kidney disease may be caused by two copies of risk variants in the APOL1 gene. However, the disease only occurs in some individuals who carry these variants. Kidney-damaging levels of APOL1 production may be activated by viral illnesses or other environmental factors. In this study, researchers investigated the factors that lead to APOL1-associated kidney disease. The team found that a type of RNA modification called adenosine-to-inosine (A-to-I) editing—carried out by adenosine deaminase acting on RNA (ADAR)—suppressed APOL1 gene expression mediated by inflammatory pathways. Without ADAR editing, APOL1’s messenger RNA triggered inflammation. These findings suggest that ADAR counters rapid production of APOL1 during acute inflammation. Authors note that this important process could impact the severity of APOL1-associated kidney disease.

Li C, Krothapalli S, Chen YM. Targeting Endoplasmic Reticulum for Novel Therapeutics and Monitoring in Acute Kidney Injury. Nephron. 2022 Sep 16:1-4. doi: 10.1159/000526050. Epub ahead of print. PMID: 36116429

Acute kidney injury (AKI) is a sudden episode of kidney failure or damage that occurs over a few hours or days. New evidence shows that endoplasmic reticulum (ER) stress—which occurs when proteins are not properly folded—is involved in AKI. However, there are currently no treatments for AKI, including ER-targeted therapies. In this study, researchers aimed to explore the role of ER in AKI. The team outlined several therapeutic chemicals that can target the ER for treatment of AKI. Additionally, researchers identified several potential ER stress biomarkers for early diagnosis and treatment response monitoring in patients with AKI. Based on this evidence, authors conclude that ER plays a critical role in the pathogenesis and progression of AKI. Authors also emphasize an urgent need to develop ER-targeted therapeutics and discover more ER stress biomarkers at the early stage of AKI.

Liu S, Bush WS, Miskimen K, Gonzalez-Vicente A, Bailey JNC, Konidari I, McCauley JL, Sedor JR, O'Toole JF, Crawford DC. T-cell receptor diversity in minimal change disease in the NEPTUNE study. Pediatr Nephrol. 2022 Aug 9. doi: 10.1007/s00467-022-05696-x. Epub ahead of print. PMID: 35943576

Minimal change disease (MCD) is one of the most common causes of childhood idiopathic nephrotic syndrome, which is characterized by severe proteinuria (high levels of protein in the urine) and edema (swelling of body parts). For most patients with MCD, proteinuria is rapidly reversible with corticosteroid therapy. However, relapses are common, and repeated courses of immunosuppressive therapy often lead to many adverse events in children. In this study, researchers explored the role of abnormal T-cell function in these outcomes. The team sequenced T-cell receptors with clinical data and blood samples from patients collected by the Nephrotic Syndrome Study Network (NEPTUNE). To assess the differences between active disease and remission states, researchers calculated several T-cell receptor diversity metrics. Resulting data do not support an obvious role of the adaptive immune system T-cells in the development of MCD. However, given the study’s limited sample size, authors note that further investigation is warranted.

McNulty MT, Fermin D, Eichinger F, Jang D, Kretzler M, Burtt NP, Pollak MR, Flannick J, Weins A, Friedman DJ; Nephrotic Syndrome Study Network (NEPTUNE), Sampson MG. A glomerular transcriptomic landscape of apolipoprotein L1 in Black patients with focal segmental glomerulosclerosis. Kidney Int. 2022 Jul;102(1):136-148. doi: 10.1016/j.kint.2021.10.041. Epub 2021 Dec 18.

Zee J, Liu Q, Smith AR, Hodgin JB, Rosenberg A, Gillespie BW, Holzman LB, Barisoni L, Mariani LH; Nephrotic Syndrome Study Network (NEPTUNE); NEPTUNE Members. Kidney Biopsy Features Most Predictive of Clinical Outcomes in the Spectrum of Minimal Change Disease and Focal Segmental Glomerulosclerosis. J Am Soc Nephrol.. 2022 Jul;33(7):1411-1426. doi: 10.1681/ASN.2021101396. Epub 2022 May 17. PMID: 35581011; PMCID: PMC9257823.

Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are kidney disorders that damage the glomeruli, which are tiny blood vessels in the kidneys. Historically, classification of these disorders has been based on limited features of the glomeruli. Because disease course and treatment response are diverse among patients, a more detailed evaluation of kidney tissue features is needed. In this study, researchers aimed to identify the most important descriptors of clinical outcomes in the Nephrotic Syndrome Study Network (NEPTUNE). The team used supervised machine learning methods—with pathology data collected through applying the NEPTUNE Digital Pathology Scoring System to NEPTUNE kidney biopsies—to evaluate predictors of disease progression, complete proteinuria remission, and treatment response. Researchers found that the most predictive descriptors of outcomes included conventional and novel histologic and ultrastructural features from both glomerular and tubulointerstitial renal compartments. Authors note that standardized reporting of these descriptors could help inform predictions for clinical outcomes.

Sealfon R, Mariani L, Avila-Casado C, Nair V, Menon R, Funk J, Wong A, Lerner G, Hayashi N, Troyanskaya O, Kretzler M, Beck LH Jr. Molecular Characterization of Membranous Nephropathy. J Am Soc Nephrol. 2022 Jun;33(6):1208-1221. doi: 10.1681/ASN.2021060784. Epub 2022 Apr 27.

Hodgin JB, Mariani LH, Zee J, Liu Q, Smith AR, Eddy S, Hartman J, Hamidi H, Gaut JP, Palmer MB, Nast CC, Chang A, Hewitt S, Gillespie BW, Kretzler M, Holzman LB, Barisoni L; Nephrotic Syndrome Study Network (NEPTUNE). Quantification of Glomerular Structural Lesions: Associations With Clinical Outcomes and Transcriptomic Profiles in Nephrotic Syndrome. Am J Kidney Dis. 2022 Jun;79(6):807-819.e1. doi: 10.1053/j.ajkd.2021.10.004. Epub 2021 Dec 3.

Classification systems for focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) need improvement. In research published in the American Journal of Kidney Diseases involving 221 patients with MCD and FSGS in the Nephrotic Syndrome Study Network (NEPTUNE), investigators applied the NEPTUNE Digital Pathology Scoring System to generate scores for 37 glomerular descriptors. Three clusters were identified. Clusters Y and Z had higher probabilities of proteinuria remission, lower risks of disease progression, and lower kidney function loss over time compared with X. Cluster X had 1,920 differentially expressed genes compared with Y+Z, which reflected activation of pathways of immune response and inflammation. Six descriptors correlated with clinical outcomes and gene expression.

Mallela SK, Merscher S, Fornoni A. Implications of Sphingolipid Metabolites in Kidney Diseases. Int J Mol Sci.. 2022 Apr 11;23(8):4244. doi: 10.3390/ijms23084244. PMID: 35457062; PMCID: PMC9025012.

Sphingolipids are lipids with complex structures that act as bioactive signaling molecules. They are involved in several cellular processes, including cell survival, proliferation, migration, and apoptosis. Abnormalities in the levels of sphingolipids are associated with several human diseases, including kidney diseases. Studies demonstrate that sphingolipids play an important role in maintaining proper renal function. Sphingolipids can alter the glomerular filtration barrier (GFB, a membrane that prevents the passage of the majority of proteins into the urine) by affecting the functioning of podocytes, which are key cellular components of the GFB. In this review paper, researchers summarize studies of the regulation of sphingolipid signaling in kidney diseases, especially in glomerular and tubulointerstitial diseases. Authors also discuss the potential to target sphingolipid pathways in developing therapeutics for the treatment of renal diseases

Watts AJB, Keller KH, Lerner G, Rosales I, Collins AB, Sekulic M, Waikar SS, Chandraker A, Riella LV, Alexander MP, Troost JP, Chen J, Fermin D, Yee JL, Sampson MG, Beck LH Jr, Henderson JM, Greka A, Rennke HG, Weins A. Discovery of Autoantibodies Targeting Nephrin in Minimal Change Disease Supports a Novel Autoimmune Etiology. J Am Soc Nephrol. 2022 Jan;33(1):238-252. doi: 10.1681/ASN.2021060794. Epub 2021 Nov 3. PMID: 34732507; PMCID: PMC8763186.

Wang CS, Troost JP, Wang Y, Greenbaum LA, Gibson K, Trachtman H, Srivastava T, Reidy K, Kaskel F, Sethna CB, Meyers K, Dell KM, Tran CL, Hingorani S, Lemley KV, Lin JJ, Gipson DS. Determinants of medication adherence in childhood nephrotic syndrome and associations of adherence with clinical outcomes. Pediatr Nephrol. Wang CS, Troost JP, Wang Y, Greenbaum LA, Gibson K, Trachtman H, Srivastava T, Reidy K, Kaskel F, Sethna CB, Meyers K, Dell KM, Tran CL, Hingorani S, Lemley KV, Lin JJ, Gipson DS. Determinants of medication adherence in childhood nephrotic syndrome and associations 2022 Jul;37(7):1585-1595. doi: 10.1007/s00467-021-05176-8. Epub 2021 Nov 18. PMID: 34796395.

Nephrotic syndrome is a group of symptoms caused by a variety of disorders that damage the kidneys. Pediatric patients with nephrotic syndrome take medications long-term with significant toxicity and complex regimens. However, not much is known about medication adherence in this population. In this study, researchers aimed to understand the determinants of medication adherence and its potential impact on clinical outcomes in childhood nephrotic syndrome. A total of 225 adolescent patients under 19 years old and caregivers completed medication adherence surveys during a 3-year follow-up. Researchers assessed the relationship between adherence and subsequent steroid response, as well as healthcare utilization. Results show that medication nonadherence is common in pediatric nephrotic syndrome. Nonadherence did not show statistically significant associations with steroid resistance or frequency of hospitalizations and emergency room visits. Authors state that more research is needed on the use of surveys in the clinical setting to identify at-risk patients, as well as ways to support families over time.

Latt KZ, Heymann J, Jessee JH, Rosenberg AZ, Berthier CC, Arazi A, Eddy S, Yoshida T, Zhao Y, Chen V, Nelson GW, Cam M, Kumar P, Mehta M, Kelly MC, Kretzler M; Nephrotic Syndrome Study Network (NEPTUNE); Accelerating Medicines Partnership in Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Consortium, Ray PE, Moxey-Mims M, Gorman GH, Lechner BL, Regunathan-Shenk R, Raj DS, Susztak K, Winkler CA, Kopp JB. Urine Single-Cell RNA Sequencing in Focal Segmental Glomerulosclerosis Reveals Inflammatory Signatures. Kidney Int Rep. 2021 Nov 25;7(2):289-304. doi: 10.1016/j.ekir.2021.11.005. PMID: 35155868; PMCID: PMC8821042.

Moran SM, Scott J, Clarkson MR, Conlon N, Dunne J, Griffin MD, Griffin TP, Groarke E, Holian J, Judge C, Wyse J, McLoughlin K, O'Hara PV, Little MA, Kretzler M; Nephrotic Syndrome Study Network (NEPTUNE). The Clinical Application of Urine Soluble CD163 in ANCA-Associated Vasculitis. J Am Soc Nephrol. 2021 Nov;32(11):2920-2932. doi: 10.1681/ASN.2021030382. Epub 2021 Sep 13. PMID: 34518279; PMCID: PMC8806104.

ANCA-associated vasculitis (AAV) is a group of diseases characterized by the destruction and inflammation of small vessels. Up to 70% of patients with AAV develop glomerulonephritis (GN), which is inflammation of the tiny filters in the kidneys (glomeruli). Of those, 26% progress to end-stage kidney disease. Researchers are seeking to develop a noninvasive biomarker of active renal vasculitis in order to reliably detect disease before irreversible organ damage occurs. In this study, researchers assessed urinary soluble CD16 (usCD16) as a potential biomarker. They established a reference range and assessed its use in several patient populations. They found that usCD16 is elevated in patients with renal vasculitis. They also found that false positive results can be corrected with urine protein normalization.

Banu K, Lin Q, Basgen JM, Planoutene M, Wei C, Reghuvaran AC, Tian X, Shi H, Garzon F, Garzia A, Chun N, Cumpelik A, Santeusanio AD, Zhang W, Das B, Salem F, Li L, Ishibe S, Cantley LG, Kaufman L, Lemley KV, Ni Z, He JC, Murphy B, Menon MC. AMPK mediates regulation of glomerular volume and podocyte survival. JCI Insight. 2021 Oct 8;6(19):e150004. doi: 10.1172/jci.insight.150004. PMID: 34473647; PMCID: PMC8525649.

Trachtman H, Laskowski J, Lee C, Renner B, Feemster A, Parikh S, Panzer SE, Zhong W, Cravedi P, Cantarelli C, Kulik L, You Z, Satchell S, Rovin B, Liu F, Kalled SL, Holers VM, Jalal D, Thurman JM. Natural antibody and complement activation characterize patients with idiopathic nephrotic syndrome. Am J Physiol Renal Physiol. 2021 Oct 1;321(4):F505-F516. doi: 10.1152/ajprenal.00041.2021. Epub 2021 Aug 30. PMID: 34459222; PMCID: PMC8560405.

Maksimowski NA, Song X, Bae EH, Reich H, John R, Pei Y, Scholey JW, Nephrotic Syndrome Study Network Neptune. Follistatin-Like-1 (FSTL1) Is a Fibroblast-Derived Growth Factor That Contributes to Progression of Chronic Kidney Disease. Int J Mol Sci. 2021;22:9513. doi: 10.3390/ijms22179513. PMID: 34502419; PMCID: PMC8431028.

Researchers seeking to better understand the progression of chronic kidney disease studied an animal model of progressive nephropathy, performing microarray analysis of the kidneys of Col4a3-/- mice at 4 and 7 weeks of age. Their goal was to identify new genes that may play a role in tubule-interstitial injury. Authors found that the gene Follistatin-like-1 (FSTL1) contributes to fibrosis (scarring), inflammation, and apoptosis (cell death) in the kidney. Their findings suggest that FSTL1 may be a new treatment target in chronic kidney disease.

Zee J, McNulty MT, Hodgin JB, Zhdanova O, Hingorani S, Jefferson JA, Gibson KL, Trachtman H, Fornoni A, Dell KM, Reich HN, Bagnasco S, Greenbaum LA, Lafayette RA, Gipson DS, Brown E, Kretzler M, Appel G, Sambandam KK, Tuttle KR, Chen D, Atkinson MA, Hogan MC, Kaskel FJ, Meyers KE, O'Toole J, Srivastava T, Sethna CB, Hladunewich MA, Lin JJ, Nast CC, Derebail VK, Patel J, Vento S, Holzman LB, Athavale AM, Adler SG, Lemley KV, Lieske JC, Hogan JJ, Gadegbeku CA, Fervenza FC, Wang CS, Matar RB, Singer P, Kopp JB, Barisoni L, Sampson MG. APOL1 genotype-associated morphologic changes among patients with focal segmental glomerulosclerosis. Pediatr Nephrol. 2021 Sep;36(9):2747-57. doi: 10.1007/s00467-021-04990-4. Epub 2021 Mar 1. PMID: 33646395; PMCID: PMC8524347. 

Maksimowski NA, Scholey JW, Williams VR, Nephrotic Syndrome Study Network (NEPTUNE). Sex and kidney ACE2 expression in primary focal segmental glomerulosclerosis (FSGS): A NEPTUNE study. PLoS ONE. 2021 Jun 7;16(6):e0252758. doi: 10.1371/journal.pone.0252758. eCollection 2021.

In this study, gene expression data and clinical variables gathered from 111 subjects with FSGS were analyzed to compare relationships between angiotensin-converting enzyme 2 (ACE2) expression, clinical variables, and pathology in males and females. Researchers concluded sex is an important determinant of ACE2 expression in the tubules of the kidney and the tissues that surround them. Sex also influences the relationships between ACE2, kidney fibrosis, and expression of genes involved in kidney inflammation.

Waller AP, Troost JP, Parikh SV, Wolfgang KJ, Rovin BH, Nieman MT, Smoyer WE, Kretzler M, Kerlin BA; NEPTUNE Investigators. Nephrotic syndrome disease activity is proportional to its associated hypercoagulopathy. Thromb Res. 2021 May;201:50-59. doi: 10.1016/j.thromres.2021.02.007. Epub 2021 Feb 16. PMID: 33636573; PMCID: PMC8096658.

This study aimed to establish the relationship between disease severity and hypercoagulopathy (an increased tendency of the blood to form clots) in human nephrotic syndrome. Consistent with previous animal model observations, researchers found that hypercoagulopathy was proportional to conventional measures of nephrotic syndrome activity, and that it improved significantly with partial or complete disease remission. Study authors expect these data will inform studies designed to stratify thrombotic risk for patients with nephrotic syndrome.

Lane BM, Murray S, Benson K, Bierzynska A, Chryst-Stangl M, Wang L, Wu G, Cavalleri G, Doyle B, Fennelly N, Dorman A, Conlon S, Vega-Warner V, Fermin D, Vijayan P, Qureshi MA, Shril S, Barua M, Hildebrandt F, Pollak M, Howell D, Sampson MG, Saleem M, Conlon PJ, Spurney R, Gbadegesin R. A rare autosomal dominant variant in Regulator of Calcineurin Type 1 (RCAN1) gene confers enhanced calcineurin activity and may cause FSGS. J Am Soc Nephrol. 2021 Apr 16;32(7):1682–95. doi: 10.1681/ASN.2020081234. Epub ahead of print. PMID: 33863784; PMCID: PMC8425665. 

Miyata KN, Lo CS, Zhao S, Liao MC, Pang Y, Chang SY, Peng J, Kretzler M, Filep JG, Ingelfinger JR, Zhang SL, Chan JSD. Angiotensin II up-regulates sodium-glucose co-transporter 2 expression and SGLT2 inhibitor attenuates Ang II-induced hypertensive renal injury in mice. Clin Sci (Lond). 2021;135:943-61. doi: 10.1042/CS20210094. PMID: 33822013; PMCID: PMC8131957. 

Shah PP, Brady TM, Meyers KEC, O'Shaughnessy MM, Gibson KL, Srivastava T, Zee J, Cattran D, Tuttle KR, Gadegbeku C, Glenn D, Derebail V, Smith A, Wang CS, Gillespie BW, Bitzer M, Sethna CB. Association of Obesity with Cardiovascular Risk Factors and Kidney Disease Outcomes in Primary Proteinuric Glomerulopathies. Nephron. 2021;145:245-55. doi: 10.1159/000513869. PMID: 33677435; PMCID: PMC8102330.

Jayapandian CP, Chen Y, Janowczyk AR, Palmer MB, Cassol CA, Sekulic M, Hodgin JB, Zee J, Hewitt SM, O'Toole J, Toro P, Sedor JR, Barisoni L, Madabhushi A, Nephrotic Syndrome Study Network (NEPTUNE). Development and evaluation of deep learning-based segmentation of histologic structures in the kidney cortex with multiple histologic stains. Kidney Int. 2021;99:86-101. doi: 10.1016/j.kint.2020.07.044. PMID: 32835732; PMCID: PMC8414393.

Wu Q, Troost JP, Dai T, Nast C, Eddy S, Wei B, Wang Y, Gipson DS, Dell KM, Gipson KL, Kretzler M, Adler S. Kidney Injury Molecule-1 Urinary Excretion and Tissue Expression Levels and the Prediction of Glomerular Disease Outcomes. Glomerular Dis. 2021;1:45-59. doi: 10.1159/000513166. PMID: 34337593; PMCID: PMC8323791.

Zhao L, Murray S, Mariani LH, Ju W. Incorporating longitudinal biomarkers for dynamic risk prediction in the era of big data: A pseudo-observation approach. Stat Med. 2020 Nov 20;39(26):3685-3699. doi: 10.1002/sim.8687. Epub 2020 Jul 27.

Barisoni L, Lafata KJ, Hewitt SM, Madabhushi A, Balis UGJ. Digital pathology and computational image analysis in nephropathology. Nat Rev Nephrol. 2020 Nov;16(11):669-685. doi: 10.1038/s41581-020-0321-6. Epub 2020 Aug 26.

Tao J, Mariani L, Eddy S, Maecker H, Kambham N, Mehta K, Hartman J, Wang W, Kretzler M, Lafayette RA. JAK-STAT Activity in Peripheral Blood Cells and Kidney Tissue in IgA Nephropathy. Clin J Am Soc Nephrol. 2020 Jul 1;15(7):973-982. doi: 10.2215/CJN.11010919. Epub 2020 Apr 30. PMID: 32354727; PMCID: PMC7341773. 

IgA nephropathy, also known as Berger’s disease, is a kidney disorder that occurs when IgA (immunoglobulin A), a protein that helps the body fight infections, settles in the kidneys. Deposits of IgA may cause the kidneys to leak blood and sometimes protein in the urine and lead to progressive kidney fibrosis or scarring. Researchers seeking to understand and target the mechanisms behind the disease undertook detailed investigations of the Janus kinase signal transducer and activator of transcription (JAK-STAT) pathway, which is believed to be an important mediator of kidney disease. They compared 77 patients with IgA nephropathy with 45 healthy subjects. Researchers found that JAK-STAT signaling was activated in patients with IgA nephropathy compared with controls, finding altered responses in peripheral immune cells and increased message and activated proteins in the kidney function. Authors say their findings strongly support that the JAK-STAT signaling pathway is altered in diverse kidney diseases, in ways that are likely unique to each disease.

Derebail VK, Rheault MN, Kerlin BA. Role of direct oral anticoagulants in patients with kidney disease. Kidney Int. 2020 Apr;97(4):664-675. doi: 10.1016/j.kint.2019.11.027. Epub 2019 Dec 24. PMID: 32107019; PMCID: PMC7093256.

Chen Y, Zee J, Smith A, Jayapandian C, Hodgin J, Howell D, Palmer M, Thomas D, Cassol C, Farris AB 3rd, Perkinson K, Madabhushi A, Barisoni L, Janowczyk A. Assessment of a computerized quantitative quality control tool for kidney whole slide image biopsies. J Pathol. 2020;253:268-78. doi: 10.1002/path.5590. PMID: 33197281; PMCID: PMC8392148. 

Jia X, Yamamura T, Gbadegesin R, McNulty MT, Song K, Nagano C, Hitomi Y, Lee D, Aiba Y, Khor SS, Ueno K, Kawai Y, Nagasaki M, Noiri E, Horinouchi T, Kaito H, Hamada R, Okamoto T, Kamei K, Kaku Y, Fujimaru R, Tanaka R, Shima Y; Research Consortium on Genetics of Childhood Idiopathic Nephrotic Syndrome in Japan, Baek J, Kang HG, Ha IS, Han KH, Yang EM; Korean Consortium of Hereditary Renal Diseases in Children, Abeyagunawardena A, Lane B, Chryst-Stangl M, Esezobor C, Solarin A; Midwest Pediatric Nephrology Consortium (Genetics of Nephrotic Syndrome Study Group), Dossier C, Deschênes G; NEPHROVIR, Vivarelli M, Debiec H, Ishikura K, Matsuo M, Nozu K, Ronco P, Cheong HI, Sampson MG, Tokunaga K, Iijima K. Common risk variants in NPHS1 and TNFSF15 are associated with childhood steroid-sensitive nephrotic syndrome. Kidney Int. 2020;98:1308-22. doi: 10.1016/j.kint.2020.05.029. PMID: 32554042; PMCID: PMC8101291. 

Chao YC, Trachtman H, Gipson DS, Spino C, Braun TM, Kidwell KM. Dynamic treatment regimens in small n, sequential, multiple assignment, randomized trials: An application in focal segmental glomerulosclerosis. Contemp Clin Trials. 2020;92:105989. doi: 10.1016/j.cct.2020.105989. PMID: 32200006; PMCID: PMC8173713. 

Merchant ML, Barati MT, Caster DJ, Hata JL, Hobeika L, Coventry S, Brier ME, Wilkey DW, Li M, Rood IM, Deegens JK, Wetzels JF, Larsen CP, Troost JP, Hodgin JB, Mariani LH, Kretzler M, Klein JB, McLeish KR. Proteomic Analysis Identifies Distinct Glomerular Extracellular Matrix in Collapsing Focal Segmental Glomerulosclerosis. J Am Soc Nephrol. 2020;31(8):1883-1904. doi: 10.1681/ASN.2019070696. PMID: 32561683; PMCID: PMC7460901. 

Menon R, Otto EA, Hoover P, Eddy S, Mariani L, Godfrey B, Berthier CC, Eichinger F, Subramanian L, Harder J, Ju W, Nair V, Larkina M, Naik AS, Luo J, Jain S, Sealfon R, Troyanskaya O, Hacohen N, Hodgin JB, Kretzler M, Kpmp KPMP; Nephrotic Syndrome Study Network (NEPTUNE). Single cell transcriptomics identifies focal segmental glomerulosclerosis remission endothelial biomarker. JCI Insight. 2020;5:e133267. doi: 10.1172/jci.insight.133267. PMID: 32107344; PMCID: PMC7213795. 

Royal V, Zee J, Liu Q, Avila-Casado C, Smith AR, Liu G, Mariani LH, Hewitt S, Holzman LB, Gillespie BW, Hodgin JB, Barisoni L. Ultrastructural Characterization of Proteinuric Patients Predicts Clinical Outcomes. J Am Soc Nephrol. 2020;31:841-54. doi: 10.1681/ASN.2019080825. PMID: 32086276; PMCID: PMC7191920. 

Gonzalez Guerrico AM, Lieske J, Klee G, Kumar S, Lopez-Baez V, Wright AM, Bobart S, Shevell D, Maldonado M, Troost JP, Hogan MC; Nephrotic Syndrome Study Network Consortium (NEPTUNE). Urinary CD80 Discriminates Among Glomerular Disease Types and Reflects Disease Activity. Kidney Int Rep. 2020;5:2021-31. doi: 10.1016/j.ekir.2020.08.001. PMID: 33163723; PMCID: PMC7609973. 

Srinivasan Sridhar V, Ambinathan JPN, Kretzler M, Pyle LL, Bjornstad P, Eddy S, Cherney DZ, Reich HN; European Renal cDNA Bank (ERCB); Nephrotic Syndrome Study Network (NEPTUNE). Renal SGLT mRNA expression in human health and disease: a study in two cohorts. Am J Physiol Renal Physiol. 2019 Nov 1;317(5):F1224-F1230. doi: 10.1152/ajprenal.00370.2019. Epub 2019 Sep 23. PMID: 31545924; PMCID: PMC6879935.

Park SJ, Kim Y, Chen YM. Endoplasmic reticulum stress and monogenic kidney diseases in precision nephrology. Pediatr Nephrol. 2019 Sep;34(9):1493-1500. doi: 10.1007/s00467-018-4031-2. Epub 2018 Aug 11.

Nihalani D, Solanki AK, Arif E, Srivastava P, Rahman B, Zuo X, Dang Y, Fogelgren B, Fermin D, Gillies CE, Sampson MG, Lipschutz JH. Disruption of the exocyst induces podocyte loss and dysfunction. J Biol Chem. 2019 Jun 28;294(26):10104-10119. doi: 10.1074/jbc.RA119.008362. Epub 2019 May 9.

Perco P, Ju W, Kerschbaum J, Leierer J, Menon R, Zhu C, Kretzler M, Mayer G, Rudnicki M; Nephrotic Syndrome Study Network (NEPTUNE). Identification of dicarbonyl and L-xylulose reductase as a therapeutic target in human chronic kidney disease. JCI Insight. 2019;4:e128120. doi: 10.1172/jci.insight.128120. PMID: 31217356; PMCID: PMC6629103.

Otalora L, Chavez E, Watford D, Tueros L, Correa M, Nair V, Ruiz P, Wahl P, Eddy S, Martini S, Kretzler M, Burke GW 3rd, Fornoni A, Merscher S. Identification of glomerular and podocyte-specific genes and pathways activated by sera of patients with focal segmental glomerulosclerosis. PLoS One. 2019;14:e0222948. doi: 10.1371/journal.pone.0222948. PMID: 31581251; PMCID: PMC6776339. 

Liu Q, Smith AR, Mariani LH, Nair V, Zee J. Methods for Assessing Longitudinal Biomarkers of Time-to-Event Outcomes in CKD: A Simulation Study. Clin J Am Soc Nephrol. 2019;14:1315-23, doi: 10.2215/CJN.00450119. PMID: 31416887; PMCID: PMC6730514.

Harder JL, Menon R, Otto EA, Zhou J, Eddy S, Wys NL, O'Connor C, Luo J, Nair V, Cebrian C, Spence JR, Bitzer M, Troyanskaya OG, Hodgin JB, Wiggins RC, Freedman BS, Kretzler M; European Renal cDNA Bank (ERCB); Nephrotic Syndrome Study Network (NEPTUNE). Organoid single cell profiling identifies a transcriptional signature of glomerular disease. JCI Insight. 2019;4:e122697. doi: 10.1172/jci.insight.122697. PMID: 30626756;PMCID: PMC6485369.

Trachtman H, Gipson DS, Lemley KV, Troost JP, Faul C, Morrison DJ, Vento SM, Ahn DH, Goldberg JD. Plasma Zonulin Levels in Childhood Nephrotic Syndrome. Front Pediatr. 2019;7:197. doi:10.3389/fped.2019.00197. PMID: 31157195;PMCID: PMC6532587.

Wang CS, Troost JP, Greenbaum LA, Srivastava T, Reidy K, Gibson K, Trachtman H, Piette JD, Sethna CB, Meyers K, Dell KM, Tran CL, Vento S, Kallem K, Herreshoff E, Hingorani S, Lemley K, Oh G, Brown E, Lin JJ, Kaskel F, Gipson DS. Text Messaging for Disease Monitoring in Childhood Nephrotic Syndrome. Kidney Int Rep. 2019;4:1066-74. doi:10.1016/j.ekir.2019.04.026. PMID: 31440697; PMCID: PMC6698307.

Troost JP, Waldo A, Carlozzi NE, Murphy S, Modersitzski F, Trachtman H, Nachman PH, Reidy KJ, Selewski DT, Herreshoff EG, Srivastava T, Gibson KL, Derebail VK, Lin JJ, Hingorani S, Fornoni A, Fervenza FC, Sambandam K, Athavale AM, Kopp JB, Reich HN, Adler SG, Greenbaum LA, Dell KM, Appel G, Wang C, Sedor J, Kaskel FJ, Lafayette RA, Atkinson MA,Lieske JC, Sethna CB, Kretzler M, Hladunewich MA, Lemley KV, Brown E,Meyers KE,Gadegbeku CA, Holzman LB,Jefferson JA, Tuttle KR, Singer P, Hogan MC, Cattran DC, Barisoni L, Gipson DS, Nephrotic Syndrome Study Network. The longitudinal relationship between patient-reported outcomes and clinical characteristics among patients with focal segmental glomerulosclerosis in the Nephrotic Syndrome Study Network. Clin Kidney J. 2019;13:597-606. doi: 10.1093/ckj/sfz092. PMID:32905199; PMCID: PMC7467600.

Zee J, Mansfield S, Mariani LH, Gillespie BW. Using All Longitudinal Data to Define Time to Specified Percentages of Estimated GFR Decline: A Simulation Study. Am J Kidney Dis. 2018;73:82-9. doi: 10.1053/j.ajkd.2018.07.009.PMID: 30249420;PMCID: PMC6309673.

Troost JP, Gipson DS, Carlozzi NE, Reeve BB, Nachman PH, Gbadegesin R, Wang J, Modersitzki F, Massengill S, Mahan JD, Liu Y, Trachtman H, Herreshoff EG, DeWalt DA, Selewski DT. Using PROMIS® to create clinically meaningful profiles of nephrotic syndrome patients. Health Psychol. 2019;38: 410-21. doi: 10.1037/hea0000679. PMID: 31045424; PMCID: PMC6499490. 

Gillies CE, Putler R, Menon R, Otto E, Yasutake K, Nair V, Hoover P, Lieb D, Li S, Eddy S, Fermin D, McNulty MT; Nephrotic Syndrome Study Network (NEPTUNE), Hacohen N, Kiryluk K, Kretzler M, Wen X, Sampson MG. An eQTL Landscape of Kidney Tissue in Human Nephrotic Syndrome. Am J Hum Genet. 2018;103:232-44. doi: 10.1016/j.ajhg.2018.07.004. PMID: 30057032; PMCID: PMC6081280. 

Troost JP, Trachtman H, Nachman PH, Kretzler M, Spino C, Komers R, Tuller S, Perumal K, Massengill SF, Kamil ES, Oh G, Selewski DT, Gipson P, Gipson DS. An Outcomes-Based Definition of Proteinuria Remission in Focal Segmental Glomerulosclerosis. Clin J Am Soc Nephrol. 2017;13:414-21. doi: 10.2215/CJN.04780517. PMID: 29167190; PMCID: PMC5967666. 

Hommos MS, Zeng C, Liu Z, Troost JP, Rosenberg AZ, Palmer M, Kremers WK, Cornell LD, Fervenza FC, Barisoni L, Rule AD. Global glomerulosclerosis with nephrotic syndrome; the clinical importance of age adjustment. Kidney Int. 2017;93:1175-85. doi: 10.1016/j.kint.2017.09.028. PMID: 29273332; PMCID: PMC5911429. 

Mariani LH, Martini S, Barisoni L, Canetta PA, Troost JP, Hodgin JB, Palmer M, Rosenberg AZ, Lemley KV, Chien HP, Zee J, Smith A, Appel GB, Trachtman H, Hewitt SM, Kretzler M, Bagnasco SM. Interstitial fibrosis scored on whole-slide digital imaging of kidney biopsies is a predictor of outcome in proteinuric glomerulopathies. Nephrol Dial Transplant. 2017;33:1-9. doi: 10.1093/ndt/gfw443; PMID: 28339906; PMCID: PMC5837529. 

Tao J, Mariani L, Eddy S, Maecker H, Kambham N, Mehta K, Hartman J, Wang W, Kretzler M, Lafayette RA. JAK-STAT signaling is activated in the kidney and peripheral blood cells of patients with focal segmental glomerulosclerosis. Kidney Int. 2018;94:795-808. doi: 10.1016/j.kint.2018.05.022. PMID: 30093081; PMCID: PMC6744284. 

Grayson PC, Eddy S, Taroni JN, Lightfoot YL, Mariani L, Parikh H, Lindenmeyer MT, Ju W, Greene CS, Godfrey B, Cohen CD, Krischer J, Kretzler M, Merkel PA; Vasculitis Clinical Research Consortium, the European Renal cDNA Bank cohort, and the Nephrotic Syndrome Study Network. Metabolic pathways and immunometabolism in rare kidney diseases. Ann Rheum Dis. 2018;77:1226-33. doi: 10.1136/annrheumdis-2017-212935. PMID: 29724730; PMCID: PMC6045442. 

Miyata KN, Nast CC, Dai T, Dukkipati R, LaPage JA, Troost JP, Schurgers LJ, Kretzler M, Adler SG. Renal matrix Gla protein expression increases progressively with CKD and predicts renal outcome. Exp Mol Pathol. 2018;105:120-9. doi: 10.1016/j.yexmp.2018.07.001. PMID: 29981754; PMCID: PMC6167754. 

Zee J, Hodgin JB, Mariani LH, Gaut JP, Palmer MB, Bagnasco SM, Rosenberg AZ, Hewitt SM, Holzman LB, Gillespie BW, Barisoni L. Reproducibility and Feasibility of Strategies for Morphologic Assessment of Renal Biopsies Using the Nephrotic Syndrome Study Network Digital Pathology Scoring System. Arch Pathol Lab Med. 2018;142:613-25. doi: 10.5858/arpa.2017-0181-OA. PMID: 29457738;PMCID: PMC5946059.

Debiec H, Dossier C, Letouzé E, Gillies CE, Vivarelli M, Putler RK, Ars E, Jacqz-Aigrain E, Elie V, Colucci M, Debette S, Amouyel P, Elalaoui SC, Sefiani A, Dubois V, Simon T, Kretzler M, Ballarin J, Emma F, Sampson MG, Deschênes G, Ronco P. Transethnic, Genome-Wide Analysis Reveals Immune-Related Risk Alleles and Phenotypic Correlates in Pediatric Steroid-Sensitive Nephrotic Syndrome. J Am Soc Nephrol. 2018;29:2000-13. doi: 10.1681/ASN.2017111185. PMID: 29903748; PMCID: PMC6050942. 

Barisoni L, Hodgin JB. Digital pathology in nephrology clinical trials, research, and pathology practice. Curr Opin Nephrol Hypertens. 2017 Nov;26(6):450-459. doi: 10.1097/MNH.0000000000000360. PMID: 28858910; PMCID: PMC5955389.

Sharma R, Waller AP, Agrawal S, Wolfgang KJ, Luu H, Shahzad K, Isermann B, Smoyer WE, Nieman MT, Kerlin BA. Thrombin-Induced Podocyte Injury Is Protease-Activated Receptor Dependent. J Am Soc Nephrol. 2017 Sep;28(9):2618-2630. doi: 10.1681/ASN.2016070789. Epub 2017 Apr 19.

Ng DK, Robertson CC, Woroniecki RP, Limou S, Gillies CE, Reidy KJ, Winkler CA, Hingorani S, Gibson KL, Hjorten R, Sethna CB, Kopp JB, Moxey-Mims M, Furth SL, Warady BA, Kretzler M, Sedor JR, Kaskel FJ, Sampson MG. APOL1-associated glomerular disease among African-American children: a collaboration of the Chronic Kidney Disease in Children (CKiD) and Nephrotic Syndrome Study Network (NEPTUNE) cohorts. Nephrol Dial Transplant. 2016;32:983-90. doi: 10.1093/ndt/gfw061. PMID: 27190333; PMCID: PMC5837652.

Sethna CB, Meyers KEC, Mariani LH, Psoter KJ, Gadegbeku CA, Gibson KL, Srivastava T, Kretzler M, Brady TM. Blood Pressure and Visit-to-Visit Blood Pressure Variability Among Individuals With Primary Proteinuric Glomerulopathies. Hypertension. 2017;70:315-23. doi: 10.1161/HYPERTENSIONAHA.117.09475. PMID: 28652469; PMCID: PMC5518633.

Barisoni L, Gimpel C, Kain R, Laurinavicius A, Bueno G, Caihong Z, Zhihong L, Schaefer F, Kretzler M, Holzman LB, Hewitt SM. Digital pathology imaging as a novel platform for standardization and globalization of quantitative nephropathology. Clin Kidney J. 2017;10:176-87. doi: 10.1093/ckj/sfw129; PMID: 28584625; PMCID: PMC5455257.

Crawford BD, Gillies CE, Robertson CC, Kretzler M, Otto EA, Vega-Warner V, Sampson MG. Evaluating Mendelian nephrotic syndrome genes for evidence for risk alleles or oligogenicity that explain heritability. Pediatr Nephrol. 2017;32:467-476. doi:10.1007/s00467-016-3513-3. PMID: 27766458; PMCID: PMC5483602. 

Beanlands H, Maione M, Poulton C, Herreshoff E, Hladunewich MA, Hailperin M, Modes MM, An L, Nunes JW, Trachtman H, Nachman P, Gipson DS. Learning to live with nephrotic syndrome: experiences of adult patients and parents of children with nephrotic syndrome. Nephrol Dial Transplant. 2017;32 (suppl_1): i98-i105. doi: 10.1093/ndt/gfw344. PMID: 28391342; PMCID: PMC5837224. 

Hladunewich MA, Beanlands H, Herreshoff E, Troost JP, Maione M, Trachtman H, Poulton C, Nachman P, Modes MM, Hailperin M, Pitter R, Gipson DS. Provider perspectives on treatment decision-making in nephrotic syndrome. Nephrol Dial Transplant. 2017;32 (suppl_1): i106-i14. doi: 10.1093/ndt/gfw309. PMID: 28391336; PMCID: PMC5837354. 

Haas ME, Levenson AE, Sun X, Liao WH, Rutkowski JM, de Ferranti SD, Schumacher VA, Scherer PE, Salant DJ, Biddinger SB. The Role of Proprotein Convertase Subtilisin/Kexin Type 9 in Nephrotic Syndrome-Associated Hypercholesterolemia. Circulation. 2016 Jul 5;134(1):61-72. doi: 10.1161/CIRCULATIONAHA.115.020912. PMID: 27358438; PMCID: PMC5345853. 

Rosenberg AZ, Palmer M, Merlino L, Troost JP, Gasim A, Bagnasco S, Avila-Casado C, Johnstone D, Hodgin JB, Conway C, Gillespie BW, Nast CC, Barisoni L, Hewitt SM. The Application of Digital Pathology to Improve Accuracy in Glomerular Enumeration in Renal Biopsies. PLoS One. 2016 Jun 16;11(6):e0156441. doi: 10.1371/journal.pone.0156441. PMID: 27310011; PMCID: PMC4911144.

Gipson DS, Troost JP, Lafayette RA, Hladunewich MA, Trachtman H, Gadegbeku CA, Sedor JR, Holzman LB, Moxey-Mims MM, Perumal K, Kaskel FJ, Nelson PJ, Tuttle KR, Bagnasco SM, Hogan MC, Dell KM, Appel GB, Lieske JC, Ilori TO, Sethna CB, Fervenza FC, Hogan SL, Nachman PH, Rosenberg AZ, Greenbaum LA, Meyers KE, Hewitt SM, Choi MJ, Kopp JB, Zhdanova O, Hodgin JB, Johnstone DB, Adler SG, Avila-Casado C, Neu AM, Hingorani SR, Lemley KV, Nast CC, Brady TM, Barisoni-Thomas L, Fornoni A, Jennette JC, Cattran DC, Palmer MB, Gibson KL, Reich HN, Mokrzycki MH, Sambandam KK, Zilleruelo GE, Licht C, Sampson MG, Song P, Mariani LH, Kretzler M. Complete Remission in the Nephrotic Syndrome Study Network. Clin J Am Soc Nephrol. 2016;11:81-9. doi: 10.2215/CJN.02560315; PMID: 26656320; PMCID: PMC4702222.

Sampson MG, Robertson CC, Martini S, Mariani LH, Lemley KV, Gillies CE, Otto EA, Kopp JB, Randolph A, Vega-Warner V, Eichinger F, Nair V, Gipson DS, Cattran DC, Johnstone DB, O'Toole JF, Bagnasco SM, Song PX, Barisoni L, Troost JP, Kretzler M, Sedor JR; Nephrotic Syndrome Study Network. Integrative Genomics Identifies Novel Associations with APOL1 Risk Genotypes in Black NEPTUNE Subjects. J Am Soc Nephrol. 2016;27:814-23. doi: 10.1681/ASN.2014111131. PMID: 26150607; PMCID: PMC4769193. 

Pedigo CE, Ducasa GM, Leclercq F, Sloan A, Mitrofanova A, Hashmi T, Molina-David J, Ge M, Lassenius MI, Forsblom C, Lehto M, Groop PH, Kretzler M, Eddy S, Martini S, Reich H, Wahl P, Ghiggeri G, Faul C, Burke GW 3rd, Kretz O, Huber TB, Mendez AJ, Merscher S, Fornoni A. Local TNF causes NFATc1-dependent cholesterol-mediated podocyte injury. J Clin Invest. 2016;126:3336-50. doi:10.1172/JCI85939. PMID: 27482889; PMCID: PMC5004940. 

Lemley KV, Bagnasco SM, Nast CC, Barisoni L, Conway CM, Hewitt SM, Song PX. Morphometry Predicts Early GFR Change in Primary Proteinuric Glomerulopathies: A Longitudinal Cohort Study Using Generalized Estimating Equations. PLoS One. 2016; 11: e0157148. doi: 10.1371/journal.pone.0157148. PMID: 27285824; PMCID: PMC4902229. 

Barisoni L, Troost JP, Nast C, Bagnasco S, Avila-Casado C, Hodgin J, Palmer M, Rosenberg A, Gasim A, Liensziewski C, Merlino L, Chien HP, Chang A, Meehan SM, Gaut J, Song P, Holzman L, Gibson D, Kretzler M, Gillespie BW, Hewitt SM. Reproducibility of the NEPTUNE descriptor-based scoring system on whole-slide images and histologic and ultrastructural digital images. Mod Pathol. 2016;29:671-84. doi: 10.1038/modpathol.2016.58. PMID: 27102348; PMCID: PMC5515468. 

Gillies CE, Otto EA, Vega-Warner V, Robertson CC, Sanna-Cherchi S, Gharavi A, Crawford B, Bhimma R, Winkler C; Nephrotic Syndrome Study Network (NEPTUNE); C-PROBE Investigator Group of the Michigan Kidney Translational Core Center, Kang HM, Sampson MG. tarSVM: Improving the accuracy of variant calls derived from microfluidic PCR-based targeted next generation sequencing using a support vector machine. BMC Bioinformatics. 2016;17:233. doi: 10.1186/s12859-016-1108-4. PMID: 27287006; PMCID: PMC4902911. 

Hogan MC, Reich HN, Nelson PJ, Adler SG, Cattran DC, Appel GB, Gipson DS, Kretzler M, Troost JP, Lieske JC. The relatively poor correlation between random and 24-hour urine protein excretion in patients with biopsy-proven glomerular diseases. Kidney Int. 2016;90:1080-9. doi: 10.1016/j.kint.2016.06.020. PMID: 27528553; PMCID: PMC5065749. 

Sampson MG, Gillies CE, Robertson CC, Crawford B, Vega-Warner V, Otto EA, Kretzler M, Kang HM. Using Population Genetics to Interrogate the Monogenic Nephrotic Syndrome Diagnosis in a Case Cohort. J Am Soc Nephrol. 2016;27:1970-83. doi: 10.1681/ASN.2015050504. PMID: 26534921; PMCID: PMC4926977. 

Kerlin BA, Waller AP, Sharma R, Chanley MA, Nieman MT, Smoyer WE. Disease Severity Correlates with Thrombotic Capacity in Experimental Nephrotic Syndrome. J Am Soc Nephrol. 2015 Dec;26(12):3009-19. doi: 10.1681/ASN.2014111097. Epub 2015 Apr 8.

Spinale JM, Mariani LH, Kapoor S, Zhang J, Weyant R, Song PX, Wong HN, Troost JP, Gadegbeku CA, Gipson DS, Kretzler M, Nihalani D, Holzman LB; Nephrotic Syndrome Study Network. A reassessment of soluble urokinase-type plasminogen activator receptor in glomerular disease. Kidney Int. 2015;87:564–74. doi:10.1038/ki.2014.346. PMID: 25354239;PMCID:PMC4344842.

Sampson MG, Hodgin JB, Kretzler M. Defining nephrotic syndrome from an integrative genomics perspective. Pediatr Nephrol. 2015;30:51-63; quiz 59. doi: 10.1007/s00467-014-2857-9. PMID: 24890338;PMCID: PMC4241380.

Nast CC, Lemley KV, Hodgin JB, Bagnasco S, Avila-Casado C, Hewitt SM, Barisoni L. Morphology in the Digital Age: Integrating High-Resolution Description of Structural Alterations With Phenotypes and Genotypes. Semin Nephrol. 2015;35:266-78. doi: 10.1016/j.semnephrol.2015.04.006. PMID: 26215864;PMCID: PMC4764351.

Hogan MC, Lieske JC, Lienczewski CC, Nesbitt LL, Wickman LT, Heyer CM, Harris PC, Ward CJ, Sundsbak JL, Manganelli L, Ju W, Kopp JB, Nelson PJ, Adler SG, Reich HN, Holzmann LB, Kretzler M, Bitzer M. Strategy and rationale for urine collection protocols employed in the NEPTUNE study. BMC Nephrol. 2015;16:190. doi: 10.1186/s12882-015-0185-3; PMID: 26577187; PMCID: PMC4650313.

Ju W, Nair V, Smith S, Zhu L, Shedden K, Song PXK, Mariani LH, Eichinger FH, Berthier CC, Randolph A, Lai JY, Zhou Y, Hawkins JJ, Bitzer M, Sampson MG, Thier M, Solier C, Duran-Pacheco GC, Duchateau-Nguyen G, Essioux L, Schott B, Formentini I, Magnone MC, Bobadilla M, Cohen CD, Bagnasco SM, Barisoni L, Lv J, Zhang H, Wang HY, Brosius FC, Gadegbeku CA, Kretzler M; ERCB, C-PROBE, NEPTUNE, and PKU-IgAN Consortium. Tissue transcriptome-driven identification of epidermal growth factor as a chronic kidney disease biomarker. Sci Transl Med. 2015,doi: 10.1126/scitranslmed.aac7071.PMID:26631632; PMCID: PMC4861144.

Moeller S, Canetta PA, Taylor AK, Arguelles-Grande C, Snyder H, Green PH, Kiryluk K, Alaedini A. Lack of serologic evidence to link IgA nephropathy with celiac disease or immune reactivity to gluten. PLoS One. 2014 Apr 14;9(4):e94677. doi: 10.1371/journal.pone.0094677. PMID: 24732864; PMCID: PMC3986214.

Canetta PA, Kiryluk K, Appel GB. Glomerular diseases: emerging tests and therapies for IgAnephropathy. Clin J AmSoc Nephrol. 2014;9:617-25; doi: 10.2215/CJN.07260713. PMID: 24071652; PMCID: PMC3944769.

Barisoni L, Nast CC, Jennette JC, Hodgin JB, Herzenberg AM, Lemley KV, Conway CM, Kopp JB, Kretzler M, Lienczewski C, Avila-Casado C, Bagnasco S, Sethi S, Tomaszewski J, Gasim AH, Hewitt SM. Digital pathology evaluation in the multicenter Nephrotic Syndrome Study Network (NEPTUNE). Clin J Am Soc Nephrol. 2013 Aug;8(8):1449-59. doi: 10.2215/CJN.08370812. Epub 2013 Feb 7. PMID: 23393107; PMCID: PMC3731905.

Gadegbeku CA, Gipson DS, Holzman LB, Ojo AO, Song PX, Barisoni L, Sampson MG, Kopp JB, Lemley KV, Nelson PJ, Lienczewski CC, Adler SG, Appel GB, Cattran DC, Choi MJ, Contreras G, Dell KM, Fervenza FC, Gibson KL, Greenbaum LA, Hernandez JD, Hewitt SM, Hingorani SR, Hladunewich M, Hogan MC, Hogan SL, Kaskel FJ, Lieske JC, Meyers KE, Nachman PH, Nast CC, Neu AM, Reich HN, Sedor JR, Sethna CB, Trachtman H, Tuttle KR, Zhdanova O, Zilleruelo GE, Kretzler M. Design of the Nephrotic Syndrome Study Network (NEPTUNE) to evaluate primary glomerular nephropathy by a multi-disciplinary approach. Kidney Int. 2013;83:749-56. doi:10.1038/ki.2012.428. PMID: 23325076; PMCID: PMC3612359.

Sampson MG, Jüppner H. Genes, Exomes, Genomes, Copy Number: What is Their Future in Pediatric Renal Disease. Curr Pediatr Rep. 2013;1:52-9. doi:10.1007/s40124-012-0001-5. PMID: 27642543; PMCID: PMC5022771. 

Holmes BM, Hollander S, Sacharow S. Perspectives and Insights Into Phenylketonuria: Patient Narratives About the Early Years Following Newborn Screening. Am J Med Genet C Semin Med Genet. 2024 Sep 17:e32110. doi: 10.1002/ajmg.c.32110. Epub ahead of print. PMID: 39285733.

Phenylketonuria (PKU) is a genetic metabolic disorder that increases the body's levels of the amino acid phenylalanine, which can build up to harmful levels if left untreated. Newborn screening for PKU began in 1963. Over the following decades, knowledge and treatment recommendations have evolved, with individual and family experiences varying widely.

In this essay, authors share patient stories about the early years following newborn screening for PKU. The team recorded interviews with patients born in the first 25 years after newborn screening for PKU began. While some of these patients were actively followed in the PKU clinic, others had been out of the clinic for many years.

The resulting stories describe different individual experiences, including diet discontinuation in childhood, changing treatment guidelines, and new treatments that have become available. Authors note that these stories highlight the challenges of the early years of newborn screening, when best practices were being discovered through trial and error.

Christ SE, Arnold G, Lichter-Konecki U, Berry GT, Grange DK, Harding CO, Jurecki E, Levy H, Longo N, Morotti H, Sacharow S, Thomas J, White DA. Initial results from the PHEFREE longitudinal natural history study: Cross-sectional observations in a cohort of individuals with phenylalanine hydroxylase (PAH) deficiency. Mol Genet Metab. 2024 Jul 22;143(1-2):108541. doi: 10.1016/j.ymgme.2024.108541. Epub ahead of print. PMID: 39059270.

Phenylalanine hydroxylase (PAH) deficiency, also known as phenylketonuria (PKU), is a genetic metabolic disorder that increases the body's levels of the amino acid phenylalanine. The last large-scale natural history study of individuals with PKU in the United States was conducted over 50 years ago. Since then, there have been significant changes in treatment recommendations and options.

In this study, researchers report initial data from the PHEFREE natural history study of individuals with PKU. The team describes the structure and methods of the study, including data from 73 participants.

Authors note that this study could help validate new neurocognitive tools for assessing individuals with PKU, as well as evaluating the long-term effects of changes in metabolic control on patient outcomes.

Martinez M, Harding CO, Schwank G, Thöny B. State-of-the-art 2023 on gene therapy for phenylketonuria. J Inherit Metab Dis. 2024 Jan;47(1):80-92. doi: 10.1002/jimd.12651. Epub 2023 Aug 3. PMID: 37401651; PMCID: PMC10764640

Phenylketonuria (PKU) is a genetic metabolic disorder that increases the body's levels of the amino acid phenylalanine, which can build up to harmful levels if left untreated. Patients with PKU are treated with dietary therapy. However, these dietary restrictions are complicated and often difficult to follow, highlighting the need for new therapies and ultimately a cure.

In this review paper, researchers summarize, compare, and evaluate state-of-the-art gene therapy approaches for PKU. Methods include recombinant viral and non-viral vector delivery; gene addition; genome, gene, or base editing; and gene insertion or replacement. A list of current and planned clinical trials for PKU gene therapy is also included.

Authors note that this review can help advance scientific understanding and efficacy testing, paving the way for safe and efficient therapies for patients with PKU.

van Spronsen FJ, Blau N, Harding C, Burlina A, Longo N, Bosch AM. Phenylketonuria. Nat Rev Dis Primers. 2021 May 20;7(1):36. doi: 10.1038/s41572-021-00267-0.

Phenylketonuria (PKU; also known as phenylalanine hydroxylase (PAH) deficiency) is an autosomal recessive disorder of phenylalanine metabolism, in which especially high phenylalanine concentrations cause brain dysfunction. If untreated, this brain dysfunction results in severe intellectual disability, epilepsy and behavioural problems. Even though PAH deficiency is the most common defect of amino acid metabolism in humans, brain dysfunction in individuals with PKU is still not well understood and further research is needed to facilitate development of pathophysiology-driven treatments.

Manzoni F, Salvatici E, Burlina A, Andrews A, Pasquali M, Longo N. Retrospective analysis of 19 patients with 6-Pyruvoyl Tetrahydropterin Synthase Deficiency: Prolactin levels inversely correlate with growth. Mol Genet Metab. 2020 Dec;131(4):380-389. doi: 10.1016/j.ymgme.2020.11.004. Epub 2020 Nov 18. PMID: 33234470; PMCID: PMC7749858.

Pyruvoyl Tetrahydropterin Synthase (PTPS) Deficiency is the most common form of BH4 (tetrahydrobiopterin) deficiency resulting in hyperphenylalaninemia. It can have variable clinical severity and there is limited information on the clinical presentation, natural history and effectiveness of newborn screening for this condition.

Harding CO. Prospects for Cell-Directed Curative Therapy of Phenylketonuria (PKU). Mol Front J. 2019 Dec;3(2):110-121. doi: 10.1142/s2529732519400145. Epub 2019 Dec 12. PMID: 32524084; PMCID: PMC7286632.

This review discusses the potential for and the limitations of permanently curative cell-directed treatment of PKU (phenylketonuria, also known as phenylalanine hydroxylase (PAH) deficiency), including liver-directed gene therapy and gene editing, if initiated during early infancy.

Levy C, Naik H, Overbey J, Hedstrom K, Wang K, McDonough C, Freeman M, Keel SB, Erwin AL, Dickey AK, Leaf RK, Quigley J, Mazepa M, Wang B, Phillips J, Parker C, McGuire B, Kazamel M, Bonkovsky H, Rudnick S, Anderson KE, Moghe A, Thapar M, Saberi B, Wheeden K, Desnick R, Balwani M; Porphyrias Consortium of the Rare Diseases Clinical Research Network. Liver involvement in a large cohort of patients with erythropoietic protoporphyria or X-linked protoporphyria. Hepatol Commun. 2025 Feb 19;9(3):e0657. doi: 10.1097/HC9.0000000000000657. PMID: 39969427; PMCID: PMC11841850.

Dickey AK, Leaf RK. Givosiran: a targeted treatment for acute intermittent porphyria. Hematology Am Soc Hematol Educ Program. 2024 Dec 6;2024(1):426-433. doi: 10.1182/hematology.2024000663.

Leaf RK, Dickey AK. Porphyria cutanea tarda: a unique iron-related disorder. Hematology Am Soc Hematol Educ Program. 2024 Dec 6;2024(1):450-456. doi: 10.1182/hematology.2024000664.

Belot A, Puy H, Hamza I, Bonkovsky HL. Update on heme biosynthesis, tissue-specific regulation, heme transport, relation to iron metabolism and cellular energy. Liver Int. 2024 Sep;44(9):2235-2250. doi: 10.1111/liv.15965. Epub 2024 Jun 18.

Leaf RK, Naik H, Jiang PY, Elmariah SB, Hodges P, Mead J, Trinidad J, Saberi B, Tran B, Valiante S, Mernick F, Leaf DE, Anderson KE, Dickey AK. Afamelanotide for Treatment of the Protoporphyrias: Impact on Quality of Life and Laboratory Parameters in a US Cohort. Life (Basel). 2024 May 28;14(6):689. doi: 10.3390/life14060689.

Balwani M, Keel S, Meissner P, Sonderup M, Stein P, Yasuda M. Case-based discussion of the acute hepatic porphyrias: Updates on pathogenesis, diagnosis and management. Liver Int. 2024 Apr 15. doi: 10.1111/liv.15924. Online ahead of print.

Dickey AK, Berkovich J, Leaf RK, Jiang PY, Lopez-Galmiche G, Rebeiz L, Wheeden K, Kochevar I, Savage W, Zhao S, Campisi E, Heo SY, Trueb J, LaRochelle EPM, Rogers J, Banks A, Chang JK. Observational pilot study of multi-wavelength wearable light dosimetry for erythropoietic protoporphyria. Int J Dermatol. 2024 Nov;63(11):1584-1591. doi: 10.1111/ijd.17166. Epub 2024 Apr 11. PMID: 38602089; PMCID: PMC11467130.

Erythropoietic protoporphyria (EPP) is a metabolic disorder characterized by the buildup of protoporphyrin, which is a light-sensitive substance. Individuals with EPP often experience severe pain from light exposure.  

In this study, researchers developed a wearable light dosimeter both to improve quality of life in patients with EPP and to capture light exposure data for future EPP clinical trials. The dosimeters work by continuously capturing light doses of UVA, blue, and red wavelengths. The team tested the devices among five individuals with EPP, each wearing two light dosimeters—one as a watch, and one as a shirt clip—for three weeks. 

Results show that wearable blue light dosimetry worn as a wristband is a promising method for measuring light exposure, as well as predicting and preventing symptoms in EPP.

Yasuda M, Lee S, Gan L, Bergonia HA, Desnick RJ, Phillips JD. Cimetidine Does Not Inhibit 5-Aminolevulinic Acid Synthase or Heme Oxygenase Activity: Implications for Treatment of Acute Intermittent Porphyria and Erythropoietic Protoporphyria. Biomolecules. 2023 Dec 24;14(1):27. doi: 10.3390/biom14010027.

Yasuda M, Keel S, Balwani M. RNA interference therapy in acute hepatic porphyrias. Blood. 2023 Nov 9;142(19):1589-1599. doi: 10.1182/blood.2022018662.

Levy C, Dickey AK, Wang B, Thapar M, Naik H, Keel SB, Saberi B, Beaven SW, Rudnick SR, Elmariah SB, Erwin AL, Goddu RJ, Hedstrom K, Leaf RK, Kazamel M, Mazepa M, Philpotts LL, Quigley J, Raef H, Ungar J, Anderson KE, Balwani M; Porphyrias Consortium of the Rare Diseases Clinical Network. Evidence based consensus guidelines for diagnosis and management of Protoporphyria-Related liver dysfunction in erythropoietic protoporphyria and X-Linked protoporphyria. Hepatology. 2023 Jul 27. doi: 10.1097/HEP.0000000000000546. Epub ahead of print. PMID: 37505211

Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are inherited, metabolic disorders characterized by the buildup of protoporphyrins (substances that bind metals to form complexes, such as the iron found in red blood cells). In addition to phototoxicity (severe pain during light exposure), patients with EPP and XLP often experience liver dysfunction. However, there is a lack of published information on the management of liver disease in these patients.

In this study, researchers established evidence-based guidelines for the diagnosis and management of liver disease in protoporphyrias. A group of 15 clinicians from the Porphyrias Consortium—with expertise in porphyrias and hepatology, hematology, and genetics—conducted a systematic literature review to develop new recommendations.

The resulting guidelines address important clinical topics in protoporphyrias and liver disease, including interventions and therapies based on severity. Authors note that these guidelines may not only improve patient care, but also inspire new collaborative research.

Leaf RK, Dickey AK. How I treat erythropoietic protoporphyria and X-linked protoporphyria. Blood. 2023 Jun 15;141(24):2921-2931. doi: 10.1182/blood.2022018688.

Applequist J, Burroughs C, Merkel PA, Rothenberg M, Trapnell B, Desnick R, Sahin M, Krischer J. Direct-to-Consumer Recruitment Methods via Traditional and Social Media to Aid in Research Accrual for Clinical Trials for Rare Diseases: Comparative Analysis Study. J Med Internet Res. 2023 Mar 14;25:e39262. doi: 10.2196/39262.

Wang B, Bonkovsky HL, Lim JK, Balwani M. AGA Clinical Practice Update on Diagnosis and Management of Acute Hepatic Porphyrias: Expert Review. Gastroenterology. 2023 Mar;164(3):484-491. doi: 10.1053/j.gastro.2022.11.034. Epub 2023 Jan 13. PMID: 36642627.

Bonkovsky HL, Rudnick SP, Ma CD, Overbey JR, Wang K, Faust D, Hallberg C, Hedstrom K, Naik H, Moghe A, Anderson KE. Ledipasvir/Sofosbuvir Is Effective as Sole Treatment of Porphyria Cutanea Tarda with Chronic Hepatitis C. Dig Dis Sci. 2023 Feb 22:1–9. doi: 10.1007/s10620-023-07859-8. Epub ahead of print. PMID: 36811718; PMCID: PMC9945827.

Kazamel M, Pischik E, Desnick RJ. Pain in acute hepatic porphyrias: Updates on pathophysiology and management. Front Neurol. 2022 Nov 21;13:1004125. doi: 10.3389/fneur.2022.1004125. PMID: 36479055; PMCID: PMC9719963.

Balwani M, Naik H, Overbey JR, Bonkovsky HL, Bissell DM, Wang B, Phillips JD, Desnick RJ, Anderson KE. A pilot study of oral iron therapy in erythropoietic protoporphyria and X-linked protoporphyria. Mol Genet Metab Rep. 2022 Nov 14;33:100939. doi: 10.1016/j.ymgmr.2022.100939. PMID: 36406817; PMCID: PMC9672425.

Ma CD, Bonkovsky HL. Elagolix is porphyrogenic and may induce porphyric attacks in patients with the acute hepatic porphyrias. Mol Genet Metab Rep. 2022 Sep 7;33:100915. doi: 10.1016/j.ymgmr.2022.100915. PMID: 36105850; PMCID: PMC9465260.

Ma CD, Bonkovsky HL. Eslicarbazepine acetate is porphyrogenic and should be used with caution in patients with the acute hepatic porphyrias. Front Pharmacol. 2022 Sep 6;13:953961. doi: 10.3389/fphar.2022.953961. PMID: 36147354; PMCID: PMC9485715.

Dickey AK, Naik H, Keel SB, Levy C, Beaven SW, Elmariah SB, Erwin AL, Goddu RJ, Hedstrom K, Leaf RK, Kazamel M, Mazepa M, Philpotts LL, Quigley J, Raef H, Rudnick SR, Saberi B, Thapar M, Ungar J, Wang B, Balwani M; Porphyrias Consortium of the Rare Diseases Clinical Research Network. Evidence-based consensus guidelines for the diagnosis and management of erythropoietic protoporphyria and X-linked protoporphyria. J Am Acad Dermatol. 2022 Aug 27:S0190-9622(22)02611-1. doi: 10.1016/j.jaad.2022.08.036. Epub ahead of print. PMID: 36041558.

Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are rare, inherited, metabolic disorders characterized by build-up of porphyrins. Porphyrins are substances that bind metals to form complexes, such as the iron found in red blood cells. The hallmark symptoms include phototoxicity (severe pain during light exposure) and photosensitivity (skin hyperreactivity to light). Due to the rarity of EPP and XLP, physicians often have limited expertise with these disorders, which can lead to delays in diagnosis. In this study, researchers developed evidence-based consensus guidelines for the diagnosis, monitoring, and management of EPP and XLP. First, the team conducted a systematic literature review. Next, they divided topics among subcommittees of experts to reach a consensus on guidelines. The new guidelines discuss biochemical and genetic testing for diagnosis, prevention of symptoms, management of acute phototoxicity, and pharmacologic (drug or medication) and non-pharmacologic treatment options. Researchers also discuss management, including the importance of ongoing monitoring, guidance on pregnancy and surgery, and the safety of other therapies. Authors note that these guidelines can aid in early diagnosis and management of these disorders.

Ma CD, Van Horn CG, Wan M, Bishop C, Bonkovsky HL. Assessment of porphyrogenicity of drugs and chemicals in selected hepatic cell culture models through a fluorescence-based screening assay. Pharmacol Res Perspect. 2022 Jun;10(3):e00951. doi: 10.1002/prp2.951. PMID: 35445802; PMCID: PMC9022196.

Acute hepatic porphyrias (AHPs)—including ALA dehydratase deficiency porphyria, acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria—are a subtype of porphyrias classified as having a hepatic (liver) origin. In patients with AHPs, some drugs and chemicals may trigger or exacerbate acute porphyric attacks. However, there is currently no standard model to assess and predict the likelihood of drugs and chemicals to induce these attacks. In this study, researchers aimed to develop a fluorescence-based in vitro assay for this purpose. The team studied four different hepatic cell culture models. They found that LMH cell cultures in multi-well plates are an inexpensive, robust, and simple system to predict the porphyrogenicity of compounds that may exacerbate the AHPs.

Farrell CP, Nicolas G, Desnick RJ, Parker CJ, Lamoril J, Gouya L, Karim Z, Tchernitchko D, Chan B, Puy H, Phillips JD. ABCB6 polymorphisms are not overly represented in patients with porphyria. Blood Adv.. 2022 Feb 8;6(3):760-766. doi: 10.1182/bloodadvances.2021005484. PMID: 34724702; PMCID: PMC8945301.

The porphyrias are a group of rare, inherited, metabolic disorders characterized by elevated porphyrin or porphyrin precursor levels that are caused by deficiencies in one of eight enzymes necessary for heme production. Recent studies have suggested that the genotype of the transporter protein ABCB6 contributes to the porphyria phenotype. To address this proposed link, researchers analyzed data from a large cohort of patients with acute hepatic porphyria and erythropoietic protoporphyria. Results showed that the ABCB6 genotype did not correlate with disease severity. Authors conclude that genotyping of ABCB6 in patients with acute hepatic porphyria and erythropoietic protoporphyria is not warranted.

Erwin AL, Balwani M. Porphyrias in the Age of Targeted Therapies. Diagnostics (Basel). 2021 Sep 29;11(10):1795. doi: 10.3390/diagnostics11101795.

Rondelli CM, Perfetto M, Danoff A, Bergonia H, Gillis S, O'Neill L, Jackson L, Nicolas G, Puy H, West R, Phillips JD, Yien YY. The ubiquitous mitochondrial protein unfoldase CLPX regulates erythroid heme synthesis by control of iron utilization and heme synthesis enzyme activation and turnover. J Biol Chem. 2021 Aug;297(2):100972. doi: 10.1016/j.jbc.2021.100972. Epub 2021 Jul 16.

Porphyrias are rare disorders caused by an abnormality in the heme production process. Heme enables our blood cells to carry oxygen and helps break down chemical compounds in the liver. Erythropoietic protoporphyria patients experience a build-up of protoporphyrin in the bone marrow, red blood cells, blood plasma, skin, and eventually liver. This buildup can cause extreme sensitivity to sunlight, liver damage, and other problems. The protein CLPX (caseinolytic mitochondrial matrix peptidase chaperone subunit X) promotes heme synthesis. Researchers seeking to better understand the ways CLPX regulates heme synthesis in red blood cells undertook genomic studies in yeast, zebrafish, and mouse models. They found that CLPX mutations may cause anemia and porphyria via dysregulation of ALAS, FECH, and PPOX activities, as well as of iron metabolism. They conclude that unraveling the complexities of CLPX function will be key for designing therapies for these rare diseases.

Wang B. Novel treatment options for acute hepatic porphyrias. Curr Opin Gastroenterol. 2021 May 1;37(3):194-199. doi: 10.1097/MOG.0000000000000734.

Wang B. The acute hepatic porphyrias. Transl Gastroenterol Hepatol. 2021 Apr 5;6:24. doi: 10.21037/tgh-2020-01. eCollection 2021.

Dickey AK, Quick C, Ducamp S, Zhu Z, Feng YA, Naik H, Balwani M, Anderson KE, Lin X, Phillips JE, Rebeiz L, Bonkovsky HL, McGuire BM, Wang B, Chasman DI, Smoller JW, Fleming MD, Christiani DC. Evidence in the UK Biobank for the underdiagnosis of erythropoietic protoporphyria. Genet Med. 2021 Jan;23(1):140-148. doi: 10.1038/s41436-020-00951-8. Epub 2020 Sep 2.

In this study of genetic data from 50,000 participants in the UK Biobank, researchers found that the number of individuals with the genetic pairing that causes EPP was seven times higher than the number of individuals who had been diagnosed. The prevalance of EPP in the data set turned out to be 1 in 17,000 people. See blog post.

Lahiji AP, Anderson KE, Chan A, Simon A, Desnick RJ, Ramanujam VMS. 5-Aminolevulinate dehydratase porphyria: Update on hepatic 5-aminolevulinic acid synthase induction and long-term response to hemin. Mol Genet Metab. 2020 Dec;131(4):418-423. doi: 10.1016/j.ymgme.2020.10.011. Epub 2020 Oct 26.

Rudnick S, Bonkovsky HL. Editorial: hepatitis C and porphyria cutanea tarda in 2020. Aliment Pharmacol Ther. 2020 Jun;51(12):1432-1434. doi: 10.1111/apt.15728.

Gouya L, Ventura P, Balwani M, Bissell DM, Rees DC, Stölzel U, Phillips JD, Kauppinen R, Langendonk JG, Desnick RJ, Deybach JC, Bonkovsky HL, Parker C, Naik H, Badminton M, Stein PE, Minder E, Windyga J, Bruha R, Cappellini MD, Sardh E, Harper P, Sandberg S, Aarsand AK, Andersen J, Alegre F, Ivanova A, Talbi N, Chan A, Querbes W, Ko J, Penz C, Liu S, Lin T, Simon A, Anderson KE. EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks. Hepatology. 2020 May;71(5):1546-1558. doi: 10.1002/hep.30936. Epub 2019 Nov 7.

Saberi B, Naik H, Overbey JR, Erwin AL, Anderson KE, Bissell DM, Bonkovsky HL, Phillips JD, Wang B, K Singal A, M McGuire B, Desnick RJ, Balwani M. Hepatocellular Carcinoma in Acute Hepatic Porphyrias: Results from the Longitudinal Study of the U.S. Porphyrias Consortium. Hepatology. 2021 May;73(5):1736-1746. doi: 10.1002/hep.31460. Epub 2020 Dec 11. PMID: 32681675.

The acute hepatic porphyrias (AHP) are a family of rare genetic diseases that present with acute attacks, nausea, and vomiting which can last for several days. These disorders can also have chronic symptoms and an increased risk for long-term manifestations. The risk for hepatocellular carcinoma (HCC) is increased in patients with acute hepatic porphyrias. In order to characterize the symptoms, outcomes, and frequency of HCC in patients with AHP in the United States, researchers undertook a multicenter, longitudinal study. Among 327 patients with AHP, 5 (1.5%) were diagnosed with HCC. Cirrhosis was not present in AHP patients with HCC, unlike what is typically seen with other chronic liver diseases. Study authors recommend that patients with AHP should be screened for HCC beginning at age 50.

Applequist J, Burroughs C, Ramirez A Jr, Merkel PA, Rothenberg ME, Trapnell B, Desnick RJ, Sahin M, Krischer JP. A novel approach to conducting clinical trials in the community setting: utilizing patient-driven platforms and social media to drive web-based patient recruitment. BMC Med Res Methodol. 2020 Mar 13;20(1):58. doi: 10.1186/s12874-020-00926-y.

Naik H, Overbey JR, Montgomery GH, Winkel G, Balwani M, Anderson KE, Bissell DM, Bonkovsky HL, Phillips JD, Wang B, McGuire B, Keel S, Levy C, Erwin A, Desnick RJ. Evaluating the Patient-Reported Outcomes Measurement Information System scales in acute intermittent porphyria. Genet Med. 2020 Mar;22(3):590-597. doi: 10.1038/s41436-019-0683-y. Epub 2019 Nov 6.

Anderson KE. Acute hepatic porphyrias: Current diagnosis & management. Mol Genet Metab. 2019 Nov;128(3):219-227. doi: 10.1016/j.ymgme.2019.07.002. Epub 2019 Jul 5.

Chen B, Wang M, Gan L, Zhang B, Desnick RJ, Yasuda M. Characterization of the hepatic transcriptome following phenobarbital induction in mice with AIP. Mol Genet Metab. 2019 Nov;128(3):382-390. doi: 10.1016/j.ymgme.2018.12.010. Epub 2019 Jan 6.

Erwin AL, Desnick RJ. Congenital erythropoietic porphyria: Recent advances. Mol Genet Metab. 2019 Nov;128(3):288-297. doi: 10.1016/j.ymgme.2018.12.008. Epub 2018 Dec 27.

Balwani M. Erythropoietic Protoporphyria and X-Linked Protoporphyria: pathophysiology, genetics, clinical manifestations, and management. Mol Genet Metab. 2019 Nov;128(3):298-303. doi: 10.1016/j.ymgme.2019.01.020. Epub 2019 Jan 24.

Phillips JD. Heme biosynthesis and the porphyrias. Mol Genet Metab. 2019 Nov;128(3):164-177. doi: 10.1016/j.ymgme.2019.04.008. Epub 2019 Apr 22.

Chen B, Whatley S, Badminton M, Aarsand AK, Anderson KE, Bissell DM, Bonkovsky HL, Cappellini MD, Floderus Y, Friesema ECH, Gouya L, Harper P, Kauppinen R, Loskove Y, Martásek P, Phillips JD, Puy H, Sandberg S, Schmitt C, To-Figueras J, Weiss Y, Yasuda M, Deybach JC, Desnick RJ. International Porphyria Molecular Diagnostic Collaborative: an evidence-based database of verified pathogenic and benign variants for the porphyrias. Genet Med. 2019 Nov;21(11):2605-2613. doi: 10.1038/s41436-019-0537-7. Epub 2019 May 10.

Yasuda M, Desnick RJ. Murine models of the human porphyrias: Contributions toward understanding disease pathogenesis and the development of new therapies. Mol Genet Metab. 2019 Nov;128(3):332-341. doi: 10.1016/j.ymgme.2019.01.007. Epub 2019 Jan 18.

Bonkovsky HL, Dixon N, Rudnick S. Pathogenesis and clinical features of the acute hepatic porphyrias (AHPs). Mol Genet Metab. 2019 Nov;128(3):213-218. doi: 10.1016/j.ymgme.2019.03.002. Epub 2019 Mar 6.

Dixon N, Li T, Marion B, Faust D, Dozier S, Molina A, Rudnick S, Bonkovsky HL. Pilot study of mitochondrial bioenergetics in subjects with acute porphyrias. Mol Genet Metab. 2019 Nov;128(3):228-235. doi: 10.1016/j.ymgme.2019.05.010. Epub 2019 May 20.

Weiss Y, Chen B, Yasuda M, Nazarenko I, Anderson KE, Desnick RJ. Porphyria cutanea tarda and hepatoerythropoietic porphyria: Identification of 19 novel uroporphyrinogen III decarboxylase mutations. Mol Genet Metab. 2019 Nov;128(3):363-366. doi: 10.1016/j.ymgme.2018.11.013. Epub 2018 Nov 28.

Naik H, Shenbagam S, Go AM, Balwani M. Psychosocial issues in erythropoietic protoporphyria - the perspective of parents, children, and young adults: A qualitative study. Mol Genet Metab. 2019 Nov;128(3):314-319. doi: 10.1016/j.ymgme.2019.01.023. Epub 2019 Jan 26.

Yasuda M, Chen B, Desnick RJ. Recent advances on porphyria genetics: Inheritance, penetrance & molecular heterogeneity, including new modifying/causative genes. Mol Genet Metab. 2019 Nov;128(3):320-331. doi: 10.1016/j.ymgme.2018.11.012. Epub 2018 Nov 30.

Parker CJ, Desnick RJ, Bissel MD, Bloomer JR, Singal A, Gouya L, Puy H, Anderson KE, Balwani M, Phillips JD. Results of a pilot study of isoniazid in patients with erythropoietic protoporphyria. Mol Genet Metab. 2019 Nov;128(3):309-313. doi: 10.1016/j.ymgme.2019.07.017. Epub 2019 Jul 31.

Pulgar VM, Yasuda M, Gan L, Desnick RJ, Bonkovsky HL. Sex differences in vascular reactivity in mesenteric arteries from a mouse model of acute intermittent porphyria. Mol Genet Metab. 2019 Nov;128(3):376-381. doi: 10.1016/j.ymgme.2019.01.005. Epub 2019 Jan 7.

Phillips J, Farrell C, Wang Y, Singal AK, Anderson K, Balwani M, Bissell M, Bonkovsky H, Seay T, Paw B, Desnick R, Bloomer J. Strong correlation of ferrochelatase enzymatic activity with Mitoferrin-1 mRNA in lymphoblasts of patients with protoporphyria. Mol Genet Metab. 2019 Nov;128(3):391-395. doi: 10.1016/j.ymgme.2018.10.005. Epub 2018 Oct 22.

Yasuda M, Gan L, Chen B, Yu C, Zhang J, Gama-Sosa MA, Pollak DD, Berger S, Phillips JD, Edelmann W, Desnick RJ. Homozygous hydroxymethylbilane synthase knock-in mice provide pathogenic insights into the severe neurological impairments present in human homozygous dominant acute intermittent porphyria. Hum Mol Genet. 2019 Jun 1;28(11):1755-1767. doi: 10.1093/hmg/ddz003.

Moghe A, Ramanujam VMS, Phillips JD, Desnick RJ, Anderson KE. Harderoporphyria: Case of lifelong photosensitivity associated with compound heterozygous coproporphyrinogen oxidase (CPOX) mutations. Mol Genet Metab Rep. 2019 Feb 19;19:100457. doi: 10.1016/j.ymgmr.2019.100457. eCollection 2019 Jun.

Chen B, Solis-Villa C, Erwin AL, Balwani M, Nazarenko I, Phillips JD, Desnick RJ, Yasuda M. Identification and characterization of 40 novel hydroxymethylbilane synthase mutations that cause acute intermittent porphyria. J Inherit Metab Dis. 2019 Jan;42(1):186-194. doi: 10.1002/jimd.12040.

Maitra D, Bragazzi Cunha J, Elenbaas JS, Bonkovsky HL, Shavit JA, Omary MB. Porphyrin-Induced Protein Oxidation and Aggregation as a Mechanism of Porphyria-Associated Cell Injury. Cell Mol Gastroenterol Hepatol. 2019;8(4):535-548. doi: 10.1016/j.jcmgh.2019.06.006. Epub 2019 Jun 21.

Yien YY, Shi J, Chen C, Cheung JTM, Grillo AS, Shrestha R, Li L, Zhang X, Kafina MD, Kingsley PD, King MJ, Ablain J, Li H, Zon LI, Palis J, Burke MD, Bauer DE, Orkin SH, Koehler CM, Phillips JD, Kaplan J, Ward DM, Lodish HF, Paw BH. FAM210B is an erythropoietin target and regulates erythroid heme synthesis by controlling mitochondrial iron import and ferrochelatase activity. J Biol Chem. 2018 Dec 21;293(51):19797-19811. doi: 10.1074/jbc.RA118.002742. Epub 2018 Oct 26.

Wang B, Rudnick S, Cengia B, Bonkovsky HL. Acute Hepatic Porphyrias: Review and Recent Progress. Hepatol Commun. 2018 Dec 20;3(2):193-206. doi: 10.1002/hep4.1297. eCollection 2019 Feb.

Salameh H, Sarairah H, Rizwan M, Kuo YF, Anderson KE, Singal AK. Relapse of porphyria cutanea tarda after treatment with phlebotomy or 4-aminoquinoline antimalarials: a meta-analysis. Br J Dermatol. 2018 Dec;179(6):1351-1357. doi: 10.1111/bjd.16741. Epub 2018 Jul 26.

Lala SM, Naik H, Balwani M. Diagnostic Delay in Erythropoietic Protoporphyria. J Pediatr. 2018 Nov;202:320-323.e2. doi: 10.1016/j.jpeds.2018.06.001. Epub 2018 Jul 2.

Bung N, Roy A, Chen B, Das D, Pradhan M, Yasuda M, New MI, Desnick RJ, Bulusu G. Human hydroxymethylbilane synthase: Molecular dynamics of the pyrrole chain elongation identifies step-specific residues that cause AIP. Proc Natl Acad Sci U S A. 2018 Apr 24;115(17):E4071-E4080. doi: 10.1073/pnas.1719267115. Epub 2018 Apr 9.

Balwani M, Wang B, Anderson KE, Bloomer JR, Bissell DM, Bonkovsky HL, Phillips JD, Desnick RJ; Porphyrias Consortium of the Rare Diseases Clinical Research Network. Acute hepatic porphyrias: Recommendations for evaluation and long-term management. Hepatology. 2017 Oct;66(4):1314-1322. doi: 10.1002/hep.29313. Epub 2017 Sep 4.

Yien YY, Ducamp S, van der Vorm LN, Kardon JR, Manceau H, Kannengiesser C, Bergonia HA, Kafina MD, Karim Z, Gouya L, Baker TA, Puy H, Phillips JD, Nicolas G, Paw BH. Mutation in human CLPX elevates levels of δ-aminolevulinate synthase and protoporphyrin IX to promote erythropoietic protoporphyria. Proc Natl Acad Sci U S A. 2017 Sep 19;114(38):E8045-E8052. doi: 10.1073/pnas.1700632114. Epub 2017 Sep 5.

Balwani M, Naik H, Anderson KE, Bissell DM, Bloomer J, Bonkovsky HL, Phillips JD, Overbey JR, Wang B, Singal AK, Liu LU, Desnick RJ. Clinical, Biochemical, and Genetic Characterization of North American Patients With Erythropoietic Protoporphyria and X-linked Protoporphyria. JAMA Dermatol. 2017 Aug 1;153(8):789-796. doi: 10.1001/jamadermatol.2017.1557.

Singal AK, Venkata KVR, Jampana S, Islam FU, Anderson KE. Hepatitis C Treatment in Patients With Porphyria Cutanea Tarda. Am J Med Sci. 2017 Jun;353(6):523-528. doi: 10.1016/j.amjms.2017.03.007. Epub 2017 Mar 8.

Lane AM, McKay JT, Bonkovsky HL. Advances in the management of erythropoietic protoporphyria - role of afamelanotide. Appl Clin Genet. 2016 Dec 12;9:179-189. doi: 10.2147/TACG.S122030. eCollection 2016.

Balwani M, Singh P, Seth A, Debnath EM, Naik H, Doheny D, Chen B, Yasuda M, Desnick RJ. Acute Intermittent Porphyria in children: A case report and review of the literature. Mol Genet Metab. 2016 Dec;119(4):295-299. doi: 10.1016/j.ymgme.2016.10.005. Epub 2016 Oct 15.

Chen B, Solis-Villa C, Hakenberg J, Qiao W, Srinivasan RR, Yasuda M, Balwani M, Doheny D, Peter I, Chen R, Desnick RJ. Acute Intermittent Porphyria: Predicted Pathogenicity of HMBS Variants Indicates Extremely Low Penetrance of the Autosomal Dominant Disease. Hum Mutat. 2016 Nov;37(11):1215-1222. doi: 10.1002/humu.23067. Epub 2016 Sep 5.

Naik H, Stoecker M, Sanderson SC, Balwani M, Desnick RJ. Experiences and concerns of patients with recurrent attacks of acute hepatic porphyria: A qualitative study. Mol Genet Metab. 2016 Nov;119(3):278-283. doi: 10.1016/j.ymgme.2016.08.006. Epub 2016 Aug 24.

Farrell CP, Overbey JR, Naik H, Nance D, McLaren GD, McLaren CE, Zhou L, Desnick RJ, Parker CJ, Phillips JD. The D519G Polymorphism of Glyceronephosphate O-Acyltransferase Is a Risk Factor for Familial Porphyria Cutanea Tarda. PLoS One. 2016 Sep 23;11(9):e0163322. doi: 10.1371/journal.pone.0163322. eCollection 2016.

Piel RB 3rd, Shiferaw MT, Vashisht AA, Marcero JR, Praissman JL, Phillips JD, Wohlschlegel JA, Medlock AE. A Novel Role for Progesterone Receptor Membrane Component 1 (PGRMC1): A Partner and Regulator of Ferrochelatase. Biochemistry. 2016 Sep 20;55(37):5204-17. doi: 10.1021/acs.biochem.6b00756. Epub 2016 Sep 9.

Merkel PA, Manion M, Gopal-Srivastava R, Groft S, Jinnah HA, Robertson D, Krischer JP; Rare Diseases Clinical Research Network. The partnership of patient advocacy groups and clinical investigators in the rare diseases clinical research network. Orphanet J Rare Dis. 2016 May 18;11(1):66. doi: 10.1186/s13023-016-0445-8.

French JB, Bonacini M, Ghabril M, Foureau D, Bonkovsky HL. Hepatotoxicity Associated with the Use of Anti-TNF-α Agents. Drug Saf. 2016 Mar;39(3):199-208. doi: 10.1007/s40264-015-0366-9.

Sachar M, Anderson KE, Ma X. Protoporphyrin IX: the Good, the Bad, and the Ugly. J Pharmacol Exp Ther. 2016 Feb;356(2):267-75. doi: 10.1124/jpet.115.228130. Epub 2015 Nov 20.

Brancaleoni V, Balwani M, Granata F, Graziadei G, Missineo P, Fiorentino V, Fustinoni S, Cappellini MD, Naik H, Desnick RJ, Di Pierro E. X-chromosomal inactivation directly influences the phenotypic manifestation of X-linked protoporphyria. Clin Genet. 2016 Jan;89(1):20-6. doi: 10.1111/cge.12562. Epub 2015 Feb 17.

Gou EW, Balwani M, Bissell DM, Bloomer JR, Bonkovsky HL, Desnick RJ, Naik H, Phillips JD, Singal AK, Wang B, Keel S, Anderson KE. Pitfalls in Erythrocyte Protoporphyrin Measurement for Diagnosis and Monitoring of Protoporphyrias. Clin Chem. 2015 Dec;61(12):1453-6. doi: 10.1373/clinchem.2015.245456. Epub 2015 Oct 19.

Wang G, Bonkovsky HL, de Lemos A, Burczynski FJ. Recent insights into the biological functions of liver fatty acid binding protein 1. J Lipid Res. 2015 Dec;56(12):2238-47. doi: 10.1194/jlr.R056705. Epub 2015 Oct 6.

O'Brien TR, Pfeiffer RM, Paquin A, Lang Kuhs KA, Chen S, Bonkovsky HL, Edlin BR, Howell CD, Kirk GD, Kuniholm MH, Morgan TR, Strickler HD, Thomas DL, Prokunina-Olsson L. Comparison of functional variants in IFNL4 and IFNL3 for association with HCV clearance. J Hepatol. 2015 Nov;63(5):1103-10. doi: 10.1016/j.jhep.2015.06.035. Epub 2015 Jul 15.

Bossi K, Lee J, Schmeltzer P, Holburton E, Groseclose G, Besur S, Hwang S, Bonkovsky HL. Homeostasis of iron and hepcidin in erythropoietic protoporphyria. Eur J Clin Invest. 2015 Oct;45(10):1032-41. doi: 10.1111/eci.12503. Epub 2015 Sep 2.

Medlock AE, Shiferaw MT, Marcero JR, Vashisht AA, Wohlschlegel JA, Phillips JD, Dailey HA. Identification of the Mitochondrial Heme Metabolism Complex. PLoS One. 2015 Aug 19;10(8):e0135896. doi: 10.1371/journal.pone.0135896. eCollection 2015.

Bergonia HA, Franklin MR, Kushner JP, Phillips JD. A method for determining δ-aminolevulinic acid synthase activity in homogenized cells and tissues. Clin Biochem. 2015 Aug;48(12):788-95. doi: 10.1016/j.clinbiochem.2015.04.023. Epub 2015 May 8.

Farrell CP, Parker CJ, Phillips JD. Exome sequencing for molecular characterization of non-HFE hereditary hemochromatosis. Blood Cells Mol Dis. 2015 Aug;55(2):101-3. doi: 10.1016/j.bcmd.2015.04.002. Epub 2015 May 1.

Egan DN, Yang Z, Phillips J, Abkowitz JL. Inducing iron deficiency improves erythropoiesis and photosensitivity in congenital erythropoietic porphyria. Blood. 2015 Jul 9;126(2):257-61. doi: 10.1182/blood-2014-07-584664. Epub 2015 May 13.

Langendonk JG, Balwani M, Anderson KE, et al. Afamelanotide for Erythropoietic Protoporphyria. N Engl J Med. Jul 2 2015;373(1):48-59. PMID: 26132941.

Ramanujam VS, Anderson KE. Porphyria Diagnostics-Part 1: A Brief Overview of the Porphyrias. Curr Protoc Hum Genet. 2015 Jul 1;86:17.20.1-17.20.26. doi: 10.1002/0471142905.hg1720s86.

Yasuda M, Erwin AL, Liu LU, Balwani M, Chen B, Kadirvel S, Gan L, Fiel MI, Gordon RE, Yu C, Clavero S, Arvelakis A, Naik H, Martin LD, Phillips JD, Anderson KE, Sadagoparamanujam VM, Florman SS, Desnick RJ. Liver Transplantation for Acute Intermittent Porphyria: Biochemical and Pathologic Studies of the Explanted Liver. Mol Med. 2015 Jun 5;21(1):487-95. doi: 10.2119/molmed.2015.00099.

Butler DF, Ginn KF, Daniel JF, Bloomer JR, Kats A, Shreve N, Myers GD. Bone marrow transplant for X-linked protoporphyria with severe hepatic fibrosis. Pediatr Transplant. 2015 Jun;19(4):E106-10. doi: 10.1111/petr.12472. Epub 2015 Apr 9.

Bissell DM, Wang B. Acute Hepatic Porphyria. J Clin Transl Hepatol. 2015 Mar;3(1):17-26. doi: 10.14218/JCTH.2014.00039. Epub 2015 Mar 15.

Bissell DM, Lai JC, Meister RK, Blanc PD. Role of delta-aminolevulinic acid in the symptoms of acute porphyria. Am J Med. 2015 Mar;128(3):313-7. doi: 10.1016/j.amjmed.2014.10.026. Epub 2014 Nov 8.

Dailey HA, Gerdes S, Dailey TA, Burch JS, Phillips JD. Noncanonical coproporphyrin-dependent bacterial heme biosynthesis pathway that does not use protoporphyrin. Proc Natl Acad Sci U S A. 2015 Feb 17;112(7):2210-5. doi: 10.1073/pnas.1416285112. Epub 2015 Feb 2.

Bonkovsky HL, Maddukuri VC, Yazici C, Anderson KE, Bissell DM, Bloomer JR, Phillips JD, Naik H, Peter I, Baillargeon G, Bossi K, Gandolfo L, Light C, Bishop D, Desnick RJ. Acute porphyrias in the USA: features of 108 subjects from porphyrias consortium. Am J Med. 2014 Dec;127(12):1233-41. doi: 10.1016/j.amjmed.2014.06.036. Epub 2014 Jul 10.

Besur S, Hou W, Schmeltzer P, Bonkovsky HL. Clinically important features of porphyrin and heme metabolism and the porphyrias. Metabolites. 2014 Nov 3;4(4):977-1006. doi: 10.3390/metabo4040977.

Yien YY, Robledo RF, Schultz IJ, Takahashi-Makise N, Gwynn B, Bauer DE, Dass A, Yi G, Li L, Hildick-Smith GJ, Cooney JD, Pierce EL, Mohler K, Dailey TA, Miyata N, Kingsley PD, Garone C, Hattangadi SM, Huang H, Chen W, Keenan EM, Shah DI, Schlaeger TM, DiMauro S, Orkin SH, Cantor AB, Palis J, Koehler CM, Lodish HF, Kaplan J, Ward DM, Dailey HA, Phillips JD, Peters LL, Paw BH. TMEM14C is required for erythroid mitochondrial heme metabolism. J Clin Invest. 2014 Oct;124(10):4294-304. doi: 10.1172/JCI76979. Epub 2014 Aug 26.

Singal AK, Parker C, Bowden C, Thapar M, Liu L, McGuire BM. Liver transplantation in the management of porphyria. Hepatology. 2014 Sep;60(3):1082-9. doi: 10.1002/hep.27086. Epub 2014 Jul 29.

Yasuda M, Gan L, Chen B, Kadirvel S, Yu C, Phillips JD, New MI, Liebow A, Fitzgerald K, Querbes W, Desnick RJ. RNAi-mediated silencing of hepatic Alas1 effectively prevents and treats the induced acute attacks in acute intermittent porphyria mice. Proc Natl Acad Sci U S A. 2014 May 27;111(21):7777-82. doi: 10.1073/pnas.1406228111. Epub 2014 May 12.

Liu LU, Phillips J, Bonkovsky H. Hepatoerythropoietic Porphyria. In: GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993. 2013 Oct 31 [updated 2022 Dec 22].

Clavero S, Ahuja Y, Bishop DF, Kwait B, Haskins ME, Giger U, Desnick RJ. Diagnosis of feline acute intermittent porphyria presenting with erythrodontia requires molecular analyses. Vet J. 2013 Dec;198(3):720-2. doi: 10.1016/j.tvjl.2013.10.008. Epub 2013 Oct 10.

Erwin A, Balwani M, Desnick RJ. Congenital Erythropoietic Porphyria. GeneReviews(R). 2013 Sep 12 [updated 2021 Apr 15]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024. PMID: 24027798.

Larion S, Caballes FR, Hwang SI, Lee JG, Rossman WE, Parsons J, Steuerwald N, Li T, Maddukuri V, Groseclose G, Finkielstein CV, Bonkovsky HL. Circadian rhythms in acute intermittent porphyria--a pilot study. Eur J Clin Invest. 2013 Jul;43(7):727-39. doi: 10.1111/eci.12102. Epub 2013 May 8.

Wang B, Bissell D, Lai J, Cimino T, Porphyrias Consortium. A Combined Clinical Index for the Diagnosis of Acute Porphyria. Paper presented at: Annual Assembly of the Swiss Society of Clinical Chemistry & International Congress of Porphyrins and Porphyrias. Paper presented at: Annual Assembly of the Swiss Society of Clinical Chemistry & International Congress of Porphyrins and Porphyrias; May 16-18, 2013; Lucerne, Switzerland.

Maddukuri V, Yazici C, Anderson K, et al. Acute intermittent porphyria [AIP] in the United States: features of the first 82 cases enrolled in the longitudinal study of the porphyria consortium [PC]. Paper presented at: Annual Assembly of the Swiss Society of Clinical Chemistry & International Congress of Porphyrins and Porphyrias. May 16-18, 2013; Lucerne, Switzerland.

Ludtke A, Yasuda M, Gan L, et al. Acute Intermittent Porphyria: Identification of 19 Novel Hydroxymethylbilane Synthase Mutations and Functional Characterization of Four Novel Missense Mutations. Paper presented at: Annual Assembly of the Swiss Society of Clinical Chemistry & International Congress of Porphyrins and Porphyrias. May 16-18, 2013; Lucerne, Switzerland.

Larion S, Caballes F, Hwang S, et al. Circadian rhythms in acute intermittent porphyria—a pilot study. Paper presented at: Annual Assembly of the Swiss Society of Clinical Chemistry & International Congress of Porphyrins and Porphyrias. May 16-18, 2013; Lucerne, Switzerland.

Balwani M, Naik H, Peter I, et al. Erythropoietic Protoporphyria and X-Linked Protoporphyria in the United States: Results from the Longitudinal Study of the NIH/RDCRN Porphyrias Consortium. Paper presented at: Annual Assembly of the Swiss Society of Clinical Chemistry & International Congress of Porphyrins and Porphyrias. May 16-18, 2013; Lucerne, Switzerland.

Naik H, Balwani M, Doheny D, Liu L, Desnick R. Experience with a Pilot Skype Internet Support Group for Symptomatic Patients with Acute Intermittent Porphyria. Paper presented at: Annual Assembly of the Swiss Society of Clinical Chemistry & International Congress of Porphyrins and Porphyrias. May 16-18, 2013; Lucerne, Switzerland.

Gou E, Singh A, Pierson K, Wilkinson G, Anderson K. Frequency of Porphyria Testing in a National Health Care Database. Paper presented at: Annual Assembly of the Swiss Society of Clinical Chemistry & International Congress of Porphyrins and Porphyrias. May 16-18, 2013; Lucerne, Switzerland.

Yazici C, Maddukuri V, Anderson K, et al. Hereditary coproporphyria [HCP] and variegate porphyria [VP] in the United States: Initial results from the longitudinal study of the porphyria consortium [PC]. Paper presented at: Annual Assembly of the Swiss Society of Clinical Chemistry & International Congress of Porphyrins and Porphyrias. May 16-18, 2013; Lucerne, Switzerland.

Singal A, Jampana S, Kormos-Hallberg C, Anderson K. Low-dose hydroxychloroquine to treat or prevent relapse of porphyria cutanea tarda during hepatitis C treatment. Paper presented at: Annual Assembly of the Swiss Society of Clinical Chemistry & International Congress of Porphyrins and Porphyrias. May 16-18, 2013; Lucerne, Switzerland.

Mittal S, Yasuda M, Desnick R, Anderson K. Metabolic Analysis in Transgenic Mouse Models of Acute Intermittent Porphyria (AIP). Paper presented at: Annual Assembly of the Swiss Society of Clinical Chemistry & International Congress of Porphyrins and Porphyrias. May 16-18, 2013; Lucerne, Switzerland.

Balwani M, Bishop D, Nazarenko I, et al. Mutation analysis of 155 North American Patients with Erythropoietic Protoporphyria reveals novel Ferrochelatase Mutations and a high prevalence of X-Linked Protoporphyria due to previous and novel 5-Aminolevulinate Synthase 2 mutations. Paper presented at: Annual Assembly of the Swiss Society of Clinical Chemistry & International Congress of Porphyrins and Porphyrias. May 16-18, 2013; Lucerne, Switzerland.

Phillips J, Warby C, Bergonia H, Marcero J, Parker C, Franklin M. Porphyria studies in Cyp1A2-/- and wild type mice suggest that heme regulation of ALA-synthase transcription and mitochondrial membrane translocation can be separated based on heme supply-and-demand. Paper presented at: Annual Assembly of the Swiss Society of Clinical Chemistry & International Congress of Porphyrins and Porphyrias. May 16-18, 2013; Lucerne, Switzerland.

Singal A, Gou E, Albuerne M, Kormos-Hallberg C, Anderson K. Relapse of porphyria cutanea tarda after achieving remission with phlebotomy or low dose hydroxychloroquine. Paper presented at: Annual Assembly of the Swiss Society of Clinical Chemistry & International Congress of Porphyrins and Porphyrias. May 16-18, 2013; Lucerne, Switzerland.

Bishop D, Tchaikovskii V, Nazarenko I, Desnick R. Synthase Gain-of-Function Mutations Causing X-Linked Protoporphyria. Paper presented at: Annual Assembly of the Swiss Society of Clinical Chemistry & International Congress of Porphyrins and Porphyrias. May 16-18, 2013; Lucerne, Switzerland.

Balwani M, Doheny D, Bishop DF, Nazarenko I, Yasuda M, Dailey HA, Anderson KE, Bissell DM, Bloomer J, Bonkovsky HL, Phillips JD, Liu L, Desnick RJ; Porphyrias Consortium of the National Institutes of Health Rare Diseases Clinical Research Network. Loss-of-function ferrochelatase and gain-of-function erythroid-specific 5-aminolevulinate synthase mutations causing erythropoietic protoporphyria and x-linked protoporphyria in North American patients reveal novel mutations and a high prevalence of X-linked protoporphyria. Mol Med. 2013 Apr 30;19(1):26-35. doi: 10.2119/molmed.2012.00340.

Bonkovsky HL, Hou W, Steuerwald N, et al. Heme status affects human hepatic messenger RNA and microRNA expression. World J Gastroenterol. Mar 14 2013;19(10):1593-1601. PMID: 23538684, PMCID: PMC3602476.

Bishop DF, Tchaikovskii V, Nazarenko I, Desnick RJ. Molecular expression and characterization of erythroid-specific 5-aminolevulinate synthase gain-of-function mutations causing X-linked protoporphyria. Mol Med. 2013 Mar 5;19(1):18-25. doi: 10.2119/molmed.2013.00003.

Bonkovsky HL. Risk factors for porphyria cutanea tarda -the iron/HFE connection. Liver Int. Jan 2013;33(1):162. PMID: 23121614.

Ludtke A, Yasuda M, Lin G, et al. Acute Intermittent Porphyria: Identification of 23 Novel Hydroxymethylbilane Synthase Mutations and Functional Characterization of Six Novel Missense Mutations. Paper presented at: ACMG Annual Clinical Genetics Meeting, Phoenix, AZ2013.

Mittal S, Anderson KE. Congenital erythropoietic porphyria. In: Rose BD, ed. UpToDate. Waltham, MA: UpToDate . 2013

Ludtke A, Yasuda M, Balwani M, et al. First US Orthotopic Liver Transplant for Intractable Acute Intermittent Porphyria. Paper presented at: The American Society of Human Genetics 63rd Annual Meeting. Boston, MA2013.

Liu LU, Phillips J, Bonkovsky H. Porphyria Cutanea Tarda, Type II. In: Pagon RA, Adam MP, Bird TD, et al., eds. GeneReviews(R). Seattle WA: University of Washington, Seattle. 1993. PMID: 23741761.

Bonkovsky HL, Guo J-T, Hou W, Li T, Narang T, Thapar M. Porphyrin and Heme Metabolism and the Porphyrias. Comprehensive Physiology: John Wiley & Sons, Inc. 2013:365-401.

Gou E, Anderson K. The Porphyrias. In: Hamblin M, Huang Y, eds. Handbook of Photomedicine. Boca Raton, FL: Taylor and Francis. 2013

Anderson KE, Singal AK. Variegate Porphyria. GeneReviews. Seattle WA: University of Washington, Seattle. 1993

Balwani M, Bloomer J, Desnick R. X-Linked Protoporphyria. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, eds. GeneReviews. Seattle WA: University of Washington, Seattle. 1993. PMID: 23409301.

Bissell DM, Wang B, Cimino T, Lai J. Hereditary Coproporphyria. In: GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993. 2012 Dec 13 [updated 2022 May 19].

Singal AK, Kormos-Hallberg C, Lee C, Sadagoparamanujam VM, Grady JJ, Freeman DH Jr, Anderson KE. Low-dose hydroxychloroquine is as effective as phlebotomy in treatment of patients with porphyria cutanea tarda. Clin Gastroenterol Hepatol. 2012 Dec;10(12):1402-9. doi: 10.1016/j.cgh.2012.08.038. Epub 2012 Sep 14.

Balwani M, Desnick RJ. The porphyrias: advances in diagnosis and treatment. Blood. 2012 Nov 29;120(23):4496-504. doi: 10.1182/blood-2012-05-423186. Epub 2012 Jul 12.

Singh A, Pierson K, Wilkinson G, Anderson K. Porphyrias: prevalence and frequency of testing in a national health care database. Paper presented at: Annual Meeting of the American Association for the Study of Liver Disease (AASLD). November 9-13, 2012; Boston, MA.

Ryan Caballes F, Sendi H, Bonkovsky HL. Hepatitis C, porphyria cutanea tarda and liver iron: an update. Liver Int. 2012 Jul;32(6):880-93. doi: 10.1111/j.1478-3231.2012.02794.x. Epub 2012 Apr 17.

Desnick RJ. The Porphyrias: Cardinal Signs and Diagnosis/Treatment. Paper presented at: American College of Medical Genetics Annual Clinical Genetics Meeting. March 31, 2012; Charlotte, NC.

Wang L, He F, Bu J, Zhen Y, Liu X, Du W, Dong J, Cooney JD, Dubey SK, Shi Y, Gong B, Li J, McBride PF, Jia Y, Lu F, Soltis KA, Lin Y, Namburi P, Liang C, Sundaresan P, Paw BH, Li W, Li DY, Phillips JD, Yang Z. ABCB6 mutations cause ocular coloboma. Am J Hum Genet. 2012 Jan 13;90(1):40-8. doi: 10.1016/j.ajhg.2011.11.026. Epub 2012 Jan 5.

Lourenco CM, Lee C, Anderson KE. Disorders of heme biosynthesis In: J-M S, Van den Berghe G, Walter JH, eds. In: J-M S, Van den Berghe G, Walter JH, eds. Inborn Metabolic Diseases: Diagnosis and Treatment. 5th ed. Berlin: Springer- Verlag. 2012:519-532.

Balwani M, Bloomer J, Desnick R. Erythropoietic Protoporphyria, Autosomal Recessive. In: GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993. 2012 Sep 27 [updated 2017 Sep 7].

Phillips JD. Side chain modification during heme biosynthesis. Handbook of Porphyrin Science, Vol 16-In: Kadish KM, Smith KM, Guilard R, eds. Handbook of Porphyrin Science. Vol 16: World Scientific Publishing Company. 2012:283- 337.

Anderson KE. The porphyrias. In: Goldman L, Schafer AI, eds. Goldman's Cecil Medicine. 24th ed. Philadelphia: Elsevier Saunders. 2012:1363-1371.

Balwani M, Desnick RJ. The porphyrias: advances in diagnosis and treatment. Hematology Am Soc Hematol Educ Program. 2012;2012:19-27. doi: 10.1182/asheducation-2012.1.19.

Phillips JD, Kushner JP, Bergonia HA, Franklin MR. Uroporphyria in the Cyp1a2-/- mouse. Blood Cells Mol Dis. 2011 Dec 15;47(4):249-54. doi: 10.1016/j.bcmd.2011.07.006. Epub 2011 Aug 30.

Hwang SI, Lee YY, Park JO, Norton HJ, Clemens E, Schrum LW, Bonkovsky HL. Effects of a single dose of oral iron on hepcidin concentrations in human urine and serum analyzed by a robust LC-MS/MS method. Clin Chim Acta. 2011 Nov 20;412(23-24):2241-7. doi: 10.1016/j.cca.2011.08.014. Epub 2011 Aug 16.

Dailey HA, Septer AN, Daugherty L, Thames D, Gerdes S, Stabb EV, Dunn AK, Dailey TA, Phillips JD. The Escherichia coli protein YfeX functions as a porphyrinogen oxidase, not a heme dechelatase. mBio. 2011 Nov 8;2(6):e00248-11. doi: 10.1128/mBio.00248-11. Print 2011.

Desnick RJ. Overview of RDCRN and Porphyrias Consortium Activities. Paper presented at: AASLD Annual Meeting. November 6, 2011; San Francisco, CA.

Wang B. PTF Experience from the Trainee Perspective. Paper presented at: AASLD Annual Meeting. November 6, 2011; San Francisco, CA.

Anderson K. The cutaneous porphyrias. Paper presented at: AASLD Annual Meeting. November 6, 2011; San Francisco, CA.

Huang Z, Chen K, Xu T, Zhang J, Li Y, Li W, Agarwal AK, Clark AM, Phillips JD, Pan X. Sampangine inhibits heme biosynthesis in both yeast and human. Eukaryot Cell. 2011 Nov;10(11):1536-44. doi: 10.1128/EC.05170-11. Epub 2011 Sep 9.

Doheny D, Nazarenko I, Balwani M, Liu L, Naik H, Anderson K, Bissell DM, Bloomer JR, Bonkovsky HL, Kushner JP, Phillips J, Bishop D, Desnick RJ. Erythropoietic Protoporphyrias: Frequency of Mutations in the Ferrochelatase Gene Causing Autosomal Recessive Erythropoietic Protoporphyria and Mutations in the 5’-Aminolevulinate Synthase 2 Gene Causing X-Linked Protoporphyria (Abstract #1338T). Paper presented at: 12th International Congress of Human Genetics/61st Annual Meeting of The American Society of Human Genetics. October 14, 2011; Montreal, Canada.

Bishop D, Tchaikovskii V, Nazarenko I, Balwani M, Doheny D, Desnick RJ. Expression and characterization of the ALAS2 carboxy-terminal gain-of-function mutations causing X-linked protoporphyria (Abstract #1157F). Paper presented at: 12th International Congress of Human Genetics/61st Annual Meeting of The American Society of Human Genetics. October 14, 2011; Montreal, Canada.

To-Figueras J, Phillips JD, Gonzalez-López JM, Badenas C, Madrigal I, González-Romarís EM, Ramos C, Aguirre JM, Herrero C. Hepatoerythropoietic porphyria due to a novel mutation in the uroporphyrinogen decarboxylase gene. Br J Dermatol. 2011 Sep;165(3):499-505. doi: 10.1111/j.1365-2133.2011.10453.x. Epub 2011 Aug 18.

Zhang J, Yasuda M, Desnick RJ, Balwani M, Bishop D, Yu C. A LC-MS/MS method for the specific, sensitive, and simultaneous quantification of 5-aminolevulinic acid and porphobilinogen. J Chromatogr B Analyt Technol Biomed Life Sci. 2011 Aug 15;879(24):2389-96. doi: 10.1016/j.jchromb.2011.06.034. Epub 2011 Jul 6.

Tian Q, Li T, Hou W, Zheng J, Schrum LW, Bonkovsky HL. Lon peptidase 1 (LONP1)-dependent breakdown of mitochondrial 5-aminolevulinic acid synthase protein by heme in human liver cells. J Biol Chem. 2011 Jul 29;286(30):26424-30. doi: 10.1074/jbc.M110.215772. Epub 2011 Jun 9.

Wang Y, Langer NB, Shaw GC, Yang G, Li L, Kaplan J, Paw BH, Bloomer JR. Abnormal mitoferrin-1 expression in patients with erythropoietic protoporphyria. Exp Hematol. 2011 Jul;39(7):784-94. doi: 10.1016/j.exphem.2011.05.003. Epub 2011 May 11.

Boynton TO, Gerdes S, Craven SH, Neidle EL, Phillips JD, Dailey HA. Discovery of a gene involved in a third bacterial protoporphyrinogen oxidase activity through comparative genomic analysis and functional complementation. Appl Environ Microbiol. 2011 Jul;77(14):4795-801. doi: 10.1128/AEM.00171-11. Epub 2011 Jun 3.

Balwani M, Grace ME, Desnick RJ. Gaucher disease: when molecular testing and clinical presentation disagree -the novel c.1226A>G(p.N370S)--RecNcil allele. J Inherit Metab Dis. 2011 Jun;34(3):789-93. doi: 10.1007/s10545-011-9307-7. Epub 2011 Mar 23.

Lakner AM, Bonkovsky HL, Schrum LW. microRNAs: fad or future of liver disease. World J Gastroenterol. May 28 2011;17(20):2536-2542. PMCID: PMC3103811.

Troadec MB, Warner D, Wallace J, Thomas K, Spangrude GJ, Phillips J, Khalimonchuk O, Paw BH, Ward DM, Kaplan J. Targeted deletion of the mouse Mitoferrin1 gene: from anemia to protoporphyria. Blood. 2011 May 19;117(20):5494-502. doi: 10.1182/blood-2010-11-319483. Epub 2011 Feb 10.

Lorenzo FRt, Phillips JD, Nussenzveig R, Lingam B, Koul PA, Schrier SL, Prchal JT. Molecular basis of two novel mutations found in type I methemoglobinemia. Blood Cells Mol Dis. Apr 15 2011;46(4):277-281. PMCID: PMC3075332.

Wickliffe JK, Abdel-Rahman SZ, Lee C, Kormos-Hallberg C, Sood G, Rondelli CM, Grady JJ, Desnick RJ, Anderson KE. CYP1A2*1F and GSTM1 alleles are associated with susceptibility to porphyria cutanea tarda. Mol Med. 2011 Mar-Apr;17(3-4):241-7. doi: 10.2119/molmed.2010.00130. Epub 2010 Oct 15. Anderson K. CYP1A2*1F and GSTM1 Alleles Are Associated with Susceptibility to Porphyria Cutanea Tarda. Poster presented at: International Porphyrins & Porphyrias Meeting; April 2011; Cardiff, Wales.

Anderson K. CYP1A2*1F and GSTM1 Alleles Are Associated with Susceptibility to Porphyria Cutanea Tarda. Poster presented at: International Porphyrins & Porphyrias Meeting; April 2011; Cardiff, Wales.

Li T, Bonkovsky HL, Guo JT. Structural analysis of heme proteins: implications for design and prediction. BMC Struct Biol. 2011 Mar 3;11:13. doi: 10.1186/1472-6807-11-13.

Machaczka M, Klimkowska M, Regenthal S, Hägglund H. Gaucher disease with foamy transformed macrophages and erythrophagocytic activity. J Inherit Metab Dis. 2011 Feb;34(1):233-5. doi: 10.1007/s10545-010-9241-0. Epub 2010 Nov 27.

Hasanoglu A, Balwani M, Kasapkara CS, Ezgü FS, Okur I, Tümer L, Cakmak A, Nazarenko I, Yu C, Clavero S, Bishop DF, Desnick RJ. Harderoporphyria due to homozygosity for coproporphyrinogen oxidase missense mutation H327R. J Inherit Metab Dis. 2011 Feb;34(1):225-31. doi: 10.1007/s10545-010-9237-9. Epub 2010 Nov 20.

Bishop DF, Clavero S, Mohandas N, Desnick RJ. Congenital erythropoietic porphyria: characterization of murine models of the severe common (C73R/C73R) and later-onset genotypes. Mol Med. 2011;17(7-8):748-56. doi: 10.2119/molmed.2010.00258. Epub 2011 Feb 25.

Mittal S, Anderson KE. Erythropoietic porphyria. In: Rose BD, ed. UpToDate. Waltham, MA: UpToDate. 2011

Tian Q, Hou W, Steuerwald NM, Schrum LW, Bonkovsky HL. Heme markedly up-regulates RNA- binding motif protein 24 gene expression in human hepatocytes. Hepatology-Abstract #895 presented at the Annual Meeting of the American Association for the Study of Liver Diseases. 2011;54(S1):780A.

[Abstract #895 presented at the Annual Meeting of the American Association for the Study of Liver Diseases]

Tian Q, Hou W, Zheng J, Schrum LW, Bonkovsky HL. LONP1-dependent breakdown of mitochondrial 5-aminolevulinicacid synthase protein by heme in human liver cells. Abstract #904 presented at the Annual Meeting of the American Association for the Study of Liver Diseases. Hepatology. 2011;54(S1):785A.

[Abstract #904 presented at the Annual Meeting of the American Association for the Study of Liver Diseases]

Hwang SI, Lee YY, Park JO, Norton HJ, Clemens E, Schrum LW, Bonkovsky HL. The measurement of hepcidin from human urine and serum to study effects of a single dose of oral iron by an optimized LC-MS/MS method. Hepatology. 2011;54(S1):931A. Abstract #1204 presented at Annual Meeting of the American Association for the Study of Liver Diseases.

[Abstract #1204 presented at Annual Meeting of the American Association for the Study of Liver Diseases]

Anderson K, Lee C, Balwani M, Desnick R. The porphyrias. In: Kliegman R, Stanton B, St. Geme J, Schor N, Behrman R, eds. Nelson Textbook of Pediatrics. 19 ed. Philadelphia, PA: Elsevier. 2011

Phillips JD, Anderson K. The Porphyrias. In: Lichtman MA, Kaushansky K, Kipps TJ, Prchal JT, Levi MM, eds. Williams Manual of Hematology. 8th ed: McGraw-Hill Professional. 2011

Hou W, Tian Q, Lu QL, Schrum LW, Bonkovsky HL. Zinc protoporphyrin, a novel endogenous HCV NS3-4A protease inhibitor, displays anti-viral activity. Presidential Poster of Distinction, presented at Annual Meeting of the American Association for the Study of Liver Diseases]. Hepatology. 2011;54(S1):128A-359A.

[Abstract #926 Presidential Poster of Distinction, presented at Annual Meeting of the American Association for the Study of Liver Diseases]

Clavero S, Bishop DF, Giger U, Haskins ME, Desnick RJ. Feline congenital erythropoietic porphyria: two homozygous UROS missense mutations cause the enzyme deficiency and porphyrin accumulation. Mol Med. 2010 Sep-Oct;16(9-10):381-8. doi: 10.2119/molmed.2010.00038. Epub 2010 May 12.

Gunn GB, Anderson KE, Patel AJ, Gallegos J, Hallberg CK, Sood G, Hatch SS, Sanguineti G. Severe radiation therapy-related soft tissue toxicity in a patient with porphyria cutanea tarda: a literature review. Head Neck. 2010 Aug;32(8):1112-7. doi: 10.1002/hed.21161.

Cantatore-Francis JL, Cohen-Pfeffer J, Balwani M, Kahn P, Lazarus HM, Desnick RJ, Schaffer JV. Hepatoerythropoietic porphyria misdiagnosed as child abuse: cutaneous, arthritic, and hematologic manifestations in siblings with a novel UROD mutation. Arch Dermatol. 2010 May;146(5):529-33. doi: 10.1001/archdermatol.2010.89.

Hou W, Tian Q, Zheng J, Bonkovsky HL. Zinc mesoporphyrin induces rapid proteasomal degradation of hepatitis C nonstructural 5A protein in human hepatoma cells. Gastroenterology. 2010 May;138(5):1909-19. doi: 10.1053/j.gastro.2009.11.001. Epub 2009 Nov 10.

Jalil S, Grady JJ, Lee C, Anderson KE. Associations among behavior-related susceptibility factors in porphyria cutanea tarda. Clin Gastroenterol Hepatol. Mar 2010;8(3):297-302, 302 e291. PMCID: PMC2834813

Crockett DK, Kushnir MM, Phillips JD, Rockwood AL. Time-of-flight mass spectrometry analysis of the ferroportin-hepcidin binding domain complex for accurate mass confirmation of bioactive hepcidin 25. Clin Chim Acta. 2010 Mar;411(5-6):453-5. doi: 10.1016/j.cca.2009.11.031. Epub 2009 Dec 3.

Clavero S, Bishop DF, Haskins ME, Giger U, Kauppinen R, Desnick RJ. Feline acute intermittent porphyria: a phenocopy masquerading as an erythropoietic porphyria due to dominant and recessive hydroxymethylbilane synthase mutations. Hum Mol Genet. 2010 Feb 15;19(4):584-96. doi: 10.1093/hmg/ddp525. Epub 2009 Nov 24.

Bishop DF, Schneider-Yin X, Clavero S, Yoo HW, Minder EI, Desnick RJ. Congenital erythropoietic porphyria: a novel uroporphyrinogen III synthase branchpoint mutation reveals underlying wild-type alternatively spliced transcripts. Blood. 2010 Feb 4;115(5):1062-9. doi: 10.1182/blood-2009-04-218016. Epub 2009 Nov 24.

Yasuda M, Bishop DF, Fowkes M, Cheng SH, Gan L, Desnick RJ. AAV8-mediated gene therapy prevents induced biochemical attacks of acute intermittent porphyria and improves neuromotor function. Mol Ther. 2010 Jan;18(1):17-22. doi: 10.1038/mt.2009.250. Epub 2009 Oct 27.

Sood G, Anderson KE. Acute intermittent porphyria. Acute intermittent porphyria. In: Rose BD, ed. UpToDate. Waltham, MA: UpToDate; . 2010

Sood G, Anderson K. Clinical manifestations and diagnosis of acute intermittent porphyria. In: Rose B, ed. UpToDate. Waltham, MA: UpToDate . 2010

Sood G, Anderson K. Management of acute intermittent porphyria. In: Rose B, ed. UpToDate. Waltham, MA. UpToDate; 2010.

Bloomer JR. Managing acute porphyrias: practice considerations in inpatient and outpatient settings. Medscape Education Gastroenterology. 2010. http://www.medscape.org/viewarticle/730948. Accessed February 28, 2013.

Bloomer JR. Porphyria, ALA-D. Rare Disease Database. 2010; http://www.rarediseases.org/rare-disease- information/rare-diseases/byID/324/viewAbstract. Accessed February 29, 2013.

Anderson KE. Porphyria-an overview. In: Rose BD, ed. UpToDate. Waltham, MA. UpToDate; 2010.

Singal A, Anderson KE. Porphyria cutanea tarda and hepatoerythropoietic porphyria. In: Rose BD, ed. UpToDate. Waltham, MA: UpToDate . 2010

Anderson KE. Porphyria, variegate. Rare Disease Database. 2010; http://www.rarediseases.org/rare-disease- information/rare-diseases/byID/324/viewAbstract. Accessed April 4, 2014.

Phillips JD, Anderson KE. The Porphyrias. In: Kaushansky K, Buetler E, Seligsohn U, Lichtman MA, Kipps TJ, Prchal JT, eds. Williams Hematology. 8th ed. New York: McGraw-Hill Medical. 2010:839-863.

Singal A, Anderson KE. Variegate porphyria. In: Rose BD, ed. UpToDate. Waltham, MA. UpToDate; 2010.

Badenas C, To-Figueras J, Phillips JD, Warby CA, Muñoz C, Herrero C. Identification and characterization of novel uroporphyrinogen decarboxylase gene mutations in a large series of porphyria cutanea tarda patients and relatives. Clin Genet. 2009 Apr;75(4):346-53. doi: 10.1111/j.1399-0004.2009.01153.x.

Anderson K, Sood G. Acute intermittent porphyria. Best Practice. London, UK: BMJ Publishing Group. 2008

Sood G, Anderson K. Porphyria Cutanea Tarda. Best Practice. London, UK: BMJ Publishing Group. 2008

Sood G, Anderson K. Porphyrias. In: Crowther M, Ginsberg J, Schunemann H, Meyer R, Lottenberg R, eds. Evidence-Based Hematology. United Kingdom: Blackwell Publishing Ltd. 2008:229-237.

Phillips JD, Kushner JP. The Porphyrias. In: Orkin SH, Nathan DG, Ginsburg D, Look AT, Fisher DE, Lux SE, eds. Nathan and Oski's Hematology of Infancy and Childhood. 7th ed. Philadelphia: Saunders . 2008

Buso H, Adam E, Arkwright PD, Bhattad S, Hamidieh AA, Behfar M, Belot A, Benezech S, Chan AY, Crow YJ, Dvorak CC, Flinn AM, Kapoor U, Lankester A, Kobayashi M, Matsumura R, Mottaghipisheh H, Okada S, Ouachee M, Parvaneh N, Ramprakash S, Satwani P, Sharafian S, Triaille C, Wynn RF, Movahedi N, Ziaee V, Williams E, Slatter M, Gennery AR. Hematopoietic Stem Cell Transplantation for C1q Deficiency: A Study on Behalf of the EBMT Inborn Errors Working Party. J Clin Immunol. 2024 Oct 29;45(1):35. doi: 10.1007/s10875-024-01819-1.

Hall G, Markle JG, Maiarana J, Martin PL, Rothman JA, Sleasman JW, Lederman H, Azar AE, Brodsky RA, Mousallem T. Case Report: Aplastic anemia related to a novel CTLA4 variant. Front Pediatr. 2024 Aug 16;12:1434076. doi: 10.3389/fped.2024.1434076. eCollection 2024.

Golloshi K, Mitchell W, Kumar D, Malik S, Parikh S, Aljudi AA, Castellino SM, Chandrakasan S. HLH and Recurrent EBV Lymphoma as the presenting manifestation of MAGT1 Deficiency: A Systematic Review of the Expanding Disease Spectrum. J Clin Immunol. 2024 Jun 19;44(7):153. doi: 10.1007/s10875-024-01749-y.

Hicks ED, Hall G, Hershfield MS, Tarrant TK, Bali P, Sleasman JW, Buckley RH, Mousallem T. Treatment with Elapegademase Restores Immunity in Infants with Adenosine Deaminase Deficient Severe Combined Immunodeficiency. J Clin Immunol. 2024 Apr 27;44(5):107. doi: 10.1007/s10875-024-01710-z.

Pavel-Dinu M, Gardner CL, Nakauchi Y, Kawai T, Delmonte OM, Palterer B, Bosticardo M, Pala F, Viel S, Malech HL, Ghanim HY, Bode NM, Kurgan GL, Detweiler AM, Vakulskas CA, Neff NF, Sheikali A, Menezes ST, Chrobok J, Hernández González EM, Majeti R, Notarangelo LD, Porteus MH. Genetically corrected RAG2-SCID human hematopoietic stem cells restore V(D)J-recombinase and rescue lymphoid deficiency. Blood Adv. 2024 Apr 9;8(7):1820-1833. doi: 10.1182/bloodadvances.2023011766.

Abraham RS, Basu A, Heimall JR, Dunn E, Yip A, Kapadia M, Kapoor N, Satter LF, Buckley R, O'Reilly R, Cuvelier GDE, Chandra S, Bednarski J, Chaudhury S, Moore TB, Haines H, Dávila Saldaña BJ, Chellapandian D, Rayes A, Chen K, Caywood E, Chandrakasan S, Lugt MTV, Ebens C, Teira P, Shereck E, Miller H, Aquino V, Eissa H, Yu LC, Gillio A, Madden L, Knutsen A, Shah AJ, DeSantes K, Barnum J, Broglie L, Joshi AY, Kleiner G, Dara J, Prockop S, Martinez C, Mousallem T, Oved J, Burroughs L, Marsh R, Torgerson TR, Leiding JW, Pai SY, Kohn DB, Pulsipher MA, Griffith LM, Notarangelo LD, Cowan MJ, Puck J, Dvorak CC, Haddad E. Relevance of lymphocyte proliferation to PHA in severe combined immunodeficiency (SCID) and T cell lymphopenia. Clin Immunol. 2024 Apr;261:109942. doi: 10.1016/j.clim.2024.109942. Epub 2024 Feb 15. PMID: 38367737; PMCID: PMC11018339.

Severe combined immunodeficiency (SCID) is a genetic disorder characterized by very low T cell numbers, leading to frequent infections and abnormal (low) function of the immune system. Phytohemagglutinin (PHA), a lectin found in red kidney beans, stimulates T cell growth. Several methods can be used to measure PHA-stimulated T cell growth. However, interpretation of results can vary based on the method used.

In this study, researchers explore how different methods of measuring PHA-stimulated T cell growth affects test results and interpretation in patients with SCID. The team analyzed data collected from 307 participants with SCID for PHA-based T cell growth, using either a radioactive or flow cytometry method.

Results showed a more accurate analysis from the flow cytometry method—especially in patients with severely low T cell numbers—suggesting that the method used to measure PHA growth impacts the interpretation of results. Authors note that this test is not essential for the diagnosis of typical SCID and should only be considered as a supportive test.

Hall G, Donkó Á, Pratt C, Kim-Chang JJ, Martin PL, Stallings AP, Sleasman JW, Holland SM, Hsu AP, Leto TL, Mousallem T. Case Report: Profound newborn leukopenia related to a novel RAC2 variant. Front Pediatr. 2024 Mar 7;12:1365187. doi: 10.3389/fped.2024.1365187. eCollection 2024.

Grunebaum E, Arnold DE, Logan B, Parikh S, Marsh RA, Griffith LM, Mallhi K, Chellapandian D, Lim SS, Deal CL, Kapoor N, Murguía-Favela L, Falcone EL, Prasad VK, Touzot F, Bleesing JJ, Chandrakasan S, Heimall JR, Bednarski JJ, Broglie LA, Chong HJ, Kapadia M, Prockop S, Dávila Saldaña BJ, Schaefer E, Bauchat AL, Teira P, Chandra S, Parta M, Cowan MJ, Dvorak CC, Haddad E, Kohn DB, Notarangelo LD, Pai SY, Puck JM, Pulsipher MA, Torgerson TR, Malech HL, Kang EM, Leiding JW. Allogeneic hematopoietic cell transplantation is effective for p47phox chronic granulomatous disease: A  Primary Immune Deficiency Treatment Consortium study. J Allergy Clin Immunol. 2024 Jan 28:S0091-6749(24)00081-2. doi: 10.1016/j.jaci.2024.01.013. Online ahead of print.

Eissa H, Thakar MS, Shah AJ, Logan BR, Griffith LM, Dong H, Parrott RE, O'Reilly RJ, Dara J, Kapoor N, Forbes Satter L, Chandra S, Kapadia M, Chandrakasan S, Knutsen A, Jyonouchi SC, Molinari L, Rayes A, Ebens CL, Teira P, Dávila Saldaña BJ, Burroughs LM, Chaudhury S, Chellapandian D, Gillio AP, Goldman F, Malech HL, DeSantes K, Cuvelier GDE, Rozmus J, Quinones R, Yu LC, Broglie L, Aquino V, Shereck E, Moore TB, Vander Lugt MT, Mousallem TI, Oved JH, Dorsey M, Abdel-Azim H, Martinez C, Bleesing JH, Prockop S, Kohn DB, Bednarski JJ, Leiding J, Marsh RA, Torgerson T, Notarangelo LD, Pai SY, Pulsipher MA, Puck JM, Dvorak CC, Haddad E, Buckley RH, Cowan MJ, Heimall J. Posttransplantation late complications increase over time for patients with SCID: A Primary Immune Deficiency Treatment Consortium (PIDTC) landmark study. J Allergy Clin Immunol. 2024 Jan;153(1):287-296. doi: 10.1016/j.jaci.2023.09.027. Epub 2023 Oct 2.

Leiding JW, Arnold DE, Parikh S, Logan B, Marsh RA, Griffith LM, Wu R, Kidd S, Mallhi K, Chellapandian D, Si Lim SJ, Grunebaum E, Falcone EL, Murguia-Favela L, Grossman D, Prasad VK, Heimall JR, Touzot F, Burroughs LM, Bleesing J, Kapoor N, Dara J, Williams O, Kapadia M, Oshrine BR, Bednarski JJ, Rayes A, Chong H, Cuvelier GDE, Forbes Satter LR, Martinez C, Vander Lugt MT, Yu LC, Chandrakasan S, Joshi A, Prockop SE, Dávila Saldaña BJ, Aquino V, Broglie LA, Ebens CL, Madden LM, DeSantes K, Milner J, Rangarajan HG, Shah AJ, Gillio AP, Knutsen AP, Miller HK, Moore TB, Graham P, Bauchat A, Bunin NJ, Teira P, Petrovic A, Chandra S, Abdel-Azim H, Dorsey MJ, Birbrayer O, Cowan MJ, Dvorak CC, Haddad E, Kohn DB, Notarangelo LD, Pai SY, Puck JM, Pulsipher MA, Torgerson TR, Malech HL, Kang EM. Genotype, oxidase status, and preceding infection or autoinflammation do not affect allogeneic HCT outcomes for CGD. Blood. 2023 Dec 14;142(24):2105-2118. doi: 10.1182/blood.2022019586. PMID: 37562003

Chronic granulomatous disease (CGD) is a type of primary immunodeficiency characterized by life-threatening infections and inflammation. Hematopoietic cell transplantation (HCT) is the definitive treatment for CGD. However, questions remain about patient selection and how active disease impacts transplant outcomes.

In this study, researchers investigated outcomes of allogeneic (donor) HCT in patients with CGD. The team performed an analysis of 391 participants treated either with or without HCT, following outcomes over several years.

Results show that HCT quickly and durably resolves CGD symptoms, lowers the burden of the disease, and has excellent survival rates. Patients with active inflammation or infection are candidates for HCT. To avoid complications from the development of additional medical conditions, authors note that HCT should be considered early in patients with CGD.

Chandrasekaran P, Han Y, Zerbe CS, Heller T, DeRavin SS, Kreuzberg SA, Marciano BE, Siu Y, Jones DR, Abraham RS, Stephens MC, Tsou AM, Snapper S, Conlan S, Subramanian P, Quinones M, Grou C, Calderon V, Deming C, Leiding JW, Arnold DE, Logan BR, Griffith LM, Petrovic A, Mousallem TI, Kapoor N, Heimall JR, Barnum JL, Kapadia M, Wright N, Rayes A, Chandra S, Broglie LA, Chellapandian D, Deal CL, Grunebaum E, Lim SS, Mallhi K, Marsh RA, Murguia-Favela L, Parikh S, Touzot F, Cowan MJ, Dvorak CC, Haddad E, Kohn DB, Notarangelo LD, Pai SY, Puck JM, Pulsipher MA, Torgerson TR, Kang EM, Malech HL, Segre JA, Bryant CE, Holland SM, Falcone EL. Intestinal microbiome and metabolome signatures in patients with chronic granulomatous disease. J Allergy Clin Immunol. 2023 Dec;152(6):1619-1633.e11. doi: 10.1016/j.jaci.2023.07.022. Epub 2023 Sep 1.

Yan KK, Condori J, Ma Z, Metais JY, Ju B, Ding L, Dhungana Y, Palmer LE, Langfitt DM, Ferrara F, Throm R, Shi H, Risch I, Bhatara S, Shaner B, Lockey TD, Talleur AC, Easton J, Meagher MM, Puck JM, Cowan MJ, Zhou S, Mamcarz E, Gottschalk S, Yu J. Integrome signatures of lentiviral gene therapy for SCID-X1 patients. Sci Adv. 2023 Oct 6;9(40):eadg9959. doi: 10.1126/sciadv.adg9959. Epub 2023 Oct 6.

Thakar MS, Logan BR, Puck JM, Dunn EA, Buckley RH, Cowan MJ, O'Reilly RJ, Kapoor N, Satter LF, Pai SY, Heimall J, Chandra S, Ebens CL, Chellapandian D, Williams O, Burroughs LM, Saldana BD, Rayes A, Madden LM, Chandrakasan S, Bednarski JJ 2nd, DeSantes KB, Cuvelier GDE, Teira P, Gillio AP, Eissa H, Knutsen AP, Goldman FD, Aquino VM, Shereck EB, Moore TB, Caywood EH, Lugt MTV, Rozmus J, Broglie L, Yu LC, Shah AJ, Andolina JR, Liu X, Parrott RE, Dara J, Prockop S, Martinez CA, Kapadia M, Jyonouchi SC, Sullivan KE, Bleesing JJ, Chaudhury S, Petrovic A, Keller MD, Quigg TC, Parikh S, Shenoy S, Seroogy C, Rubin T, Decaluwe H, Routes JM, Torgerson TR, Leiding JW, Pulsipher MA, Kohn DB, Griffith LM, Haddad E, Dvorak CC, Notarangelo LD.. Measuring the effect of newborn screening on survival after haematopoietic cell transplantation for severe combined immunodeficiency: a 36-year longitudinal study from the Primary Immune Deficiency Treatment Consortium. Lancet. 2023 Jul 8;402(10396):129-140. doi: 10.1016/S0140-6736(23)00731-6. Epub 2023 Jun 20. PMID: 37352885

Severe combined immunodeficiency (SCID) is a severe form of primary immune deficiency characterized by extreme weakness or absence of immune system function. SCID is fatal, unless durable adaptive immunity is established—most commonly through allogeneic hematopoietic cell transplantation (HCT).

In this study, researchers from the Primary Immune Deficiency Treatment Consortium (PIDTC) explored factors affecting the survival of individuals with SCID over almost four decades. The team focused on the effects of population-based newborn screening for SCID, analyzing transplantation-related data from children with SCID treated at 34 PIDTC sites.

Results show that population-based newborn screening has helped to identify infants with SCID early in life, increasing the likelihood of prompt HCT prior to the development of serious infections. Authors state that public health programs worldwide can benefit from this demonstration of the value of newborn screening for SCID.

Schuetz C, Gerke J, Ege M, Walter J, Kusters M, Worth A, Kanakry JA, Dimitrova D, Wolska-Kuśnierz B, Chen K, Unal E, Karakukcu M, Pashchenko O, Leiding J, Kawai T, Amrolia PJ, Berghuis D, Buechner J, Buchbinder D, Cowan MJ, Gennery AR, Güngör T, Heimall J, Miano M, Meyts I, Morris EC, Rivière J, Sharapova SO, Shaw PJ, Slatter M, Honig M, Veys P, Fischer A, Cavazzana M, Moshous D, Schulz A, Albert MH, Puck JM, Lankester AC, Notarangelo LD, Neven B. Hypomorphic RAG deficiency: impact of disease burden on survival and thymic recovery argues for early diagnosis and HSCT. Blood. 2023 Feb 16;141(7):713-724. doi: 10.1182/blood.2022017667.

Pavel-Dinu M, Borna S, Bacchetta R. Rare immune diseases paving the road for genome editing-based precision medicine. Front Genome Ed. 2023 Feb 8;5:1114996. doi: 10.3389/fgeed.2023.1114996. eCollection 2023.

Labrosse R, Boufaied I, Bourdin B, Gona S, Randolph HE, Logan BR, Bourbonnais S, Berthe C, Chan W, Buckley RH, Parrott RE, Cuvelier GDE, Kapoor N, Chandra S, Dávila Saldaña BJ, Eissa H, Goldman FD, Heimall J, O'Reilly R, Chaudhury S, Kolb EA, Shenoy S, Griffith LM, Pulsipher M, Kohn DB, Notarangelo LD, Pai SY, Cowan MJ, Dvorak CC, Haddad É, Puck JM, Barreiro LB, Decaluwe H. Aberrant T-cell exhaustion in severe combined immunodeficiency survivors with poor T-cell reconstitution after transplantation. J Allergy Clin Immunol. 2023 Jan;151(1):260-271. doi: 10.1016/j.jaci.2022.08.004. Epub 2022 Aug 17.

Biggs CM, Cordeiro-Santanach A, Prykhozhij SV, Deveau AP, Lin Y, Del Bel KL, Orben F, Ragotte RJ, Saferali A, Mostafavi S, Dinh L, Dai D, Weinacht KG, Dobbs K, Ott de Bruin L, Sharma M, Tsai K, Priatel JJ, Schreiber RA, Rozmus J, Hosking MC, Shopsowitz KE, McKinnon ML, Vercauteren S, Seear M, Notarangelo LD, Lynn FC, Berman JN, Turvey SE. Human JAK1 gain of function causes dysregulated myelopoeisis and severe allergic inflammation. JCI Insight. 2022 Dec 22;7(24):e150849. doi: 10.1172/jci.insight.150849. PMID: 36546480; PMCID: PMC9869972.

Primary atopic disorders are a group of rare inherited conditions that cause severe allergic disease. Each of these disorders is monogenic—controlled by a single gene—and causes its own unique condition. Studying primary atopic disorders teaches us about the genes and biology underlying allergic disease. We can then apply these lessons learned to identify better treatments for both primary atopic disorders and common allergic conditions. 

In this study, researchers explored a germline gain-of-function variant in the JAK1 gene, which is a cause of severe atopy (the genetic predisposition to developing allergic diseases) and eosinophilia (an unusually high number of a type of white blood cell called eosinophils). To investigate how enhanced JAK1 signaling promotes allergic inflammation, the team performed RNA sequencing of human whole blood, induced pluripotent stem cells, and zebrafish carrying the JAK1 gain-of-function variant.

Results reveal that the JAK1 gain-of-function variant causes dysregulated myelopoiesis (production of blood cells in bone marrow) and severe allergic inflammation. For two pediatric patients carrying the variant, researchers found that long-term treatment with the drug ruxolitinib remarkably improved their growth, eosinophilia, and clinical features of allergic inflammation. Authors note that this study highlights the role of JAK1 signaling in atopic immune dysregulation, as well as the clinical impact of medications inhibiting JAK1 and JAK2 in treating eosinophilic and allergic disease. 

Cowan MJ, Yu J, Facchino J, Fraser-Browne C, Sanford U, Kawahara M, Dara J, Long-Boyle J, Oh J, Chan W, Chag S, Broderick L, Chellapandian D, Decaluwe H, Golski C, Hu D, Kuo CY, Miller HK, Petrovic A, Currier R, Hilton JF, Punwani D, Dvorak CC, Malech HL, McIvor RS, Puck JM. Lentiviral Gene Therapy for Artemis-Deficient SCID. N Engl J Med. 2022 Dec 22;387(25):2344-2355. doi: 10.1056/NEJMoa2206575. PMID: 36546626.

Artemis-deficient severe combined immunodeficiency (ART-SCID) is a rare form of primary immune deficiency caused by mutations in the DCLRE1C gene. Allogeneic hematopoietic-cell transplantation, the standard treatment for patients with SCID, can effectively treat other forms of SCID. However, ART-SCID does not respond well to this therapy, highlighting the need for alternative treatments. In this study, researchers evaluated the effects of transfusing lentiviral gene-corrected autologous CD34+ bone marrow cells in 10 infants with newly diagnosed ART-SCID. The team followed these patients for a median of 31.2 months. Findings showed that infusion of these bone marrow cells—after conditioning with a low dose of the chemotherapy drug busulfan—resulted in genetically corrected and functional T and B cells. Authors state that larger studies of longer duration are needed to further assess the safety and efficacy of this approach.

Dvorak CC, Haddad E, Heimall J, Dunn E, Cowan MJ, Pai SY, Kapoor N, Satter LF, Buckley RH, O'Reilly RJ, Chandra S, Bednarski JJ, Williams O, Rayes A, Moore TB, Ebens CL, Davila Saldana BJ, Petrovic A, Chellapandian D, Cuvelier GDE, Vander Lugt MT, Caywood EH, Chandrakasan S, Eissa H, Goldman FD, Shereck E, Aquino VM, Desantes KB, Madden LM, Miller HK, Yu L, Broglie L, Gillio A, Shah AJ, Knutsen AP, Andolina JP, Joshi AY, Szabolcs P, Kapadia M, Martinez CA, Parrot RE, Sullivan KE, Prockop SE, Abraham RS, Thakar MS, Leiding JW, Kohn DB, Pulsipher MA, Griffith LM, Notarangelo LD, Puck JM. The diagnosis of severe combined immunodeficiency: Implementation of the PIDTC 2022 Definitions. J Allergy Clin Immunol. 2022 Nov 28:S0091-6749(22)01478-6. doi: 10.1016/j.jaci.2022.10.021. Epub ahead of print. PMID: 36456360.

In 2014, the Primary Immune Deficiency Treatment Consortium (PIDTC) published criteria developed for the diagnosis and classification of severe combined immunodeficiency (SCID) patients enrolling in their protocols. Since then, newborn screening for SCID has become increasingly common, as well as more rapid and less costly genetic sequencing. In light of these advances, the PIDTC updated their definitions in 2022. In this study, researchers compared the performance of the original versus the updated definitions. The team analyzed 379 patients who were proposed for enrollment in a PIDTC prospective protocol that follows SCID patients longitudinally, focusing on the ability to distinguish patients with various subtypes of SCID. Results showed that the 2022 definitions described SCID and its subtypes more precisely than the 2014 definitions. Authors state that these updates can facilitate improved analyses of SCID characteristics and outcomes.

Dvorak CC, Haddad E, Heimall J, Dunn E, Buckley RH, Kohn DB, Cowan MJ, Pai SY, Griffith LM, Cuvelier GDE, Eissa H, Shah AJ, O'Reilly RJ, Pulsipher MA, Wright NAM, Abraham RS, Satter LF, Notarangelo LD, Puck JM. The diagnosis of severe combined immunodeficiency (SCID): The Primary Immune Deficiency Treatment Consortium (PIDTC) 2022 Definitions. J Allergy Clin Immunol. 2022 Nov 28:S0091-6749(22)01479-8. doi: 10.1016/j.jaci.2022.10.022. Epub ahead of print. PMID: 36456361.

Severe combined immunodeficiency (SCID) is a severe form of primary immune deficiency characterized by extreme weakness or absence of immune system function, manifesting at birth. SCID results from abnormalities in responses of both T cells and B cells, which are types of white blood cells needed for immune system function. In 2014, the Primary Immune Deficiency Treatment Consortium (PIDTC) published criteria used to qualify patients for enrollment in their prospective and retrospective studies of SCID. In this article, researchers update the criteria, incorporating contemporary diagnostic approaches. These include increased availability of gene sequencing, as well as widespread population-based newborn screening for SCID. This article proposes that these criteria be used to establish a diagnosis of SCID in 2022. Authors state that the new definitions allow for more precise categorization of patients with SCID and atypical or leaky SCID. However, the definitions do not imply a preferred treatment strategy.

Puck JM. A Spot of Good News: Israeli Experience With SCID Newborn Screening. J Allergy Clin Immunol Pract. 2022 Oct;10(10):2732-2733. doi: 10.1016/j.jaip.2022.08.014.

Arnold DE, Chellapandian D, Parikh S, Mallhi K, Marsh RA, Heimall JR, Grossman D, Chitty-Lopez M, Murguia-Favela L, Gennery AR, Boulad F, Arbuckle E, Cowan MJ, Dvorak CC, Griffith LM, Haddad E, Kohn DB, Notarangelo LD, Pai SY, Puck JM, Pulsipher MA, Torgerson T, Kang EM, Malech HL, Leiding JW. Granulocyte Transfusions in Patients with Chronic Granulomatous Disease Undergoing Hematopoietic Cell Transplantation or Gene Therapy. J Clin Immunol. 2022 Jul;42(5):1026-1035. doi: 10.1007/s10875-022-01261-1. Epub 2022 Apr 21. PMID: 35445907; PMCID: PMC9022412.

Chandrakasan S, Chandra S, Prince C, Kobrynski LJ, Lucas L, Patel K, Walter J, Buckley RH, Meisel R, Ghosh S, Parikh SH. HSCT using carrier donors for CD40L deficiency results in excellent immune function and higher CD40L expression in cTfh. Blood Adv. 2022 Jun 28;6(12):3751-3755. doi: 10.1182/bloodadvances.2021006905. PMID: 35443026.

PIDTC: HSCT using carrier donors for CD40L deficiency results in excellent immune function and higher CD40L expression in cTfh CD40 ligand (CD40L) deficiency is a rare X-linked immunodeficiency disorder that leads to recurrent bacterial infections. Not much is known about the immune status of CD40L-deficient carriers, or possible outcomes of hematopoietic stem cell transplantation (HSCT) using these carriers as donors for CD40L-deficient patients. In this study, researchers evaluated the immune profiles of 7 carriers—including 4 who acted as HSCT donors for family members with CD40L deficiency—and characterized their HSCT outcomes. Results show that most carriers with CD40L deficiency have a normal immune profile with differential high CD40L expression in circulating T follicular helper (cTfh) cells, which are critical for immune response. The team also reported excellent long-term immune reconstitution in CD40L-deficient patients after HSCT using carrier donors. Authors state that HSCT using X-linked carriers seems to be safe and results in excellent outcomes. Authors also note that this decision should be individualized and driven by the biology of the disease. Note: First author Shanmuganathan Chandrakasan, MD, received the 2017 PIDTC Fellowship Award.

Cuvelier GDE, Logan BR, Prockop S, Buckley RH, Kuo CY, Griffith LM, Liu X, Yip A, Hershfield M, Ayoub P, Moore TB, Dorsey M, O'Reilly RJ, Kapoor N, Pai SY, Kapadia M, Ebens CL, Forbes Satter LR, Burroughs L, Petrovic A, Chellapandian D, Heimall J, Shyr D, Rayes A, Bednarski JJ, Chandra S, Chandrakasan S, Gilio AP, Madden LM, Quigg TC, Caywood EH, Dávila Saldaña BJ, DeSantes K, Eissa H, Goldman FD, Rozmus J, Shah A, Vander Lugt MT, Thakar MS, Parrott RE, Martinez CA, Leiding JW, Torgerson TR, Pulsipher MA, Notarangelo LD, Cowan MJ, Dvorak CC, Haddad E, Puck JM, Kohn DB. Outcomes Following Treatment for Adenosine Deaminase Deficient Severe Combined Immunodeficiency: A Report from the PIDTC. Blood. 2022 Jun 7:blood.2022016196. doi: 10.1182/blood.2022016196. Epub ahead of print. PMID: 35671392.

Kumar D, Rostad CA, Jaggi P, Villacis Nunez DS, Prince C, Lu A, Hussaini L, Nguyen TH, Malik S, Ponder LA, Shenoy SPV, Anderson EJ, Briones M, Sanz I, Prahalad S, Chandrakasan S. Distinguishing immune activation and inflammatory signatures of multisystem inflammatory syndrome in children (MIS-C) versus hemophagocytic lymphohistiocytosis (HLH). J Allergy Clin Immunol. 2022 May;149(5):1592-1606.e16. doi: 10.1016/j.jaci.2022.02.028. Epub 2022 Mar 15. PMID: 35304157; PMCID: PMC8923010.

Blom M, Zetterström RH, Stray-Pedersen A, Gilmour K, Gennery AR, Puck JM, van der Burg M. Recommendations for uniform definitions used in newborn screening for severe combined immunodeficiency. J Allergy Clin Immunol. 2022 Apr;149(4):1428-1436. doi: 10.1016/j.jaci.2021.08.026. Epub 2021 Sep 16.

Delmonte OM, Castagnoli R, Yu J, Dvorak CC, Cowan MJ, Dávila Saldaña BJ, De Ravin SS, Mamcarz E, Chang CK, Daley SR, Griffith LM, Notarangelo LD, Puck JM. Poor T-cell receptor β repertoire diversity early posttransplant for severe combined immunodeficiency predicts failure of immune reconstitution. J Allergy Clin Immunol. 2022 Mar;149(3):1113-1119. doi: 10.1016/j.jaci.2021.07.029. Epub 2021 Aug 9. PMID: 34384841; PMCID: PMC9132846.

Severe combined immunodeficiency (SCID) is a form of primary immune deficiency characterized by impaired T-cell development. Following hematopoietic cell transplantation (HCT) for SCID, development of a diverse T-cell receptor β (TRB) repertoire is associated with immune recovery. In this study, researchers investigated whether longitudinal analysis of the TRB repertoire would accurately describe T-cell receptor diversity and composition following HCT for SCID. Using high-throughput sequencing, the team studied the TRB repertoire in 27 infants with SCID at 3, 6, and 12 months and yearly posttreatment(s). Results showed that TRB repertoire after HCT for SCID provides a quantitative and qualitative measure of diversity of T-cell reconstitution. Authors note that this analysis can help identify patients who may require a second intervention.

Kumar D, Prince C, Bennett CM, Briones M, Lucas L, Russell A, Patel K, Chonat S, Graciaa S, Edington H, White MH, Kobrynski L, Abdalgani M, Parikh S, Chandra S, Bleesing J, Marsh R, Park S, Waller EK, Prahalad S, Chandrakasan S. T-follicular helper cell expansion and chronic T-cell activation are characteristic immune anomalies in Evans syndrome. Blood. 2022 Jan 20;139(3):369-383. doi: 10.1182/blood.2021012924.

Puck JM, Gennery AR. Establishing Newborn Screening for SCID in the USA; Experience in California. Int J Neonatal Screen. 2021 Oct 31;7(4):72. doi: 10.3390/ijns7040072. PMID: 34842619; PMCID: PMC8628983.

Shamriz O, Kumar D, Shim J, Briones M, Quarmyne MO, Chonat S, Lucas L, Edington H, White MH, Mahajan A, Park S, Chandrakasan S. T Cell-Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis (HLH) Occurs in Non-Asians and Is Associated with a T Cell Activation State that Is Comparable to Primary HLH. J Clin Immunol. 2021 Oct;41(7):1582-1596. doi: 10.1007/s10875-021-01073-9. Epub 2021 Jun 26.

Smith H, Scalchunes C, Cowan MJ, Puck J, Heimall J. Expectations and experience: Parent and patient perspectives regarding treatment for Severe Combined Immunodeficiency (SCID). Clin Immunol. 2021 Aug;229:108778. doi: 10.1016/j.clim.2021.108778. Epub 2021 Jun 16. PMID: 34144198; PMCID: PMC8559521.

Severe combined immunodeficiency (SCID) is a group of rare disorders caused by mutations in different genes involved in the development and function of infection-fighting immune cells. Infants with SCID are treated with hematopoietic cell transplantation (HCT, also called bone marrow transplantation or stem cell transplantation) or gene therapy (an experimental form of treatment that uses transfer of genetic material into the cell of a patient to treat or stop disease). To test parent and patient expectations and experience with these treatments, researchers distributed 151 surveys to families of patients with SCID treated with HCT or gene therapy. They found that 37% of respondents expected the therapy would lead to a “cure” and 43% expected it would last a lifetime. Researchers found that varying interpretations of the word “cure” led to misunderstandings regarding the need for continued medical evaluations and therapies. They concluded that clear communication about the importance of lifelong follow-up, regardless of treatment outcome, is needed to optimize health and quality of life.

Forlanini F, Dara J, Dvorak CC, Cowan MJ, Puck JM, Dorsey MJ. Unknown cytomegalovirus serostatus in primary immunodeficiency disorders: A new category of transplant recipients. Transpl Infect Dis. 2021 Apr;23(2):e13504. doi: 10.1111/tid.13504. Epub 2020 Nov 29.

Narain S, Stefanov DG, Chau AS, Weber AG, Marder G, Kaplan B, Malhotra P, Bloom O, Liu A, Lesser ML, Hajizadeh N; Northwell COVID-19 Research Consortium. Comparative Survival Analysis of Immunomodulatory Therapy for Coronavirus Disease 2019 Cytokine Storm. Chest. 2021 Mar;159(3):933-948. doi: 10.1016/j.chest.2020.09.275. Epub 2020 Oct 17.

Currier R, Puck JM. SCID newborn screening: What we've learned. J Allergy Clin Immunol. 2021 Feb;147(2):417-426. doi: 10.1016/j.jaci.2020.10.020.

Maron G, Kaste S, Bahrami A, Neel M, Malech HL, Puck JM, Cowan MJ, Gottschalk S, Mamcarz E. Successful SCID gene therapy in infant with disseminated BCG. J Allergy Clin Immunol Pract. 2021 Feb;9(2):993-995.e1. doi: 10.1016/j.jaip.2020.09.004. Epub 2020 Sep 16.

Buchbinder D, Walter JE, Butte MJ, Chan WY, Chitty Lopez M, Dimitriades VR, Dorsey MJ, Nugent DJ, Puck JM, Singh J, Collins CA. When Screening for Severe Combined Immunodeficiency (SCID) with T Cell Receptor Excision Circles Is Not SCID: a Case-Based Review. J Clin Immunol. 2021 Feb;41(2):294-302. doi: 10.1007/s10875-020-00931-2. Epub 2021 Jan 7. PMID: 33411155; PMCID: PMC8179373.

Dorsey MJ, Wright NAM, Chaimowitz NS, Dávila Saldaña BJ, Miller H, Keller MD, Thakar MS, Shah AJ, Abu-Arja R, Andolina J, Aquino V, Barnum JL, Bednarski JJ, Bhatia M, Bonilla FA, Butte MJ, Bunin NJ, Chandra S, Chaudhury S, Chen K, Chong H, Cuvelier GDE, Dalal J, DeFelice ML, DeSantes KB, Forbes LR, Gillio A, Goldman F, Joshi AY, Kapoor N, Knutsen AP, Kobrynski L, Lieberman JA, Leiding JW, Oshrine B, Patel KP, Prockop S, Quigg TC, Quinones R, Schultz KR, Seroogy C, Shyr D, Siegel S, Smith AR, Torgerson TR, Vander Lugt MT, Yu LC, Cowan MJ, Buckley RH, Dvorak CC, Griffith LM, Haddad E, Kohn DB, Logan B, Notarangelo LD, Pai SY, Puck J, Pulsipher MA, Heimall J. Infections in Infants with SCID: Isolation, Infection Screening, and Prophylaxis in PIDTC Centers. J Clin Immunol. 2021 Jan;41(1):38-50. doi: 10.1007/s10875-020-00865-9. Epub 2020 Oct 2.

Chau AS, Weber AG, Maria NI, Narain S, Liu A, Hajizadeh N, Malhotra P, Bloom O, Marder G, Kaplan B. The Longitudinal Immune Response to Coronavirus Disease 2019: Chasing the Cytokine Storm. Arthritis Rheumatol. 2021 Jan;73(1):23-35. doi: 10.1002/art.41526. Epub 2020 Dec 1.

Chan AY, Torgerson TR. Primary immune regulatory disorders: a growing universe of immune dysregulation. Curr Opin Allergy Clin Immunol. 2020 Dec;20(6):582-590. doi: 10.1097/ACI.0000000000000689.

Meitlis I, Allenspach EJ, Bauman BM, Phan IQ, Dabbah G, Schmitt EG, Camp ND, Torgerson TR, Nickerson DA, Bamshad MJ, Hagin D, Luthers CR, Stinson JR, Gray J, Lundgren I, Church JA, Butte MJ, Jordan MB, Aceves SS, Schwartz DM, Milner JD, Schuval S, Skoda-Smith S, Cooper MA, Starita LM, Rawlings DJ, Snow AL, James RG. Multiplexed Functional Assessment of Genetic Variants in CARD11. Am J Hum Genet. 2020 Nov 12:S0002-9297(20)30373-6. doi: 10.1016/j.ajhg.2020.10.015. Epub ahead of print. PMID: 33202260. PMCID: PMC7820631.

There has been a rapid increase in the availability and utilization of genetic testing in medicine, but the interpretation of these genetic results is often lagging. Patients often get reports labeling variants of “uncertain significance”, which should not be used for medical decision making. This hinders precision medicine. There are many pieces of data that clinicians and geneticists use to interpret variants as either benign or disease-causing including functional testing. Often this time-consuming process follows variant identification and delays treatment. In this study, we focused on a novel approach to simultaneously screen the functional effect of a large number of variants in the gene CARD11, an adaptor protein that expresses blocking or gain-offunction variants associated with distinct immunodeficiencies. We used genome editing to make a population of cells with all possible genetic changes at the same time to functionally screen them to provide a database to provide up front predictions. This information can now be utilized together with family history, clinical symptoms and other laboratory testing to aid in diagnosis. We generated functional scores for 2,542 coding and 38 noncoding variants of CARD11 and applied our predictions to new patients with novel mutations and compared to traditional methods. The classification of reported clinical variants was sensitive (94.6%) and specific (88.9%), which rendered the data immediately useful for interpretation of seven coding and splicing variants implicated in immunodeficiency ISSUE 12 |WINTER 2020| PAGE 6 found in our clinic. This approach is generalizable for variant interpretation in many other clinically actionable genes, in any relevant cell type.

Bosticardo M, Pala F, Calzoni E, Delmonte OM, Dobbs K, Gardner CL, Sacchetti N, Kawai T, Garabedian EK, Draper D, Bergerson JRE, DeRavin SS, Freeman AF, Güngör T, Hartog N, Holland SM, Kohn DB, Malech HL, Markert ML, Weinacht KG, Villa A, Seet CS, Montel-Hagen A, Crooks GM, Notarangelo LD. Artificial thymic organoids represent a reliable tool to study T-cell differentiation in patients with severe T-cell lymphopenia. Blood Adv. 2020 Jun 23;4(12):2611-2616. doi: 10.1182/bloodadvances.2020001730.

Bifsha P, Leiding JW, Pai SY, Colamartino ABL, Hartog N, Church JA, Oshrine BR, Puck JM, Markert ML, Haddad E. Diagnostic assay to assist clinical decisions for unclassified severe combined immune deficiency. Blood Adv. 2020 Jun 23;4(12):2606-2610. doi: 10.1182/bloodadvances.2020001736.

Burroughs LM, Petrovic A, Brazauskas R, Liu X, Griffith LM, Ochs HD, Bleesing JJ, Edwards S, Dvorak CC, Chaudhury S, Prockop SE, Quinones R, Goldman FD, Quigg TC, Chandrakasan S, Smith AR, Parikh S, Dávila Saldaña BJ, Thakar MS, Phelan R, Shenoy S, Forbes LR, Martinez C, Chellapandian D, Shereck E, Miller HK, Kapoor N, Barnum JL, Chong H, Shyr DC, Chen K, Abu-Arja R, Shah AJ, Weinacht KG, Moore TB, Joshi A, DeSantes KB, Gillio AP, Cuvelier GDE, Keller MD, Rozmus J, Torgerson T, Pulsipher MA, Haddad E, Sullivan KE, Logan BR, Kohn DB, Puck JM, Notarangelo LD, Pai SY, Rawlings DJ, Cowan MJ. Excellent outcomes following hematopoietic cell transplantation for Wiskott-Aldrich syndrome: a PIDTC report. Blood. 2020 Jun 4;135(23):2094-2105. doi: 10.1182/blood.2019002939.

We are excited to share the results of our paper, “Excellent Outcomes Following Hematopoietic Cell Transplantation for Wiskott-Aldrich Syndrome: A PIDTC Report” that was recently published in the medical journal, Blood in June 2020. PIDTC 6904 is a clinical research study of the outcomes of patients with Wiskott-Aldrich syndrome who have undergone transplant at PIDTC centers. The study was open at over 42 PIDTC centers and has enrolled over 300 patients across North America! Patients with Wiskott-Aldrich syndrome (WAS) are at increased risk for lifethreatening infections, bleeding complications, and autoimmune problems due to their disease. Transplant is the primary curative approach, with the goal of correcting the underlying immune and platelet problems. In our first paper, we did a retrospective study of 129 patients with WAS who had undergone transplantation at PIDTC centers from 2005-2015. Importantly, we found excellent survival (>90%) following transplant regardless of what type of donor (sibling or unrelated donor) or hematopoietic cell source (bone marrow, peripheral blood, or cord blood) was used. Age at transplant remained a key factor with better survival in patients who were younger than age 5 years at the time of transplant versus those who were older. This finding highlights the importance of performing the transplant early in the course of the disease before the patient develops complications which can make it more difficult to do the transplant safely. We also looked at how the type of conditioning the patient received (full intensity versus reduced intensity) affects transplant outcomes. We did not find a difference in survival; however, we did find a difference in engraftment (how well the transplant took) with higher donor cell percentage in patients who received Busulfan-based conditioning regimens versus other reduced intensity regimens. Higher donor cell percentage in turn was needed to correct the platelet count. Which conditioning regimen is best remains an unanswered question that we are hoping to study further in our next paper, which includes more retrospective cases and data from patients who enrolled in our prospective natural history study. Additional studies are also needed that look at the long-term outcomes of patients who have undergone transplant. This study highlights the importance of centers working together to advance patient care, particularly for patients with rare diseases. The PIDTC is a consortium of 43 centers in North America whose shared goal is to improve the outcomes of patients with rare, life threatening, inherited disorders of the immune system ISSUE 12 |WINTER 2020| PAGE 10 including WAS, severe combined immunodeficiency (SCID), chronic granulomatous disease (CGD), and primary immune regulatory disorders. We would like to thank all the patients and families who made this work possible!

Takushi SE, Paik NY, Fedanov A, Prince C, Doering CB, Spencer HT, Chandrakasan S. Lentiviral Gene Therapy for Familial Hemophagocytic Lymphohistiocytosis Type 3, Caused by UNC13D Genetic Defects. Hum Gene Ther. 2020 Jun;31(11-12):626-638. doi: 10.1089/hum.2019.329.

Weber AG, Chau AS, Egeblad M, Barnes BJ, Janowitz T. Nebulized in-line endotracheal dornase alfa and albuterol administered to mechanically ventilated COVID-19 patients: A case series. medRxiv. 2020 May 15:2020.05.13.20087734. doi: 10.1101/2020.05.13.20087734. Preprint.

Chan AY, Leiding JW, Liu X, Logan BR, Burroughs LM, Allenspach EJ, Skoda-Smith S, Uzel G, Notarangelo LD, Slatter M, Gennery AR, Smith AR, Pai SY, Jordan MB, Marsh RA, Cowan MJ, Dvorak CC, Craddock JA, Prockop SE, Chandrakasan S, Kapoor N, Buckley RH, Parikh S, Chellapandian D, Oshrine BR, Bednarski JJ, Cooper MA, Shenoy S, Davila Saldana BJ, Forbes LR, Martinez C, Haddad E, Shyr DC, Chen K, Sullivan KE, Heimall J, Wright N, Bhatia M, Cuvelier GDE, Goldman FD, Meyts I, Miller HK, Seidel MG, Vander Lugt MT, Bacchetta R, Weinacht KG, Andolina JR, Caywood E, Chong H, de la Morena MT, Aquino VM, Shereck E, Walter JE, Dorsey MJ, Seroogy CM, Griffith LM, Kohn DB, Puck JM, Pulsipher MA, Torgerson TR. Hematopoietic Cell Transplantation in Patients With Primary Immune Regulatory Disorders (PIRD): A Primary Immune Deficiency Treatment Consortium (PIDTC) Survey. Front Immunol. 2020 Feb 21;11:239. doi: 10.3389/fimmu.2020.00239. eCollection 2020.

Primary Immune Regulatory Disorders (PIRD) are a new group of conditions where the immune system is not responding and regulating the immune response appropriately. These diseases can affect multiple organs and are often cared for by many different specialists. Thus, little is known about the natural history of this group of diseases and the ideal treatment for PIRD. To help us better understand this group of disorders, we conducted a survey among 30 centers in the PIDTC and 3 centers in Europe to look at the outcome of patients that have been transplanted for PIRD. We collected data on 226 patients who had received a transplant for a PIRD condition. Roughly 75% of patients had a genetic diagnosis and a quarter did not. Most patients developed symptoms within a year of age. Almost all organ systems were affected, and many patients had multiple affected organs. The most common problems included gastrointestinal issues, blood count issues (autoimmune cytopenias), and rashes. The main reason for transplant was autoimmune problems (41%), and the next most common reason was infections (26%). Roughly a quarter of the patients had multiple reasons for transplant. Nearly all of the patients were transplanted before 18 years of age, and approximately a quarter of the patients were transplanted before a year of age. More than half of patients had resolution of their symptoms, and the overall 5-year survival for transplanted PIRD patients was 67%. This is the first study to look at transplant for PIRD and highlights a need to improve our understanding of this condition and what therapies are ideal for treating this group. This survey served as the basis for the development of the 6906 protocol which will focus on studying the natural history of PIRD to improve survival for patients with this condition.

Amatuni GS, Sciortino S, Currier RJ, Naides SJ, Church JA, Puck JM. Reference intervals for lymphocyte subsets in preterm and term neonates without immune defects. J Allergy Clin Immunol. 2019 Dec;144(6):1674-1683. doi: 10.1016/j.jaci.2019.05.038. Epub 2019 Jun 18.

Shah AJ, Sokolic R, Logan B, Yin Z, Iyengar S, Scalchunes C, Mangurian C, Albert M, Cowan MJ. Quality of Life of Patients with Wiskott Aldrich Syndrome and X-Linked Thrombocytopenia: a Study of the Primary Immune Deficiency Consortium (PIDTC), Immune Deficiency Foundation, and the Wiskott-Aldrich Foundation. J Clin Immunol. 2019 Nov;39(8):786-794. doi: 10.1007/s10875-019-00689-2. Epub 2019 Oct 16.

Marsh RA, Leiding JW, Logan BR, Griffith LM, Arnold DE, Haddad E, Falcone EL, Yin Z, Patel K, Arbuckle E, Bleesing JJ, Sullivan KE, Heimall J, Burroughs LM, Skoda-Smith S, Chandrakasan S, Yu LC, Oshrine BR, Cuvelier GDE, Thakar MS, Chen K, Teira P, Shenoy S, Phelan R, Forbes LR, Chellapandian D, Dávila Saldaña BJ, Shah AJ, Weinacht KG, Joshi A, Boulad F, Quigg TC, Dvorak CC, Grossman D, Torgerson T, Graham P, Prasad V, Knutsen A, Chong H, Miller H, de la Morena MT, DeSantes K, Cowan MJ, Notarangelo LD, Kohn DB, Stenger E, Pai SY, Routes JM, Puck JM, Kapoor N, Pulsipher MA, Malech HL, Parikh S, Kang EM; submitted on behalf of the Primary Immune Deficiency Treatment Consortium. Chronic Granulomatous Disease-Associated IBD Resolves and Does Not Adversely Impact Survival Following Allogeneic HCT. J Clin Immunol. 2019 Oct;39(7):653-667. doi: 10.1007/s10875-019-00659-8. Epub 2019 Aug 2.

Mangurian C, Scalchunes C, Yoo J, Logan B, Henderson T, Iyengar S, Smith H, Cowan MJ. Psychosocial services for primary immunodeficiency disorder families during hematopoietic cell transplantation: A descriptive study. Palliat Support Care. 2019 Aug;17(4):409-414. doi: 10.1017/S1478951518000603.

Dvorak CC, Long-Boyle J, Dara J, Melton A, Shimano KA, Huang JN, Puck JM, Dorsey MJ, Facchino J, Chang CK, Cowan MJ. Low Exposure Busulfan Conditioning to Achieve Sufficient Multilineage Chimerism in Patients with Severe Combined Immunodeficiency. Biol Blood Marrow Transplant. 2019 Jul;25(7):1355-1362. doi: 10.1016/j.bbmt.2019.03.008. Epub 2019 Mar 12.

Ferrua F, Galimberti S, Courteille V, Slatter MA, Booth C, Moshous D, Neven B, Blanche S, Cavazzana M, Laberko A, Shcherbina A, Balashov D, Soncini E, Porta F, Al-Mousa H, Al-Saud B, Al-Dhekri H, Arnaout R, Formankova R, Bertrand Y, Lange A, Smart J, Wolska-Kusnierz B, Aquino VM, Dvorak CC, Fasth A, Fouyssac F, Heilmann C, Hoenig M, Schuetz C, Kelečić J, Bredius RGM, Lankester AC, Lindemans CA, Suarez F, Sullivan KE, Albert MH, Kałwak K, Barlogis V, Bhatia M, Bordon V, Czogala W, Alonso L, Dogu F, Gozdzik J, Ikinciogullari A, Kriván G, Ljungman P, Meyts I, Mustillo P, Smith AR, Speckmann C, Sundin M, Keogh SJ, Shaw PJ, Boelens JJ, Schulz AS, Sedlacek P, Veys P, Mahlaoui N, Janda A, Davies EG, Fischer A, Cowan MJ, Gennery AR; SCETIDE, PIDTC, EBMT & ESID IEWP. Hematopoietic stem cell transplantation for CD40 ligand deficiency: Results from an EBMT/ESID-IEWP-SCETIDE-PIDTC study. J Allergy Clin Immunol. 2019 Jun;143(6):2238-2253. doi: 10.1016/j.jaci.2018.12.1010. Epub 2019 Jan 17.

Yoo J, Halley MC, Lown EA, Yank V, Ort K, Cowan MJ, Dorsey MJ, Smith H, Iyengar S, Scalchunes C, Mangurian C. Supporting caregivers during hematopoietic cell transplantation for children with primary immunodeficiency disorders. J Allergy Clin Immunol. 2019 Jun;143(6):2271-2278. doi: 10.1016/j.jaci.2018.10.017. Epub 2018 Oct 25.

Mamcarz E, Zhou S, Lockey T, Abdelsamed H, Cross SJ, Kang G, Ma Z, Condori J, Dowdy J, Triplett B, Li C, Maron G, Aldave Becerra JC, Church JA, Dokmeci E, Love JT, da Matta Ain AC, van der Watt H, Tang X, Janssen W, Ryu BY, De Ravin SS, Weiss MJ, Youngblood B, Long-Boyle JR, Gottschalk S, Meagher MM, Malech HL, Puck JM, Cowan MJ, Sorrentino BP. Lentiviral Gene Therapy Combined with Low-Dose Busulfan in Infants with SCID-X1. N Engl J Med. 2019 Apr 18;380(16):1525-1534. doi: 10.1056/NEJMoa1815408.

Kohn DB, Hershfield MS, Puck JM, Aiuti A, Blincoe A, Gaspar HB, Notarangelo LD, Grunebaum E. Consensus approach for the management of severe combined immune deficiency caused by adenosine deaminase deficiency. J Allergy Clin Immunol. 2019 Mar;143(3):852-863. doi: 10.1016/j.jaci.2018.08.024. Epub 2018 Sep 5.

Amatuni GS, Currier RJ, Church JA, Bishop T, Grimbacher E, Nguyen AA, Agarwal-Hashmi R, Aznar CP, Butte MJ, Cowan MJ, Dorsey MJ, Dvorak CC, Kapoor N, Kohn DB, Markert ML, Moore TB, Naides SJ, Sciortino S, Feuchtbaum L, Koupaei RA, Puck JM. Newborn Screening for Severe Combined Immunodeficiency and T-cell Lymphopenia in California, 2010-2017. Pediatrics. 2019 Feb;143(2):e20182300. doi: 10.1542/peds.2018-2300.

Dorsey MJ, Puck JM. Newborn Screening for Severe Combined Immunodeficiency in the United States: Lessons Learned. Immunol Allergy Clin North Am. 2019 Feb;39(1):1-11. doi: 10.1016/j.iac.2018.08.002. Epub 2018 Nov 1.

Puck JM. Newborn screening for severe combined immunodeficiency and T-cell lymphopenia. Immunol Rev. 2019 Jan;287(1):241-252. doi: 10.1111/imr.12729.

Dvorak CC, Haddad E, Buckley RH, Cowan MJ, Logan B, Griffith LM, Kohn DB, Pai SY, Notarangelo L, Shearer W, Prockop S, Kapoor N, Heimall J, Chaudhury S, Shyr D, Chandra S, Cuvelier G, Moore T, Shenoy S, Goldman F, Smith AR, Sunkersett G, Vander Lugt M, Caywood E, Quigg T, Torgerson T, Chandrakasan S, Craddock J, Dávila Saldaña BJ, Gillio A, Shereck E, Aquino V, DeSantes K, Knutsen A, Thakar M, Yu L, Puck JM. The genetic landscape of severe combined immunodeficiency in the United States and Canada in the current era (2010-2018). J Allergy Clin Immunol. 2019 Jan;143(1):405-407. doi: 10.1016/j.jaci.2018.08.027. Epub 2018 Sep 5.

Sullivan KE, Conrad M, Kelsen JR. Very early-onset inflammatory bowel disease: an integrated approach. Curr Opin Allergy Clin Immunol. 2018 Dec;18(6):459-469. doi: 10.1097/ACI.0000000000000484.

Belderbos ME, Gennery AR, Dvorak CC, Blok HJ, Eikema DJ, Silva JMF, Veys P, Neven B, Buckley R, Cole T, Cowan MJ, Goebel WS, Hoenig M, Kuo CY, Stiehm ER, Wynn R, Bierings M; Inborn Errors Working Party of the European Group for Blood and Marrow Transplantation and the Primary Immune Deficiency Treatment Consortium. Outcome of domino hematopoietic stem cell transplantation in human subjects: An international case series. J Allergy Clin Immunol. 2018 Nov;142(5):1628-1631.e4. doi: 10.1016/j.jaci.2018.06.030. Epub 2018 Jul 5.

Chinen J, Cowan MJ. Advances and highlights in primary immunodeficiencies in 2017. J Allergy Clin Immunol. 2018 Oct;142(4):1041-1051. doi: 10.1016/j.jaci.2018.08.016. Epub 2018 Aug 29.

Buchbinder D, Smith MJ, Kawahara M, Cowan MJ, Buzby JS, Abraham RS. Application of a radiosensitivity flow assay in a patient with DNA ligase 4 deficiency. Blood Adv. 2018 Aug 14;2(15):1828-1832. doi: 10.1182/bloodadvances.2018016113.

Haddad E, Logan BR, Griffith LM, et al. SCID genotype and 6-month post-transplant CD4 count predict survival and immune recovery: a PIDTC retrospective study. Blood. Aug 2018. PMID: 30154114. Pending PMCID.

Puck JM. Lessons for Sequencing from the Addition of Severe Combined Immunodeficiency to Newborn Screening Panels. Hastings Cent Rep. 2018 Jul;48 Suppl 2(Suppl 2):S7-S9. doi: 10.1002/hast.875.

Miggelbrink AM, Logan BR, Buckley RH, Parrott RE, Dvorak CC, Kapoor N, Abdel-Azim H, Prockop SE, Shyr D, Decaluwe H, Hanson IC, Gillio A, Dávila Saldaña BJ, Eibel H, Hopkins G, Walter JE, Whangbo JS, Kohn DB, Puck JM, Cowan MJ, Griffith LM, Haddad E, O'Reilly RJ, Notarangelo LD, Pai SY. B-cell differentiation and IL-21 response in IL2RG/JAK3 SCID patients after hematopoietic stem cell transplantation. Blood. 2018 Jun 28;131(26):2967-2977. doi: 10.1182/blood-2017-10-809822. Epub 2018 May 4.

Kuo CY, Long JD, Campo-Fernandez B, de Oliveira S, Cooper AR, Romero Z, Hoban MD, Joglekar AV, Lill GR, Kaufman ML, Fitz-Gibbon S, Wang X, Hollis RP, Kohn DB. Site-Specific Gene Editing of Human Hematopoietic Stem Cells for X-Linked Hyper-IgM Syndrome. Cell Rep. 2018 May 29;23(9):2606-2616. doi: 10.1016/j.celrep.2018.04.103.

Barzaghi F, Amaya Hernandez LC, Neven B, Ricci S, Kucuk ZY, Bleesing JJ, Nademi Z, Slatter MA, Ulloa ER, Shcherbina A, Roppelt A, Worth A, Silva J, Aiuti A, Murguia-Favela L, Speckmann C, Carneiro-Sampaio M, Fernandes JF, Baris S, Ozen A, Karakoc-Aydiner E, Kiykim A, Schulz A, Steinmann S, Notarangelo LD, Gambineri E, Lionetti P, Shearer WT, Forbes LR, Martinez C, Moshous D, Blanche S, Fisher A, Ruemmele FM, Tissandier C, Ouachee-Chardin M, Rieux-Laucat F, Cavazzana M, Qasim W, Lucarelli B, Albert MH, Kobayashi I, Alonso L, Diaz De Heredia C, Kanegane H, Lawitschka A, Seo JJ, Gonzalez-Vicent M, Diaz MA, Goyal RK, Sauer MG, Yesilipek A, Kim M, Yilmaz-Demirdag Y, Bhatia M, Khlevner J, Richmond Padilla EJ, Martino S, Montin D, Neth O, Molinos-Quintana A, Valverde-Fernandez J, Broides A, Pinsk V, Ballauf A, Haerynck F, Bordon V, Dhooge C, Garcia-Lloret ML, Bredius RG, Kałwak K, Haddad E, Seidel MG, Duckers G, Pai SY, Dvorak CC, Ehl S, Locatelli F, Goldman F, Gennery AR, Cowan MJ, Roncarolo MG, Bacchetta R; Primary Immune Deficiency Treatment Consortium (PIDTC) and the Inborn Errors Working Party (IEWP) of the European Society for Blood and Marrow Transplantation (EBMT). Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study. J Allergy Clin Immunol. 2018 Mar;141(3):1036-1049.e5. doi: 10.1016/j.jaci.2017.10.041. Epub 2017 Dec 11.

Langelier C, Zinter MS, Kalantar K, Yanik GA, Christenson S, O'Donovan B, White C, Wilson M, Sapru A, Dvorak CC, Miller S, Chiu CY, DeRisi JL. Metagenomic Sequencing Detects Respiratory Pathogens in Hematopoietic Cellular Transplant Patients. Am J Respir Crit Care Med. 2018 Feb 15;197(4):524-528. doi: 10.1164/rccm.201706-1097LE.

Leiding JW, Okada S, Hagin D, Abinun M, Shcherbina A, Balashov DN, Kim VHD, Ovadia A, Guthery SL, Pulsipher M, Lilic D, Devlin LA, Christie S, Depner M, Fuchs S, van Royen-Kerkhof A, Lindemans C, Petrovic A, Sullivan KE, Bunin N, Kilic SS, Arpaci F, Calle-Martin O, Martinez-Martinez L, Aldave JC, Kobayashi M, Ohkawa T, Imai K, Iguchi A, Roifman CM, Gennery AR, Slatter M, Ochs HD, Morio T, Torgerson TR; Inborn Errors Working Party of the European Society for Blood and Marrow Transplantation and the Primary Immune Deficiency Treatment Consortium. Hematopoietic stem cell transplantation in patients with gain-of-function signal transducer and activator of transcription 1 mutations. J Allergy Clin Immunol. 2018 Feb;141(2):704-717.e5. doi: 10.1016/j.jaci.2017.03.049. Epub 2017 Jun 7.

Slack J, Albert MH, Balashov D, Belohradsky BH, Bertaina A, Bleesing J, Booth C, Buechner J, Buckley RH, Ouachée-Chardin M, Deripapa E, Drabko K, Eapen M, Feuchtinger T, Finocchi A, Gaspar HB, Ghosh S, Gillio A, Gonzalez-Granado LI, Grunebaum E, Güngör T, Heilmann C, Helminen M, Higuchi K, Imai K, Kalwak K, Kanazawa N, Karasu G, Kucuk ZY, Laberko A, Lange A, Mahlaoui N, Meisel R, Moshous D, Muramatsu H, Parikh S, Pasic S, Schmid I, Schuetz C, Schulz A, Schultz KR, Shaw PJ, Slatter MA, Sykora KW, Tamura S, Taskinen M, Wawer A, Wolska-Kuśnierz B, Cowan MJ, Fischer A, Gennery AR; Inborn Errors Working Party of the European Society for Blood and Marrow Transplantation and the European Society for Immunodeficiencies; Stem Cell Transplant for Immunodeficiencies in Europe (SCETIDE); Center for International Blood and Marrow Transplant Research; Primary Immunodeficiency Treatment Consortium. Outcome of hematopoietic cell transplantation for DNA double-strand break repair disorders. J Allergy Clin Immunol. 2018 Jan;141(1):322-328.e10. doi: 10.1016/j.jaci.2017.02.036. Epub 2017 Apr 7.

Heimall J, Logan BR, Cowan MJ, Notarangelo LD, Griffith LM, Puck JM, Kohn DB, Pulsipher MA, Parikh S, Martinez C, Kapoor N, O'Reilly R, Boyer M, Pai SY, Goldman F, Burroughs L, Chandra S, Kletzel M, Thakar M, Connelly J, Cuvelier G, Davila Saldana BJ, Shereck E, Knutsen A, Sullivan KE, DeSantes K, Gillio A, Haddad E, Petrovic A, Quigg T, Smith AR, Stenger E, Yin Z, Shearer WT, Fleisher T, Buckley RH, Dvorak CC. Immune reconstitution and survival of 100 SCID patients post-hematopoietic cell transplant: a PIDTC natural history study. Blood. 2017 Dec 21;130(25):2718-2727. doi: 10.1182/blood-2017-05-781849. Epub 2017 Oct 11.

Biggs CM, Haddad E, Issekutz TB, Roifman CM, Turvey SE. Newborn screening for severe combined immunodeficiency: a primer for clinicians. CMAJ. 2017 Dec 18;189(50):E1551-E1557. doi: 10.1503/cmaj.170561.

Rowe JH, Stadinski BD, Henderson LA, Ott de Bruin L, Delmonte O, Lee YN, de la Morena MT, Goyal RK, Hayward A, Huang CH, Kanariou M, King A, Kuijpers TW, Soh JY, Neven B, Walter JE, Huseby ES, Notarangelo LD. Abnormalities of T-cell receptor repertoire in CD4(+) regulatory and conventional T cells in patients with RAG mutations: Implications for autoimmunity. J Allergy Clin Immunol. 2017 Dec;140(6):1739-1743.e7. doi: 10.1016/j.jaci.2017.08.001. Epub 2017 Aug 31.

Heimall J, Cowan MJ. Long term outcomes of severe combined immunodeficiency: therapy implications. Expert Rev Clin Immunol. 2017 Nov;13(11):1029-1040. doi: 10.1080/1744666X.2017.1381558. Epub 2017 Sep 23.

Ivaturi V, Dvorak CC, Chan D, Liu T, Cowan MJ, Wahlstrom J, Stricherz M, Jennissen C, Orchard PJ, Tolar J, Pai SY, Huang L, Aweeka F, Long-Boyle J. Pharmacokinetics and Model-Based Dosing to Optimize Fludarabine Therapy in Pediatric Hematopoietic Cell Transplant Recipients. Biol Blood Marrow Transplant. 2017 Oct;23(10):1701-1713. doi: 10.1016/j.bbmt.2017.06.021. Epub 2017 Jul 3.

Dvorak CC, Puck JM, Wahlstrom JT, Dorsey M, Melton A, Cowan MJ. Neurologic event-free survival demonstrates a benefit for SCID patients diagnosed by newborn screening. Blood Adv. 2017 Sep 5;1(20):1694-1698. doi: 10.1182/bloodadvances.2017010835. eCollection 2017 Sep 12.

Heimall J, Buckley RH, Puck J, Fleisher TA, Gennery AR, Haddad E, Neven B, Slatter M, Roderick S, Baker KS, Dietz AC, Duncan C, Griffith LM, Notarangelo L, Pulsipher MA, Cowan MJ. Recommendations for Screening and Management of Late Effects in Patients with Severe Combined Immunodeficiency after Allogenic Hematopoietic Cell Transplantation: A Consensus Statement from the Second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects after Pediatric HCT. Biol Blood Marrow Transplant. 2017 Aug;23(8):1229-1240. doi: 10.1016/j.bbmt.2017.04.026. Epub 2017 May 4.

Dvorak CC, Patel K, Puck JM, Wahlstrom J, Dorsey MJ, Adams R, Facchino J, Cowan MJ. Unconditioned unrelated donor bone marrow transplantation for IL7Rα- and Artemis-deficient SCID. Bone Marrow Transplant. 2017 Jul;52(7):1036-1038. doi: 10.1038/bmt.2017.74. Epub 2017 Apr 24.

Hoenig M, Lagresle-Peyrou C, Pannicke U, Notarangelo LD, Porta F, Gennery AR, Slatter M, Cowan MJ, Stepensky P, Al-Mousa H, Al-Zahrani D, Pai SY, Al Herz W, Gaspar HB, Veys P, Oshima K, Imai K, Yabe H, Noroski LM, Wulffraat NM, Sykora KW, Soler-Palacin P, Muramatsu H, Al Hilali M, Moshous D, Debatin KM, Schuetz C, Jacobsen EM, Schulz AS, Schwarz K, Fischer A, Friedrich W, Cavazzana M; European Society for Blood and Marrow Transplantation (EBMT) Inborn Errors Working Party. Reticular dysgenesis: international survey on clinical presentation, transplantation, and outcome. Blood. 2017 May 25;129(21):2928-2938. doi: 10.1182/blood-2016-11-745638. Epub 2017 Mar 22.

de la Morena MT, Leonard D, Torgerson TR, Cabral-Marques O, Slatter M, Aghamohammadi A, Chandra S, Murguia-Favela L, Bonilla FA, Kanariou M, Damrongwatanasuk R, Kuo CY, Dvorak CC, Meyts I, Chen K, Kobrynski L, Kapoor N, Richter D, DiGiovanni D, Dhalla F, Farmaki E, Speckmann C, Español T, Shcherbina A, Hanson IC, Litzman J, Routes JM, Wong M, Fuleihan R, Seneviratne SL, Small TN, Janda A, Bezrodnik L, Seger R, Raccio AG, Edgar JD, Chou J, Abbott JK, van Montfrans J, González-Granado LI, Bunin N, Kutukculer N, Gray P, Seminario G, Pasic S, Aquino V, Wysocki C, Abolhassani H, Dorsey M, Cunningham-Rundles C, Knutsen AP, Sleasman J, Costa Carvalho BT, Condino-Neto A, Grunebaum E, Chapel H, Ochs HD, Filipovich A, Cowan M, Gennery A, Cant A, Notarangelo LD, Roifman CM. Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation. J Allergy Clin Immunol. 2017 Apr;139(4):1282-1292. doi: 10.1016/j.jaci.2016.07.039. Epub 2016 Sep 30.

Heimall J, Puck J, Buckley R, Fleisher TA, Gennery AR, Neven B, Slatter M, Haddad E, Notarangelo LD, Baker KS, Dietz AC, Duncan C, Pulsipher MA, Cowan MJ. Current Knowledge and Priorities for Future Research in Late Effects after Hematopoietic Stem Cell Transplantation (HCT) for Severe Combined Immunodeficiency Patients: A Consensus Statement from the Second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects after Pediatric HCT. Biol Blood Marrow Transplant. 2017 Mar;23(3):379-387. doi: 10.1016/j.bbmt.2016.12.619. Epub 2017 Jan 6.

Dorsey MJ, Dvorak CC, Cowan MJ, Puck JM. Treatment of infants identified as having severe combined immunodeficiency by means of newborn screening. J Allergy Clin Immunol. 2017 Mar;139(3):733-742. doi: 10.1016/j.jaci.2017.01.005.

Kumánovics A, Lee YN, Close DW, Coonrod EM, Ujhazi B, Chen K, MacArthur DG, Krivan G, Notarangelo LD, Walter JE. Estimated disease incidence of RAG1/2 mutations: A case report and querying the Exome Aggregation Consortium. J Allergy Clin Immunol. 2017 Feb;139(2):690-692.e3. doi: 10.1016/j.jaci.2016.07.027. Epub 2016 Sep 5.

Wahlstrom J, Patel K, Eckhert E, Kong D, Horn B, Cowan MJ, Dvorak CC. Transplacental maternal engraftment and posttransplantation graft-versus-host disease in children with severe combined immunodeficiency. J Allergy Clin Immunol. 2017 Feb;139(2):628-633.e10. doi: 10.1016/j.jaci.2016.04.049. Epub 2016 Jun 16.

Punwani D, Kawahara M, Yu J, Sanford U, Roy S, Patel K, Carbonaro DA, Karlen AD, Khan S, Cornetta K, Rothe M, Schambach A, Kohn DB, Malech HL, McIvor RS, Puck JM, Cowan MJ. Lentivirus Mediated Correction of Artemis-Deficient Severe Combined Immunodeficiency. Hum Gene Ther. 2017 Jan;28(1):112-124. doi: 10.1089/hum.2016.064. Epub 2016 Sep 7.

Dietz AC, Duncan CN, Alter BP, Bresters D, Cowan MJ, Notarangelo L, Rosenberg PS, Shenoy S, Skinner R, Walters MC, Wagner J, Baker KS, Pulsipher MA. The Second Pediatric Blood and Marrow Transplant Consortium International Consensus Conference on Late Effects after Pediatric Hematopoietic Cell Transplantation: Defining the Unique Late Effects of Children Undergoing Hematopoietic Cell Transplantation for Immune Deficiencies, Inherited Marrow Failure Disorders, and Hemoglobinopathies. Biol Blood Marrow Transplant. 2017 Jan;23(1):24-29. doi: 10.1016/j.bbmt.2016.10.004. Epub 2016 Oct 11.

Lee YN, Frugoni F, Dobbs K, Tirosh I, Du L, Ververs FA, Ru H, Ott de Bruin L, Adeli M, Bleesing JH, Buchbinder D, Butte MJ, Cancrini C, Chen K, Choo S, Elfeky RA, Finocchi A, Fuleihan RL, Gennery AR, El-Ghoneimy DH, Henderson LA, Al-Herz W, Hossny E, Nelson RP, Pai SY, Patel NC, Reda SM, Soler-Palacin P, Somech R, Palma P, Wu H, Giliani S, Walter JE, Notarangelo LD. Characterization of T and B cell repertoire diversity in patients with RAG deficiency. Sci Immunol. 2016 Dec 16;1(6):eaah6109. doi: 10.1126/sciimmunol.aah6109. Epub 2016 Dec 16.

Jackson SW, Scharping NE, Jacobs HM, Wang S, Chait A, Rawlings DJ. Cutting Edge: BAFF Overexpression Reduces Atherosclerosis via TACI-Dependent B Cell Activation. J Immunol. 2016 Dec 15;197(12):4529-4534. doi: 10.4049/jimmunol.1601198. Epub 2016 Nov 11.

Punwani D, Zhang Y, Yu J, Cowan MJ, Rana S, Kwan A, Adhikari AN, Lizama CO, Mendelsohn BA, Fahl SP, Chellappan A, Srinivasan R, Brenner SE, Wiest DL, Puck JM. Multisystem Anomalies in Severe Combined Immunodeficiency with Mutant BCL11B. N Engl J Med. 2016 Dec 1;375(22):2165-2176. doi: 10.1056/NEJMoa1509164.

Chinen J, Notarangelo LD, Shearer WT. Advances in clinical immunology in 2015. J Allergy Clin Immunol. 2016 Dec;138(6):1531-1540. doi: 10.1016/j.jaci.2016.10.005.

Schussler E, Beasley MB, Maglione PJ. Lung Disease in Primary Antibody Deficiencies. J Allergy Clin Immunol Pract. 2016 Nov-Dec;4(6):1039-1052. doi: 10.1016/j.jaip.2016.08.005.

Cowan MJ. The Primary Immune Deficiency Treatment Consortium: how can it improve definitive therapy for PID?. Expert Rev Clin Immunol. 2016 Oct;12(10):1007-9. doi: 10.1080/1744666X.2016.1216317. Epub 2016 Jul 29.

Brauer PM, Pessach IM, Clarke E, Rowe JH, Ott de Bruin L, Lee YN, Dominguez-Brauer C, Comeau AM, Awong G, Felgentreff K, Zhang YH, Bredemeyer A, Al-Herz W, Du L, Ververs F, Kennedy M, Giliani S, Keller G, Sleckman BP, Schatz DG, Bushman FD, Notarangelo LD, Zúñiga-Pflücker JC. Modeling altered T-cell development with induced pluripotent stem cells from patients with RAG1-dependent immune deficiencies. Blood. 2016 Aug 11;128(6):783-93. doi: 10.1182/blood-2015-10-676304. Epub 2016 Jun 14.

Griffith LM, Cowan MJ, Notarangelo LD, Kohn DB, Puck JM, Shearer WT, Burroughs LM, Torgerson TR, Decaluwe H, Haddad E; workshop participants. Primary Immune Deficiency Treatment Consortium (PIDTC) update. J Allergy Clin Immunol. 2016 Aug;138(2):375-85. doi: 10.1016/j.jaci.2016.01.051. Epub 2016 Apr 22.

Selleri S, Bifsha P, Civini S, Pacelli C, Dieng MM, Lemieux W, Jin P, Bazin R, Patey N, Marincola FM, Moldovan F, Zaouter C, Trudeau LE, Benabdhalla B, Louis I, Beauséjour C, Stroncek D, Le Deist F, Haddad E. Human mesenchymal stromal cell-secreted lactate induces M2-macrophage differentiation by metabolic reprogramming. Oncotarget. 2016 May 24;7(21):30193-210. doi: 10.18632/oncotarget.8623.

Merkel PA, Manion M, Gopal-Srivastava R, Groft S, Jinnah HA, Robertson D, Krischer JP; Rare Diseases Clinical Research Network. The partnership of patient advocacy groups and clinical investigators in the rare diseases clinical research network. Orphanet J Rare Dis. 2016 May 18;11(1):66. doi: 10.1186/s13023-016-0445-8.

De Ravin SS, Wu X, Moir S, Anaya-O'Brien S, Kwatemaa N, Littel P, Theobald N, Choi U, Su L, Marquesen M, Hilligoss D, Lee J, Buckner CM, Zarember KA, O'Connor G, McVicar D, Kuhns D, Throm RE, Zhou S, Notarangelo LD, Hanson IC, Cowan MJ, Kang E, Hadigan C, Meagher M, Gray JT, Sorrentino BP, Malech HL, Kardava L. Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency. Sci Transl Med. 2016 Apr 20;8(335):335ra57. doi: 10.1126/scitranslmed.aad8856.

Chan AY, Punwani D, Kadlecek TA, Cowan MJ, Olson JL, Mathes EF, Sunderam U, Fu SM, Srinivasan R, Kuriyan J, Brenner SE, Weiss A, Puck JM. A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70. J Exp Med. 2016 Feb 8;213(2):155-65. doi: 10.1084/jem.20150888. Epub 2016 Jan 18.

Burbank AJ, Shah SN, Montgomery M, Peden D, Tarrant TK, Weimer ET. Clinically focused exome sequencing identifies an homozygous mutation that confers DOCK8 deficiency. Pediatr Allergy Immunol. 2016 Feb;27(1):96-8. doi: 10.1111/pai.12451. Epub 2015 Oct 12.

Walter JE, Rosen LB, Csomos K, Rosenberg JM, Mathew D, Keszei M, Ujhazi B, Chen K, Lee YN, Tirosh I, Dobbs K, Al-Herz W, Cowan MJ, Puck J, Bleesing JJ, Grimley MS, Malech H, De Ravin SS, Gennery AR, Abraham RS, Joshi AY, Boyce TG, Butte MJ, Nadeau KC, Balboni I, Sullivan KE, Akhter J, Adeli M, El-Feky RA, El-Ghoneimy DH, Dbaibo G, Wakim R, Azzari C, Palma P, Cancrini C, Capuder K, Condino-Neto A, Costa-Carvalho BT, Oliveira JB, Roifman C, Buchbinder D, Kumanovics A, Franco JL, Niehues T, Schuetz C, Kuijpers T, Yee C, Chou J, Masaad MJ, Geha R, Uzel G, Gelman R, Holland SM, Recher M, Utz PJ, Browne SK, Notarangelo LD. Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency. J Clin Invest. 2015 Nov 2;125(11):4135-48. doi: 10.1172/JCI80477. Epub 2015 Oct 12.

Cowan MJ, Gennery AR. Radiation-sensitive severe combined immunodeficiency: The arguments for and against conditioning before hematopoietic cell transplantation--what to do?. J Allergy Clin Immunol. 2015 Nov;136(5):1178-85. doi: 10.1016/j.jaci.2015.04.027. Epub 2015 Jun 6.

Zinter MS, Dvorak CC, Spicer A, Cowan MJ, Sapru A. New Insights Into Multicenter PICU Mortality Among Pediatric Hematopoietic Stem Cell Transplant Patients. Crit Care Med. 2015 Sep;43(9):1986-94. doi: 10.1097/CCM.0000000000001085.

Shah SN, Todoric K, Tarrant TK. Improved outcomes on subcutaneous IgG in patients with humoral immunodeficiency and co-morbid bowel disease. Clin Case Rep Rev. 2015 Jul 28;1(7):151-152. doi: 10.15761/CCRR.1000149.

Chiang N, Dalli J, Colas RA, Serhan CN. Identification of resolvin D2 receptor mediating resolution of infections and organ protection. J Exp Med. 2015 Jul 27;212(8):1203-17. doi: 10.1084/jem.20150225. Epub 2015 Jul 20.

Rissone A, Weinacht KG, la Marca G, Bishop K, Giocaliere E, Jagadeesh J, Felgentreff K, Dobbs K, Al-Herz W, Jones M, Chandrasekharappa S, Kirby M, Wincovitch S, Simon KL, Itan Y, DeVine A, Schlaeger T, Schambach A, Sood R, Notarangelo LD, Candotti F. Reticular dysgenesis-associated AK2 protects hematopoietic stem and progenitor cell development from oxidative stress. J Exp Med. 2015 Jul 27;212(8):1185-202. doi: 10.1084/jem.20141286. Epub 2015 Jul 6.

Chinen J, Notarangelo LD, Shearer WT. Advances in basic and clinical immunology in 2014. J Allergy Clin Immunol. May 2015;135(5):1132-1141. PMID: 25956014. Pending PMCID.

Zheng P, Noroski LM, Hanson IC, et al. Molecular mechanisms of functional natural killer deficiency in patients with partial DiGeorge syndrome. J Allergy Clin Immunol. May 2015;135(5):1293-1302. PMID: 25748067, PMCID: PMC5540306 

Kwan A, Hu D, Song M, Gomes H, Brown DR, Bourque T, Gonzalez-Espinosa D, Lin Z, Cowan MJ, Puck JM. Successful newborn screening for SCID in the Navajo Nation. Clin Immunol. 2015 May;158(1):29-34. doi: 10.1016/j.clim.2015.02.015. Epub 2015 Mar 8.

Kwan A, Puck JM. History and current status of newborn screening for severe combined immunodeficiency. Semin Perinatol. 2015 Apr;39(3):194-205. doi: 10.1053/j.semperi.2015.03.004. Epub 2015 Apr 30.

Long-Boyle JR, Savic R, Yan S, Bartelink I, Musick L, French D, Law J, Horn B, Cowan MJ, Dvorak CC. Population pharmacokinetics of busulfan in pediatric and young adult patients undergoing hematopoietic cell transplant: a model-based dosing algorithm for personalized therapy and implementation into routine clinical use. Ther Drug Monit. 2015 Apr;37(2):236-45. doi: 10.1097/FTD.0000000000000131.

Wahlstrom JT, Dvorak CC, Cowan MJ. Hematopoietic Stem Cell Transplantation for Severe Combined Immunodeficiency. Curr Pediatr Rep. 2015 Mar 1;3(1):1-10. doi: 10.1007/s40124-014-0071-7.

Bunupuradah T, Hansudewechakul R, Kosalaraksa P, et al. HLA-DRB1454 and predictors of new-onset asthma in HIV-infected Thai children. Clin Immunol. Mar 2015;157(1):26-29. PMID: 25546395. Pending PMCID.

Niss O, Sholl A, Bleesing JJ, Hildeman DA. IL-10/Janus kinase/signal transducer and activator of transcription 3 signaling dysregulates Bim expression in autoimmune lymphoproliferative syndrome. J Allergy Clin Immunol. 2015 Mar;135(3):762-70. doi: 10.1016/j.jaci.2014.07.020. Epub 2014 Aug 28.

Punwani D, Wang H, Chan AY, Cowan MJ, Mallott J, Sunderam U, Mollenauer M, Srinivasan R, Brenner SE, Mulder A, Claas FH, Weiss A, Puck JM. Combined immunodeficiency due to MALT1 mutations, treated by hematopoietic cell transplantation. J Clin Immunol. 2015 Feb;35(2):135-46. doi: 10.1007/s10875-014-0125-1. Epub 2015 Jan 28.

Punwani D, Pelz B, Yu J, Arva NC, Schafernak K, Kondratowicz K, Makhija M, Puck JM. Coronin-1A: immune deficiency in humans and mice. J Clin Immunol. 2015 Feb;35(2):100-7. doi: 10.1007/s10875-015-0130-z. Epub 2015 Feb 10.

Buchbinder D, Baker R, Lee YN, Ravell J, Zhang Y, McElwee J, Nugent D, Coonrod EM, Durtschi JD, Augustine NH, Voelkerding KV, Csomos K, Rosen L, Browne S, Walter JE, Notarangelo LD, Hill HR, Kumánovics A. Identification of patients with RAG mutations previously diagnosed with common variable immunodeficiency disorders. J Clin Immunol. 2015 Feb;35(2):119-24. doi: 10.1007/s10875-014-0121-5. Epub 2014 Dec 17.

Walter JE, Lo MS, Kis-Toth K, Tirosh I, Frugoni F, Lee YN, Csomos K, Chen K, Pillai S, Dunham J, Tsokos GC, Luning Prak ET, Notarangelo LD. Impaired receptor editing and heterozygous RAG2 mutation in a patient with systemic lupus erythematosus and erosive arthritis. J Allergy Clin Immunol. 2015 Jan;135(1):272-3. doi: 10.1016/j.jaci.2014.07.063. Epub 2014 Oct 11.

Abolhassani H, Wang N, Aghamohammadi A, Rezaei N, Lee YN, Frugoni F, Notarangelo LD, Pan-Hammarström Q, Hammarström L. A hypomorphic recombination-activating gene 1 (RAG1) mutation resulting in a phenotype resembling common variable immunodeficiency. J Allergy Clin Immunol. 2014 Dec;134(6):1375-1380. doi: 10.1016/j.jaci.2014.04.042. Epub 2014 Jul 2.

Pai SY, Cowan MJ. Stem cell transplantation for primary immunodeficiency diseases: the North American experience. Curr Opin Allergy Clin Immunol. 2014 Dec;14(6):521-6. doi: 10.1097/ACI.0000000000000115.

Dvorak CC, Hassan A, Slatter MA, Hönig M, Lankester AC, Buckley RH, Pulsipher MA, Davis JH, Güngör T, Gabriel M, Bleesing JH, Bunin N, Sedlacek P, Connelly JA, Crawford DF, Notarangelo LD, Pai SY, Hassid J, Veys P, Gennery AR, Cowan MJ. Comparison of outcomes of hematopoietic stem cell transplantation without chemotherapy conditioning by using matched sibling and unrelated donors for treatment of severe combined immunodeficiency. J Allergy Clin Immunol. 2014 Oct;134(4):935-943.e15. doi: 10.1016/j.jaci.2014.06.021. Epub 2014 Aug 7.

Mandala WL, Ananworanich J, Apornpong T, et al. Control lymphocyte subsets: can one country's values serve for another's?. J Allergy Clin Immunol. Sep 2014;134(3):759-761 e758. PMID: 25171870, PMCID: PMC4150016.

Kwan A, Abraham RS, Currier R, Brower A, Andruszewski K, Abbott JK, Baker M, Ballow M, Bartoshesky LE, Bonilla FA, Brokopp C, Brooks E, Caggana M, Celestin J, Church JA, Comeau AM, Connelly JA, Cowan MJ, Cunningham-Rundles C, Dasu T, Dave N, De La Morena MT, Duffner U, Fong CT, Forbes L, Freedenberg D, Gelfand EW, Hale JE, Hanson IC, Hay BN, Hu D, Infante A, Johnson D, Kapoor N, Kay DM, Kohn DB, Lee R, Lehman H, Lin Z, Lorey F, Abdel-Mageed A, Manning A, McGhee S, Moore TB, Naides SJ, Notarangelo LD, Orange JS, Pai SY, Porteus M, Rodriguez R, Romberg N, Routes J, Ruehle M, Rubenstein A, Saavedra-Matiz CA, Scott G, Scott PM, Secord E, Seroogy C, Shearer WT, Siegel S, Silvers SK, Stiehm ER, Sugerman RW, Sullivan JL, Tanksley S, Tierce ML 4th, Verbsky J, Vogel B, Walker R, Walkovich K, Walter JE, Wasserman RL, Watson MS, Weinberg GA, Weiner LB, Wood H, Yates AB, Puck JM, Bonagura VR. Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States. JAMA. 2014 Aug 20;312(7):729-38. doi: 10.1001/jama.2014.9132.

Pai SY, Logan BR, Griffith LM, Buckley RH, Parrott RE, Dvorak CC, Kapoor N, Hanson IC, Filipovich AH, Jyonouchi S, Sullivan KE, Small TN, Burroughs L, Skoda-Smith S, Haight AE, Grizzle A, Pulsipher MA, Chan KW, Fuleihan RL, Haddad E, Loechelt B, Aquino VM, Gillio A, Davis J, Knutsen A, Smith AR, Moore TB, Schroeder ML, Goldman FD, Connelly JA, Porteus MH, Xiang Q, Shearer WT, Fleisher TA, Kohn DB, Puck JM, Notarangelo LD, Cowan MJ, O'Reilly RJ. Transplantation outcomes for severe combined immunodeficiency, 2000-2009. N Engl J Med. 2014 Jul 31;371(5):434-46. doi: 10.1056/NEJMoa1401177.

Chinen J, Notarangelo LD, Shearer WT. Advances in basic and clinical immunology in 2013. J Allergy Clin Immunol. 2014 Apr;133(4):967-76. doi: 10.1016/j.jaci.2014.01.026. Epub 2014 Feb 28.

Lee YN, Frugoni F, Dobbs K, Walter JE, Giliani S, Gennery AR, Al-Herz W, Haddad E, LeDeist F, Bleesing JH, Henderson LA, Pai SY, Nelson RP, El-Ghoneimy DH, El-Feky RA, Reda SM, Hossny E, Soler-Palacin P, Fuleihan RL, Patel NC, Massaad MJ, Geha RS, Puck JM, Palma P, Cancrini C, Chen K, Vihinen M, Alt FW, Notarangelo LD. A systematic analysis of recombination activity and genotype-phenotype correlation in human recombination-activating gene 1 deficiency. J Allergy Clin Immunol. 2014 Apr;133(4):1099-108. doi: 10.1016/j.jaci.2013.10.007. Epub 2013 Nov 28.

Shearer WT, Dunn E, Notarangelo LD, Dvorak CC, Puck JM, Logan BR, Griffith LM, Kohn DB, O'Reilly RJ, Fleisher TA, Pai SY, Martinez CA, Buckley RH, Cowan MJ. Establishing diagnostic criteria for severe combined immunodeficiency disease (SCID), leaky SCID, and Omenn syndrome: the Primary Immune Deficiency Treatment Consortium experience. J Allergy Clin Immunol. 2014 Apr;133(4):1092-8. doi: 10.1016/j.jaci.2013.09.044. Epub 2013 Nov 28.

Medical Advisory Committee of the Immune Deficiency Foundation, Shearer WT, Fleisher TA, Buckley RH, Ballas Z, Ballow M, Blaese RM, Bonilla FA, Conley ME, Cunningham-Rundles C, Filipovich AH, Fuleihan R, Gelfand EW, Hernandez-Trujillo V, Holland SM, Hong R, Lederman HM, Malech HL, Miles S, Notarangelo LD, Ochs HD, Orange JS, Puck JM, Routes JM, Stiehm ER, Sullivan K, Torgerson T, Winkelstein J. Recommendations for live viral and bacterial vaccines in immunodeficient patients and their close contacts. J Allergy Clin Immunol. 2014 Apr;133(4):961-6. doi: 10.1016/j.jaci.2013.11.043. Epub 2014 Feb 28.

Chen K, Wu W, Mathew D, Zhang Y, Browne SK, Rosen LB, McManus MP, Pulsipher MA, Yandell M, Bohnsack JF, Jorde LB, Notarangelo LD, Walter JE. Autoimmunity due to RAG deficiency and estimated disease incidence in RAG1/2 mutations. J Allergy Clin Immunol. 2014 Mar;133(3):880-2.e10. doi: 10.1016/j.jaci.2013.11.038. Epub 2014 Jan 25.

Griffith LM, Cowan MJ, Notarangelo LD, Kohn DB, Puck JM, Pai SY, Ballard B, Bauer SC, Bleesing JJ, Boyle M, Brower A, Buckley RH, van der Burg M, Burroughs LM, Candotti F, Cant AJ, Chatila T, Cunningham-Rundles C, Dinauer MC, Dvorak CC, Filipovich AH, Fleisher TA, Bobby Gaspar H, Gungor T, Haddad E, Hovermale E, Huang F, Hurley A, Hurley M, Iyengar S, Kang EM, Logan BR, Long-Boyle JR, Malech HL, McGhee SA, Modell F, Modell V, Ochs HD, O'Reilly RJ, Parkman R, Rawlings DJ, Routes JM, Shearer WT, Small TN, Smith H, Sullivan KE, Szabolcs P, Thrasher A, Torgerson TR, Veys P, Weinberg K, Zuniga-Pflucker JC; workshop participants. Primary Immune Deficiency Treatment Consortium (PIDTC) report. J Allergy Clin Immunol. 2014 Feb;133(2):335-47. doi: 10.1016/j.jaci.2013.07.052. Epub 2013 Oct 15.

Haddad E, Allakhverdi Z, Griffith LM, Cowan MJ, Notarangelo LD. Survey on retransplantation criteria for patients with severe combined immunodeficiency. J Allergy Clin Immunol. 2014 Feb;133(2):597-9. doi: 10.1016/j.jaci.2013.10.022. Epub 2013 Dec 10.

Schuetz C, Neven B, Dvorak CC, Leroy S, Ege MJ, Pannicke U, Schwarz K, Schulz AS, Hoenig M, Sparber-Sauer M, Gatz SA, Denzer C, Blanche S, Moshous D, Picard C, Horn BN, de Villartay JP, Cavazzana M, Debatin KM, Friedrich W, Fischer A, Cowan MJ. SCID patients with ARTEMIS vs RAG deficiencies following HCT: increased risk of late toxicity in ARTEMIS-deficient SCID. Blood. 2014 Jan 9;123(2):281-9. doi: 10.1182/blood-2013-01-476432. Epub 2013 Oct 21.

Johnson TS, Terrell CE, Millen SH, Katz JD, Hildeman DA, Jordan MB. Etoposide selectively ablates activated T cells to control the immunoregulatory disorder hemophagocytic lymphohistiocytosis. J Immunol. 2014 Jan 1;192(1):84-91. doi: 10.4049/jimmunol.1302282. Epub 2013 Nov 20.

Savic RM, Cowan MJ, Dvorak CC, Pai SY, Pereira L, Bartelink IH, Boelens JJ, Bredius RG, Wynn RF, Cuvelier GD, Shaw PJ, Slatter MA, Long-Boyle J. Effect of weight and maturation on busulfan clearance in infants and small children undergoing hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2013 Nov;19(11):1608-14. doi: 10.1016/j.bbmt.2013.08.014. Epub 2013 Sep 9.

Henderson LA, Frugoni F, Hopkins G, de Boer H, Pai SY, Lee YN, Walter JE, Hazen MM, Notarangelo LD. Expanding the spectrum of recombination-activating gene 1 deficiency: a family with early-onset autoimmunity. J Allergy Clin Immunol. 2013 Oct;132(4):969-71.e1-2. doi: 10.1016/j.jaci.2013.06.032. Epub 2013 Jul 24.

Dvorak CC, Cowan MJ, Logan BR, Notarangelo LD, Griffith LM, Puck JM, Kohn DB, Shearer WT, O'Reilly RJ, Fleisher TA, Pai SY, Hanson IC, Pulsipher MA, Fuleihan R, Filipovich A, Goldman F, Kapoor N, Small T, Smith A, Chan KW, Cuvelier G, Heimall J, Knutsen A, Loechelt B, Moore T, Buckley RH. The natural history of children with severe combined immunodeficiency: baseline features of the first fifty patients of the primary immune deficiency treatment consortium prospective study 6901. J Clin Immunol. 2013 Oct;33(7):1156-64. doi: 10.1007/s10875-013-9917-y. Epub 2013 Jul 2.

Chen R, Giliani S, Lanzi G, Mias GI, Lonardi S, Dobbs K, Manis J, Im H, Gallagher JE, Phanstiel DH, Euskirchen G, Lacroute P, Bettinger K, Moratto D, Weinacht K, Montin D, Gallo E, Mangili G, Porta F, Notarangelo LD, Pedretti S, Al-Herz W, Alfahdli W, Comeau AM, Traister RS, Pai SY, Carella G, Facchetti F, Nadeau KC, Snyder M, Notarangelo LD. Whole-exome sequencing identifies tetratricopeptide repeat domain 7A (TTC7A) mutations for combined immunodeficiency with intestinal atresias. J Allergy Clin Immunol. 2013 Sep;132(3):656-664.e17. doi: 10.1016/j.jaci.2013.06.013. Epub 2013 Jul 4.

Teigland CL, Parrott RE, Buckley RH. Long-term outcome of non-ablative booster BMT in patients with SCID. Bone Marrow Transplant. 2013 Aug;48(8):1050-5. doi: 10.1038/bmt.2013.6. Epub 2013 Feb 11.

Kwan A, Church JA, Cowan MJ, Agarwal R, Kapoor N, Kohn DB, Lewis DB, McGhee SA, Moore TB, Stiehm ER, Porteus M, Aznar CP, Currier R, Lorey F, Puck JM. Newborn screening for severe combined immunodeficiency and T-cell lymphopenia in California: results of the first 2 years. J Allergy Clin Immunol. 2013 Jul;132(1):140-50. doi: 10.1016/j.jaci.2013.04.024.

Horn B, Cowan MJ. Unresolved issues in hematopoietic stem cell transplantation for severe combined immunodeficiency: need for safer conditioning and reduced late effects. J Allergy Clin Immunol. 2013 May;131(5):1306-11. doi: 10.1016/j.jaci.2013.03.014.

Selleri S, Dieng MM, Nicoletti S, Louis I, Beausejour C, Le Deist F, Haddad E. Cord-blood-derived mesenchymal stromal cells downmodulate CD4+ T-cell activation by inducing IL-10-producing Th1 cells. Stem Cells Dev. 2013 Apr 1;22(7):1063-75. doi: 10.1089/scd.2012.0315. Epub 2013 Jan 4.

Haddad E, Leroy S, Buckley RH. B-cell reconstitution for SCID: should a conditioning regimen be used in SCID treatment?. J Allergy Clin Immunol. 2013 Apr;131(4):994-1000. doi: 10.1016/j.jaci.2013.01.047. Epub 2013 Mar 5.

Gelfand EW, Ochs HD, Shearer WT. Controversies in IgG replacement therapy in patients with antibody deficiency diseases. J Allergy Clin Immunol. Apr 2013;131(4):1001-1005. PMID: 23540617. Pending PMCID.

Henderson LA, Frugoni F, Hopkins G, Al-Herz W, Weinacht K, Comeau AM, Bonilla FA, Notarangelo LD, Pai SY. First reported case of Omenn syndrome in a patient with reticular dysgenesis. J Allergy Clin Immunol. 2013 Apr;131(4):1227-30, 1230.e1-3. doi: 10.1016/j.jaci.2012.07.045. Epub 2012 Sep 24.

Cattaneo F, Recher M, Masneri S, Baxi SN, Fiorini C, Antonelli F, Wysocki CA, Calderon JG, Eibel H, Smith AR, Bonilla FA, Tsitsikov E, Giliani S, Notarangelo LD, Pai SY. Hypomorphic Janus kinase 3 mutations result in a spectrum of immune defects, including partial maternal T-cell engraftment. J Allergy Clin Immunol. 2013 Apr;131(4):1136-45. doi: 10.1016/j.jaci.2012.12.667. Epub 2013 Feb 4.

Chinen J, Notarangelo LD, Shearer WT. Advances in basic and clinical immunology in 2012. J Allergy Clin Immunol. Mar 2013;131(3):675-682. PMID: 23374612. Pending PMCID.

Buckley RH, Win CM, Moser BK, Parrott RE, Sajaroff E, Sarzotti-Kelsoe M. Post-transplantation B cell function in different molecular types of SCID. J Clin Immunol. Jan 2013;33(1):96-110. PMID: 23001410, PMCID: PMC3549311.

Mangurian C, Cowan MJ. The missing vital sign. BMJ. 2013;347:f4163. PMID: 23833077, PMCID: PMC4688548.

Punwani D, Gonzalez-Espinosa D, Comeau AM, Dutra A, Pak E, Puck J. Cellular calibrators to quantitate T-cell receptor excision circles (TRECs) in clinical samples. Mol Genet Metab. 2012 Nov;107(3):586-91. doi: 10.1016/j.ymgme.2012.09.018. Epub 2012 Sep 21.

Chan SK, Shearer WT. HCT survival in ADA-SCID: what's the buzz?. Blood. Oct 25 2012;120 (17):3392-3393. PMID: 23100302. Pending PMCID.

Taylor PA, Kelly RM, Bade ND, Smith MJ, Stefanski HE, Blazar BR. FTY720 markedly increases alloengraftment but does not eliminate host anti-donor T cells that cause graft rejection on its withdrawal. Biol Blood Marrow Transplant. Sep 2012;18(9):1341-1352. PMID: 22728248, PMCID: PMC3520609.

Leechawengwongs E, Shearer WT. Lymphoma complicating primary immunodeficiency syndromes. Curr Opin Hematol. Jul 2012;19(4):305-312. PMID: 22525579. Pending PMCID.

Roberts JL, Buckley RH, Luo B, et al. CD45-deficient severe combined immunodeficiency caused by uniparental disomy. Proc Natl Acad Sci USA. Jun 26 2012;109(26):10456-10461. PMID: 22689986, PMCID: PMC3387083.

Puck JM. Laboratory technology for population-based screening for severe combined immunodeficiency in neonates: the winner is T-cell receptor excision circles. J Allergy Clin Immunol. 2012 Mar;129(3):607-16. doi: 10.1016/j.jaci.2012.01.032. Epub 2012 Jan 29.

Hanson IC, Shearer WT. Ruling out HIV infection when testing for severe combined immunodeficiency and other T-cell deficiencies. J Allergy Clin Immunol. Mar 2012;129(3):875-876 e875. PMID: 22386446. Pending PMCID.

Buckley RH. The long quest for neonatal screening for severe combined immunodeficiency. J Allergy Clin Immunol. Mar 2012;129(3):597-604; quiz 605-596. PMID: 22277203, PMCID: PMC3294102.

Chinen J, Shearer WT. Advances in basic and clinical immunology in 2011. J Allergy Clin Immunol. Feb 2012;129(2):342-348. PMID: 22206779, PMCID: PMC3279946.

Siberry GK, Leister E, Jacobson DL, et al. Increased risk of asthma and atopic dermatitis in perinatally HIV-infected children and adolescents. Clin Immunol. Feb 2012;142(2):201-208. PMID: 22094294, PMCID: PMC3273595.

Martinez CA, Shah S, Shearer WT, et al. Excellent survival after sibling or unrelated donor stem cell transplantation for chronic granulomatous disease. J Allergy Clin Immunol. Jan 2012;129(1):176-183. PMID: 22078471. Pending PMCID.

Recher M, Berglund LJ, Avery DT, Cowan MJ, Gennery AR, Smart J, Peake J, Wong M, Pai SY, Baxi S, Walter JE, Palendira U, Tangye GA, Rice M, Brothers S, Al-Herz W, Oettgen H, Eibel H, Puck JM, Cattaneo F, Ziegler JB, Giliani S, Tangye SG, Notarangelo LD. IL-21 is the primary common γ chain-binding cytokine required for human B-cell differentiation in vivo. Blood. 2011 Dec 22;118(26):6824-35. doi: 10.1182/blood-2011-06-362533. Epub 2011 Oct 28.

Puck JM. Neonatal screening for severe combined immunodeficiency. Curr Opin Pediatr. 2011 Dec;23(6):667-73. doi: 10.1097/MOP.0b013e32834cb9b0.

Puck JM. The case for newborn screening for severe combined immunodeficiency and related disorders. Ann N Y Acad Sci. 2011 Dec;1246:108-17. doi: 10.1111/j.1749-6632.2011.06346.x.

Tison BE, Nicholas SK, Abramson SL, et al. Autoimmunity in a cohort of 130 pediatric patients with partial DiGeorge syndrome. J Allergy Clin Immunol. Nov 2011;128(5):1115-1117 e1111-1113. PMID: 21835443. Pending PMCID.

Yu GP, Nadeau KC, Berk DR, de Saint Basile G, Lambert N, Knapnougel P, Roberts J, Kavanau K, Dunn E, Stiehm ER, Lewis DB, Umetsu DT, Puck JM, Cowan MJ. Genotype, phenotype, and outcomes of nine patients with T-B+NK+ SCID. Pediatr Transplant. 2011 Nov;15(7):733-41. doi: 10.1111/j.1399-3046.2011.01563.x. Epub 2011 Aug 23.

Marcus N, Takada H, Law J, Cowan MJ, Gil J, Regueiro JR, Plaza Lopez de Sabando D, Lopez-Granados E, Dalal J, Friedrich W, Manfred H, Hanson IC, Grunebaum E, Shearer WT, Roifman CM. Hematopoietic stem cell transplantation for CD3δ deficiency. J Allergy Clin Immunol. 2011 Nov;128(5):1050-7. doi: 10.1016/j.jaci.2011.05.031. Epub 2011 Jul 16.

Becker-Herman S, Meyer-Bahlburg A, Schwartz MA, Jackson SW, Hudkins KL, Liu C, Sather BD, Khim S, Liggitt D, Song W, Silverman GJ, Alpers CE, Rawlings DJ. WASp-deficient B cells play a critical, cell-intrinsic role in triggering autoimmunity. J Exp Med. Sep 26 2011;208(10):2033-2042. PMID: 21875954, PMCID: PMC3182055.

Moratto D, Giliani S, Bonfim C, Mazzolari E, Fischer A, Ochs HD, Cant AJ, Thrasher AJ, Cowan MJ, Albert MH, Small T, Pai SY, Haddad E, Lisa A, Hambleton S, Slatter M, Cavazzana-Calvo M, Mahlaoui N, Picard C, Torgerson TR, Burroughs L, Koliski A, Neto JZ, Porta F, Qasim W, Veys P, Kavanau K, Hönig M, Schulz A, Friedrich W, Notarangelo LD. Long-term outcome and lineage-specific chimerism in 194 patients with Wiskott-Aldrich syndrome treated by hematopoietic cell transplantation in the period 1980-2009: an international collaborative study. Blood. 2011 Aug 11;118(6):1675-84. doi: 10.1182/blood-2010-11-319376. Epub 2011 Jun 9.

Nicholas S, Krance RA, Hanson IC, et al. Early versus delayed diagnosis of SCID: triumph versus tragedy. Clin Immunol. Jun 2011;139(3):360-362. PMID: 21497138. Pending PMCID.

Buckley RH. Transplantation of hematopoietic stem cells in human severe combined immunodeficiency: longterm outcomes. Immunol Res. Apr 2011;49(1-3):25-43. PMID: 21116871, PMCID: PMC3798033.

Okocha IU, Hanson CG, Chinen J, Shearer WT. Decline of antibodies in XLA infant: when to start IVIG. Allergy. 2011 Mar;66(3):434-5. doi: 10.1111/j.1398-9995.2010.02481.x. Epub 2010 Sep 7.

Segal BH, Veys P, Malech H, Cowan MJ. Chronic granulomatous disease: lessons from a rare disorder. Biol Blood Marrow Transplant. 2011 Jan;17(1 Suppl):S123-31. doi: 10.1016/j.bbmt.2010.09.008.

Zemble R, Luning Prak E, McDonald K, McDonald-McGinn D, Zackai E, Sullivan K. Secondary immunologic consequences in chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Clin Immunol. 2010 Sep;136(3):409-18. doi: 10.1016/j.clim.2010.04.011. Epub 2010 May 15.

Walter JE, Rucci F, Patrizi L, Recher M, Regenass S, Paganini T, Keszei M, Pessach I, Lang PA, Poliani PL, Giliani S, Al-Herz W, Cowan MJ, Puck JM, Bleesing J, Niehues T, Schuetz C, Malech H, DeRavin SS, Facchetti F, Gennery AR, Andersson E, Kamani NR, Sekiguchi J, Alenezi HM, Chinen J, Dbaibo G, ElGhazali G, Fontana A, Pasic S, Detre C, Terhorst C, Alt FW, Notarangelo LD. Expansion of immunoglobulin-secreting cells and defects in B cell tolerance in Rag-dependent immunodeficiency. J Exp Med. 2010 Jul 5;207(7):1541-54. doi: 10.1084/jem.20091927. Epub 2010 Jun 14.

Buckley RH. B-cell function in severe combined immunodeficiency after stem cell or gene therapy: a review. J Allergy Clin Immunol. Apr 2010;125(4):790-797. PMID: 20371393, PMCID: PMC2857969.

Chinen J, Shearer WT. Advances in basic and clinical immunology in 2009. J Allergy Clin Immunol. Mar 2010;125(3):563-568. PMID: 20226292, PMCID: PMC2841291.

Dvorak CC, Cowan MJ. Radiosensitive severe combined immunodeficiency disease. Immunol Allergy Clin North Am. 2010 Feb;30(1):125-42. doi: 10.1016/j.iac.2009.10.004.

Chinen J, Shearer WT. Secondary immunodeficiencies, including HIV infection. J Allergy Clin Immunol. 2010 Feb; 125(2 Suppl 2):S195-203. PMID: 20042227. Pending PMCID.

Griffith LM, Cowan MJ, Notarangelo LD, Puck JM, Buckley RH, Candotti F, Conley ME, Fleisher TA, Gaspar HB, Kohn DB, Ochs HD, O'Reilly RJ, Rizzo JD, Roifman CM, Small TN, Shearer WT; Workshop Participants. Improving cellular therapy for primary immune deficiency diseases: recognition, diagnosis, and management. J Allergy Clin Immunol. 2009 Dec;124(6):1152-60.e12. doi: 10.1016/j.jaci.2009.10.022.

Patel NC, Chinen J, Rosenblatt HM, et al. Outcomes of patients with severe combined immunodeficiency treated with hematopoietic stem cell transplantation with and without preconditioning. J Allergy Clin Immunol. Nov 2009;124(5):1062-1069 e1061-1064. PMID: 19895994, PMCID: PMC3271026.

Sarzotti-Kelsoe M, Win CM, Parrott RE, et al. Thymic output, T-cell diversity, and T-cell function in long-term human SCID chimeras. Blood. Aug 13 2009;114(7):1445-1453. PMID: 19433858, PMCID: PMC2727406.

Chinen J, Shearer WT. Advances in basic and clinical immunology in 2008. J Allergy Clin Immunol. Feb 2009;123(2):328-332. PMID: 19203657. Pending PMCID.

Griffith LM, Cowan MJ, Kohn DB, Notarangelo LD, Puck JM, Schultz KR, Buckley RH, Eapen M, Kamani NR, O'Reilly RJ, Parkman R, Roifman CM, Sullivan KE, Filipovich AH, Fleisher TA, Shearer WT. Allogeneic hematopoietic cell transplantation for primary immune deficiency diseases: current status and critical needs. J Allergy Clin Immunol. 2008 Dec;122(6):1087-96. doi: 10.1016/j.jaci.2008.09.045. Epub 2008 Nov 6.

Patel NC, Chinen J, Rosenblatt HM, et al. Long-term outcomes of nonconditioned patients with severe combined immunodeficiency transplanted with HLA-identical or haploidentical bone marrow depleted of T cells with anti-CD6 mAb. J Allergy Clin Immunol. Dec 2008;122(6):1185-1193. PMID: 19084111. Pending PMCID.

Shearer WT, Notarangelo LD, Griffith LM. Treatment of immunodeficiency: long-term outcome and quality of life. J Allergy Clin Immunol. Dec 2008;122(6):1065-1068. PMID: 19084107. Pending PMCID.

Simpson K, Elsbecker SA, Barber JR, Bryan K, Berry SA. Maternal Health Outcomes in Ornithine Transcarbamylase Deficiency: A Comparative Analysis of Pregnancies in Symptomatic and Asymptomatic Heterozygotes. Mol Genet Metab. Mol Genet Metab. 2025 April;144(4):109083. doi: 10.1016/j.ymgme.2025.109083

Chanvanichtrakool M, Schreiber JM, Chen WL, Barber J, Zhang A, Ah Mew N, Schulze A, Wilkening G, Nagamani SCS, Gropman A; Urea Cycle Disease Consortium. Unraveling the Link: Seizure Characteristics and Ammonia Levels in Urea Cycle Disorder during Hyperammonemic Crises. Pediatr Neurol. 2024 Oct;159:48-55. doi: 10.1016/j.pediatrneurol.2024.06.013. Epub 2024 Jun 29. PMID: 39121557; PMCID: PMC11381174.

Urea cycle disorders (UCDs) are a group of inherited, metabolic disorders characterized by hyperammonemia (high blood ammonia levels). Individuals with UCDs may experience symptoms including developmental delays, buildup of fluid around the brain, and seizures.

In this study, researchers investigated the link between seizures and hyperammonemic crises in individuals with UCDs. Among 85 UCD patients, the team reviewed medical records for evidence of seizures during hyperammonemic crises as well as initial levels of ammonia and glutamine.

Results showed that 66% of UCD patients experienced hyperammonemic crises, with 13% of these patients experiencing seizures. Findings also revealed that initial ammonia and glutamine levels can help determine the risk of seizures. Authors note that this study highlights the utility of electroencephalogram monitoring during crises for patients who present with clinical seizures or who have encephalopathy (brain disease) with high ammonia levels.

Sen K, Izem R, Long Y, Jiang J, Konczal LL, McCarter RJ; Members of the Urea Cycle Disorders Consortium (UCDC); Gropman AL, Bedoyan JK. Are asymptomatic carriers of OTC deficiency always asymptomatic? A multicentric retrospective study of risk using the UCDC longitudinal study database. Mol Genet Geonomic Med. 2024 Apr;12(4):e2443. doi: 10.1002/mgg3.2443. PMID: 38634223; PMCID: PMC11024633.

Ornithine transcarbamylase deficiency (OTCD) is a type of urea cycle disorder characterized by hyperammonemia (high blood ammonia levels) due to deficiency or absence of an enzyme needed to convert nitrogen from protein into urea (a waste product). Because OTCD is caused by an X-linked mutation in the OTC gene, the majority of patients with severe presentation of OTC deficiency are male, as they have only one X chromosome. Although 80% of females with OTCD are typically thought to remain asymptomatic, not much is known about their clinical characteristics and long-term health vulnerabilities. 

In this study, researchers explored the factors that might predict development of defined complications and serious illness in apparent asymptomatic females with OTCD. The team reviewed data from 302 females enrolled in the Urea Cycle Disorders Consortium (UCDC) longitudinal natural history study. Researchers also performed several types of neuroimaging studies in a female patient with OTCD.

Results show that these patients can experience neuropsychiatric and behavioral symptoms as well as an increased risk of hyperammonemia later in life, demonstrating that asymptomatic females with OTCD are not always asymptomatic. Authors note that these findings can aid in the development of a risk calculator and improve guidelines for management of these patients, paving the way for potential new therapies.

Posset R, Garbade SF, Gleich F, Nagamani SCS, Gropman AL, Epp F, Ramdhouni N, Druck AC, Hoffmann GF, Kölker S, Zielonka M; Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD) consortia study group. Impact of supplementation with L-citrulline/arginine after liver transplantation in individuals with Urea Cycle Disorders. Mol Genet Metab. 2024 Mar;141(3):108112. doi: 10.1016/j.ymgme.2023.108112. Epub 2023 Dec 10. PMID: 38301530.

Urea cycle disorders (UCDs) are genetic disorders that result in a deficiency of one of the six enzymes in the urea cycle, causing hyperammonemia (high blood ammonia levels). When medical management is not enough to prevent hyperammonemia, patients with UCDs may undergo liver transplantation. Both before and after transplant, these patients often receive L-citrulline or L-arginine supplements to help their bodies eliminate ammonia. However, not much is known about the impact of long-term supplementation.

In this pilot study, researchers investigated the effects of long-term L-citrulline or L-arginine supplementation in patients with UCDs who have undergone liver transplantation. The team used data collected from longitudinal observational studies to compare outcomes of 16 patients who received these supplements long-term with 36 patients who were not supplemented over the course of 4 or 5 years after transplant.

Results suggest that although supplementation with L-citrulline or L-arginine is often continued after transplant, in this pilot study, such supplementation was not associated with health-related outcomes or biochemical responses. Authors note that analyzing larger samples over longer observation periods will provide more insight into the usefulness of long-term supplementation.

Posset R, Garbade SF, Gleich F, Scharre S, Okun JG, Gropman AL, Nagamani SCS, Druck AC, Epp F, Hoffmann GF, Kölker S, Zielonka M; Urea Cycle Disorders Consortium (UCDC); European registry and network for Intoxication type Metabolic Diseases (E-IMD) Consortia Study Group. Severity-adjusted evaluation of liver transplantation on health outcomes in urea cycle disorders. Genet Med. 2023 Dec 3;26(4):101039. doi: 10.1016/j.gim.2023.101039. Epub ahead of print. PMID: 38054409.

Urea cycle disorders (UCDs) are a group of inherited, metabolic disorders characterized by hyperammonemia (high blood ammonia levels). Patients with UCD may undergo liver transplantation when medical management is not enough to prevent hyperammonemia. However, not much is known about how the effects of transplant compare to medical management alone.

In this study, researchers classified patients into “severe” and “attenuated” categories based on genetic information and a novel enzyme activity test. Then, using data collected from longitudinal observational studies, they compared the health-related outcomes in patients who underwent liver transplantation vs medical management. 

Results show that liver transplantation led to greater metabolic stability without the need for protein restriction or nitrogen-scavenging therapy. However, while transplantation led to more favorable growth outcomes, it was not associated with improved neurocognitive outcomes compared to long-term medical management.

Lichter-Konecki U, Sanz JH; Urea Cycle Disorders Consortium; McCarter R. Relationship between longitudinal changes in neuropsychological outcome and disease biomarkers in urea cycle disorders. Pediatr Res. 2023 Dec;94(6):2005-2015. doi: 10.1038/s41390-023-02722-y. Epub 2023 Jul 15.

Glinton KE, Minard CG, Liu N, Sun Q, Elsea SH, Burrage LC, Nagamani SCS. Monitoring the treatment of urea cycle disorders using phenylbutyrate metabolite analyses: Still many lessons to learn. Mol Genet Metab. 2023 Nov;140(3):107699. doi: 10.1016/j.ymgme.2023.107699. Epub 2023 Sep 11.

Posset R, Zielonka M, Gleich F, Garbade SF, Hoffmann GF, Kölker S; Urea Cycle Disorders Consortium (UCDC) and European registry and network for Intoxication type Metabolic Diseases (E-IMD) Consortia Study Group. The challenge of understanding and predicting phenotypic diversity in urea cycle disorders. J Inherit Metab Dis. 2023 Nov;46(6):1007-1016. doi: 10.1002/jimd.12678. Epub 2023 Oct 10.

Murali CN, Barber JR, McCarter R, Zhang A, Gallant N, Simpson K, Dorrani N, Wilkening GN, Hays RD, Lichter-Konecki U; Members of the Urea Cycle Disorders Consortium; Burrage LC, Nagamani SCS. Health-related quality of life in a systematically assessed cohort of children and adults with urea cycle disorders. Mol Genet Metab. 2023 Sep 8;140(3):107696. doi: 10.1016/j.ymgme.2023.107696. Epub ahead of print. PMID: 37690181

Urea cycle disorders (UCDs) are a group of inherited, metabolic disorders characterized by hyperammonemia (high blood ammonia levels). Accumulation of ammonia is toxic to the nervous system, resulting in neurological symptoms that can impact health-related quality of life (HRQoL). However, only a few studies have systematically investigated the impact of UCDs on HRQoL.

In this study, researchers assessed HRQoL in a large cohort of children and adults with UCDs. The team reviewed HRQoL and clinical data from a Urea Cycle Disorders Consortium longitudinal study; compared to healthy individuals and those with PKU and diabetes; and assessed relationships between HRQoL, UCD diagnosis, and disease severity.

Results show that individuals with UCDs have worse HRQoL compared to healthy individuals and those with PKU and diabetes. Authors state that future work should focus on the impact of liver transplantation and other clinical variables on HRQoL in UCDs.

Ladha FA, Le Mons C, Craigen WJ, Magoulas PL, Marom R, Lewis AM. Barriers to a successful healthcare transition for individuals with urea cycle disorders. Mol Genet Metab. 2023 Jul;139(3):107609. doi: 10.1016/j.ymgme.2023.107609. Epub 2023 May 15.

Scharre S, Posset R, Garbade SF, Gleich F, Seidl MJ, Druck AC, Okun JG, Gropman AL, Nagamani SCS, Hoffmann GF, Kölker S, Zielonka M; Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD) Consortia Study Group. Predicting the disease severity in male individuals with ornithine transcarbamylase deficiency. Ann Clin Transl Neurol. 2022 Oct 10. doi: 10.1002/acn3.51668. Epub ahead of print. PMID: 36217298.

Ornithine transcarbamylase deficiency (OTC-D) is an X-linked disorder and the most common type of urea cycle disorder. Patients with OTC-D can present with a variable spectrum of disease severity, ranging from no symptoms to lethal hyperammonemia (high blood ammonia levels). Therefore, predicting disease course at an early stage is important to personalize therapies for individual patients, which can include medical treatment or liver transplantation. In this study, researchers developed a new cell-based system to assess the residual enzyme activity associated with various disease-causing genetic changes in the OTC gene. Using this system, they were able to correlate residual enzymatic OTC activities with clinical and biochemical outcome parameters of 119 male individuals with OTC-D. Results show that residual enzymatic OTC activity can distinguish individuals with a severe form of OTC-D from those with milder forms of the disorder. As a reliable predictor of disease severity in OTC-D, this classification system could help guide therapeutic strategies and counseling of patients and parents.

Khaksari K, Chen WL, Gropman AL. Review of Applications of Near-Infrared Spectroscopy in Two Rare Disorders with Executive and Neurological Dysfunction: UCD and PKU. Genes (Basel). 2022 Sep 21;13(10):1690. doi: 10.3390/genes13101690. PMID: 36292574; PMCID: PMC9602148.

Urea cycle disorders (UCD) and phenylketonuria (PKU) are two types of genetic, metabolic disorders characterized by neurological symptoms. As with many rare diseases, small population size can make these disorders challenging to study. Tools such as functional neuroimaging are developed to help generate biomarkers, collect baseline data, and measure treatment effects in patients with neurological disorders. However, the cost and infrastructure requirements of these tools have limited their availability. To address this challenge, researchers and clinicians are developing new tools that are non-invasive, portable, and inexpensive. In this review article, researchers discuss the use of functional near-infrared spectroscopy (fNIRS)—a non-invasive, portable tool that uses blood oxygenation to view the brain—in patients with UCD and PKU. Authors consider the ability of fNIRS to obtain biomarkers for screening and monitoring these diseases.

Izem R, McCarter R. Randomized and non-randomized designs for causal inference with longitudinal data in rare disorders. Orphanet J Rare Dis. 2021 Nov 23;16(1):491. doi: 10.1186/s13023-021-02124-5. PMID: 34814939; PMCID: PMC8609847.

Sound study design and causal inference methods are essential to demonstrate the therapeutic efficacy, safety, and effectiveness of new therapies. In the rare diseases setting, the small patient population size, genotypic and phenotypic diversity, and the complexity and incomplete understanding of the disorder's progression challenge the use of typical parallel control designs. This paper reviews longitudinal designs and draws the parallel between some new and existing randomized studies in rare diseases and their less well-known controlled observational study designs. Authors provide examples of analyses in multiple rare disorders, including urea cycle disorder and cystic fibrosis.

Lerner S, Eilam R, Adler L, Baruteau J, Kreiser T, Tsoory M, Brandis A, Mehlman T, Ryten M, Botia JA, Ruiz SG, Garcia AC, Dionisi-Vici C, Ranucci G, Spada M, Mazkereth R, McCarter R, Izem R, Balmat TJ, Richesson R; Members of the UCDC, Gazit E, Nagamani SCS, Erez A. ASL expression in ALDH1A1+ neurons in the substantia nigra metabolically contributes to neurodegenerative phenotype. Hum Genet. 2021 Oct;140(10):1471-1485. doi: 10.1007/s00439-021-02345-5. Epub 2021 Aug 21.

In the liver, the enzymes argininosuccinate lyase (ASL) and argininosuccinate synthase 1 (ASS1) are required to convert waste-nitrogen to urea. Loss of activity for either enzyme causes argininosuccinate lyase deficiency and citrullinemia type 1, respectively. These two disorders are a subset of the classical inborn errors of metabolism called urea cycle disorders (UCD), characterized by episodes of hyperammonemia. ASL deficiency can also result in impaired nitric oxide (NO) synthesis, decreased tyrosine hydroxylase (TH) activity, and low dopamine and norepinephrine levels in the neuronal cells. Both dopamine and norepinephrine are important neurotransmitters, and their deficiency has been associated with neurodegenerative disorders, including Parkinson's Disease. In this study, researchers used a mouse model with loss of ASL in catecholamine neurons to test the hypothesis that decreased activity of ASL and TH would contribute to neurodegeneration. They found that neuronal loss of ASL results in catecholamine deficiency, in accumulation and formation of tyrosine aggregates, in elevation of α-synuclein, and phenotypically in motor and cognitive deficits. Study authors say their data point to a potential metabolic link between accumulations of tyrosine and seeding of pathological aggregates in neurons as initiators for the pathological processes involved in neurodegeneration. They suggest that regulating NO levels may be beneficial for the treatment of catecholamine-related neurodegenerative disorders.

Liu N, Xiao J, Gijavanekar C, Pappan KL, Glinton KE, Shayota BJ, Kennedy AD, Sun Q, Sutton VR, Elsea SH. Comparison of Untargeted Metabolomic Profiling vs Traditional Metabolic Screening to Identify Inborn Errors of Metabolism. JAMA Netw Open. 2021 Jul 1;4(7):e2114155. doi: 10.1001/jamanetworkopen.2021.14155.

Inborn errors of metabolism (IEMs) are rare genetic disorders in which the body cannot properly turn food into energy. Newborn screening (NBS) has improved diagnosis of these diseases, but gaps remain as many of these rare diseases are not included on NBS panels. In this study, researchers evaluated the usefulness of untargeted metabolomics as a primary screening tool, comparing the diagnostic rate of clinical metabolomics to traditional newborn screening. They found that untargeted metabolomics improved the diagnostic rate for IEMs six-fold when compared to the traditional NBS approach. The metabolomics approach also identified a broader spectrum of IEMs. Authors say these data support the use of clinical untargeted metabolomics in screening for IEMs and suggest that broader screening approaches should be considered to help diagnose these rare diseases.

Sen K, Anderson AA, Whitehead MT, Gropman AL. Review of Multi-Modal Imaging in Urea Cycle Disorders: The Old, the New, the Borrowed, and the Blue. Front Neurol. 2021 Apr 28;12:632307. doi: 10.3389/fneur.2021.632307. eCollection 2021.

Nagamani SCS, Ali S, Izem R, Schady D, Masand P, Shneider BL, Leung DH, Burrage LC. Biomarkers for liver disease in urea cycle disorders. Mol Genet Metab. 2021 Apr 8:S1096-7192(21)00685-5. doi: 10.1016/j.ymgme.2021.04.001. Online ahead of print.

Stergachis AB, Krier JB, Merugumala SK, Berry GT, Lin AP. Clinical utility of brain MRS imaging of patients with adult-onset non-cirrhotic hyperammonemia. Mol Genet Metab Rep. 2021 Mar 13;27:100742. doi: 10.1016/j.ymgmr.2021.100742. eCollection 2021 Jun.

Sen K, Castillo Pinto C, Gropman AL. Expanding Role of Proton Magnetic Resonance Spectroscopy: Timely Diagnosis and Treatment Initiation in Partial Ornithine Transcarbamylase Deficiency. J Pediatr Genet. 2021 Mar;10(1):77-80. doi: 10.1055/s-0040-1709670. Epub 2020 Apr 23.

McGowan M, Ferreira C, Whitehead M, Basu SK, Chang T, Gropman A. The Application of Neurodiagnostic Studies to Inform the Acute Management of a Newborn Presenting With Sarbamoyl Shosphate Synthetase 1 Deficiency. Child Neurol Open. 2021 Jan 22;8:2329048X20985179. doi: 10.1177/2329048X20985179. eCollection 2021 Jan-Dec.

Sen K, Whitehead M, Castillo Pinto C, Caldovic L, Gropman A. Fifteen years of urea cycle disorders brain research: Looking back, looking forward. Anal Biochem. 2022 Jan 1;636:114343. doi: 10.1016/j.ab.2021.114343. Epub 2021 Oct 9. PMID: 34637785; PMCID: PMC8671367.

This new review paper highlights the evolving knowledge about the impact of urea cycle disorders (UCD) and hyperammonemia (HA) in particular on neurological injury and recovery. It discusses the use of electroencephalography (EEG) and magnetic resonance imaging (MRI) to study and evaluate prognostic factors for risk and recovery. It recognizes the work of others and discusses the UCDC's prior work and future research priorities, as well as lessons learned over 15 years of neuroimaging research. Key learnings include the identification of the insular cortex as the area most vulnerable to hyperammonemia in UCD. Elevated glutamine and decreased myoinosital have been identified as key brain biomarkers on proton magnetic resonance spectroscopy (MRS), with decreased choline seen over time in patients with repeat HA episodes. Slow recovery of brain glutamine after recovery from hyperammonemia is common. Researchers have found that 1H-MRS, a non-invasive technique that enables the detection, identification, and quantification of biochemical compounds or metabolites in the brain tissue, is most sensitive for proximal UCD and is often abnormal with elevated glutamine, before routine T1 and T2 sequences on MRI show abnormalities. In addition, our work demonstrates that more than one-third of female carriers of OTCD have the biochemical phenotype of UCD on MRS including mildly elevated glutamine and lower than normal myoinositol. 1H-MRS should be added to the clinical routine in patients with known and suspected metabolic conditions.

Posset R, Kölker S, Gleich F, Okun JG, Gropman AL, Nagamani SCS, Scharre S, Probst J, Walter ME, Hoffmann GF, Garbade SF, Zielonka M; Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD) consortia study group. Severity-adjusted evaluation of newborn screening on the metabolic disease course in individuals with cytosolic urea cycle disorders. Mol Genet Metab. 2020 Dec;131(4):390-397. doi: 10.1016/j.ymgme.2020.10.013. Epub 2020 Nov 7.

Anderson AA, Gropman A, Le Mons C, Stratakis CA, Gandjbakhche AH. Hemodynamics of Prefrontal Cortex in Ornithine Transcarbamylase Deficiency: A Twin Case Study. Front Neurol. 2020 Aug 14;11:809. doi: 10.3389/fneur.2020.00809. PMID: 32922350; PMCID: PMC7456944.

Sen K, Whitehead MT, Gropman AL. Multimodal imaging in urea cycle-related neurological disease - What can imaging after hyperammonemia teach us. Transl Sci Rare Dis. 2020 Aug 3;5(1-2):87-95. doi: 10.3233/TRD-200048.

Posset R, Garbade SF, Gleich F, Gropman AL, de Lonlay P, Hoffmann GF, Garcia-Cazorla A, Nagamani SCS, Baumgartner MR, Schulze A, Dobbelaere D, Yudkoff M, Kölker S, Zielonka M; Urea Cycle Disorders Consortium (UCDC); European registry and network for Intoxication type Metabolic Diseases (E-IMD). Long-term effects of medical management on growth and weight in individuals with urea cycle disorders. Sci Rep. 2020 Jul 20;10(1):11948. doi: 10.1038/s41598-020-67496-3.

Imagawa E, Diaz GA, Oishi K. A novel Romani microdeletion variant in the promoter sequence of ASS1 causes citrullinemia type I. Imagawa E. 2020 Jun 29;24:100619. doi: 10.1016/j.ymgmr.2020.100619. PMID: 32637322; PMCID: PMC7330059.

Zielonka M, Garbade SF, Gleich F, Okun JG, Nagamani SCS, Gropman AL, Hoffmann GF, Kölker S, Posset R; Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD) Consortia Study Group. From genotype to phenotype: Early prediction of disease severity in argininosuccinic aciduria. Hum Mutat. 2020 May;41(5):946-960. doi: 10.1002/humu.23983. Epub 2020 Jan 30.

Argininosuccinic aciduria (ASA), caused by a deficiency in argininosuccinate lyase (ASL), is one of the more common urea cycle disorder subtypes. ASA has a wide range of symptoms ranging from mild disease to individuals with significant neurocognitive deficiencies. In this study, researchers analyzed previously collected patient data and correlated these with a new method of enzymatic testing for ASL to determine if the activity level of ASL was a reliable predictor of disease severity. The data was collected from the Longitudinal Study of UCD conducted by the Urea Cycle Disorders Consortium (UCDC) and the European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD). The results showed that individuals with ASA with 8% or less ASL activity had higher initial ammonia levels and more frequent hyperammonemic episodes per year, and those with 8.7% or less ASL activity had increased liver damage. Overall, older ASL patients performed worse than younger ASL patients, which points to the possibility of chronic cognitive deterioration. The difference was more pronounced for those with ASL activity below 24.3%, suggesting additional underlying factors that affect cognition below a certain level of ASL activity. Based on the outcomes of this and previous studies, there is a possibility that ASL activity levels could help caregivers predict disease severity in ASA patients and inform the development of more effective, individualized treatments.

Barkovich E, Gropman AL. Late Onset Ornithine Transcarbamylase Deficiency Triggered by an Acute Increase in Protein Intake: A Review of 10 Cases Reported in the Literature. Case Rep Genet. 2020 Apr 25;2020:7024735. doi: 10.1155/2020/7024735. PMID: 32373372; PMCID: PMC7197010. 

Rech ME, McCarthy JM, Chen CA, Edmond JC, Shah VS, Bosch DGM, Berry GT, Williams L, Madan-Khetarpal S, Niyazov D, Shaw-Smith C, Kovar EM, Lupo PJ, Schaaf CP. Phenotypic expansion of Bosch-Boonstra-Schaaf optic atrophy syndrome and further evidence for genotype-phenotype correlations. Am J Med Genet A. 2020 Apr 10. doi: 10.1002/ajmg.a.61580. PMID: 32275123.

Anderson A, Gropman A, Le Mons C, Stratakis C, Gandjbakhche A. Evaluation of neurocognitive function of prefrontal cortex in ornithine transcarbamylase deficiency. Mol Genet Metab. 2020 Mar;129(3):207-212. doi: 10.1016/j.ymgme.2019.12.014. Epub 2020 Jan 10. PMID: 31952925. Full Text.

Burrage LC, Madan S, Li X, Ali S, Mohammad M, Stroup BM, Jiang MM, Cela R, Bertin T, Jin Z, Dai J, Guffey D, Finegold M; Members of the Urea Cycle Disorders Consortium (UCDC), Nagamani S, Minard CG, Marini J, Masand P, Schady D, Shneider BL, Leung DH, Bali D, Lee B. Chronic liver disease and impaired hepatic glycogen metabolism in argininosuccinate lyase deficiency. JCI Insight. 2020 Feb 27;5(4):e132342. doi: 10.1172/jci.insight.132342.

In this study, researchers reviewed participant data from the Urea Cycle Disorders Consortium’s (UCDC) Longitudinal Study that included all types of UCD. The data suggested that individuals with argininosuccinate lyase deficiency (ASLD) and arginase deficiency had a higher prevalence of liver injury as compared to other types of UCD. Researchers assessed liver disease in individuals with ASLD and a laboratory mouse model of ASLD. Around 37% individuals with ASLD had increased ALT levels. Some of the ASLD participants were noted to have increased liver stiffness but normal ALT and AST levels. The results showed that a quarter of the participants with normal ALT levels had abnormal liver imaging or testing. The ASLD study mice also developed chronic liver damage. These mice had excessive hepatic glycogen, liver enlargement, and increased ALT and AST levels. Hepatic glycogen accumulation has also been found in other types of UCD. More research is needed to identify the role of hepatic glycogen in UCD, as it is unknown whether it leads to, is the cause of, or is at all connected to damage in the liver. This study shows the need to identify additional biomarkers of liver damage in UCD.

Berry SA, Coughlin CR 2nd, McCandless S, McCarter R, Seminara J, Yudkoff M, LeMons C. Developing interactions with industry in rare diseases: lessons learned and continuing challenges. Genet Med. 2020 Jan;22(1):219-226. doi: 10.1038/s41436-019-0616-9. Epub 2019 Jul 24.

The NIH established the Rare Diseases Clinical Research Network to address the unique challenges of performing research on rare diseases. The UCDC was one of the original ten consortia established. Based in part on financial incentives associated with the Orphan Drug Act of 1983 (a United States law that helped catalyze the development of drugs for rare diseases), biopharmaceutical and investment entities have an intense interest in engaging with rare disease research consortia like the UCDC, which have compiled potentially valuable longitudinal data characterizing outcomes in a relatively large number of affected individuals. Natural history data from the longitudinal study are invaluable not only for the many exploratory studies conducted by the UCDC, but also to industry partners seeking to develop new therapeutics to improve the lives of UCD patients and ultimately a cure. This publication discusses the ways in which the UCDC navigates industry relationships in the pursuit of developing therapeutics for UCD patients. For example, the UCDC has developed a method for evaluating partnerships with private entities, established an Industry Relations Committee in 2015 to develop guiding principles, a policy and procedures for interacting with industry (including protection of data privacy), and managing investigator conflict of interest. By building a framework for industry partnerships that guides us in resolving inevitable challenges, the UCDC can pursue novel and promising collaborations that can lead to breakthroughs in treatment for patients.

Gropman AL, Anderson A. Novel imaging technologies for genetic diagnoses in the inborn errors of metabolism. J Transl Genet Genom. 2020;4:429-445. doi: 10.20517/jtgg.2020.09. Epub 2020 Nov 13.

Lerner S, Anderzhanova E, Verbitsky S, Eilam R, Kuperman Y, Tsoory M, Kuznetsov Y, Brandis A, Mehlman T, Mazkereth R; UCDC Neuropsychologists, McCarter R, Segal M, Nagamani SCS, Chen A, Erez A. ASL Metabolically Regulates Tyrosine Hydroxylase in the Nucleus Locus Coeruleus. Cell Rep. 2019 Nov 19;29(8):2144-2153.e7. doi: 10.1016/j.celrep.2019.10.043.

The researchers developed a laboratory mouse model with ASL deficiency in specific regions of the brain and showed that argininosuccinate lyase (ASL) is required for the normal function of the nucleus locus coeruleus (LC) in the brain. LC is the main source of norepinephrine in the brain (an important chemical messenger in the brain and a stress hormone). Loss of ASL in the LC results in low amounts of nitric oxide (NO) which leads to the reduced amount and activity of tyrosine hydroxylase (TH), an enzyme needed to produce dopamine and norepinephrine. The mice with ASL deficiency in LC showed decreased amounts of dopamine and norepinephrine in the brain, displayed higher blood pressure, increased motor activity, and increased sensitivity to develop seizures. Treatment of these mice with donor NO resulted in lower blood pressure and less seizure activity. Behavioral data previously collected from the Longitudinal Study of UCDs (Urea Cycle Disorders) conducted by the Urea Cycle Disorders Consortium showed 55% of participants with ASLD displayed lower attention spans during study visits, compared to 39.4% of participants with another UCD—argininosuccinate synthase deficiency (ASS1D/Citrullinemia). The results were similar for participants who did not have any documented episodes of hyperammonemia, which can affect behavior and cognition. Eighteen percent of participants with ASS1D without documented hyperammonemic events self-reported lower attention spans, compared to 54% of participants with ASLD. More research into the unique neurocognitive characteristics of ASLD will help improve treatment and management.

Liu XB, Haney JR, Cantero G, Lambert JR, Otero-Garcia M, Truong B, Gropman A, Cobos I, Cederbaum SD, Lipshutz GS. Hepatic arginase deficiency fosters dysmyelination during postnatal CNS development. JCI Insight. 2019 Sep 5;4(17):e130260. doi: 10.1172/jci.insight.130260.

Arginase deficiency is classified as a urea cycle disorder (UCD), as arginase is necessary in the breakdown of ammonia in the body. However, unlike other urea cycle disorders, hyperammonemia is uncommon with arginase deficiency. Complications that arise in this disorder such as paralysis, muscle stiffening, involuntary muscle contractions and overactive reflexes are also associated with cerebral palsy. Additionally, complications in arginase deficiency often occur later compared to other UCDs. In this study, researchers found that mice with arginase deficiency had abnormal myelin pattern in the brain and the spinal cord. Treatment of these arginase deficiency mice with arginase 1 gene therapy rescued these abnormal myelin patterns. Due to its unique characteristics among urea cycle disorders, the researchers suggest arginase deficiency be categorized as a leukodystrophy, a group of rare metabolic genetic disorders that affect the brain and spinal cord. This study did not label the cause of muscle and nerve failure within the disorder, yet supports the importance of ongoing neonatal screening, early intervention to normalize arginase production in the body. They also suggest that early postnatal liver-based gene therapy may be of use in preventing neurological abnormalities.

Zielonka M, Kölker S, Gleich F, Stützenberger N, Nagamani SCS, Gropman AL, Hoffmann GF, Garbade SF, Posset R; Urea Cycle Disorders Consortium (UCDC) and the European Registry and Network for Intoxication type Metabolic Diseases (E-IMD) Consortia Study Group. Early prediction of phenotypic severity in Citrullinemia Type 1. Ann Clin Transl Neurol. 2019 Sep;6(9):1858-1871. doi: 10.1002/acn3.50886. Epub 2019 Aug 30.

Citrullinemia type1(ASS1D), also known as argininosuccinate synthase deficiency (ASS1D), is an inherited UCD that is detectable by newborn screening. The severity of the disease is variable, with health outcomes ranging from dangerous levels of hyperammonemic brain damage to mild, unnoticeable symptoms. Infant mortality rate for this disease has remained high over the decades despite the implementation of early treatment interventions. In this study, researchers evaluated a new test that could possibly predict the severity of ASS1D , based on the activity level of the enzyme argininosuccinate synthetase 1 (ASS1), which has been shown in previous studies to predict the severity of other inborn errors of metabolism. Participant data was collected from the Longitudinal Study of UCD conducted by the Urea Cycle Disorders Consortium (UCDC) and the European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD). The researchers used a newly established assay to measure enzymatic activity of ASS1. The results showed that participants with ASS1D with ASS1 activity at 8.1% or lower experienced more frequent and severe hyperammonemic events and poorer cognitive function than participants with ASS1 activity above 8.1%. Additionally, participants with 26.6% or lower ASS1 activity had participated in special education programs, and those with 19.3% or lower ASS1 activity suffered more often from movement disorders. Participants with 4.8% or lower ASS1 activity were more likely to undergo liver transplantation. These results suggest that this enzymatic activity method could be useful in the clinical outcome prediction.

Burrage LC, Thistlethwaite L, Stroup BM, Sun Q, Miller MJ, Nagamani SCS, Craigen W, Scaglia F, Sutton VR, Graham B, Kennedy AD; Members of the UCDC,, Milosavljevic A, Lee BH, Elsea SH. Untargeted metabolomic profiling reveals multiple pathway perturbations and new clinical biomarkers in urea cycle disorders. Genet Med. 2019 Sep;21(9):1977-1986. doi: 10.1038/s41436-019-0442-0. Epub 2019 Jan 23.

Urea cycle disorders (UCDs) are screened and diagnosed through the use of biochemical and molecular testing. If biomarkers of UCDs, such as elevated (higher) levels of ammonia and arginine, are present in a patient’s screening tests, an analysis of their genetic composition (makeup) will confirm the disorder. However, this may not be a reliable method of diagnosis in all cases, as ornithine transcarbamylase deficiency (OTCD) can be difficult to identify due to the nature of the disorder. Untargeted metabolomic profiling has become an important tool in diagnosis and management of UCDs because it is able to detect biomarkers of UCDs that might not be captured by the traditional methods of diagnosis. In this study, samples from 48 subjects that were collected during routine clinical visits and samples from the Urea Cycle Disorders Consortium (UCDC) Longitudinal Study were analyzed with metabolomic profiling. Results from the analyses found known biomarkers of UCDs.

Diaz GA, Schulze A, Longo N, Rhead W, Feigenbaum A, Wong D, Merritt JL 2nd, Berquist W, Gallagher RC, Bartholomew D, McCandless SE, Smith WE, Harding CO, Zori R, Lichter-Konecki U, Vockley J, Canavan C, Vescio T, Holt RJ, Berry SA. Long-term safety and efficacy of glycerol phenylbutyrate for the management of urea cycle disorder patients. Mol Genet Metab. 2019 Jul 10. pii: S1096-7192(19)30323-3. PMID: 31326288. Full Text.

Waisbren SE, Stefanatos AK, Kok TMY, Ozturk-Hismi B. Neuropsychological attributes of urea cycle disorders: A systematic review of the literature. J Inherit Metab Dis. 2019 Jul 3. PMID: 31268178, Full Text.

Posset R, Gropman AL, Nagamani SCS, Burrage LC, Bedoyan JK, Wong D, Berry GT, Baumgartner MR, Yudkoff M, Zielonka M, Hoffmann GF, Burgard P, Schulze A, McCandless SE, Garcia-Cazorla A, Seminara J, Garbade SF, Kölker S; Urea Cycle Disorders Consortium and the European Registry and Network for Intoxication Type Metabolic Diseases Consortia Study Group. Impact of Diagnosis and Therapy on Cognitive Function in Urea Cycle Disorders. Ann Neurol. 2019 Jul;86(1):116-128. doi: 10.1002/ana.25492. Epub 2019 May 13.

As intellectual and developmental disabilities are common in individuals diagnosed with urea cycle disorders (UCD), the purpose of this study was to evaluate the impact of diagnostic and treatment methods on cognitive outcomes such as thinking, reasoning, remembering, imagining, and learning. Results from neurocognitive testing of 503 individuals with UCD enrolled in the Longitudinal Study of UCD conducted by the UCD Consortium (UCDC) and the European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD) from 2006 to 2016 were studied. IQ scores less than 70, indicating intellectual disability, were associated with UCD type and early disease onset. The height of initial peak plasma ammonium level was associated with poorer neurocognitive outcomes in proximal UCDs (CPS1, OTCD). Individuals with citrullinemia (argininosuccinate synthetase deficiency, ASS1D) and argininosuccinate lyase deficiency (ASLD) who were identified by newborn screening but did not have symptoms at diagnosis had better outcomes than those diagnosed after having symptoms. Additionally, early liver transplantation appeared to be beneficial.

Uittenbogaard M, Brantner CA, Fang Z, Wong LJ, Gropman A, Chiaramello A. The m.11778 A > G variant associated with the coexistence of Leber's hereditary optic neuropathy and multiple sclerosis-like illness dysregulates the metabolic interplay between mitochondrial oxidative phosphorylation and glycolysis. Mitochondrion. 2019 May;46:187-194. doi: 10.1016/j.mito.2018.06.001. Epub 2018 Jun 8.

Buerger C, Garbade SF, Dietrich Alber F, Waisbren SE, McCarter R, Kölker S, Burgard P; Urea Cycle Disorders Consortium. Impairment of cognitive function in ornithine transcarbamylase deficiency is global rather than domain-specific and is associated with disease onset, sex, maximum ammonium, and number of hyperammonemic events. J Inherit Metab Dis. 2019 Mar;42(2):243-253. doi: 10.1002/jimd.12013. Epub 2019 Jan 22.

Ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle disorder (UCD). OTCD presents with a wide range of symptom severity. In this study, the number of hyperammonaemic events, clinical findings, and cognitive functioning domains—intelligence (IQ), executive function, memory, visuomotor integration and visual perception—were compared across groups. The groups were separated according to disease onset type— late disease onset (clinical symptoms at more than 28 days old), early disease onset (clinical symptoms at 28 days old or less), or asymptomatic—sex, and age. Participant information collected by the Urea Cycle Disorders Consortium (UCDC) through the Longitudinal Study between 2006 and 2014 served as the data source, to include 300 OTCD participants who underwent psychological evaluations. Although mean scores of late onset and asymptomatic individuals were within 1 SD of the population norm (IQ = 85-115, which is the normal range for individuals with-out UCD, as well), asymptomatic participants attained significantly higher scores than late onset participants and males scored higher than females. Intelligence scores proved to correlate with overall cognitive functioning. The correlation between maximum ammonia concentration and intelligence correlated significantly higher in early onset than in late onset participants (i.e. higher ammonia levels correlated with lower IQ). Correlation between the number of hyperammonemic events and intelligence scores were similar for early onset and late onset individuals. The number of clinical symptoms was significantly associated with intelligence, but not with scores in other domains. Results suggest that OTCD has a global impact on cognitive functioning rather than a specific effect on distinct cognitive domains (executive function, memory, visual-motor integration, visual perception).

Posset R, Garbade SF, Boy N, Burlina AB, Dionisi-Vici C, Dobbelaere D, Garcia-Cazorla A, de Lonlay P, Teles EL, Vara R, Mew NA, Batshaw ML, Baumgartner MR, McCandless SE, Seminara J, Summar M, Hoffmann GF, Kölker S, Burgard P; Additional individual contributors of the UCDC and the E-IMD consortium. Transatlantic combined and comparative data analysis of 1095 patients with urea cycle disorders-A successful strategy for clinical research of rare diseases. J Inherit Metab Dis. 2019 Jan;42(1):93-106. doi: 10.1002/jimd.12031.

Ah Mew N, Cnaan A, McCarter R, Choi H, Glass P, Rice K, Scavo L, Gillespie CW, Diaz GA, Berry GT, Wong D, Konczal L, McCandless SE, Coughlin CR, II, Weisfeld-Adams JD, Ficicioglu C, Yudkoff M, Enns GM, Lichter-Konecki U, Gallagher R, Tuchman M. Conducting an investigator-initiated randomized double-blinded intervention trial in acute decompensation of inborn errors of metabolism: Lessons from the N-Carbamylglutamate Consortium. Transl Sci Rare Dis. 2018 Dec 20;3(3-4):157-170. doi: 10.3233/TRD-180031. PMID: 30613471; PMCID: PMC6311376.

Inborn errors of metabolism (IEMs), such as urea cycle disorders (UCDs), fall within the category of ultra-rare disorders in which 1 in 50,000 people have the disorder, many of whom die during childhood. This publication focuses on the challenges the N-carbamylglutamate Consortium (NCGC) faced while conducting two trials for N-carbamylglutamate (NCG), an approved treatment for N-acetylglutamate synthetase (NAGS) deficiency, one of the UCD subtypes that causes hyperammonemia. Among the topics discussed is the difficulty of recruiting and retaining eligible participants; enrollment numbers are largely affected by the small participant selection pools characteristic of rare diseases and missed opportunities to refer patients to open studies during routine clinical visits. It is preferable to enroll participants during non-crisis situations in order to avoid an exaggeration of the expected number of hyperammonemia events that could occur during a study. Partnerships with patient advocacy groups such as the National Urea Cycle Disorders Foundation (NUCDF) are crucial for rare disease studies as they pro-vide opportunities for researchers to educate and reach out to potential participants and their families and caregivers. Introspective publications such as this are valuable in the evaluation and improvement of study methods.

Wiwattanadittakul N, Prust M, Gaillard WD, Massaro A, Vezina G, Tsuchida TN, Gropman AL. The utility of EEG monitoring in neonates with hyperammonemia due to inborn errors of metabolism. Mol Genet Metab. 2018 Nov;125(3):235-240. doi: 10.1016/j.ymgme.2018.08.011. Epub 2018 Aug 24.

Continuous video electroencephalogram (cvEEG) is the long-term video monitoring of electrical activity in the brain. The typical length of an electroencephalogram (EEG) test is between 30 to 60 minutes, where as a cvEEG test can last for days at a time. Most infant seizures do not have clinical symptoms and can only be detected by an EEG, making cvEEG the preferred method for monitoring seizures associated with acute brain injury; however, the benefits of using cvEEG on infants with in-born errors of metabolism have not been determined. In this study, researchers analyzed the medical records of eight infants who experienced hyperammonemia due to inborn errors of metabolism and received prolonged EEG tests at Children's National Medical Center, Washington, D.C., between January 2009 and March 2017. The results showed that seven of the infants had seizures, and six had seizures that could only be detected by EEG. Although there was evidence that elevated levels of blood ammonia and glutamine—common symptoms of urea cycle disorders—had a possible connection to seizure activity on EEG, it is important to note that some of the infants, after receiving medication that normalized their blood ammonia and glutamine levels, continued to have seizures (Figure 5). Seizures were also detected by EEG before blood ammonia levels spiked and occurred within 24 to 36 hours of clinical symptoms. These and other findings documented in the study suggest the importance of long-term cvEEG in the evaluation of inborn errors of metabolism.

Uittenbogaard M, Gropman A, Brantner CA, Chiaramello A. Novel metabolic signatures of compound heterozygous Szt2 variants in a case of early-onset of epileptic encephalopathy. Clin Case Rep. 2018 Oct 25;6(12):2376-2384. doi: 10.1002/ccr3.1868. eCollection 2018 Dec.

Kho J, Tian X, Wong WT, Bertin T, Jiang MM, Chen S, Jin Z, Shchelochkov OA, Burrage LC, Reddy AK, Jiang H, Abo-Zahrah R, Ma S, Zhang P, Bissig KD, Kim JJ, Devaraj S, Rodney GG, Erez A, Bryan NS, Nagamani SCS, Lee BH. Argininosuccinate Lyase Deficiency Causes an Endothelial-Dependent Form of Hypertension. Am J Hum Genet. 2018 Aug 2;103(2):276-287. doi: 10.1016/j.ajhg.2018.07.008.

Key Point: A chemical deficiency associated with ASLD often leads to high blood pressure. Nitric oxide supplementation is currently being investigated in clinical trials as a treatment option for individuals with ASLD. In this study, the investigators used mice with argininosuccinate lyase deficiency (ASLD) and cells from patients with ASLD to study the mechanisms involved in causing high blood pressure in this disorder, which is the second most common UCD (Figure 4). The investigators show that loss of the urea cycle enzyme ASL in the lining cells of the blood vessels leads to reduction of a chemical called nitric oxide (NO) and an increase in oxidative stress that lead to vascular dysfunction. Using data from a human trial that was funded by the Urea Cycle Disorders Consortium (UCDC), they also show that the blood pressure in individuals with ASLD can be elevated. The results of this study can have potential treatment implications. Currently, nitric oxide supplementation is being investigated in clinical trials as a treatment option for individuals with ASLD.

Posset R, Garbade SF, Boy N, Burlina AB, Dionisi-Vici C, Dobbelaere D, Garcia-Cazorla A, de Lonlay P, Teles EL, Vara R, Ah Mew N, Batshaw ML, Baumgartner MR, McCandless SE, Seminara J, Summar ML, Hoffmann GF, Kölker S, Burgard P; on behalf of the UCDC and the E-IMD consortium. Transatlantic combined and comparative data analysis of 1095 patients with urea cycle disorders – a successful strategy for clinical research of rare diseases. J Inherit Metab Dis. 2018 Jul 4. PMID: 29974348.

The Urea Cycle Disorders Consortium (UCDC) and the European Registry and Network for Intoxication Type Metabolic Disorders (E-IMD) collaborated to compare the prevalence and characteristics of urea cycle disorders (UCDs) in North America and Europe. The UCDC Longitudinal Study data was used for North America. Combining registries from both consortia, researchers looked at the medical histories of over 1,000 patients with UCD for information such as UCD type, late disease onset (clinical symptoms at more than 28 days old) or early dis-ease onset (clinical symptoms at 28 days old or less), and age of diagnosis. In North America and Europe, Ornithine Transcarbamylase Deficiency (OTCD ) and late disease onset were the most common; however, the lack of early onset reports may have been caused by the voluntary nature of the registries, as the severe symptoms associated with early onset UCDs could make participation more difficult. The data also showed that the delay between age of clinical symptoms and age of diagnosis was shorter for early onset patients, which was likely due to the higher visibility of symptoms such as seizures.

Nagamani SCS, Agarwal U, Tam A, Azamian M, McMeans A, Didelija IC, Mohammad MA, Marini JC. A randomized trial to study the comparative efficacy of phenylbutyrate and benzoate on nitrogen excretion and ureagenesis in healthy volunteers. Genet Med. 2018 Jul;20(7):708-716. doi: 10.1038/gim.2017.167. Epub 2017 Oct 12.

Waisbren SE, Cuthbertson D, Burgard P, Holbert A, McCarter R, Cederbaum S; Members of the Urea Cycle Disorders Consortium. Biochemical markers and neuropsychological functioning in distal urea cycle disorders. J Inherit Metab Dis. 2018 Jul;41(4):657-667. doi: 10.1007/s10545-017-0132-5. Epub 2018 Feb 8.

The urea cycle breaks down ammonia into urea, which is then excreted (released) through urine; urea cycle disorders (UCDs) occur when a step in the urea cycle process is disrupted. Ammonia accumulation is shared amongst the different UCD types, but each individual UCD can have distinctive (unique) effects on the body. This report examines links between biochemical markers (ammonia, glutamine, arginine, citrulline) and neuropsychological test results in three UCD subtypes - argininosuccinic acid synthetase deficiency (ASD or citrullinemia type I), argininosuccinic acid lyase deficiency (ASA or ALD), and arginase deficiency (ARGD). Using data previously collected by the Urea Cycle Disorders Consortium’s Longitudinal Study, the investigators evaluated the neuropsychological tests and lab results of 145 participants (Figure 2). The neurological tests measured for intelligence (IQ), verbal and visual abilities, motor function and memory. As a result, the mean full scale IQ was below the population mean of 100 ± 15 for all groups: (ASD = 79 ± 24; ASA = 71 ± 21; ARGD = 65 ± 19), and the greatest deficits were noted in visual performance and motor skills for all groups. The biomarkers that most reliably indicated poor overall neuropsychological performance were ammonia and citrulline for ASD participants; ammonia, glutamine, and citrulline for ASA participants; and arginine, ammonia and citrulline for ARGD participants. Recognizing biomarker profiles is useful in deter-mining the most appropriate treatments.

Merritt JL 2nd, Brody LL, Pino G, Rinaldo P. Newborn screening for proximal urea cycle disorders: Current evidence supporting recommendations for newborn screening. Mol Genet Metab. 2018 Jun;124(2):109-113. doi: 10.1016/j.ymgme.2018.04.006. Epub 2018 Apr 20. PubMed PMID: 29703588.

Uittenbogaard M, Brantner CA, Fang Z, Wong LC, Gropman A, Chiaramello A. Novel insights into the functional metabolic impact of an apparent de novo m.8993T>G variant in the MT-ATP6 gene associated with maternally inherited form of Leigh Syndrome. Mol Genet Metab. 2018 May;124(1):71-81. doi: 10.1016/j.ymgme.2018.03.011. Epub 2018 Mar 27.

Uittenbogaard M, Brantner CA, Chiaramello A. Epigenetic modifiers promote mitochondrial biogenesis and oxidative metabolism leading to enhanced differentiation of neuroprogenitor cells. Cell Death Dis. 2018 Mar 2;9(3):360. doi: 10.1038/s41419-018-0396-1.

Sin YY, Ballantyne LL, Richmond CR, Funk CD. Transplantation of Gene-Edited Hepatocyte-like Cells Modestly Improves Survival of Arginase-1-Deficient Mice. Mol Ther Nucleic Acids. 2018 Mar 2;10:122-130. doi: 10.1016/j.omtn.2017.11.012. Epub 2017 Dec 1.

This study, funded by a Urea Cycle Disorders Consortium (UCDC) training grant, focused on the possibility of incorporating gene editing in a preclinical animal model for treatment of urea cycle disorder (UCD), specifically arginase deficiency. Induced pluripotent stem cells (iPSCs), or cells that can become any type of cell in the body, were turned into hepatocyte-like cells (HLCs), or liver cells. The HLCs were transplanted into mice with arginase deficiency, and investigators monitored the mice for signs that the HLCs were producing arginase enzyme. The results showed 5% liver regeneration, low productions of arginase, and a maximum lifespan of 22 days compared to 14 days in arginase-deficient mice that were not trans-planted. Although the initial proof of concept study showed minimal improvements, the research suggests that there might be a place for such therapies in the future.

Jichlinski A, Clarke L, Whitehead MT, Gropman A. "Cerebral palsy" in a patient with arginase deficiency. Semin Pediatr Neurol. 2018;26:110-114. Full Text.

Meyburg J, Opladen T, Spiekerkötter U, Schlune A, Schenk JP, Schmidt J, Weitz J, Okun J, Bürger F, Omran TB, Abdoh G, Al Rifai H, Monavari A, Konstantopoulou V, Kölker S, Yudkoff M, Hoffmann GF. Human heterologous liver cells transiently improve hyperammonemia and ureagenesis in individuals with severe urea cycle disorders. J Inherit Metab Dis. 2018;41:81-90. PMID: 29027067.

*Lindsay C, Burrage, Brendan Lee, and Sandesh C, S Nagamani. Urea Cycle Disorders. Rudolph Pediatrics, Chapter 141, p 23rd Edition, McGraw Hill. 2018

Schrier Vergano SA, Le Mons C. Hyperammonemia in Neonates: Looking beyond sepsis. Neonatology Today. 2017 Dec, Vol 13/Issue 12, pp 15-16. Online Full Text.

Sin YY, Price PR, Ballantyne LL, Funk CD. Proof-of-Concept Gene Editing for the Murine Model of Inducible Arginase-1 Deficiency. Sci Rep. 2017 May 31;7(1):2585. doi: 10.1038/s41598-017-02927-2.

Shi D, Zhao G, Ah Mew N, Tuchman M. Precision medicine in rare disease: Mechanisms of disparate effects of N-carbamyl-l-glutamate on mutant CPS1 enzymes. Mol Genet Metab. 2017 Mar;120(3):198–206. PMID: 28007335, PMCID: PMC5346444.

Longo N , Holt RJ. Glycerol phenylbutyrate for the maintenance treatment of patients with deficiencies in enzymes of the urea cycle. Expert Opin. on Orphan Drugs. 5 (12) (2017), pp. 999-1010. Full Text.

Nettesheim S, Kölker S, Karall D, Häberle J, Posset R, Hoffmann GF, Heinrich B, Gleich F, Garbade SF; Arbeitsgemeinschaft für Pädiatrische Stoffwechselstörungen (APS); European registry and network for Intoxication type Metabolic Diseases (E-IMD); Erhebungseinheit für Seltene Pädiatrische Erkrankungen in Deutschland (ESPED); Austrian Metabolic Group; Swiss Paediatric Surveillance Unit (SPSU). Incidence, disease onset and short-term outcome in urea cycle disorders -cross-border surveillance in Germany, Austria and Switzerland. Orphanet J Rare Dis. 2017;12:111. PMID: 28619060, PMCID: PMC5472961.

Berry SA, Longo N, Diaz GA, McCandless SE, Smith WE, Harding CO, Zori R, Ficicioglu C, Lichter-Konecki U, Robinson B, Vockley J. Safety and efficacy of glycerol phenylbutyrate for management of urea cycle disorders in patients aged 2 months to 2 years. Mol Genet Metab. 2017;122(3):46-53. PMID: 28916119, Full Text.

Butler MG, Lee J, Cox DM, Manzardo AM, Gold JA, Miller JL, Roof E, Dykens E, Kimonis V, Driscoll DJ. Growth Charts for Prader-Willi Syndrome During Growth Hormone Treatment. Clin Pediatr (Phila). 2016 Sep;55(10):957-74. doi: 10.1177/0009922815617973. Epub 2016 Feb 3.

Shchelochkov OA ,Dickinson K , Scharschmidt BF , Lee B, Marino M, Le Mons C. Barriers to drug adherence in the treatment of urea cycle disorders: assessment of patient, caregiver and provider perspectives. Mol Genet Metab Rep. 2016 Jul 20:8:43-7. doi: 10.1016/j.ymgmr.2016.07.003. eCollection 2016 Sep.

Waisbren SE, Gropman AL; Members of the Urea Cycle Disorders Consortium (UCDC), Batshaw ML. Improving long term outcomes in urea cycle disorders-report from the Urea Cycle Disorders Consortium. J Inherit Metab Dis. 2016 Jul;39(4):573-84. doi: 10.1007/s10545-016-9942-0. Epub 2016 May 23.

Atwal PS, Medina CR, Burrage LC, Sutton VR. Nineteen-year follow-up of a patient with severe glutathione synthetase deficiency. J Hum Genet. 2016 Jul;61(7):669-72. doi: 10.1038/jhg.2016.20. Epub 2016 Mar 17.

Shapiro E, Bernstein J, Adams HR, Barbier AJ, Buracchio T, Como P, Delaney KA, Eichler F, Goldsmith JC, Hogan M, Kovacs S, Mink JW, Odenkirchen J, Parisi MA, Skrinar A, Waisbren SE, Mulberg AE. Neurocognitive clinical outcome assessments for inborn errors of metabolism and other rare conditions. Mol Genet Metab. 2016 Jun;118(2):65-9. doi: 10.1016/j.ymgme.2016.04.006. Epub 2016 Apr 14.

Merkel PA, Manion M, Gopal-Srivastava R, Groft S, Jinnah HA, Robertson D, Krischer JP; Rare Diseases Clinical Research Network. The partnership of patient advocacy groups and clinical investigators in the rare diseases clinical research network. Orphanet J Rare Dis. 2016 May 18;11(1):66. doi: 10.1186/s13023-016-0445-8.

Laemmle A, Gallagher RC, Keogh A, Stricker T, Gautschi M, Nuoffer JM, Baumgartner MR, Häberle J. Frequency and Pathophysiology of Acute Liver Failure in Ornithine Transcarbamylase Deficiency (OTCD). PLoS One. 2016 Apr 12;11(4):e0153358. doi: 10.1371/journal.pone.0153358. eCollection 2016.

Burrage LC, Miller MJ, Wong LJ, Kennedy AD, Sutton VR, Sun Q, Elsea SH, Graham BH. Elevations of C14:1 and C14:2 Plasma Acylcarnitines in Fasted Children: A Diagnostic Dilemma. J Pediatr. 2016 Feb;169:208-13.e2. doi: 10.1016/j.jpeds.2015.10.045. Epub 2015 Nov 18.

Lee B, Diaz GA, Rhead W, Lichter-Konecki U, Feigenbaum A, Berry SA, Le Mons C, Bartley J, Longo N, Nagamani SC, Berquist W, Gallagher RC, Harding CO, McCandless SE, Smith W, Schulze A, Marino M, Rowell R, Coakley DF, Mokhtarani M, Scharschmidt BF. Glutamine and hyperammonemic crises in patients with urea cycle disorders. Mol Genet Metab. 2016 Jan;117(1):27-32. doi: 10.1016/j.ymgme.2015.11.005. Epub 2015 Nov 11.

Opladen T, Lindner M, Das AM, Marquardt T, Khan A, Emre SH, Burton BK, Barshop BA, Böhm T, Meyburg J, Zangerl K, Mayorandan S, Burgard P, Dürr UH, Rosenkranz B, Rennecke J, Derbinski J, Yudkoff M, Hoffmann GF. In vivo monitoring of urea cycle activity with (13)C-acetate as a tracer of ureagenesis. Mol Genet Metab. 2016 Jan;117(1):19-26. doi: 10.1016/j.ymgme.2015.11.007. Epub 2015 Nov 14.

Posset R, Garcia-Cazorla A, Valayannopoulos V, Teles EL, Dionisi-Vici C, Brassier A, Burlina AB, Burgard P, Cortès-Saladelafont E, Dobbelaere D, Couce ML, Sykut-Cegielska J, Häberle J, Lund AM, Chakrapani A, Schiff M, Walter JH, Zeman J, Vara R, Kölker S, additional individual contributors of the E-IMD consortium. Age at disease onset and peak ammonium level rather than interventional variables predict the neurological outcome in urea cycle disorders. J Inherit Metab Dis. 2016;39:661-672. PMID: 27106216.

Jamiolkowski D, Kölker S, Glahn EM, Barić I, Zeman J, Baumgartner MR, Mühlhausen C, Garcia-Cazorla A, Gleich F, Haege G, Burgard P; E-IMD consortium. Behavioural and emotional problems, intellectual impairment and health-related quality of life in patients with organic acidurias and urea cycle disorders. J Inherit Metab Dis. 2016; 39: 231-41. PMID: 26310964.

Barkovich E, Robinson C, Gropman A. Brain biomarkers and neuroimaging to diagnose urea cycle disorders and assess prognosis. Expert Opinion on Orphan Drugs. 4:11, 1123-1132. Abstract.

Krivitzky LS, Walsh KS, Fisher EL, Berl MM. Executive functioning profiles from the BRIEF across pediatric medical disorders: Age and diagnosis factors. Child Neuropsychol. 2016;22(7):870-88. doi: 10.1080/09297049.2015.1054272. Epub 2015 Jul 6.

Heringer J, Valayannopoulos V, Lund AM, Wijburg FA, Freisinger P, Barić I, Baumgartner MR, Burgard P, Burlina AB, Chapman KA, I Saladelafont EC, Karall D, Mühlhausen C, Riches V, Schiff M, Sykut-Cegielska J, Walter JH, Zeman J, Chabrol B, Kölker S, additional individual contributors of the E-IMD consortium. Impact of age at onset and newborn screening on outcome in organic acidurias. J Inherit Metab Dis. 2015 Dec 21. PMID: 26689403, Full Text (with PubMed access).

Burrage LC, Charng WL, Eldomery MK, Willer JR, Davis EE, Lugtenberg D, Zhu W, Leduc MS, Akdemir ZC, Azamian M, Zapata G, Hernandez PP, Schoots J, de Munnik SA, Roepman R, Pearring JN, Jhangiani S, Katsanis N, Vissers LE, Brunner HG, Beaudet AL, Rosenfeld JA, Muzny DM, Gibbs RA, Eng CM, Xia F, Lalani SR, Lupski JR, Bongers EM, Yang Y. De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome. Am J Hum Genet. 2015 Dec 3;97(6):904-13. doi: 10.1016/j.ajhg.2015.11.006.

*Sin YY, Baron G, Schulze A, Funk CD. Arginase-1 deficiency. J Mol Med (Berl). 2015 Dec;93(12):1287-96. PMID: 26467175.

Burrage LC, Sun Q, Elsea SH, Jiang MM, Nagamani SC, Frankel AE, Stone E, Alters SE, Johnson DE, Rowlinson SW, Georgiou G; Members of Urea Cycle Disorders Consortium, Lee BH. Human recombinant arginase enzyme reduces plasma arginine in mouse models of arginase deficiency. Hum Mol Genet. 2015 Nov 15;24(22):6417-27. doi: 10.1093/hmg/ddv352. Epub 2015 Sep 10.

Miller MJ, Burrage LC, Gibson JB, Strenk ME, Lose EJ, Bick DP, Elsea SH, Sutton VR, Sun Q, Graham BH, Craigen WJ, Zhang VW, Wong LJ. Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States. Mol Genet Metab. 2015 Nov;116(3):139-45. doi: 10.1016/j.ymgme.2015.08.011. Epub 2015 Sep 2.

Kolker S, Garcia-Cazorla A, Valayannopoulos V, Lund AM, Burlina AB, Sykut-Cegielska J, Wijburg FA, Teles EL, Zeman J, Dionisi-Vici C, Barić I, Karall D, Augoustides-Savvopoulou P, Aksglaede L, Arnoux JB, Avram P, Baumgartner MR, Blasco-Alonso J, Chabrol B, Chakrapani A, Chapman K, I Saladelafont EC, Couce ML, de Meirleir L, Dobbelaere D, Dvorakova V, Furlan F, Gleich F, Gradowska W, Grünewald S, Jalan A, Häberle J, Haege G, Lachmann R, Laemmle A, Langereis E, de Lonlay P, Martinelli D, Matsumoto S, Mühlhausen C, de Baulny HO, Ortez C, Peña-Quintana L, Ramadža DP, Rodrigues E, Scholl-Bürgi S, Sokal E, Staufner C, Summar ML, Thompson N, Vara R, Pinera IV, Walter JH, Williams M, Burgard P. The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation. J Inherit Metab Dis. 2015 Nov;38(6):1041-1057. PMID: 25875215, Full Text  (with PubMed access).

Kolker S, Valayannopoulos V, Burlina AB, Sykut-Cegielska, Wijburg FA, Teles EL, Zeman J, Dionisi-Vici C, Barić I, Karall D, Arnoux JB, Avram P, Baumgartner MR, Blasco-Alonso J, Boy SP, Rasmussen MB, Burgard P, Chabrol B, Chakrapani A, Chapman K, Cortès I Saladelafont E, Couce ML, de Meirleir L, Dobbelaere D, Furlan F, Gleich F, González MJ, Gradowska W, Grünewald S, Honzik T, Hörster F, Ioannou H, Jalan A, Häberle J, Haege G, Langereis E, de Lonlay P, Martinelli D, Matsumoto S, Mühlhausen C, Murphy E, de Baulny HO, Ortez C, Pedrón CC, Pintos-Morell G, Pena-Quintana L, Ramadža DP, Rodrigues E, Scholl-Bürgi S, Sokal E, Summar ML, Thompson N, Vara R, Pinera IV, Walter JH, Williams M, Lund AM, Garcia-Cazorla A. The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2: the evolving clinical phenotype. J Inherit Metab Dis. 2015 Nov;38(6):1059-1074. PMID: 25875216, Full Text (with PubMed access).

Pferdehirt R, Jain M, Blazo MA, Lee B, Burrage LC. Catel-Manzke Syndrome: Further Delineation of the Phenotype Associated with Pathogenic Variants in TGDS. Mol Genet Metab Rep. 2015 Sep 1;4:89-91. doi: 10.1016/j.ymgmr.2015.08.003.

Nagamani SC, Diaz GA, Rhead W, Berry SA, Le Mons C, Lichter-Konecki U, Bartley J, Feigenbaum A, Schulze A, Longo N, Berquist W, Gallagher R, Bartholomew D, Harding CO, Korson MS, McCandless SE, Smith W, Vockley J, Kronn D, Zori R, Cederbaum S, Merritt JL 2nd, Wong D, Coakley DF, Scharschmidt BF, Dickinson K, Marino M, Lee BH, Mokhtarani M. Self-reported treatment-associated symptoms among patients with urea cycle disorders participating in glycerol phenylbutyrate clinical trials. Mol Genet Metab. 2015 Sep-Oct;116(1-2):29-34. doi: 10.1016/j.ymgme.2015.08.002. Epub 2015 Aug 5.

Shi D, Allewell NM, Tuchman M. From Genome to Structure and Back Again: A Family Portrait of the Transcarbamylases. Int J Mol Sci. 2015 Aug 12;16(8):18836-64. doi: 10.3390/ijms160818836.

Boyer SW, Barclay LJ, Burrage LC. Inherited Metabolic Disorders: Aspects of Chronic Nutrition Management. Nutr Clin Pract. 2015 Aug;30(4):502-10. doi: 10.1177/0884533615586201. Epub 2015 Jun 16.

Lee B, Diaz GA, Rhead W, Lichter-Konecki U, Feigenbaum A, Berry SA, Le Mons C, Bartley JA, Longo N, Nagamani SC, Berquist W, Gallagher R, Bartholomew D, Harding CO, Korson MS, McCandless SE, Smith W, Cederbaum S, Wong D, Merritt JL 2nd, Schulze A, Vockley J, Kronn D, Zori R, Summar M, Milikien DA, Marino M, Coakley DF, Mokhtarani M; UCD Consortium, Scharschmidt BF. Blood ammonia and glutamine as predictors of hyperammonemic crises in patients with urea cycle disorder. Genet Med. 2015 Jul;17(7):561-8. doi: 10.1038/gim.2014.148. Epub 2014 Dec 11.

Pacheco-Colón I, Washington SD, Sprouse C, Helman G, Gropman AL, VanMeter JW. Reduced Functional Connectivity of Default Mode and Set-Maintenance Networks in Ornithine Transcarbamylase Deficiency. PLoS One. 2015 Jun 11;10(6):e0129595. doi: 10.1371/journal.pone.0129595. eCollection 2015.

Shi D, Allewell NM, Tuchman M. The N-Acetylglutamate Synthase Family: Structures, Function and Mechanisms. Int J Mol Sci. 2015 Jun 9;16(6):13004-22. doi: 10.3390/ijms160613004.

Caldovic L, Abdikarim I, Narain S, Tuchman M, Morizono H. Genotype-Phenotype Correlations in Ornithine Transcarbamylase Deficiency: A Mutation Update. J Genet Genomics. 2015 May 20;42(5):181-94. doi: 10.1016/j.jgg.2015.04.003. Epub 2015 May 19.

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Chong JX, Burrage LC, Beck AE, Marvin CT, McMillin MJ, Shively KM, Harrell TM, Buckingham KJ, Bacino CA, Jain M, Alanay Y, Berry SA, Carey JC, Gibbs RA, Lee BH, Krakow D, Shendure J, Nickerson DA; University of Washington Center for Mendelian Genomics, Bamshad MJ. Autosomal-Dominant Multiple Pterygium Syndrome Is Caused by Mutations in MYH3. Am J Hum Genet. 2015 May 7;96(5):841-9. doi: 10.1016/j.ajhg.2015.04.004.

Zhao G, Jin Z, Allewell NM, Tuchman M, Shi D. Structures of the N-acetyltransferase domain of Xylella fastidiosa N-acetyl-L-glutamate synthase/kinase with and without a His tag bound to N-acetyl-L-glutamate. Acta Crystallogr F Struct Biol Commun. 2015 Jan 1;71(Pt 1):86-95. doi: 10.1107/S2053230X14026788. Epub 2015 Jan 1.

Kolker S, Dobbelaere D, Haberle J, Burgard P, Gleich F, Summar ML, Hannigan S, Parker S, Chakrapani A, Baumgartner MR, and on behalf of the E-IMD Consortium. Networking across borders for individuals with organic acidurias and urea cycle disorders: The E-IMD Consortium. JIMD Reports. 2015;22:29-38. PMID: 25701269, PMCID: PMC4486274.

Pacheco-Colón I, Fricke S, Gropman A. Role of brain imaging for demonstrating ammonia-induced changes. In Current Approach to Hyperammonemia. Johannes Häberle (ed). eBook, Future Medicine. 2014

Burrage LC, Nagamani SC, Campeau PM, Lee BH. Branched-chain amino acid metabolism: from rare Mendelian diseases to more common disorders. Hum Mol Genet. 2014 Sep 15;23(R1):R1-8. doi: 10.1093/hmg/ddu123. Epub 2014 Mar 20.

Pacheco-Colón I, Fricke S, VanMeter J, Gropman AL. Advances in urea cycle neuroimaging: Proceedings from the 4th International Symposium on urea cycle disorders, Barcelona, Spain, September 2013. Mol Genet Metab. 2014 Sep-Oct;113(1-2):118-26. doi: 10.1016/j.ymgme.2014.05.005. Epub 2014 May 20.

Batshaw ML, Tuchman M, Summar M, Seminara J; Members of the Urea Cycle Disorders Consortium. A longitudinal study of urea cycle disorders. Mol Genet Metab. 2014 Sep-Oct;113(1-2):127-30. doi: 10.1016/j.ymgme.2014.08.001. Epub 2014 Aug 10.

Sprouse C, King J, Helman G, Pacheco-Colón I, Shattuck K, Breeden A, Seltzer R, VanMeter JW, Gropman AL. Investigating neurological deficits in carriers and affected patients with ornithine transcarbamylase deficiency. Mol Genet Metab. 2014 Sep-Oct;113(1-2):136-41. doi: 10.1016/j.ymgme.2014.05.007. Epub 2014 May 20.

Burrage LC, Jain M, Gandolfo L, Lee BH; Members of the Urea Cycle Disorders Consortium, Nagamani SC. Sodium phenylbutyrate decreases plasma branched-chain amino acids in patients with urea cycle disorders. Mol Genet Metab. 2014 Sep-Oct;113(1-2):131-5. doi: 10.1016/j.ymgme.2014.06.005. Epub 2014 Jul 3.

Ah Mew N, McCarter R, Daikhin Y, Lichter-Konecki U, Nissim I, Yudkoff M, Tuchman M. Augmenting ureagenesis in patients with partial carbamyl phosphate synthetase 1 deficiency with N-carbamyl-L-glutamate. J Pediatr. 2014 Aug;165(2):401-403.e3. doi: 10.1016/j.jpeds.2014.04.012. Epub 2014 May 29.

Helman G, Pacheco-Colón I, Gropman AL. The urea cycle disorders. Semin Neurol. 2014 Jul;34(3):341-9. doi: 10.1055/s-0034-1386771. Epub 2014 Sep 5.

Batshaw ML, Groft SC, Krischer JP. Research into rare diseases of childhood. JAMA. 2014 May 7;311(17):1729-30. doi: 10.1001/jama.2013.285873.

Berry SA, Lichter-Konecki U, Diaz GA, McCandless SE, Rhead W, Smith W, Lemons C, Nagamani SC, Coakley DF, Mokhtarani M, Scharschmidt BF, Lee B. Glycerol phenylbutyrate treatment in children with urea cycle disorders: pooled analysis of short and long-term ammonia control and outcomes. Mol Genet Metab. 2014 May;112(1):17-24. doi: 10.1016/j.ymgme.2014.02.007. Epub 2014 Feb 21.

Gallagher RC, Lam C, Wong D, Cederbaum S, Sokol RJ. Significant hepatic involvement in patients with ornithine transcarbamylase deficiency. J Pediatr. 2014 Apr;164(4):720-725.e6. doi: 10.1016/j.jpeds.2013.12.024. Epub 2014 Jan 30.

Caldovic L, Haskins N, Mumo A, Majumdar H, Pinter M, Tuchman M, Krufka A. Expression pattern and biochemical properties of zebrafish N-acetylglutamate synthase. PLoS One. 2014 Jan 22;9(1):e85597. doi: 10.1371/journal.pone.0085597. eCollection 2014.

Mew NA, Yudkoff M, Tuchman M. Stable isotopes in the diagnosis and treatment of inherited hyperammonemia. J Pediatr Biochem. 2014 Jan 1;4(1):57-63. doi: 10.3233/JPB-140106.

Landau YE, Lichter-Konecki U, Levy HL. Genomics in newborn screening. J Pediatr. 2014 Jan;164(1):14-9. doi: 10.1016/j.jpeds.2013.07.028. Epub 2013 Aug 27.

Mokhtarani M, Diaz GA, Rhead W, Berry SA, Lichter-Konecki U, Feigenbaum A, Schulze A, Longo N, Bartley J, Berquist W, Gallagher R, Smith W, McCandless SE, Harding C, Rockey DC, Vierling JM, Mantry P, Ghabril M, Brown RS Jr, Dickinson K, Moors T, Norris C, Coakley D, Milikien DA, Nagamani SC, Lemons C, Lee B, Scharschmidt BF. Elevated phenylacetic acid levels do not correlate with adverse events in patients with urea cycle disorders or hepatic encephalopathy and can be predicted based on the plasma PAA to PAGN ratio. Mol Genet Metab. 2013 Dec;110(4):446-53. doi: 10.1016/j.ymgme.2013.09.017. Epub 2013 Oct 8.

McGuire PJ, Lee HS; members of the Urea Cycle Disorders Consoritum, Summar ML. Infectious precipitants of acute hyperammonemia are associated with indicators of increased morbidity in patients with urea cycle disorders. J Pediatr. 2013 Dec;163(6):1705-1710.e1. doi: 10.1016/j.jpeds.2013.08.029. Epub 2013 Sep 29.

You X, Adjouadi M, Wang J, Guillen MR, Bernal B, Sullivan J, Donner E, Bjornson B, Berl M, Gaillard WD. A decisional space for fMRI pattern separation using the principal component analysis--a comparative study of language networks in pediatric epilepsy. Hum Brain Mapp. 2013 Sep;34(9):2330-42. doi: 10.1002/hbm.22069. Epub 2012 Mar 28.

Summar ML, Koelker S, Freedenberg D, Le Mons C, Haberle J, Lee HS, Kirmse B; European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD) Electronic address: http://wwwe-imdorg/en/indexphtml; Members of the Urea Cycle Disorders Consortium (UCDC) Electronic address: http://rarediseasesnetworkepiusfedu/ucdc/. The incidence of urea cycle disorders. Mol Genet Metab. 2013 Sep-Oct;110(1-2):179-80. doi: 10.1016/j.ymgme.2013.07.008. Epub 2013 Jul 18.

Zhong L, Li S, Li M, Xie J, Zhang Y, Lee B, Batshaw ML, Wilson JM, Gao G. Vector sequences are not detected in tumor tissue from research subjects with ornithine transcarbamylase deficiency who previously received adenovirus gene transfer. Hum Gene Ther. 2013 Sep;24(9):814-9. doi: 10.1089/hum.2013.118.

Lichter-Konecki U, Caldovic L, Morizono H, Simpson K. Ornithine Transcarbamylase Deficiency. In: GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993. 2013 Aug 29 [updated 2022 May 26].

Gunz AC, Choong K, Potter M, Miller E. Magnetic resonance imaging findings and neurodevelopmental outcomes in neonates with urea-cycle defects. Int Med Case Rep J. 2013 Aug 19;6:41-8. doi: 10.2147/IMCRJ.S43513. PMID: 23983495; PMCID: PMC3751504.

Zhao G, Haskins N, Jin Z, M Allewell N, Tuchman M, Shi D. Structure of N-acetyl-L-glutamate synthase/kinase from Maricaulis maris with the allosteric inhibitor L-arginine bound. Biochem Biophys Res Commun. 2013 Aug 9;437(4):585-90. doi: 10.1016/j.bbrc.2013.07.003. Epub 2013 Jul 10.

Lotrecchiano, GR. A dynamical approach toward understanding mechanisms of team science: change, kinship, tension, and heritage in a transdisciplinary team. Clin Transl Sci. 2013 Aug;6(4): 267–278. PMID: 23919361, PMCID: PMC5350836.

Lichter-Konecki U, Nadkarni V, Moudgil A, Cook N, Poeschl J, Meyer MT, Dimmock D, Baumgart S. Feasibility of adjunct therapeutic hypothermia treatment for hyperammonemia and encephalopathy due to urea cycle disorders and organic acidemias. Mol Genet Metab. 2013 Aug;109(4):354-9. doi: 10.1016/j.ymgme.2013.05.014. Epub 2013 May 29.

Zhao G, Jin Z, Allewell NM, Tuchman M, Shi D. Crystal structure of the N-acetyltransferase domain of human N-acetyl-L-glutamate synthase in complex with N-acetyl-L-glutamate provides insights into its catalytic and regulatory mechanisms. PLoS One. 2013 Jul 24;8(7):e70369. doi: 10.1371/journal.pone.0070369. Print 2013.

Monteleone JP, Mokhtarani M, Diaz GA, Rhead W, Lichter-Konecki U, Berry SA, Lemons C, Dickinson K, Coakley D, Lee B, Scharschmidt BF. Population pharmacokinetic modeling and dosing simulations of nitrogen-scavenging compounds: disposition of glycerol phenylbutyrate and sodium phenylbutyrate in adult and pediatric patients with urea cycle disorders. J Clin Pharmacol. 2013 Jul;53(7):699-710. doi: 10.1002/jcph.92. Epub 2013 Jun 15.

Diaz GA, Krivitzky LS, Mokhtarani M, Rhead W, Bartley J, Feigenbaum A, Longo N, Berquist W, Berry SA, Gallagher R, Lichter-Konecki U, Bartholomew D, Harding CO, Cederbaum S, McCandless SE, Smith W, Vockley G, Bart SA, Korson MS, Kronn D, Zori R, Merritt JL 2nd, C S Nagamani S, Mauney J, Lemons C, Dickinson K, Moors TL, Coakley DF, Scharschmidt BF, Lee B. Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate. Hepatology. 2013 Jun;57(6):2171-9. doi: 10.1002/hep.26058. Epub 2013 Jan 3.

Smith W, Diaz GA, Lichter-Konecki U, Berry SA, Harding CO, McCandless SE, LeMons C, Mauney J, Dickinson K, Coakley DF, Moors T, Mokhtarani M, Scharschmidt BF, Lee B. Ammonia control in children ages 2 months through 5 years with urea cycle disorders: comparison of sodium phenylbutyrate and glycerol phenylbutyrate. J Pediatr. 2013 Jun;162(6):1228-34, 1234.e1. doi: 10.1016/j.jpeds.2012.11.084. Epub 2013 Jan 13.

Gropman AL, Prust M, Breeden A, Fricke S, VanMeter J. Urea cycle defects and hyperammonemia: effects on functional imaging. Metab Brain Dis. 2013 Jun;28(2):269-75. doi: 10.1007/s11011-012-9348-0. Epub 2012 Nov 13.

Gropman AL, Shattuck K, Prust MJ, Seltzer RR, Breeden AL, Hailu A, Rigas A, Hussain R, VanMeter J. Altered neural activation in ornithine transcarbamylase deficiency during executive cognition: an fMRI study. Hum Brain Mapp. 2013 Apr;34(4):753-61. doi: 10.1002/hbm.21470. Epub 2011 Nov 23.

Ferriero R, Manco G, Lamantea E, Nusco E, Ferrante MI, Sordino P, Stacpoole PW, Lee B, Zeviani M, Brunetti-Pierri N. Phenylbutyrate therapy for pyruvate dehydrogenase complex deficiency and lactic acidosis. Sci Transl Med. 2013 Mar 6;5(175):175ra31. doi: 10.1126/scitranslmed.3004986.

Ah Mew N, Krivitzky L, McCarter R, Batshaw M, Tuchman M; Urea Cycle Disorders Consortium of the Rare Diseases Clinical Research Network. Clinical outcomes of neonatal onset proximal versus distal urea cycle disorders do not differ. J Pediatr. 2013 Feb;162(2):324-9.e1. doi: 10.1016/j.jpeds.2012.06.065. Epub 2012 Aug 15.

Tuchman S, Asico LD, Escano C, Bobb DA, Ray PE. Development of an animal model of nephrocalcinosis via selective dietary sodium and chloride depletion. Pediatr Res. 2013 Feb;73(2):194-200. doi: 10.1038/pr.2012.172. Epub 2012 Nov 22.

Zhao G, Allewell NM, Tuchman M, Shi D. Structure of the complex of Neisseria gonorrhoeae N-acetyl-L-glutamate synthase with a bound bisubstrate analog. Biochem Biophys Res Commun. 2013 Jan 25;430(4):1253-8. doi: 10.1016/j.bbrc.2012.12.064. Epub 2012 Dec 20.

Cartagena A, Prasad AN, Rupar CA, Strong M, Tuchman M, Ah Mew N, Prasad C. Recurrent encephalopathy: NAGS (N-acetylglutamate synthase) deficiency in adults. Can J Neurol Sci. 2013 Jan;40(1):3-9. doi: 10.1017/s0317167100012877.

*Sin YY, Ballantyne LL, Mukherjee K, St Amand T, Kyriakopoulou L, Schulze A, Funk CD. Inducible arginase 1 deficiency in mice leads to hyperargininemia and altered amino acid metabolism. PLoS One. 2013;8(11):e80001. PMID: 24224027, PMCID: PMC3817112.

Gropman AL. Patterns of brain injury in inborn errors of metabolism. Semin Pediatr Neurol. 2012 Dec;19(4):203-10. doi: 10.1016/j.spen.2012.09.007.

Nagamani SC, Shchelochkov OA, Mullins MA, Carter S, Lanpher BC, Sun Q, Kleppe S, Erez A, O'Brian Smith E, Marini JC; Members of the Urea Cycle Disorders Consortium, Lee B. A randomized controlled trial to evaluate the effects of high-dose versus low-dose of arginine therapy on hepatic function tests in argininosuccinic aciduria. Mol Genet Metab. 2012 Nov;107(3):315-21. doi: 10.1016/j.ymgme.2012.09.016. Epub 2012 Sep 17.

Mokhtarani M, Diaz GA, Rhead W, Lichter-Konecki U, Bartley J, Feigenbaum A, Longo N, Berquist W, Berry SA, Gallagher R, Bartholomew D, Harding CO, Korson MS, McCandless SE, Smith W, Vockley J, Bart S, Kronn D, Zori R, Cederbaum S, Dorrani N, Merritt JL 2nd, Sreenath-Nagamani S, Summar M, Lemons C, Dickinson K, Coakley DF, Moors TL, Lee B, Scharschmidt BF. Urinary phenylacetylglutamine as dosing biomarker for patients with urea cycle disorders. Mol Genet Metab. 2012 Nov;107(3):308-14. doi: 10.1016/j.ymgme.2012.08.006. Epub 2012 Aug 18.

Nagamani SC, Lee B, Erez A. Optimizing therapy for argininosuccinic aciduria. Mol Genet Metab. 2012 Sep;107(1-2):10-4. doi: 10.1016/j.ymgme.2012.07.009. Epub 2012 Jul 20.

Fike CD, Sidoryk-Wegrzynowicz M, Aschner M, Summar M, Prince LS, Cunningham G, Kaplowitz M, Zhang Y, Aschner JL. Prolonged hypoxia augments L-citrulline transport by system A in the newborn piglet pulmonary circulation. Cardiovasc Res. 2012 Aug 1;95(3):375-84. doi: 10.1093/cvr/cvs186. Epub 2012 Jun 6.

Armstrong CL, Shera DM, Lustig RA, Phillips PC. Phase measurement of cognitive impairment specific to radiotherapy. Int J Radiat Oncol Biol Phys. 2012 Jul 1;83(3):e319-24. doi: 10.1016/j.ijrobp.2011.12.083. Epub 2012 Mar 13.

Nagamani SC, Campeau PM, Shchelochkov OA, Premkumar MH, Guse K, Brunetti-Pierri N, Chen Y, Sun Q, Tang Y, Palmer D, Reddy AK, Li L, Slesnick TC, Feig DI, Caudle S, Harrison D, Salviati L, Marini JC, Bryan NS, Erez A, Lee B. Nitric-oxide supplementation for treatment of long-term complications in argininosuccinic aciduria. Am J Hum Genet. 2012 May 4;90(5):836-46. doi: 10.1016/j.ajhg.2012.03.018. Epub 2012 Apr 26.

Nagamani SC, Erez A, Lee B. Argininosuccinate lyase deficiency. Genet Med. 2012 May;14(5):501-7. doi: 10.1038/gim.2011.1. Epub 2012 Jan 5.

Mitchell S, Welch-Burke T, Dumitrescu L, Lomenick JP, Murdock DG, Crawford DC, Summar M. Peptide tyrosine tyrosine levels are increased in patients with urea cycle disorders. Mol Genet Metab. 2012 May;106(1):39-42. doi: 10.1016/j.ymgme.2012.02.011. Epub 2012 Feb 22.

Wilson JM, Shchelochkov OA, Gallagher RC, Batshaw ML. Hepatocellular carcinoma in a research subject with ornithine transcarbamylase deficiency. Mol Genet Metab. 2012 Feb;105(2):263-5. doi: 10.1016/j.ymgme.2011.10.016. Epub 2011 Nov 7.

Payne AS, Freishtat RJ. Conserved steroid hormone homology converges on nuclear factor κB to modulate inflammation in asthma. J Investig Med. 2012 Jan;60(1):13-7. doi: 10.2310/JIM.0b013e31823d7989.

Best BM, Capparelli EV, Diep H, Rossi SS, Farrell MJ, Williams E, Lee G, van den Anker JN, Rakhmanina N. Pharmacokinetics of lopinavir/ritonavir crushed versus whole tablets in children. J Acquir Immune Defic Syndr. 2011 Dec 1;58(4):385-91. doi: 10.1097/QAI.0b013e318232b057.

Stemmy EJ, Benton AS, Lerner J, Alcala S, Constant SL, Freishtat RJ. Extracellular cyclophilin levels associate with parameters of asthma in phenotypic clusters. J Asthma. 2011 Dec;48(10):986-993. doi: 10.3109/02770903.2011.623334. Epub 2011 Oct 14.

Erez A, Nagamani SC, Shchelochkov OA, Premkumar MH, Campeau PM, Chen Y, Garg HK, Li L, Mian A, Bertin TK, Black JO, Zeng H, Tang Y, Reddy AK, Summar M, O'Brien WE, Harrison DG, Mitch WE, Marini JC, Aschner JL, Bryan NS, Lee B. Requirement of argininosuccinate lyase for systemic nitric oxide production. Nat Med. 2011 Nov 13;17(12):1619-26. doi: 10.1038/nm.2544.

Prust MJ, Gropman AL, Hauser N. New frontiers in neuroimaging applications to inborn errors of metabolism. Mol Genet Metab. 2011 Nov;104(3):195-205. doi: 10.1016/j.ymgme.2011.06.020. Epub 2011 Jun 30.

Heibel SK, Ah Mew N, Caldovic L, Daikhin Y, Yudkoff M, Tuchman M. N-carbamylglutamate enhancement of ureagenesis leads to discovery of a novel deleterious mutation in a newly defined enhancer of the NAGS gene and to effective therapy. Hum Mutat. 2011 Oct;32(10):1153-60. doi: 10.1002/humu.21553. Epub 2011 Sep 9.

Jain-Ghai S, Nagamani SC, Blaser S, Siriwardena K, Feigenbaum A. Arginase I deficiency: severe infantile presentation with hyperammonemia: more common than reported?. Mol Genet Metab. 2011 Sep-Oct;104(1-2):107-11. doi: 10.1016/j.ymgme.2011.06.025. Epub 2011 Jul 13.

Ah Mew N, Caldovic L. N-acetylglutamate synthase deficiency: an insight into the genetics, epidemiology, pathophysiology, and treatment. Appl Clin Genet. 2011 Aug 24;4:127-35. doi: 10.2147/TACG.S12702. Print 2011.

Lichter-Konecki U, Diaz GA, Merritt JL 2nd, Feigenbaum A, Jomphe C, Marier JF, Beliveau M, Mauney J, Dickinson K, Martinez A, Mokhtarani M, Scharschmidt B, Rhead W. Ammonia control in children with urea cycle disorders (UCDs); phase 2 comparison of sodium phenylbutyrate and glycerol phenylbutyrate. Mol Genet Metab. 2011 Aug;103(4):323-9. doi: 10.1016/j.ymgme.2011.04.013. Epub 2011 May 5.

Klein CJ, Villavicencio SA, Schweitzer A, Bethepu JS, Hoffman HJ, Mirza NM. Energy prediction equations are inadequate for obese Hispanic youth. J Am Diet Assoc. 2011 Aug;111(8):1204-10. doi: 10.1016/j.jada.2011.05.010.

Nissim I, Horyn O, Nissim I, Daikhin Y, Caldovic L, Barcelona B, Cervera J, Tuchman M, Yudkoff M. Down-regulation of hepatic urea synthesis by oxypurines: xanthine and uric acid inhibit N-acetylglutamate synthase. J Biol Chem. 2011 Jun 24;286(25):22055-68. doi: 10.1074/jbc.M110.209023. Epub 2011 May 3.

Häberle J, Shchelochkov OA, Wang J, Katsonis P, Hall L, Reiss S, Eeds A, Willis A, Yadav M, Summar S; Urea Cycle Disorders Consortium, Lichtarge O, Rubio V, Wong LJ, Summar M. Molecular defects in human carbamoy phosphate synthetase I: mutational spectrum, diagnostic and protein structure considerations. Hum Mutat. 2011 Jun;32(6):579-89. doi: 10.1002/humu.21406. Epub 2011 May 5.

Marini JC, Lanpher BC, Scaglia F, O'Brien WE, Sun Q, Garlick PJ, Jahoor F, Lee B. Phenylbutyrate improves nitrogen disposal via an alternative pathway without eliciting an increase in protein breakdown and catabolism in control and ornithine transcarbamylase-deficient patients. Am J Clin Nutr. 2011 Jun;93(6):1248-54. doi: 10.3945/ajcn.110.009043. Epub 2011 Apr 13.

Morgan TM, Schlegel C, Edwards KM, Welch-Burke T, Zhu Y, Sparks R, Summar M; Urea Cycle Disorders Consortium. Vaccines are not associated with metabolic events in children with urea cycle disorders. Pediatrics. 2011 May;127(5):e1147-53. doi: 10.1542/peds.2010-1628. Epub 2011 Apr 11.

Lavine JE, Schwimmer JB, Van Natta ML, Molleston JP, Murray KF, Rosenthal P, Abrams SH, Scheimann AO, Sanyal AJ, Chalasani N, Tonascia J, Ünalp A, Clark JM, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR; Nonalcoholic Steatohepatitis Clinical Research Network. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA. 2011 Apr 27;305(16):1659-68. doi: 10.1001/jama.2011.520.

Erez A, Shchelochkov OA, Plon SE, Scaglia F, Lee B. Insights into the pathogenesis and treatment of cancer from inborn errors of metabolism. Am J Hum Genet. 2011 Apr 8;88(4):402-21. doi: 10.1016/j.ajhg.2011.03.005.

Flynn PM, Cunningham CK, Rudy B, Wilson CM, Kapogiannis B, Worrell C, Bethel J, Monte D, Bojan K; Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN). Hepatitis B vaccination in HIV-infected youth: a randomized trial of three regimens. J Acquir Immune Defic Syndr. 2011 Apr;56(4):325-32. doi: 10.1097/QAI.0b013e318203e9f2.

Busse WW, Morgan WJ, Gergen PJ, Mitchell HE, Gern JE, Liu AH, Gruchalla RS, Kattan M, Teach SJ, Pongracic JA, Chmiel JF, Steinbach SF, Calatroni A, Togias A, Thompson KM, Szefler SJ, Sorkness CA. Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children. N Engl J Med. 2011 Mar 17;364(11):1005-15. doi: 10.1056/NEJMoa1009705.

Dickson PI, Pariser AR, Groft SC, Ishihara RW, McNeil DE, Tagle D, Griebel DJ, Kaler SG, Mink JW, Shapiro EG, Bjoraker KJ, Krivitzky L, Provenzale JM, Gropman A, Orchard P, Raymond G, Cohen BH, Steiner RD, Goldkind SF, Nelson RM, Kakkis E, Patterson MC. Research challenges in central nervous system manifestations of inborn errors of metabolism. Mol Genet Metab. 2011 Mar;102(3):326-38. doi: 10.1016/j.ymgme.2010.11.164. Epub 2010 Dec 2.

Erez A, Nagamani SC, Lee B. Argininosuccinate lyase deficiency-argininosuccinic aciduria and beyond. Am J Med Genet C Semin Med Genet. 2011 Feb 15;157C(1):45-53. doi: 10.1002/ajmg.c.30289. Epub 2011 Feb 10.

Brunetti-Pierri N, Lanpher B, Erez A, Ananieva EA, Islam M, Marini JC, Sun Q, Yu C, Hegde M, Li J, Wynn RM, Chuang DT, Hutson S, Lee B. Phenylbutyrate therapy for maple syrup urine disease. Hum Mol Genet. 2011 Feb 15;20(4):631-40. doi: 10.1093/hmg/ddq507. Epub 2010 Nov 23.

*Sandesh C Sreenath Nagamani,  Ayelet Erez, Brendan Lee. Argininosuccinate Lyase deficiency. (February 2011): in GeneReviews: Pagon RA, Bird TD, Dolan CR, Stephens K, editors. Seattle (WA): University of Washington, Seattle, 1993-2011 . Feb 03. Featured e-book on NCBI Bookshelf, Full Text.

Nelson JE, Wilson L, Brunt EM, Yeh MM, Kleiner DE, Unalp-Arida A, Kowdley KV; Nonalcoholic Steatohepatitis Clinical Research Network. Relationship between the pattern of hepatic iron deposition and histological severity in nonalcoholic fatty liver disease. Hepatology. 2011 Feb;53(2):448-57. doi: 10.1002/hep.24038. Epub 2010 Nov 29.

Wang J, Shchelochkov OA, Zhan H, Li F, Chen LC, Brundage EK, Pursley AN, Schmitt ES, Häberle J, Wong LJ. Molecular characterization of CPS1 deletions by array CGH. Mol Genet Metab. 2011 Jan;102(1):103-6. doi: 10.1016/j.ymgme.2010.08.020. Epub 2010 Sep 19.

Vadivel A, Aschner JL, Rey-Parra GJ, Magarik J, Zeng H, Summar M, Eaton F, Thébaud B. L-citrulline attenuates arrested alveolar growth and pulmonary hypertension in oxygen-induced lung injury in newborn rats. Pediatr Res. 2010 Dec;68(6):519-25. doi: 10.1203/PDR.0b013e3181f90278.

Gropman AL, Gertz B, Shattuck K, Kahn IL, Seltzer R, Krivitsky L, Van Meter J. Diffusion tensor imaging detects areas of abnormal white matter microstructure in patients with partial ornithine transcarbamylase deficiency. AJNR Am J Neuroradiol. 2010 Oct;31(9):1719-23. doi: 10.3174/ajnr.A2122. Epub 2010 May 20.

*Shchelochkov OA, Li FY, Wang J, Zhan H, Towbin JA, Jefferies JL, Wong LJ, Scaglia F. Milder clinical course of Type IV 3-methylglutaconic aciduria due to a novel mutation in TMEM70. Mol Genet Metab. 2010 Oct-Nov;101(2-3):282-5. doi: 10.1016/j.ymgme.2010.07.012. Epub 2010 Jul 24. PMID: 20728387.

Gropman AL, Batshaw ML. Epigenetics, copy number variation, and other molecular mechanisms underlying neurodevelopmental disabilities: new insights and diagnostic approaches. J Dev Behav Pediatr. 2010 Sep;31(7):582-91. doi: 10.1097/DBP.0b013e3181ee384e.

Ah Mew N, McCarter R, Daikhin Y, Nissim I, Yudkoff M, Tuchman M. N-carbamylglutamate augments ureagenesis and reduces ammonia and glutamine in propionic acidemia. Pediatrics. 2010 Jul;126(1):e208-14. doi: 10.1542/peds.2010-0008. Epub 2010 Jun 21.

Lee B, Rhead W, Diaz GA, Scharschmidt BF, Mian A, Shchelochkov O, Marier JF, Beliveau M, Mauney J, Dickinson K, Martinez A, Gargosky S, Mokhtarani M, Berry SA. Phase 2 comparison of a novel ammonia scavenging agent with sodium phenylbutyrate in patients with urea cycle disorders: safety, pharmacokinetics and ammonia control. Mol Genet Metab. 2010 Jul;100(3):221-8. doi: 10.1016/j.ymgme.2010.03.014. Epub 2010 Mar 23.

Quintero-Rivera F,  Deignan J, Peredo J,  Grody W, Crandall B,  Sims M, Cederbaum S. An exon 1 deletion in OTC identified using chromosomal microarray analyses in a mother and her two affected deceased newborns: implications for the prenatal diagnosis of ornithine transcarbamylase deficiency. Mol Genet Metab. 2010;101:413-416. PMID: 20817516, Full Text (with PubMed access).

Cunningham CK, Rudy BJ, Xu J, Bethel J, Kapogiannis BG, Ahmad S, Wilson CM, Flynn PM; Adolescent Medicine Trials Network for HIV/AIDS Interventions. Randomized trial to determine safety and immunogenicity of two strategies for hepatitis B vaccination in healthy urban adolescents in the United States. Pediatr Infect Dis J. 2010 Jun;29(6):530-4. doi: 10.1097/INF.0b013e3181d285c7.

Mehta N, Cunningham CK, Flynn P, Pepe J, Obaro S, Kapogiannis BG, Bethel J, Luzuriaga K; Adolescent Trials Network for HIV/AIDS Interventions. Impaired generation of hepatitis B virus-specific memory B cells in HIV infected individuals following vaccination. Vaccine. 2010 May 7;28(21):3672-8. doi: 10.1016/j.vaccine.2010.03.022. Epub 2010 Mar 28.

Gropman A. Brain imaging in urea cycle disorders. Mol Genet Metab. 2010;100 Suppl 1(Suppl 1):S20-30. doi: 10.1016/j.ymgme.2010.01.017. Epub 2010 Feb 13.

Oldham MS, VanMeter JW, Shattuck KF, Cederbaum SD, Gropman AL. Diffusion tensor imaging in arginase deficiency reveals damage to corticospinal tracts. Pediatr Neurol. 2010 Jan;42(1):49-52. doi: 10.1016/j.pediatrneurol.2009.07.017.

Uittenbogaard M, Baxter KK, Chiaramello A. NeuroD6 genomic signature bridging neuronal differentiation to survival via the molecular chaperone network. J Neurosci Res. 2010 Jan;88(1):33-54. doi: 10.1002/jnr.22182.

Campeau PM, Pivalizza PJ, Miller G, McBride K, Karpen S, Goss J, Lee BH. Early orthotopic liver transplantation in urea cycle defects: follow up of a developmental outcome study. Mol Genet Metab. 2010;100 Suppl 1(Suppl 1):S84-7. doi: 10.1016/j.ymgme.2010.02.012. Epub 2010 Feb 19.

Seminara J, Tuchman M, Krivitzky L, Krischer J, Lee HS, Lemons C, Baumgartner M, Cederbaum S, Diaz GA, Feigenbaum A, Gallagher RC, Harding CO, Kerr DS, Lanpher B, Lee B, Lichter-Konecki U, McCandless SE, Merritt JL, Oster-Granite ML, Seashore MR, Stricker T, Summar M, Waisbren S, Yudkoff M, Batshaw ML. Establishing a consortium for the study of rare diseases: The Urea Cycle Disorders Consortium. Mol Genet Metab. 2010;100 Suppl 1(Suppl 1):S97-105. doi: 10.1016/j.ymgme.2010.01.014. Epub 2010 Feb 10.

Deignan JL, De Deyn PP, Cederbaum SD, Fuchshuber A, Roth B, Gsell W,  Marescau B. Guanidino compound levels in blood, cerebrospinal fluid, and postmortem brain material of patients with argininemia. Mol Genet Metab. 2010;100 (suppl):S31-S36. PMID: 20176499, Full Text (with PubMed access).

Yudkoff M, Ah Mew N, Daikhin Y, Horyn O, Nissim I, Nissim I, Payan I, Tuchman M. Measuring in vivo ureagenesis with stable isotopes. Mol Genet Metab. 2010;100 Suppl 1(Suppl 1):S37-41. doi: 10.1016/j.ymgme.2010.02.017. Epub 2010 Feb 26.

Caldovic L, Ah Mew N, Shi D, Morizono H, Yudkoff M, Tuchman M. N-acetylglutamate synthase: structure, function and defects. Mol Genet Metab. 2010;100 Suppl 1(Suppl 1):S13-9. doi: 10.1016/j.ymgme.2010.02.018. Epub 2010 Feb 26.

Yerys BE, Wallace GL, Sokoloff JL, Shook DA, James JD, Kenworthy L. Attention deficit/hyperactivity disorder symptoms moderate cognition and behavior in children with autism spectrum disorders. Autism Res. 2009 Dec;2(6):322-33. doi: 10.1002/aur.103.

Ah Mew N, Payan I, Daikhin Y, Nissim I, Nissim I, Tuchman M, Yudkoff M. Effects of a single dose of N-carbamylglutamate on the rate of ureagenesis. Mol Genet Metab. 2009 Dec;98(4):325-30. doi: 10.1016/j.ymgme.2009.07.010. Epub 2009 Jul 14.

Gropman AL, Sailasuta N, Harris KC, Abulseoud O, Ross BD. Ornithine transcarbamylase deficiency with persistent abnormality in cerebral glutamate metabolism in adults. Radiology. 2009 Sep;252(3):833-41. doi: 10.1148/radiol.2523081878. Epub 2009 Jun 30.

Mc Guire PJ, Parikh A, Diaz GA. Profiling of oxidative stress in patients with inborn errors of metabolism. Mol Genet Metab. 2009 Sep-Oct;98(1-2):173-180. PMID: 19604711, PMCID: PMC2915835.

Brunetti-Pierri N, Erez A, Shchelochkov O, Craigen W, Lee B. Systemic hypertension in two patients with ASL deficiency: a result of nitric oxide deficiency?. Mol Genet Metab. 2009 Sep-Oct;98(1-2):195-7. doi: 10.1016/j.ymgme.2009.06.006. Epub 2009 Jun 13.

Krivitzky L, Babikian T, Lee HS, Thomas NH, Burk-Paull KL, Batshaw ML. Intellectual, adaptive, and behavioral functioning in children with urea cycle disorders. Pediatr Res. 2009 Jul;66(1):96-101. doi: 10.1203/PDR.0b013e3181a27a16.

Venkateswaran L, Scaglia F, McLin V, Hertel P, Shchelochkov OA, Karpen S, Mahoney D Jr, Yee DL. Ornithine transcarbamylase deficiency: a possible risk factor for thrombosis. Pediatr Blood Cancer. 2009 Jul;53(1):100-2. doi: 10.1002/pbc.22016.

Neill MA, Aschner J, Barr F, Summar ML. Quantitative RT-PCR comparison of the urea and nitric oxide cycle gene transcripts in adult human tissues. Mol Genet Metab. 2009 Jun;97(2):121-7. doi: 10.1016/j.ymgme.2009.02.009. Epub 2009 Mar 3.

Richesson RL, Lee HS, Cuthbertson D, Lloyd J, Young K, Krischer JP. An automated communication system in a contact registry for persons with rare diseases: scalable tools for identifying and recruiting clinical research participants. Contemp Clin Trials. 2009 Jan;30(1):55-62. doi: 10.1016/j.cct.2008.09.002. Epub 2008 Sep 7.

Griggs RC, Batshaw M, Dunkle M, Gopal-Srivastava R, Kaye E, Krischer J, Nguyen T, Paulus K, Merkel PA; Rare Diseases Clinical Research Network. Clinical research for rare disease: opportunities, challenges, and solutions. Mol Genet Metab. 2009 Jan;96(1):20-6. doi: 10.1016/j.ymgme.2008.10.003. Epub 2008 Nov 13.

Wu X, Ghimbovschi S, Aujla PK, Rose MC, Peña MT. Expression profiling of inflammatory mediators in pediatric sinus mucosa. Arch Otolaryngol Head Neck Surg. 2009 Jan;135(1):65-72. doi: 10.1001/archoto.2008.505.

Mitchell S, Ellingson C, Coyne T, Hall L, Neill M, Christian N, Higham C, Dobrowolski SF, Tuchman M, Summar M; Urea Cycle Disorder Consortium. Genetic variation in the urea cycle: a model resource for investigating key candidate genes for common diseases. Hum Mutat. 2009 Jan;30(1):56-60. doi: 10.1002/humu.20813.

Shchelochkov OA, Li F, Geraghty MT, Gallagher RC, Van Hove JL, Lichter-Konecki U, Fernhoff PM, Copeland S, Reimschisel,T, Cederbaum S, Lee B, Chinault AC, Wong L. High-frequency detection of deletions and variable rearrangements at the ornithine transcarbamylase (OTC) locus by oligonucleotide Array CGH. Mol Genet Metab. 2009;96: 97-105. PMID: 19138872, Full Text (with PubMed access).

Sailasuta N, Robertson LW, Harris KC, Gropman AL, Allen PS, Ross BD. Clinical NOE 13C MRS for neuropsychiatric disorders of the frontal lobe. J Magn Reson. 2008 Dec;195(2):219-25. doi: 10.1016/j.jmr.2008.09.012. Epub 2008 Sep 17.

Dimmock DP, Trapane P, Feigenbaum A, Keegan CE, Thoene J, Cederbaum S, Gibson J, Gambello M, Muenzer J, Vaux K, O'Brien WO, Fang P. The role of molecular testing and enzyme analysis in the management of hypomorphic citrullinemia. Am J Med Genet A. 2008 Nov 15;146A(22):2885-90. doi: 10.1002/ajmg.a.32527. Erratum in: Am J Med Genet A. 2010 Apr;152A(4):1061. PMID: 18925679; PMCID: PMC2597641.

Patrick TB, Richesson R, Andrews JE, Folk LC. SNOMED CT coding variation and grouping for "other findings" in a longitudinal study on urea cycle disorders. AMIA Annu Symp Proc. 2008 Nov 6:2008:11-5.

Summar ML, Dobbelaere D, Brusilow S, Lee B. Diagnosis, symptoms, frequency and mortality of 260 patients with urea cycle disorders from a 21-year, multicentre study of acute hyperammonaemic episodes. Acta Paediatr. 2008 Oct;97(10):1420-5. doi: 10.1111/j.1651-2227.2008.00952.x. Epub 2008 Jul 17.

Gropman AL, Fricke ST, Seltzer RR, Hailu A, Adeyemo A, Sawyer A, van Meter J, Gaillard WD, McCarter R, Tuchman M, Batshaw M; Urea Cycle Disorders Consortium. 1H MRS identifies symptomatic and asymptomatic subjects with partial ornithine transcarbamylase deficiency. Mol Genet Metab. 2008 Sep-Oct;95(1-2):21-30. doi: 10.1016/j.ymgme.2008.06.003. Epub 2008 Jul 26.

Deardorff MA, Gaddipati H, Kaplan P, Sanchez-Lara PA, Sondheimer N, Spinner NB, Hakonarson H, Ficicioglu C, Ganesh J, Markello T, Loechelt B, Zand DJ, Yudkoff M, Lichter-Konecki U. Complex management of a patient with a contiguous Xp11.4 gene deletion involving ornithine transcarbamylase: a role for detailed molecular analysis in complex presentations of classical diseases. Mol Genet Metab. 2008 Aug;94(4):498-502. doi: 10.1016/j.ymgme.2008.04.011. Epub 2008 Jun 3.

Tuchman M, Lee B, Lichter-Konecki U, Summar ML, Yudkoff M, Cederbaum SD, Kerr DS, Diaz GA, Seashore MR, Lee HS, McCarter RJ, Krischer JP, Batshaw ML; Urea Cycle Disorders Consortium of the Rare Diseases Clinical Research Network. Cross-sectional multicenter study of patients with urea cycle disorders in the United States. Mol Genet Metab. 2008 Aug;94(4):397-402. doi: 10.1016/j.ymgme.2008.05.004. Epub 2008 Jun 17.

Tuchman M, Caldovic L, Daikhin Y, Horyn O, Nissim I, Nissim I, Korson M, Burton B, Yudkoff M. N-carbamylglutamate markedly enhances ureagenesis in N-acetylglutamate deficiency and propionic acidemia as measured by isotopic incorporation and blood biomarkers. Pediatr Res. 2008 Aug;64(2):213-7. doi: 10.1203/PDR.0b013e318179454b.

Brunetti-Pierri N, Clarke C, Mane V, Palmer DJ, Lanpher B, Sun Q, O'Brien W, Lee B. Phenotypic correction of ornithine transcarbamylase deficiency using low dose helper-dependent adenoviral vectors. J Gene Med. 2008 Aug;10(8):890-896. PMID: 18563850, PMCID: PMC2766563.

Lichter-Konecki U. Profiling of astrocyte properties in the hyperammonaemic brain: shedding new light on the pathophysiology of the brain damage in hyperammonaemia. J Inherit Metab Dis. 2008 Aug;31(4):492-502. doi: 10.1007/s10545-008-0834-9. Epub 2008 Aug 9.

Nissim I, Horyn O, Nissim I, Daikhin Y, Wehrli SL, Yudkoff M. 3-isobutylmethylxanthine inhibits hepatic urea synthesis: protection by agmatine. J Biol Chem. 2008 May 30;283(22):15063-71. doi: 10.1074/jbc.M800163200. Epub 2008 Mar 28.

Zhu Y, Wang Z, Miller DJ, Clarke R, Xuan J, Hoffman EP, Wang Y. A ground truth based comparative study on clustering of gene expression data. Front Biosci. 2008 May 1;13:3839-49. doi: 10.2741/2972.

Gropman AL, Seltzer RR, Yudkoff M, Sawyer A, VanMeter J, Fricke ST. 1H MRS allows brain phenotype differentiation in sisters with late onset ornithine transcarbamylase deficiency (OTCD) and discordant clinical presentations. Mol Genet Metab. 2008 May;94(1):52-60. doi: 10.1016/j.ymgme.2007.12.008. Epub 2008 Feb 11.

Lichter-Konecki U, Mangin JM, Gordish-Dressman H, Hoffman EP, Gallo V. Gene expression profiling of astrocytes from hyperammonemic mice reveals altered pathways for water and potassium homeostasis in vivo. Glia. 2008 Mar;56(4):365-77. doi: 10.1002/glia.20624.

*Gropman AL, Rigas A. Neurometabolic disorders: urea-cycle disorder, outcomes, development and treatment. Pediatric Health. 2008;2(6):701-713. Full Text.

Cotton RG, Auerbach AD, Beckmann JS, Blumenfeld OO, Brookes AJ, Brown AF, Carrera P, Cox DW, Gottlieb B, Greenblatt MS, Hilbert P, Lehvaslaiho H, Liang P, Marsh S, Nebert DW, Povey S, Rossetti S, Scriver CR, Summar M, Tolan DR, Verma IC, Vihinen M, den Dunnen JT. Recommendations for locusspecific databases and their curation. Hum Mutat. 2008;29(1):2-5. PMID: 18157828, PMCID: PMC2752432.

Gropman AL, Summar M, Leonard JV. Neurological implications of urea cycle disorders. J Inherit Metab Dis. 2007 Nov;30(6):865-79. doi: 10.1007/s10545-007-0709-5. Epub 2007 Nov 23.

Eeds AM, Mortlock D, Wade-Martins R, Summar ML. Assessing the functional characteristics of synonymous and nonsynonymous mutation candidates by use of large DNA constructs. Am J Hum Genet. 2007 Apr;80(4):740-50. doi: 10.1086/513287. Epub 2007 Mar 8.

Dimmock DP, Kobayashi K, Iijima M, Tabata A, Wong LJ, Lee B, Saheki T, Scaglia F. Citrin deficiency: A novel cause of failure to thrive that responds to a high protein, low carbohydrate diet. Pediatrics. 2007;119:e773-e777. PMID: 17332192, Full Text (with PubMed access).

Caldovic L, Morizono H, Tuchman M. Mutations and polymorphisms in the human N-acetylglutamate synthase gene. Hum Mutat. 2007;28:754-759. PMID: 17421020, Full Text.

*Marini JC, Lanpher B, Scaglia F, Carter S, Garlick PJ, Jahoor F, Lee B. Phenylbutyrate reduces plasma leucine concentrations without affecting the flux of leucine. FASEB Journal. 2007;21:A335. Abstract.

*Scaglia F, Lanpher B, Marini J, Lee B. Role of branched chain amino acids in patients with urea cycle disorders. In: Bachmann C, Haberle J, Leonard JV (eds). Pathophysiology and Management of Hyperammonemia. SPS Publications . 2007: p.65-75. 

Dobrowolski SF, Ellingson C, Caldovic L, Tuchman M. Streamlined assessment of gene variants by high resolution melt profiling utilizing the ornithine transcarbamylase gene as a model system. Hum Mutat. 2007;28:1133-1140. PMID: 17565723.

Yudkoff M, Daikhin Y, Melø TM, Nissim I, Sonnewald U, Nissim I. The ketogenic diet and brain metabolism of amino acids: relationship to the anticonvulsant effect. Annu Rev Nutr. 2007;27:415-30. doi: 10.1146/annurev.nutr.27.061406.093722.

*EA Crombez, SD Cederbaum. Urea cycle disorders. In: Schapira AHV (ed) Neurology and Clinical Neuroscience. Mosby . 2007, chapter 110, pp1469-1476.

Eeds AM, Hall LD, Yadav M, Willis A, Summar S, Putnam A, Barr F, Summar ML. The frequent observation of evidence for nonsense-mediated decay in RNA from patients with carbamyl phosphate synthetase I deficiency. Mol Genet Metab. 2006 Sep-Oct;89(1-2):80-6. doi: 10.1016/j.ymgme.2006.04.006. Epub 2006 Jun 5.

Lanpher B, Brunetti-Pierri N, Lee B. Inborn errors of metabolism: the flux from Mendelian to complex diseases. Nat Rev Genet. 2006 Jun;7(6):449-60. doi: 10.1038/nrg1880.

Camacho JA, Mardach MR, Rioseco-Camacho N, Ruiz-Pesini E, Derbeneva O, Andrade D, Zaldivar F, Qu Y, Cederbaum SD. Clinical and functional characterization of a human ORNT1mutation (T32R) in the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome. Pediatr Res. 2006;60:423-429. PMID: 16940241, Full Text.

Yamaguchi S, Brailey LL, Morizono H, Lynch MG, Bale AE, Tuchman M. Mutations and polymorphisms in the human ornithine transcarbamylase gene. Hum Mutat. 2006;27:626-632. PMID: 11793468, Full Text.

Lee B, Singh RH, Rhead WJ, Sniderman King L, Smith W, Summar ML. Considerations in the difficult-to-manage urea cycle disorder patient. Crit Care Clin. 2005 Oct;21(4 Suppl):S19-25. doi: 10.1016/j.ccc.2005.05.001.

Sniderman King L, Singh RH, Rhead WJ, Smith W, Lee B, Summar ML. Genetic counseling issues in urea cycle disorders. Crit Care Clin. 2005 Oct;21(4 Suppl):S37-44. doi: 10.1016/j.ccc.2005.08.001.

Singh RH, Rhead WJ, Smith W, Lee B, Sniderman King L, Summar M. Nutritional management of urea cycle disorders. Crit Care Clin. 2005 Oct;21(4 Suppl):S27-35. doi: 10.1016/j.ccc.2005.08.003.

Summar ML, Barr F, Dawling S, Smith W, Lee B, Singh RH, Rhead WJ, Sniderman King L, Christman BW. Unmasked adult-onset urea cycle disorders in the critical care setting. Crit Care Clin. 2005 Oct;21(4 Suppl):S1-8. doi: 10.1016/j.ccc.2005.05.002.

Smith W, Kishnani PS, Lee B, Singh RH, Rhead WJ, Sniderman King L, Smith M, Summar M. Urea cycle disorders: clinical presentation outside the newborn period. Crit Care Clin. 2005 Oct;21(4 Suppl):S9-17. doi: 10.1016/j.ccc.2005.05.007.

Hulgan T, Haas DW, Haines JL, Ritchie MD, Robbins GK, Shafer RW, Clifford DB, Kallianpur AR, Summar M, Canter JA. Mitochondrial haplogroups and peripheral neuropathy during antiretroviral therapy: an adult AIDS clinical trials group study. AIDS. 2005 Sep 2;19(13):1341-9. doi: 10.1097/01.aids.0000180786.02930.a1.

Crombez EA, Cederbaum SD. Hyperargininemia due to liver arginase deficiency. Mol Genet Metab. 2005 Mar;84(3):243-51. doi: 10.1016/j.ymgme.2004.11.004. Epub 2004 Dec 19.

Ensenauer R, Tuchman M, El-Youssef M, Kotagal S, Ishitani MB, Matern D, Babovic-Vuksanovic D. Management and outcome of neonatal-onset ornithine transcarbamylase deficiency following liver transplantation at 60 days of life. Mol Genet Metab. 2005;84:363-366 PMID: 15781198, Full Text (with PubMed access).

Scaglia F, Brunetti-Pierri N, Kleppe S, Marini J, Carter S, Garlick P, Jahoor F, O'Brien W, Lee B. Clinical consequences of urea cycle enzyme deficiencies and potential links to arginine and nitric oxide metabolism. J Nutr. 2004 Oct;134(10 Suppl):2775S-2782S; discussion 2796S-2797S. doi: 10.1093/jn/134.10.2775S.

Caldovic L, Morizono H, Daikhin Y, Nissim I, McCarter RJ, Yudkoff M, Tuchman M. Restoration of ureagenesis in N-acetylglutamate synthase deficiency by N-carbamylglutamate. J Pediatr. 2004 Oct;145(4):552-4. doi: 10.1016/j.jpeds.2004.06.047.

Mian A, McCormack WM Jr, Mane V, Kleppe S, Ng P, Finegold M, O'Brien WE, Rodgers JR, Beaudet AL, Lee B. Long-term correction of ornithine transcarbamylase deficiency by WPRE-mediated overexpression using a helper-dependent adenovirus. Mol Ther. 2004 Sep;10(3):492-9. doi: 10.1016/j.ymthe.2004.05.036.

Gropman AL, Batshaw ML. Cognitive outcome in urea cycle disorders. Mol Genet Metab. 2004 Apr;81 Suppl 1:S58-62. doi: 10.1016/j.ymgme.2003.11.016.

Scaglia F, Carter S, O’Brien W, Lee B. Effect of alternative pathway therapy on branched chain amino acid metabolism in urea cycle disorder patients. Mol Genet Metab. 2004 Apr;81 Suppl 1:S79-85. doi: 10.1016/j.ymgme.2003.11.017. PMID: 15050979.

Summar ML, Hall LD, Christman B, Barr F, Smith H, Kallianpur A, Brown N, Yadav M, Willis A, Eeds A, Cermak E, Summar S, Wilson A, Arvin M, Putnam A, Wills M, Cunningham G. Environmentally determined genetic expression: clinical correlates with molecular variants of carbamyl phosphate synthetase I. Mol Genet Metab. 2004;81(Suppl 1):S12-S19. PMID: 15050969, Full Text (with PubMed access).

Rohininath T, Costello DJ, Lynch T, Monavari A, Tuchman M, Treacy EP. Fatal presentation of ornithine transcarbamylase deficiency in a 62-year-old man and family studies. J Inherit Metab Dis. 2004;27:285-288. PMID: 15243986.

Tuchman M. Hyperammonemia: are the burdens too grave? Case study. Ethics Intellect Disabil. 2004;8:1,3. PMID: 15835081.

Kasumov T, Brunengraber LL, Comte B, Puchowicz MA, Jobbins K, Thomas K, David F, Kinman R, Wehrli S, Dahms W, Kerr D, Nissim I, Brunengraber H. New secondary metabolites of phenylbutyrate in humans and rats. Drug Metab Dispos. 2004;32:10-19. PMID: 14709615, Full Text.

MacArthur RB, Altincatal A, Tuchman M. Pharmacokinetics of sodium phenylacetate and sodium benzoate following intravenous administration as both a bolus and continuous infusion to healthy adult volunteers. Mol Genet Metab. 2004;Suppl:67-73. PMID: 15050977, Full Text (with PubMed access).

Tuchman M. Urea cycle disorders workshop introduction. Mol Genet Metab. 2004;81(Suppl):3. Full Text.

Kleppe S, Mian A, Lee B. Urea Cycle Disorders. Curr Treat Options Neurol. 2003 Jul;5(4):309-319. doi: 10.1007/s11940-003-0037-5.

Takanashi JI, Barkovich AJ, Cheng SF, Weisiger K, Zlatunich CO, Mudge C, Rosenthal P, Tuchman M, Packman S. Brain MR imaging in neonatal hyperammonemic encephalopathy resulting from proximal urea cycle disorders. Am J Neuroradiol. 2003;24:1184-1187. PMID: 12812952, Full Text.

Summar ML, Hall LD, Eeds AM, Hutcheson HB, Kuo AN, Willis AS, Rubio V, Arvin MK, Schofield JP, Dawson EP. Characterization of genomic structure and polymorphisms in the human carbamyl phosphate synthetase I gene. Gene. 2003;311:51-57. PMID: 12853138, Full Text (with PubMed access).

Scaglia F, Rosenberger J, Henry J, Lee B, Reeds P. Differential utilization of systemic and enteral ammonia for urea synthesis in control subjects and carriers for ornithine transcarbamylase deficiency. Am J Clin Nutr. 2003;78:749-755. PMID: 14522733, Full Text.

Barr FE, Beverley H, VanHook K, Cermak E, Christian K, Drinkwater D, Dyer K, Raggio NT, Moore JH, Christman B, Summar M. Effect of cardiopulmonary bypass on urea cycle intermediates and nitric oxide levels after congenital heart surgery. J Pediatr. 2003;142(1):26-30. PMID: 12520250, Full Text (with PubMed access).

Caldovic L, Morizono M, Panglao M, Cheng SF, Packman S, Tuchman M. Null mutations in the Nacetylglutamate synthase gene associated with acute neonatal disease and hyperammonemia. Hum Genet. 2003;112:364-368. PMID: 12594532, Full Text (with PubMed access).

Cunningham KY, Hur B, Gupta VK, Koster MJ, Weyand CM, Cuthbertson D, Khalidi NA, Koening CL, Langford CA, McAlear CA, Monach PA, Moreland LW, Pagnoux C, Rhee RL, Seo P, Merkel PA, Warrington KJ, Sung J. Plasma proteome profiling in giant cell arteritis. Ann Rheum Dis. 2024 Nov 14;83(12):1762-1772. doi: 10.1136/ard-2024-225868.

Banerjee S, Rose E, Panicker S, Dugan J, Khalidi N, Koening CL, Langford CA, Monach PA, Pagnoux C, McAlear CA, Merkel PA; Vasculitis Clinical Research Consortium. Signal Regulatory Protein α Expression in Systemic Vasculitis. ACR Open Rheumatol. 2024 Jul 15. doi: 10.1002/acr2.11716. Online ahead of print.

Karadag O, Bolek EC, Ayan G, Mohammad AJ, Grayson PC, Pagnoux C, Martín-Nares E, Monti S, Abe Y, Alberici F, Alibaz-Oner F, Cuthbertson D, Dagna L, Direskeneli H, Khalidi NA, Koening C, Langford CA, McAlear CA, Monach PA, Moroni L, Padoan R, Seo P, Warrington KJ, Hocevar A, Hinojosa-Azaola A, Furuta S, Emmi G, Ozen S, Jayne D, Merkel PA; GLOBAL-PAN Collaborators. Clinical Characteristics and Outcomes of Polyarteritis Nodosa: An International Study. Arthritis Rheumatol. 2024 Feb 12. doi: 10.1002/art.42817. Online ahead of print.

Bloom JL, Pickett-Nairn K, Silveira L, Fuhlbrigge RC, Cuthbertson D, Akuthota P, Corbridge TC, Khalidi NA, Koening CL, Langford CA, McAlear CA, Monach PA, Moreland LW, Pagnoux C, Rhee RL, Seo P, Silver J, Specks U, Warrington KJ, Wechsler ME, Merkel PA; Vasculitis Clinical Research Consortium. The Association Between Age at Diagnosis and Disease Characteristics and Damage in Patients With ANCA-Associated Vasculitis. Arthritis Rheumatol. 2023 Dec;75(12):2216-2227. doi: 10.1002/art.42651. Epub 2023 Oct 5.

Michailidou D, Grayson PC, Hermanson P, Chapa JAG, Cuthbertson D, Khalidi NA, Koening CL, Langford CA, McAlear CA, Moreland LW, Pagnoux C, Seo P, Sreih AG, Warrington KJ, Monach PA, Merkel PA, Lood C. Mitochondrial-mediated inflammation and platelet activation in giant cell arteritis. Clin Immunol. 2023 Oct;255:109746. doi: 10.1016/j.clim.2023.109746. Epub 2023 Aug 23.

Almaani S, Song H, Suthanthira M, Toy C, Fussner LA, Meara A, Nagaraja H, Cuthbertson D, Khalidi NA, Koening CL, Langford CA, McAlear CA, Moreland LW, Pagnoux C, Seo P, Specks U, Sreih AG, Warrington KJ, Monach PA, Merkel PA, Rovin B, Birmingham D. Urine and Plasma Complement Ba Levels During Disease Flares in Patients With Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis. Kidney Int Rep. 2023 Aug 20;8(11):2421-2427. doi: 10.1016/j.ekir.2023.08.017. eCollection 2023 Nov.

Junek ML, Zhao L, Garner S, Cuthbertson D, Pagnoux C, Koening CL, Langford CA, McAlear CA, Monach PA, Moreland LW, Rhee RL, Seo P, Specks U, Sreih AG, Warrington K, Wechsler ME, Merkel PA, Khalidi NA. Ocular manifestations of ANCA-associated vasculitis. Rheumatology (Oxford). 2023 Jul 5;62(7):2517-2524. doi: 10.1093/rheumatology/keac663.

Smith RM, Jones RB, Specks U, Bond S, Nodale M, Al-Jayyousi R, Andrews J, Bruchfeld A, Camilleri B, Carette S, Cheung CK, Derebail V, Doulton T, Ferraro A, Forbess L, Fujimoto S, Furuta S, Gewurz-Singer O, Harper L, Ito-Ihara T, Khalidi N, Klocke R, Koening C, Komagata Y, Langford C, Lanyon P, Luqmani R, McAlear C, Moreland LW, Mynard K, Nachman P, Pagnoux C, Peh CA, Pusey C, Ranganathan D, Rhee RL, Spiera R, Sreih AG, Tesar V, Walters G, Wroe C, Jayne D, Merkel PA; RITAZAREM co-investigators.. Rituximab versus azathioprine for maintenance of remission for patients with ANCA-associated vasculitis and relapsing disease: an international randomised controlled trial. Ann Rheum Dis. 2023 Jul;82(7):937-944. doi: 10.1136/ard-2022-223559. Epub 2023 Mar 23.

Ortiz-Fernández L, Carmona EG, Kerick M, Lyons P, Carmona FD, López Mejías R, Khor CC, Grayson PC, Tombetti E, Jiang L, Direskeneli H, Saruhan-Direskeneli G, Callejas-Rubio JL, Vaglio A, Salvarani C, Hernández-Rodríguez J, Cid MC, Morgan AW, Merkel PA, Burgner D, Smith KG, Gonzalez-Gay MA, Sawalha AH, Martin J, Marquez A. Identification of new risk loci shared across systemic vasculitides points towards potential target genes for drug repurposing. Ann Rheum Dis. 2023 Jun;82(6):837-847. doi: 10.1136/ard-2022-223697. Epub 2023 Feb 16.

Michailidou D, Kuley R, Wang T, Hermanson P, Grayson PC, Cuthbertson D, Khalidi NA, Koening CL, Langford CA, McAlear CA, Moreland LW, Pagnoux C, Seo P, Specks U, Sreih AG, Warrington KJ, Monach PA, Merkel PA, Lood C. Neutrophil extracellular trap formation in anti-neutrophil cytoplasmic antibody-associated and large-vessel vasculitis. Clin Immunol. 2023 Apr;249:109274. doi: 10.1016/j.clim.2023.109274. Epub 2023 Mar 4.

Applequist J, Burroughs C, Merkel PA, Rothenberg M, Trapnell B, Desnick R, Sahin M, Krischer J. Direct-to-Consumer Recruitment Methods via Traditional and Social Media to Aid in Research Accrual for Clinical Trials for Rare Diseases: Comparative Analysis Study. J Med Internet Res. 2023 Mar 14;25:e39262. doi: 10.2196/39262.

Doubelt I, Cuthbertson D, Carette S, Khalidi NA, Koening CL, Langford C, McAlear CA, Moreland LW, Monach P, Seo P, Specks U, Warrington KJ, Merkel PA, Pagnoux C. Vitamin D status in ANCA-associated vasculitis. Rheumatol Adv Pract. 2023 Feb 10;7(1):rkad021. doi: 10.1093/rap/rkad021. eCollection 2023.PMID: 36874269.

Kermani TA, Cuthbertson D, Carette S, Khalidi NA, Koening CL, Langford CA, McAlear CA, Monach PA, Moreland L, Pagnoux C, Seo P, Specks U, Sreih A, Warrington KJ, Merkel PA; Vasculitis Clinical Research Consortium. Hypothyroidism in vasculitis. Rheumatology (Oxford). 2022 Jul 6;61(7):2942-2950. doi: 10.1093/rheumatology/keab817.

Michailidou D, Duvvuri B, Kuley R, Cuthbertson D, Grayson PC, Khalidi NA, Koening CL, Langford CA, McAlear CA, Moreland LW, Pagnoux C, Seo P, Specks U, Sreih AG, Warrington KJ, Mustelin T, Monach PA, Merkel PA, Lood C.. Neutrophil activation in patients with anti-neutrophil cytoplasmic autoantibody-associated vasculitis and large-vessel vasculitis. Arthritis Res Ther. 2022 Jun 29;24(1):160. doi: 10.1186/s13075-022-02849-z.

Doubelt I, Springer JM, Kermani TA, Sreih AG, Burroughs C, Cuthbertson D, Carette S, Khalidi NA, Koening CL, Langford C, McAlear CA, Moreland LW, Monach PA, Shaw DG, Seo P, Specks U, Warrington KJ, Young K, Merkel PA, Pagnoux C. Self-Reported Data and Physician-Reported Data in Patients With Eosinophilic Granulomatosis With Polyangiitis: Comparative Analysis. Interact J Med Res. 2022 May 25;11(1):e27273. doi: 10.2196/27273.PMID: 35612893.

Hatemi G, Meara A, Özgüler Y, Direskeneli H, Mahr A, Shea B, Cam E, Gul A, Yazici Y, Tugwell P, Yazici H, Merkel PA; Outcome Measures in Rheumatology Behçet's Syndrome Working Group. Core Set of Domains for Outcome Measures in Behçet's Syndrome. Arthritis Care Res (Hoboken). 2022 Apr;74(4):691-699. doi: 10.1002/acr.24511. Epub 2022 Mar 4.

Sattui SE, Conway R, Putman MS, Seet AM, Gianfrancesco MA, Beins K, Hill C, Liew D, Mackie SL, Mehta P, Neill L, Gomez G, Salinas MIH, Maldonado FN, Mariz HA, de Sousa Studart SA, Araujo NC, Knight A, Rozza D, Quartuccio L, Samson M, Bally S, Maria AT, Chazerain P, Hasseli R, Müller-Ladner U, Hoyer BF, Voll R, Torres RP, Luis M, Ribeirio SLE, Al-Emadi S, Sparks JA, Hsu TY, D'Silva KM, Patel NJ, Wise L, Gilbert E, Almada MV, Duarte-García A, Ugarte-Gil M, Jacobsohn L, Izadi Z, Strangfeld A, Mateus EF, Hyrich KL, Gossec L, Carmona L, Lawson-Tovey S, Kearsley-Fleet L, Schaefer M, Sirotich E, Hausmann JS, Sufka P, Bhana S, Liew JW, Grainger R, Machado PM, Wallace ZS, Yazdany J, Robinson PC; Global Rheumatology Alliance. Outcomes of COVID-19 in patients with primary systemic vasculitis or polymyalgia rheumatica from the COVID-19 Global Rheumatology Alliance physician registry: a retrospective cohort study. Lancet Rheumatol. 2021 Dec;3(12):e855-e864. doi: 10.1016/S2665-9913(21)00316-7. Epub 2021 Nov 5.

Monach PA, Warner RL, Lew R, Tómasson G, Specks U, Stone JH, Fervenza FC, Hoffman GS, Kallenberg CGM, Langford CA, Seo P, St Clair EW, Spiera R, Johnson KJ, Merkel PA. Serum Biomarkers of Disease Activity in Longitudinal Assessment of Patients with ANCA-Associated Vasculitis. ACR Open Rheumatol. 2021 Nov 18. doi: 10.1002/acr2.11366. Online ahead of print.

Monach PA, Branch-Elliman W. Reconsidering 'minimal risk' to expand the repertoire of trials with waiver of informed consent for research. BMJ Open. 2021 Sep 14;11(9):e048534. doi: 10.1136/bmjopen-2020-048534.

Mehta P, Sattui SE, van der Geest KSM, Brouwer E, Conway R, Putman MS, Robinson PC, Mackie SL. Giant Cell Arteritis and COVID-19: Similarities and Discriminators. A Systematic Literature Review. J Rheumatol. 2021 Jul;48(7):1053-1059. doi: 10.3899/jrheum.200766. Epub 2020 Oct 15.

Doubelt I, Cuthbertson D, Carette S, Chung SA, Forbess LJ, Khalidi NA, Koening CL, Langford C, McAlear CA, Moreland LW, Monach PA, Seo P, Specks U, Spiera RF, Springer JM, Sreih AG, Warrington KJ, Merkel PA, Pagnoux C; Vasculitis Clinical Research Consortium. Clinical Manifestations and Long-Term Outcomes of Eosinophilic Granulomatosis With Polyangiitis in North America. ACR Open Rheumatol. 2021 May 25. doi: 10.1002/acr2.11263. Online ahead of print.

Sreih AG, Cronin K, Shaw DG, Young K, Burroughs C, Kullman J, Machireddy K, McAlear CA, Merkel PA; Vasculitis Patient-Powered Research Network. Diagnostic delays in vasculitis and factors associated with time to diagnosis. Orphanet J Rare Dis. 2021 Apr 21;16(1):184. doi: 10.1186/s13023-021-01794-5.

Mustapha N, Barra L, Carette S, Cuthbertson D, Khalidi NA, Koening CL, Langford CA, McAlear CA, Milman N, Moreland LW, Monach PA, Seo P, Specks U, Sreih AG, Ytterberg SY, Merkel PA, Pagnoux C; Canadian Vasculitis Research Network (CanVasc) and Vasculitis Clinical Research Consortium (VCRC). Efficacy of leflunomide in the treatment of vasculitis. Clin Exp Rheumatol. 2021 Mar-Apr;39 Suppl 129(2):114-118. doi: 10.55563/clinexprheumatol/ve38dj. Epub 2020 Nov 10.PMID: 33200732.

Schnappauf O, Sampaio Moura N, Aksentijevich I, Stoffels M, Ombrello AK, Hoffmann P, Barron K, Remmers EF, Hershfield M, Kelly SJ; NISC Comparative Sequencing Program; Cuthbertson D, Carette S, Chung SA, Forbess L, Khalidi NA, Koening CL, Langford CA, McAlear CA, Monach PA, Moreland L, Pagnoux C, Seo P, Springer JM, Sreih AG, Warrington KJ, Ytterberg SR, Kastner DL, Grayson PC, Merkel PA; Vasculitis Clinical Research Consortium. Sequence-Based Screening of Patients With Idiopathic Polyarteritis Nodosa, Granulomatosis With Polyangiitis, and Microscopic Polyangiitis for Deleterious Genetic Variants in ADA2. Arthritis Rheumatol. 2021 Mar;73(3):512-519. doi: 10.1002/art.41549. Epub 2021 Feb 3.PMID: 33021335.

Robinette ML, Rao DA, Monach PA. The Immunopathology of Giant Cell Arteritis Across Disease Spectra. Front Immunol. 2021 Feb 25;12:623716. doi: 10.3389/fimmu.2021.623716. eCollection 2021.

Ortiz-Fernández L, Saruhan-Direskeneli G, Alibaz-Oner F, Kaymaz-Tahra S, Coit P, Kong X, Kiprianos AP, Maughan RT, Aydin SZ, Aksu K, Keser G, Kamali S, Inanc M, Springer J, Akar S, Onen F, Akkoc N, Khalidi NA, Koening C, Karadag O, Kiraz S, Forbess L, Langford CA, McAlear CA, Ozbalkan Z, Yavuz S, Çetin GY, Alpay-Kanitez N, Chung S, Ates A, Karaaslan Y, McKinnon-Maksimowicz K, Monach PA, Ozer HTE, Seyahi E, Fresko I, Cefle A, Seo P, Warrington KJ, Ozturk MA, Ytterberg SR, Cobankara V, Onat AM, Duzgun N, Bıcakcıgil M, Yentür SP, Lally L, Manfredi AA, Baldissera E, Erken E, Yazici A, Kısacık B, Kaşifoğlu T, Dalkilic E, Cuthbertson D, Pagnoux C, Sreih A, Reales G, Wallace C, Wren JD, Cunninghame-Graham DS, Vyse TJ, Sun Y, Chen H, Grayson PC, Tombetti E, Jiang L, Mason JC, Merkel PA, Direskeneli H, Sawalha AH. Identification of susceptibility loci for Takayasu arteritis through a large multi-ancestral genome-wide association study. Am J Hum Genet. 2021 Jan 7;108(1):84-99. doi: 10.1016/j.ajhg.2020.11.014. Epub 2020 Dec 11.

Mackie SL, Brouwer E, Conway R, van der Geest KSM, Mehta P, Mollan SP, Neill L, Putman M, Robinson PC, Sattui SE. Clinical pathways for patients with giant cell arteritis during the COVID-19 pandemic: an international perspective. Lancet Rheumatol. 2021 Jan;3(1):e71-e82. doi: 10.1016/S2665-9913(20)30386-6. Epub 2020 Dec 8.

Navarro-Millán I, Sattui SE, Lakhanpal A, Zisa D, Siegel CH, Crow MK. Use of Anakinra to Prevent Mechanical Ventilation in Severe COVID-19: A Case Series. Arthritis Rheumatol. 2020 Dec;72(12):1990-1997. doi: 10.1002/art.41422. Epub 2020 Nov 4.

Gribbons KB, Ponte C, Carette S, Craven A, Cuthbertson D, Hoffman GS, Khalidi NA, Koening CL, Langford CA, Maksimowicz-McKinnon K, McAlear CA, Monach PA, Moreland LW, Pagnoux C, Quinn KA, Robson JC, Seo P, Sreih AG, Suppiah R, Warrington KJ, Ytterberg SR, Luqmani R, Watts R, Merkel PA, Grayson PC. Patterns of Arterial Disease in Takayasu Arteritis and Giant Cell Arteritis. Arthritis Care Res (Hoboken). 2020 Nov;72(11):1615-1624. doi: 10.1002/acr.24055.

Smith RM, Jones RB, Specks U, Bond S, Nodale M, Aljayyousi R, Andrews J, Bruchfeld A, Camilleri B, Carette S, Cheung CK, Derebail V, Doulton T, Forbess L, Fujimoto S, Furuta S, Gewurz-Singer O, Harper L, Ito-Ihara T, Khalidi N, Klocke R, Koening C, Komagata Y, Langford C, Lanyon P, Luqmani RA, Makino H, McAlear CA, Monach P, Moreland LW, Mynard K, Nachman P, Pagnoux C, Pearce F, Peh CA, Pusey C, Ranganathan D, Rhee RL, Spiera R, Sreih AG, Tesar V, Walters G, Weisman MH, Wroe C, Merkel PA, Jayne D; RITAZAREM coinvestigators; RITAZAREM co-investigators. Rituximab as therapy to induce remission after relapse in ANCA-associated vasculitis. Ann Rheum Dis. 2020 Sep;79(9):1243-1249. doi: 10.1136/annrheumdis-2019-216863. Epub 2020 Jun 24.PMID: 32581088.

Quinn KA, Gribbons KB, Carette S, Cuthbertson D, Khalidi NA, Koening CL, Langford CA, McAlear CA, Monach PA, Moreland LW, Pagnoux C, Seo P, Sreih AG, Warrington KJ, Ytterberg SR, Novakovich E, Merkel PA, Grayson PC. Patterns of clinical presentation in Takayasu's arteritis. Semin Arthritis Rheum. 2020 Aug;50(4):576-581. doi: 10.1016/j.semarthrit.2020.04.012. Epub 2020 May 19.

Springer JM, Kermani TA, Sreih A, Shaw DG, Young K, Burroughs CM, Merkel PA. Clinical Characteristics of an Internet-Based Cohort of Patient-Reported Diagnosis of Granulomatosis With Polyangiitis and Microscopic Polyangiitis: Observational Study. J Med Internet Res. 2020 Jul 20;22(7):e17231. doi: 10.2196/17231.

Rodriguez-Pla A, Warner RL, Cuthbertson D, Carette S, Khalidi NA, Koening CL, Langford CA, McAlear CA, Moreland LW, Pagnoux C, Seo P, Specks U, Sreih AG, Ytterberg SR, Johnson KJ, Merkel PA, Monach PA; Vasculitis Clinical Research Consortium. Evaluation of Potential Serum Biomarkers of Disease Activity in Diverse Forms of Vasculitis. J Rheumatol. 2020 Jul 1;47(7):1001-1010. doi: 10.3899/jrheum.190093. Epub 2019 Sep 1.

Walsh M, Merkel PA, Jayne DRW. Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis. Reply. N Engl J Med. 2020 May 28;382(22):2169. doi: 10.1056/NEJMc2004843.

Goel R, Gribbons KB, Carette S, Cuthbertson D, Hoffman GS, Joseph G, Khalidi NA, Koening CL, Kumar S, Langford C, Maksimowicz-McKinnon K, McAlear CA, Monach PA, Moreland LW, Nair A, Pagnoux C, Quinn KA, Ravindran R, Seo P, Sreih AG, Warrington KJ, Ytterberg SR, Merkel PA, Danda D, Grayson PC. Derivation of an angiographically based classification system in Takayasu's arteritis: an observational study from India and North America. Rheumatology (Oxford). 2020 May 1;59(5):1118-1127. doi: 10.1093/rheumatology/kez421.

Micheletti RG, Pagnoux C, Tamura RN, Grayson PC, McAlear CA, Borchin R, Krischer JP, Merkel PA; Vasculitis Clinical Research Consortium. Protocol for a randomized multicenter study for isolated skin vasculitis (ARAMIS) comparing the efficacy of three drugs: azathioprine, colchicine, and dapsone. Trials. 2020 Apr 28;21(1):362. doi: 10.1186/s13063-020-04285-3.

Applequist J, Burroughs C, Ramirez A Jr, Merkel PA, Rothenberg ME, Trapnell B, Desnick RJ, Sahin M, Krischer JP. A novel approach to conducting clinical trials in the community setting: utilizing patient-driven platforms and social media to drive web-based patient recruitment. BMC Med Res Methodol. 2020 Mar 13;20(1):58. doi: 10.1186/s12874-020-00926-y.

Walsh M, Merkel PA, Peh CA, Szpirt WM, Puéchal X, Fujimoto S, Hawley CM, Khalidi N, Floßmann O, Wald R, Girard LP, Levin A, Gregorini G, Harper L, Clark WF, Pagnoux C, Specks U, Smyth L, Tesar V, Ito-Ihara T, de Zoysa JR, Szczeklik W, Flores-Suárez LF, Carette S, Guillevin L, Pusey CD, Casian AL, Brezina B, Mazzetti A, McAlear CA, Broadhurst E, Reidlinger D, Mehta S, Ives N, Jayne DRW; PEXIVAS Investigators. Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis. N Engl J Med. 2020 Feb 13;382(7):622-631. doi: 10.1056/NEJMoa1803537.

Moran SM, Monach PA, Zgaga L, Cuthbertson D, Carette S, Khalidi NA, Koening CL, Langford CA, McAlear CA, Moreland L, Pagnoux C, Seo P, Specks U, Sreih A, Wyse J, Ytterberg SR, Merkel PA, Little MA; Vasculitis Clinical Research Consortium. Urinary soluble CD163 and monocyte chemoattractant protein-1 in the identification of subtle renal flare in anti-neutrophil cytoplasmic antibody-associated vasculitis. Nephrol Dial Transplant. 2020 Feb 1;35(2):283-291. doi: 10.1093/ndt/gfy300.

Quinn KA, Rosenblum JS, Rimland CA, Gribbons KB, Ahlman MA, Grayson PC. Imaging acquisition technique influences interpretation of positron emission tomography vascular activity in large-vessel vasculitis. Semin Arthritis Rheum. 2020 Feb;50(1):71-76. doi: 10.1016/j.semarthrit.2019.07.008. Epub 2019 Jul 24.

Banerjee S, Quinn KA, Gribbons KB, Rosenblum JS, Civelek AC, Novakovich E, Merkel PA, Ahlman MA, Grayson PC. Effect of Treatment on Imaging, Clinical, and Serologic Assessments of Disease Activity in Large-vessel Vasculitis. J Rheumatol. 2020 Jan;47(1):99-107. doi: 10.3899/jrheum.181222. Epub 2019 Mar 15.

Quinn KA, Gelbard A, Sibley C, Sirajuddin A, Ferrada MA, Chen M, Cuthbertson D, Carette S, Khalidi NA, Koening CL, Langford CA, McAlear CA, Monach PA, Moreland LW, Pagnoux C, Seo P, Specks U, Sreih AG, Ytterberg SR, Merkel PA, Grayson PC. Subglottic stenosis and endobronchial disease in granulomatosis with polyangiitis. Rheumatology (Oxford). 2019 Dec 1;58(12):2203-2211. doi: 10.1093/rheumatology/kez217.

Berti A, Warner R, Johnson K, Cornec D, Schroeder DR, Kabat BF, Langford CA, Kallenberg CGM, Seo P, Spiera RF, St Clair EW, Fervenza FC, Stone JH, Monach PA, Specks U, Merkel PA; RAVE-ITN Research Group. The association of serum interleukin-6 levels with clinical outcomes in antineutrophil cytoplasmic antibody-associated vasculitis. J Autoimmun. 2019 Dec;105:102302. doi: 10.1016/j.jaut.2019.07.001. Epub 2019 Jul 15.

Wallace ZS, Fu X, Liao K, Kallenberg CGM, Langford CA, Merkel PA, Monach P, Seo P, Specks U, Spiera R, St Clair EW, Zhang Y, Choi H, Stone JH. Disease Activity, Antineutrophil Cytoplasmic Antibody Type, and Lipid Levels in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. Arthritis Rheumatol. 2019 Nov;71(11):1879-1887. doi: 10.1002/art.41006. Epub 2019 Sep 16.

Ozguler Y, Merkel PA, Gurcan M, Bocage C, Eriksen W, Kutlubay Z, Hatemi G, Cronholm PF; OMERACT Behçet's Syndrome Working Group. Patients' experiences with Behçet's syndrome: structured interviews among patients with different types of organ involvement. Clin Exp Rheumatol. 2019 Nov-Dec;37 Suppl 121(6):28-34. Epub 2019 Apr 12.

Milman N, McConville E, Robson JC, Boonen A, Tugwell P, Wells GA, Chaudhuri D, Dawson J, Tomasson G, Ashdown S, Gebhart D, Lanier G, Peck J, McAlear CA, Kellom KS, Cronholm PF, Merkel PA. Updating OMERACT Core Set of Domains for ANCA-associated Vasculitis: Patient Perspective Using the International Classification of Function, Disability, and Health. J Rheumatol. 2019 Oct;46(10):1415-1420. doi: 10.3899/jrheum.181073. Epub 2019 Feb 1.

Aydin SZ, Robson JC, Sreih AG, Hill C, Alibaz-Oner F, Mackie S, Beard S, Gul A, Hatemi G, Kermani TA, Mahr A, Meara A, Milman N, Shea B, Tómasson G, Tugwell P, Direskeneli H, Merkel PA. Update on Outcome Measure Development in Large-vessel Vasculitis: Report from OMERACT 2018. J Rheumatol. 2019 Sep;46(9):1198-1201. doi: 10.3899/jrheum.181072. Epub 2019 Mar 15.

Tomasson G, Farrar JT, Cuthbertson D, McAlear CA, Ashdown S, Cronholm PF, Dawson J, Gebhart D, Lanier G, Luqmani RA, Milman N, Peck J, Robson JC, Shea JA, Carette S, Khalidi N, Koening CL, Langford CA, Monach PA, Moreland L, Pagnoux C, Specks U, Sreih AG, Ytterberg SR, Merkel PA; Vasculitis Clinical Research Consortium. Feasibility and Construct Validation of the Patient Reported Outcomes Measurement Information System in Systemic Vasculitis. J Rheumatol. 2019 Aug;46(8):928-934. doi: 10.3899/jrheum.171405. Epub 2019 Mar 1.

Taroni JN, Grayson PC, Hu Q, Eddy S, Kretzler M, Merkel PA, Greene CS. MultiPLIER: A Transfer Learning Framework for Transcriptomics Reveals Systemic Features of Rare Disease. Cell Syst. 2019 May 22;8(5):380-394.e4. doi: 10.1016/j.cels.2019.04.003.

Pagnoux C, Nair P, Xi Y, Khalidi NA, Carette S, Cuthbertson D, Grayson PC, Koening CL, Langford CA, McAlear CA, Moreland LW, Monach PA, Seo P, Specks U, Sreih AG, Ytterberg SR, Tyrrell PN, Merkel PA; Vasculitis Clinical Research Consortium. Serum cytokine and chemokine levels in patients with eosinophilic granulomatosis with polyangiitis, hypereosinophilic syndrome, or eosinophilic asthma. Clin Exp Rheumatol. 2019 Mar-Apr;37 Suppl 117(2):40-44. Epub 2019 Jan 14.

Lee KS, Kronbichler A, Pereira Vasconcelos DF, Pereira da Silva FR, Ko Y, Oh YS, Eisenhut M, Merkel PA, Jayne D, Amos CI, Siminovitch KA, Rahmattulla C, Lee KH, Shin JI. Genetic Variants in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Bayesian Approach and Systematic Review. J Clin Med. 2019 Feb 21;8(2):266. doi: 10.3390/jcm8020266.

Kermani TA, Diab S, Sreih AG, Cuthbertson D, Borchin R, Carette S, Forbess L, Koening CL, McAlear CA, Monach PA, Moreland L, Pagnoux C, Seo P, Spiera RF, Warrington KJ, Ytterberg SR, Langford CA, Merkel PA, Khalidi NA; Vasculitis Clinical Research Consortium. Arterial lesions in giant cell arteritis: A longitudinal study. Semin Arthritis Rheum. 2019 Feb;48(4):707-713. doi: 10.1016/j.semarthrit.2018.05.002. Epub 2018 May 9.

Young K, Kaminstein D, Olivos A, Burroughs C, Castillo-Lee C, Kullman J, McAlear C, Shaw DG, Sreih A, Casey G; Vasculitis Patient-Powered Research Network, Merkel PA. Patient involvement in medical research: what patients and physicians learn from each other. Orphanet J Rare Dis. 2019 Jan 24;14(1):21. doi: 10.1186/s13023-018-0969-1.

Sreih AG, Ezzedine R, Leng L, Fan J, Yao J, Reid D, Piecychna M, Carette S, Cuthbertson D, Dellaripa P, Hoffman GS, Khalidi NA, Koening CL, Langford CA, Mahr A, McAlear CA, Maksimowicz-Mckinnon K, Monach PA, Seo P, Specks U, St Clair EW, Stone JH, Ytterberg SR, Edberg J, Merkel PA, Bucala R. Role of Macrophage Migration Inhibitory Factor in Granulomatosis With Polyangiitis. Arthritis Rheumatol. 2018 Dec;70(12):2077-2086. doi: 10.1002/art.40655. Epub 2018 Oct 22.

Conklin LS, Merkel PA, Pachman LM, Parikh H, Tawalbeh S, Damsker JM, Cuthbertson DD, Morgan GA, Monach PA, Hathout Y, Nagaraju K, van den Anker J, McAlear CA, Hoffman EP. Serum biomarkers of glucocorticoid response and safety in anti-neutrophil cytoplasmic antibody-associated vasculitis and juvenile dermatomyositis. Steroids. 2018 Dec;140:159-166. doi: 10.1016/j.steroids.2018.10.008. Epub 2018 Oct 21.

Rhee RL, Holweg CTJ, Wong K, Cuthbertson D, Carette S, Khalidi NA, Koening CL, Langford CA, McAlear CA, Monach PA, Moreland LW, Pagnoux C, Seo P, Specks U, Sreih AG, Ytterberg SR, Merkel PA; Vasculitis Clinical Research Consortium. Serum periostin as a biomarker in eosinophilic granulomatosis with polyangiitis. PLoS One. 2018 Oct 11;13(10):e0205768. doi: 10.1371/journal.pone.0205768. eCollection 2018.

Springer JM, Monach P, Cuthbertson D, Carette S, Khalidi NA, McAlear CA, Pagnoux C, Seo P, Warrington KJ, Ytterberg SR, Hoffman G, Langford C, Hamilton T, Foell D, Vogl T, Holzinger D, Merkel PA, Roth J, Hajj-Ali RA. Serum S100 Proteins as a Marker of Disease Activity in Large Vessel Vasculitis. J Clin Rheumatol. 2018 Oct;24(7):393-395. doi: 10.1097/RHU.0000000000000729.

Quinn KA, Ahlman MA, Malayeri AA, Marko J, Civelek AC, Rosenblum JS, Bagheri AA, Merkel PA, Novakovich E, Grayson PC. Comparison of magnetic resonance angiography and (18)F-fluorodeoxyglucose positron emission tomography in large-vessel vasculitis. Ann Rheum Dis. 2018 Aug;77(8):1165-1171. doi: 10.1136/annrheumdis-2018-213102. Epub 2018 Apr 17.

Robson JC, Dawson J, Doll H, Cronholm PF, Milman N, Kellom K, Ashdown S, Easley E, Gebhart D, Lanier G, Mills J, Peck J, Luqmani RA, Shea J, Tomasson G, Merkel PA. Validation of the ANCA-associated vasculitis patient-reported outcomes (AAV-PRO) questionnaire. Ann Rheum Dis. 2018 Aug;77(8):1157-1164. doi: 10.1136/annrheumdis-2017-212713. Epub 2018 Apr 25.

Berti A, Warner R, Johnson K, Cornec D, Schroeder D, Kabat B, Langford CA, Hoffman GS, Fervenza FC, Kallenberg CGM, Seo P, Spiera R, St Clair EW, Brunetta P, Stone JH, Merkel PA, Specks U, Monach PA; RAVE-ITN Research Group. Brief Report: Circulating Cytokine Profiles and Antineutrophil Cytoplasmic Antibody Specificity in Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. Arthritis Rheumatol. 2018 Jul;70(7):1114-1121. doi: 10.1002/art.40471. Epub 2018 May 7.

Byram K, Hajj-Ali RA, Calabrese L. CNS Vasculitis: an Approach to Differential Diagnosis and Management. Curr Rheumatol Rep. 2018 May 30;20(7):37. doi: 10.1007/s11926-018-0747-z.

Ortiz-Fernández L, Carmona FD, López-Mejías R, González-Escribano MF, Lyons PA, Morgan AW, Sawalha AH, Merkel PA, Smith KGC, González-Gay MA, Martín J; Spanish GCA Study Group, UK GCA Consortium, Turkish Takayasu Study Group, Vasculitis Clinical Research Consortium, IgAV Study Group, AAV Study group. Cross-phenotype analysis of Immunochip data identifies KDM4C as a relevant locus for the development of systemic vasculitis. Ann Rheum Dis. 2018 Apr;77(4):589-595. doi: 10.1136/annrheumdis-2017-212372. Epub 2018 Jan 27.

Robson JC, Dawson J, Cronholm PF, Ashdown S, Easley E, Kellom KS, Gebhart D, Lanier G, Milman N, Peck J, Luqmani RA, Shea JA, Tomasson G, Merkel PA. Patient perceptions of glucocorticoids in anti-neutrophil cytoplasmic antibody-associated vasculitis. Rheumatol Int. 2018 Apr;38(4):675-682. doi: 10.1007/s00296-017-3855-6. Epub 2017 Nov 9.

Grayson PC, Alehashemi S, Bagheri AA, Civelek AC, Cupps TR, Kaplan MJ, Malayeri AA, Merkel PA, Novakovich E, Bluemke DA, Ahlman MA. (18) F-Fluorodeoxyglucose-Positron Emission Tomography As an Imaging Biomarker in a Prospective, Longitudinal Cohort of Patients With Large Vessel Vasculitis. Arthritis Rheumatol. 2018 Mar;70(3):439-449. doi: 10.1002/art.40379. Epub 2018 Feb 6.

Barra L, Borchin RL, Burroughs C, Casey GC, McAlear CA, Sreih AG, Young K, Merkel PA, Pagnoux C; Vasculitis Clinical Research Consortium and the Vasculitis Patient-Powered Research Network. Impact of vasculitis on employment and income. Clin Exp Rheumatol. 2018 Mar-Apr;36 Suppl 111(2):58-64. Epub 2018 Jan 10.

Kermani TA, Sreih AG, Cuthbertson D, Carette S, Hoffman GS, Khalidi NA, Koening CL, Langford CA, McAlear CA, Monach PA, Moreland L, Pagnoux C, Seo P, Warrington KJ, Ytterberg SR, Merkel PA; Vasculitis Clinical Research Consortium. Evaluation of damage in giant cell arteritis. Rheumatology (Oxford). 2018 Feb 1;57(2):322-328. doi: 10.1093/rheumatology/kex397.

Robson JC, Dawson J, Cronholm PF, Milman N, Kellom KS, Ashdown S, Easley E, Farrar JT, Gebhart D, Lanier G, McAlear CA, Peck J, Luqmani RA, Shea JA, Tomasson G, Merkel PA. Health-related quality of life in ANCA-associated vasculitis and item generation for a disease-specific patient-reported outcome measure. Patient Relat Outcome Meas. 2018 Jan 4;9:17-34. doi: 10.2147/PROM.S144992. eCollection 2018.

Grayson PC, Eddy S, Taroni JN, Lightfoot YL, Mariani L, Parikh H, Lindenmeyer MT, Ju W, Greene CS, Godfrey B, Cohen CD, Krischer J, Kretzler M, Merkel PA; Vasculitis Clinical Research Consortium, the European Renal cDNA Bank cohort, and the Nephrotic Syndrome Study Network. Metabolic pathways and immunometabolism in rare kidney diseases. Ann Rheum Dis. 2018;77:1226-33. doi: 10.1136/annrheumdis-2017-212935. PMID: 29724730; PMCID: PMC6045442. 

Aydin SZ, Direskeneli H, Merkel PA; International Delphi on Disease Activity Assessment in Large-vessel Vasculitis. Assessment of Disease Activity in Large-vessel Vasculitis: Results of an International Delphi Exercise. J Rheumatol. 2017 Dec;44(12):1928-1932. doi: 10.3899/jrheum.161269. Epub 2017 Sep 1.

Sreih AG, Alibaz-Oner F, Kermani TA, Aydin SZ, Cronholm PF, Davis T, Easley E, Gul A, Mahr A, McAlear CA, Milman N, Robson JC, Tomasson G, Direskeneli H, Merkel PA. Development of a Core Set of Outcome Measures for Large-vessel Vasculitis: Report from OMERACT 2016. J Rheumatol. 2017 Dec;44(12):1933-1937. doi: 10.3899/jrheum.161467. Epub 2017 Sep 1.

Hatemi G, Meara A, Ozguler Y, Direskeneli H, Mahr A, Easley E, Gurcan M, Davis T, Gul A, Yazici Y, Zottenberg K, Esatoglu SN, Erer B, Kamali S, Yazici H, Cronholm PF, Merkel PA. Developing a Core Set of Outcome Measures for Behçet Disease: Report from OMERACT 2016. J Rheumatol. 2017 Nov;44(11):1750-1753. doi: 10.3899/jrheum.161352. Epub 2017 Apr 1.

Robson JC, Tomasson G, Milman N, Ashdown S, Boonen A, Casey GC, Cronholm PF, Cuthbertson D, Dawson J, Direskeneli H, Easley E, Kermani TA, Farrar JT, Gebhart D, Lanier G, Luqmani RA, Mahr A, McAlear CA, Peck J, Shea B, Shea JA, Sreih AG, Tugwell PS, Merkel PA. OMERACT Endorsement of Patient-reported Outcome Instruments in Antineutrophil Cytoplasmic Antibody-associated Vasculitis. J Rheumatol. 2017 Oct;44(10):1529-1535. doi: 10.3899/jrheum.161139. Epub 2017 Sep 1.

Mackie SL, Twohig H, Neill LM, Harrison E, Shea B, Black RJ, Kermani TA, Merkel PA, Mallen CD, Buttgereit F, Mukhtyar C, Simon LS, Hill CL; OMERACT PMR Working Group. The OMERACT Core Domain Set for Outcome Measures for Clinical Trials in Polymyalgia Rheumatica. J Rheumatol. 2017 Oct;44(10):1515-1521. doi: 10.3899/jrheum.161109. Epub 2017 Aug 1.

Merkel PA, Xie G, Monach PA, Ji X, Ciavatta DJ, Byun J, Pinder BD, Zhao A, Zhang J, Tadesse Y, Qian D, Weirauch M, Nair R, Tsoi A, Pagnoux C, Carette S, Chung S, Cuthbertson D, Davis JC Jr, Dellaripa PF, Forbess L, Gewurz-Singer O, Hoffman GS, Khalidi N, Koening C, Langford CA, Mahr AD, McAlear C, Moreland L, Seo EP, Specks U, Spiera RF, Sreih A, St Clair EW, Stone JH, Ytterberg SR, Elder JT, Qu J, Ochi T, Hirano N, Edberg JC, Falk RJ, Amos CI, Siminovitch KA; Vasculitis Clinical Research Consortium. Identification of Functional and Expression Polymorphisms Associated With Risk for Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis. Arthritis Rheumatol. 2017 May;69(5):1054-1066. doi: 10.1002/art.40034. Epub 2017 Apr 6.

Langford CA, Cuthbertson D, Ytterberg SR, Khalidi N, Monach PA, Carette S, Seo P, Moreland LW, Weisman M, Koening CL, Sreih AG, Spiera R, McAlear CA, Warrington KJ, Pagnoux C, McKinnon K, Forbess LJ, Hoffman GS, Borchin R, Krischer JP, Merkel PA; Vasculitis Clinical Research Consortium. A Randomized, Double-Blind Trial of Abatacept (CTLA-4Ig) for the Treatment of Giant Cell Arteritis. Arthritis Rheumatol. 2017 Apr;69(4):837-845. doi: 10.1002/art.40044. Epub 2017 Mar 3.

Langford CA, Cuthbertson D, Ytterberg SR, Khalidi N, Monach PA, Carette S, Seo P, Moreland LW, Weisman M, Koening CL, Sreih AG, Spiera R, McAlear CA, Warrington KJ, Pagnoux C, McKinnon K, Forbess LJ, Hoffman GS, Borchin R, Krischer JP, Merkel PA; Vasculitis Clinical Research Consortium. A Randomized, Double-Blind Trial of Abatacept (CTLA-4Ig) for the Treatment of Takayasu Arteritis. Arthritis Rheumatol. 2017 Apr;69(4):846-853. doi: 10.1002/art.40037. Epub 2017 Mar 8.

Carmona FD, Coit P, Saruhan-Direskeneli G, Hernández-Rodríguez J, Cid MC, Solans R, Castañeda S, Vaglio A, Direskeneli H, Merkel PA, Boiardi L, Salvarani C, González-Gay MA, Martín J, Sawalha AH; Spanish GCA Study Group; Italian GCA Study Group; Turkish Takayasu Study Group; Vasculitis Clinical Research Consortium. Analysis of the common genetic component of large-vessel vasculitides through a meta-Immunochip strategy. Sci Rep. 2017 Mar 9;7:43953. doi: 10.1038/srep43953.

Gopaluni S, Smith RM, Lewin M, McAlear CA, Mynard K, Jones RB, Specks U, Merkel PA, Jayne DR; RITAZAREM Investigators. Rituximab versus azathioprine as therapy for maintenance of remission for anti-neutrophil cytoplasm antibody-associated vasculitis (RITAZAREM): study protocol for a randomized controlled trial. Trials. 2017 Mar 7;18(1):112. doi: 10.1186/s13063-017-1857-z.

Milman N, Boonen A, Tugwell P, Merkel PA; OMERACT Vasculitis Working Group. Clinicians' perspective on key domains in ANCA-associated vasculitis: a Delphi exercise. Scand J Rheumatol. 2017 Mar;46(2):112-117. doi: 10.1080/03009742.2016.1188980. Epub 2016 Jul 20.

Soowamber M, Weizman AV, Pagnoux C. Gastrointestinal aspects of vasculitides. Nat Rev Gastroenterol Hepatol. 2017 Mar;14(3):185-194. doi: 10.1038/nrgastro.2016.179. Epub 2016 Nov 23.

Oommen E, Hummel A, Allmannsberger L, Cuthbertson D, Carette S, Pagnoux C, Hoffman GS, Jenne DE, Khalidi NA, Koening CL, Langford CA, McAlear CA, Moreland L, Seo P, Sreih A, Ytterberg SR, Merkel PA, Specks U, Monach PA; Vasculitis Clinical Research Consortium. IgA antibodies to myeloperoxidase in patients with eosinophilic granulomatosis with polyangiitis (Churg-Strauss). Clin Exp Rheumatol. 2017 Mar-Apr;35 Suppl 103(1):98-101. Epub 2017 Mar 1.

Krischer J, Cronholm PF, Burroughs C, McAlear CA, Borchin R, Easley E, Davis T, Kullman J, Carette S, Khalidi N, Koening C, Langford CA, Monach P, Moreland L, Pagnoux C, Specks U, Sreih AG, Ytterberg S, Merkel PA; Vasculitis Clinical Research Consortium. Experience With Direct-to-Patient Recruitment for Enrollment Into a Clinical Trial in a Rare Disease: A Web-Based Study. J Med Internet Res. 2017 Feb 28;19(2):e50. doi: 10.2196/jmir.6798.

Selewski DT, Thompson A, Kovacs S, Papadopoulos EJ, Carlozzi NE, Trachtman H, Troost JP, Merkel PA, Gipson DS. Patient-Reported Outcomes in Glomerular Disease. Clin J Am Soc Nephrol. 2017 Jan 6;12(1):140-148. doi: 10.2215/CJN.13231215. Epub 2016 Jun 3.

Carmona FD, Vaglio A, Mackie SL, Hernández-Rodríguez J, Monach PA, Castañeda S, Solans R, Morado IC, Narváez J, Ramentol-Sintas M, Pease CT, Dasgupta B, Watts R, Khalidi N, Langford CA, Ytterberg S, Boiardi L, Beretta L, Govoni M, Emmi G, Bonatti F, Cimmino MA, Witte T, Neumann T, Holle J, Schönau V, Sailler L, Papo T, Haroche J, Mahr A, Mouthon L, Molberg Ø, Diamantopoulos AP, Voskuyl A, Brouwer E, Daikeler T, Berger CT, Molloy ES, O'Neill L, Blockmans D, Lie BA, Mclaren P, Vyse TJ, Wijmenga C, Allanore Y, Koeleman BPC; Spanish CGA Group; UKGCA Consortium; Vasculitis Clinical Research Consortium, Barrett JH, Cid MC, Salvarani C, Merkel PA, Morgan AW, González-Gay MA, Martín J. A Genome-wide Association Study Identifies Risk Alleles in Plasminogen and P4HA2 Associated with Giant Cell Arteritis. Am J Hum Genet. 2017 Jan 5;100(1):64-74. doi: 10.1016/j.ajhg.2016.11.013. Epub 2016 Dec 29.

Sreih AG, Annapureddy N, Springer J, Casey G, Byram K, Cruz A, Estephan M, Frangiosa V, George MD, Liu M, Parker A, Sangani S, Sharim R, Merkel PA; Vasculitis Patient-Powered Research Network. Development and validation of case-finding algorithms for the identification of patients with anti-neutrophil cytoplasmic antibody-associated vasculitis in large healthcare administrative databases. Pharmacoepidemiol Drug Saf. 2016 Dec;25(12):1368-1374. doi: 10.1002/pds.4116. Epub 2016 Nov 1.

Bingham CO 3rd, Bartlett SJ, Merkel PA, Mielenz TJ, Pilkonis PA, Edmundson L, Moore E, Sabharwal RK. Using patient-reported outcomes and PROMIS in research and clinical applications: experiences from the PCORI pilot projects. Qual Life Res. 2016 Aug;25(8):2109-16. doi: 10.1007/s11136-016-1246-1. Epub 2016 Feb 25.

Saleh M, Turesson C, Englund M, Merkel PA, Mohammad AJ. Visual Complications in Patients with Biopsy-proven Giant Cell Arteritis: A Population-based Study. J Rheumatol. 2016 Aug;43(8):1559-65. doi: 10.3899/jrheum.151033. Epub 2016 Jun 1.

Kermani TA, Cuthbertson D, Carette S, Hoffman GS, Khalidi NA, Koening CL, Langford CA, McKinnon-Maksimowicz K, McAlear CA, Monach PA, Seo P, Warrington KJ, Ytterberg SR, Merkel PA, Matteson EL; Vasculitis Clinical Research Consortium. The Birmingham Vasculitis Activity Score as a Measure of Disease Activity in Patients with Giant Cell Arteritis. J Rheumatol. 2016 Jun;43(6):1078-84. doi: 10.3899/jrheum.151063. Epub 2016 Apr 1.

Merkel PA, Manion M, Gopal-Srivastava R, Groft S, Jinnah HA, Robertson D, Krischer JP; Rare Diseases Clinical Research Network. The partnership of patient advocacy groups and clinical investigators in the rare diseases clinical research network. Orphanet J Rare Dis. 2016 May 18;11(1):66. doi: 10.1186/s13023-016-0445-8.

Sy A, Khalidi N, Dehghan N, Barra L, Carette S, Cuthbertson D, Hoffman GS, Koening CL, Langford CA, McAlear C, Moreland L, Monach PA, Seo P, Specks U, Sreih A, Ytterberg SR, Van Assche G, Merkel PA, Pagnoux C; Vasculitis Clinical Research Consortium (VCRC); Canadian Vasculitis Network (CanVasc). Vasculitis in patients with inflammatory bowel diseases: A study of 32 patients and systematic review of the literature. Semin Arthritis Rheum. 2016 Feb;45(4):475-82. doi: 10.1016/j.semarthrit.2015.07.006. Epub 2015 Jul 26.

Tamura RN, Krischer JP, Pagnoux C, Micheletti R, Grayson PC, Chen YF, Merkel PA. A small n sequential multiple assignment randomized trial design for use in rare disease research. Contemp Clin Trials. 2016 Jan;46:48-51. doi: 10.1016/j.cct.2015.11.010. Epub 2015 Nov 14.

Hatemi G, Ozguler Y, Direskeneli H, Mahr A, Gul A, Levi V, Aydin SZ, Mumcu G, Sertel-Berk O, Stevens RM, Yazici H, Merkel PA. Current Status, Goals, and Research Agenda for Outcome Measures Development in Behçet Syndrome: Report from OMERACT 2014. J Rheumatol. 2015 Dec;42(12):2436-41. doi: 10.3899/jrheum.141147. Epub 2015 Sep 15.

Aydin SZ, Direskeneli H, Sreih A, Alibaz-Oner F, Gul A, Kamali S, Hatemi G, Kermani T, Mackie SL, Mahr A, Meara A, Milman N, Nugent H, Robson J, Tomasson G, Merkel PA. Update on Outcome Measure Development for Large Vessel Vasculitis: Report from OMERACT 12. J Rheumatol. 2015 Dec;42(12):2465-9. doi: 10.3899/jrheum.141144. Epub 2015 Jun 15.

Robson JC, Milman N, Tomasson G, Dawson J, Cronholm PF, Kellom K, Shea J, Ashdown S, Boers M, Boonen A, Casey GC, Farrar JT, Gebhart D, Krischer J, Lanier G, McAlear CA, Peck J, Sreih AG, Tugwell PS, Luqmani RA, Merkel PA. Exploration, Development, and Validation of Patient-reported Outcomes in Antineutrophil Cytoplasmic Antibody-associated Vasculitis Using the OMERACT Process. J Rheumatol. 2015 Nov;42(11):2204-9. doi: 10.3899/jrheum.141143. Epub 2015 Sep 1.

Grayson PC, Monach PA, Pagnoux C, Cuthbertson D, Carette S, Hoffman GS, Khalidi NA, Koening CL, Langford CA, Maksimowicz-McKinnon K, Seo P, Specks U, Ytterberg SR, Merkel PA; Vasculitis Clinical Research Consortium. Value of commonly measured laboratory tests as biomarkers of disease activity and predictors of relapse in eosinophilic granulomatosis with polyangiitis. Rheumatology (Oxford). 2015 Aug;54(8):1351-9. doi: 10.1093/rheumatology/keu427. Epub 2014 Nov 17.

Kermani TA, Warrington KJ, Cuthbertson D, Carette S, Hoffman GS, Khalidi NA, Koening CL, Langford CA, Maksimowicz-McKinnon K, McAlear CA, Monach PA, Seo P, Merkel PA, Ytterberg SR; Vasculitis Clinical Research Consortium. Disease Relapses among Patients with Giant Cell Arteritis: A Prospective, Longitudinal Cohort Study. J Rheumatol. 2015 Jul;42(7):1213-7. doi: 10.3899/jrheum.141347. Epub 2015 Apr 15.

Grayson PC, Carmona-Rivera C, Xu L, Lim N, Gao Z, Asare AL, Specks U, Stone JH, Seo P, Spiera RF, Langford CA, Hoffman GS, Kallenberg CG, St Clair EW, Tchao NK, Ytterberg SR, Phippard DJ, Merkel PA, Kaplan MJ, Monach PA; Rituximab in ANCA-Associated Vasculitis-Immune Tolerance Network Research Group. Neutrophil-Related Gene Expression and Low-Density Granulocytes Associated With Disease Activity and Response to Treatment in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. Arthritis Rheumatol. 2015 Jul;67(7):1922-32. doi: 10.1002/art.39153.

McGeoch L, Carette S, Cuthbertson D, Hoffman GS, Khalidi N, Koening CL, Langford CA, McAlear CA, Moreland L, Monach PA, Seo P, Specks U, Ytterberg SR, Merkel PA, Pagnoux C; Vasculitis Clinical Research Consortium. Cardiac Involvement in Granulomatosis with Polyangiitis. J Rheumatol. 2015 Jul;42(7):1209-12. doi: 10.3899/jrheum.141513. Epub 2015 May 1.

Grayson PC, Steiling K, Platt M, Berman JS, Zhang X, Xiao J, Alekseyev YO, Liu G, Monach PA, Kaplan MJ, Spira A, Merkel PA. Defining the nasal transcriptome in granulomatosis with polyangiitis (Wegener's). Arthritis Rheumatol. 2015 May;67(8):2233-9. doi: 10.1002/art.39185.

Renauer PA, Saruhan-Direskeneli G, Coit P, Adler A, Aksu K, Keser G, Alibaz-Oner F, Aydin SZ, Kamali S, Inanc M, Carette S, Cuthbertson D, Hoffman GS, Akar S, Onen F, Akkoc N, Khalidi NA, Koening C, Karadag O, Kiraz S, Langford CA, Maksimowicz-McKinnon K, McAlear CA, Ozbalkan Z, Ates A, Karaaslan Y, Duzgun N, Monach PA, Ozer HT, Erken E, Ozturk MA, Yazici A, Cefle A, Onat AM, Kisacik B, Pagnoux C, Kasifoglu T, Seyahi E, Fresko I, Seo P, Sreih AG, Warrington KJ, Ytterberg SR, Cobankara V, Cunninghame-Graham DS, Vyse TJ, Pamuk ON, Tunc SE, Dalkilic E, Bicakcigil M, Yentur SP, Wren JD, Merkel PA, Direskeneli H, Sawalha AH. Identification of Susceptibility Loci in IL6, RPS9/LILRB3, and an Intergenic Locus on Chromosome 21q22 in Takayasu Arteritis in a Genome-Wide Association Study. Arthritis Rheumatol. 2015 May;67(5):1361-8. doi: 10.1002/art.39035.

Carmona FD, Mackie SL, Martín JE, Taylor JC, Vaglio A, Eyre S, Bossini-Castillo L, Castañeda S, Cid MC, Hernández-Rodríguez J, Prieto-González S, Solans R, Ramentol-Sintas M, González-Escribano MF, Ortiz-Fernández L, Morado IC, Narváez J, Miranda-Filloy JA; Spanish GCA Group, Beretta L, Lunardi C, Cimmino MA, Gianfreda D, Santilli D, Ramirez GA, Soriano A, Muratore F, Pazzola G, Addimanda O, Wijmenga C, Witte T, Schirmer JH, Moosig F, Schönau V, Franke A, Palm Ø, Molberg Ø, Diamantopoulos AP, Carette S, Cuthbertson D, Forbess LJ, Hoffman GS, Khalidi NA, Koening CL, Langford CA, McAlear CA, Moreland L, Monach PA, Pagnoux C, Seo P, Spiera R, Sreih AG, Warrington KJ, Ytterberg SR, Gregersen PK, Pease CT, Gough A, Green M, Hordon L, Jarrett S, Watts R, Levy S, Patel Y, Kamath S, Dasgupta B, Worthington J, Koeleman BP, de Bakker PI, Barrett JH, Salvarani C, Merkel PA, González-Gay MA, Morgan AW, Martín J. A large-scale genetic analysis reveals a strong contribution of the HLA class II region to giant cell arteritis susceptibility. Am J Hum Genet. 2015 Apr 2;96(4):565-80. doi: 10.1016/j.ajhg.2015.02.009. Epub 2015 Mar 26.

Dejaco C, Oppl B, Monach P, Cuthbertson D, Carette S, Hoffman G, Khalidi N, Koening C, Langford C, McKinnon-Maksimowicz K, Seo P, Specks U, Ytterberg S, Merkel PA, Zwerina J. Serum biomarkers in patients with relapsing eosinophilic granulomatosis with polyangiitis (Churg-Strauss). PLoS One. 2015 Mar 26;10(3):e0121737. doi: 10.1371/journal.pone.0121737. eCollection 2015.

Pagnoux C, Carette S, Khalidi NA, Walsh M, Hiemstra TF, Cuthbertson D, Langford C, Hoffman G, Koening CL, Monach PA, Moreland L, Mouthon L, Seo P, Specks U, Ytterberg S, Westman K, Hoglund P, Harper L, Flossman O, Luqmani R, Savage CO, Rasmussen N, de Groot K, Tesar V, Jayne D, Merkel PA, Guillevin L; french Vasculitis Study Group (FVSG), European Vasculitis Society (EUVAS) and Vasculitis Clinical Research Consortium (VCRC). Comparability of patients with ANCA-associated vasculitis enrolled in clinical trials or in observational cohorts. Clin Exp Rheumatol. 2015 Mar-Apr;33(2 Suppl 89):S-77-83. Epub 2015 May 26.

Aydin SZ, Merkel PA, Direskeneli H. Outcome measures for Takayasu's arteritis. Curr Opin Rheumatol. 2015 Jan;27(1):32-7. doi: 10.1097/BOR.0000000000000129.

Mooney J, Spalding N, Poland F, Grayson P, Leduc R, McAlear CA, Richesson RL, Shereff D, Merkel PA, Watts RA. The informational needs of patients with ANCA-associated vasculitis-development of an informational needs questionnaire. Rheumatology (Oxford). 2014 Aug;53(8):1414-21. doi: 10.1093/rheumatology/keu026. Epub 2014 Mar 12.

Langford CA, Monach PA, Specks U, Seo P, Cuthbertson D, McAlear CA, Ytterberg SR, Hoffman GS, Krischer JP, Merkel PA; Vasculitis Clinical Research Consortium. An open-label trial of abatacept (CTLA4-IG) in non-severe relapsing granulomatosis with polyangiitis (Wegener's). Ann Rheum Dis. 2014 Jul;73(7):1376-9. doi: 10.1136/annrheumdis-2013-204164. Epub 2013 Dec 9.

Grayson PC, Amudala NA, McAlear CA, Leduc RL, Shereff D, Richesson R, Fraenkel L, Merkel PA. Causal attributions about disease onset and relapse in patients with systemic vasculitis. J Rheumatol. 2014 May;41(5):923-30. doi: 10.3899/jrheum.131096. Epub 2014 Mar 15.

Merkel PA, Aydin SZ, Boers M, Cornell C, Direskeneli H, Gebhart D, Hatemi G, Luqmani R, Matteson EL, Milman N, Robson J, Seo P, Tomasson G. Current status of outcome measure development in vasculitis. J Rheumatol. 2014 Mar;41(3):593-8. doi: 10.3899/jrheum.131248. Epub 2014 Jan 15.

Hatemi G, Merkel PA, Hamuryudan V, Boers M, Direskeneli H, Aydin SZ, Yazici H. Outcome measures used in clinical trials for Behçet syndrome: a systematic review. J Rheumatol. 2014 Mar;41(3):599-612. doi: 10.3899/jrheum.131249. Epub 2014 Feb 1.

Monach PA. Biomarkers in vasculitis. Curr Opin Rheumatol. 2014 Jan;26(1):24-30. doi: 10.1097/BOR.0000000000000009.

Kermani TA, Warrington KJ, Crowson CS, Ytterberg SR, Hunder GG, Gabriel SE, Matteson EL. Large-vessel involvement in giant cell arteritis: a population-based cohort study of the incidence-trends and prognosis. Ann Rheum Dis. 2013 Dec;72(12):1989-94. doi: 10.1136/annrheumdis-2012-202408. Epub 2012 Dec 19.

Grayson PC, Amudala NA, Mcalear CA, Leduc RL, Shereff D, Richesson R, Fraenkel L, Merkel PA. Illness perceptions and fatigue in systemic vasculitis. Arthritis Care Res (Hoboken). 2013 Nov;65(11):1835-43. doi: 10.1002/acr.22069.

Grayson PC, Cuthbertson D, Carette S, Hoffman GS, Khalidi NA, Koening CL, Langford CA, Maksimowicz-McKinnon K, Monach PA, Seo P, Specks U, Ytterberg SR, Merkel PA; Vasculitis Clinical Research Consortium. New features of disease after diagnosis in 6 forms of systemic vasculitis. J Rheumatol. 2013 Nov;40(11):1905-12. doi: 10.3899/jrheum.121473. Epub 2013 Aug 1.

Hinkofer LC, Seidel SA, Korkmaz B, Silva F, Hummel AM, Braun D, Jenne DE, Specks U. A monoclonal antibody (MCPR3-7) interfering with the activity of proteinase 3 by an allosteric mechanism. J Biol Chem. 2013 Sep 13;288(37):26635-48. doi: 10.1074/jbc.M113.495770. Epub 2013 Jul 31.

Xie G, Roshandel D, Sherva R, Monach PA, Lu EY, Kung T, Carrington K, Zhang SS, Pulit SL, Ripke S, Carette S, Dellaripa PF, Edberg JC, Hoffman GS, Khalidi N, Langford CA, Mahr AD, St Clair EW, Seo P, Specks U, Spiera RF, Stone JH, Ytterberg SR, Raychaudhuri S, de Bakker PI, Farrer LA, Amos CI, Merkel PA, Siminovitch KA. Association of granulomatosis with polyangiitis (Wegener's) with HLA-DPB1*04 and SEMA6A gene variants: evidence from genome-wide analysis. Arthritis Rheum. 2013 Sep;65(9):2457-68. doi: 10.1002/art.38036.

Saruhan-Direskeneli G, Hughes T, Aksu K, Keser G, Coit P, Aydin SZ, Alibaz-Oner F, Kamalı S, Inanc M, Carette S, Hoffman GS, Akar S, Onen F, Akkoc N, Khalidi NA, Koening C, Karadag O, Kiraz S, Langford CA, McAlear CA, Ozbalkan Z, Ates A, Karaaslan Y, Maksimowicz-McKinnon K, Monach PA, Ozer HT, Seyahi E, Fresko I, Cefle A, Seo P, Warrington KJ, Ozturk MA, Ytterberg SR, Cobankara V, Onat AM, Guthridge JM, James JA, Tunc E, Duzgun N, Bıcakcıgil M, Yentür SP, Merkel PA, Direskeneli H, Sawalha AH. Identification of multiple genetic susceptibility loci in Takayasu arteritis. Am J Hum Genet. 2013 Aug 8;93(2):298-305. doi: 10.1016/j.ajhg.2013.05.026. Epub 2013 Jul 3.

Schmidt J, Kermani TA, Bacani AK, Crowson CS, Cooper LT, Matteson EL, Warrington KJ. Diagnostic features, treatment, and outcomes of Takayasu arteritis in a US cohort of 126 patients. Mayo Clin Proc. 2013 Aug;88(8):822-30. doi: 10.1016/j.mayocp.2013.04.025. Epub 2013 Jul 10.

de Boysson H, Boutemy J, Creveuil C, Ollivier Y, Letellier P, Pagnoux C, Bienvenu B. Is there a place for cyclophosphamide in the treatment of giant-cell arteritis? A case series and systematic review. Semin Arthritis Rheum. 2013 Aug;43(1):105-12. doi: 10.1016/j.semarthrit.2012.12.023. Epub 2013 Feb 27.

Clowse ME, Richeson RL, Pieper C, Merkel PA; Vasculitis Clinical Research Consortium. Pregnancy outcomes among patients with vasculitis. Arthritis Care Res (Hoboken). 2013 Aug;65(8):1370-4. doi: 10.1002/acr.21983.

Monach PA, Warner RL, Tomasson G, Specks U, Stone JH, Ding L, Fervenza FC, Fessler BJ, Hoffman GS, Iklé D, Kallenberg CG, Krischer J, Langford CA, Mueller M, Seo P, St Clair EW, Spiera R, Tchao N, Ytterberg SR, Johnson KJ, Merkel PA. Serum proteins reflecting inflammation, injury and repair as biomarkers of disease activity in ANCA-associated vasculitis. Ann Rheum Dis. 2013 Aug;72(8):1342-50. doi: 10.1136/annrheumdis-2012-201981. Epub 2012 Sep 12.

Samson M, Puéchal X, Devilliers H, Ribi C, Cohen P, Stern M, Pagnoux C, Mouthon L, Guillevin L; French Vasculitis Study Group. Long-term outcomes of 118 patients with eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) enrolled in two prospective trials. J Autoimmun. 2013 Jun;43:60-9. doi: 10.1016/j.jaut.2013.03.003. Epub 2013 Apr 13.

Mahr A, Katsahian S, Varet H, Guillevin L, Hagen EC, Höglund P, Merkel PA, Pagnoux C, Rasmussen N, Westman K, Jayne DR; French Vasculitis Study Group (FVSG) and the European Vasculitis Society (EUVAS). Revisiting the classification of clinical phenotypes of anti-neutrophil cytoplasmic antibody-associated vasculitis: a cluster analysis. Ann Rheum Dis. 2013 Jun;72(6):1003-10. doi: 10.1136/annrheumdis-2012-201750. Epub 2012 Sep 8.

Kermani TA, Warrington KJ. Comment on: How common is inflammatory marker-negative disease in giant cell arteritis?. Eye (Lond). 2013 May;27(5):677-8. doi: 10.1038/eye.2013.19. Epub 2013 Mar 8.

McGeoch L, Silecky WB, Maher J, Carette S, Pagnoux C. Temporal arteritis in the young. Joint Bone Spine. 2013 May;80(3):324-7. doi: 10.1016/j.jbspin.2012.09.012. Epub 2012 Nov 9.

Lieberthal JG, Cuthbertson D, Carette S, Hoffman GS, Khalidi NA, Koening CL, Langford CA, Maksimowicz-McKinnon K, Seo P, Specks U, Ytterberg SR, Merkel PA, Monach PA; Vasculitis Clinical Research Consortium. urinary biomarkers in relapsing antineutrophil cytoplasmic antibody-associated vasculitis. J Rheumatol. 2013 May;40(5):674-83. doi: 10.3899/jrheum.120879. Epub 2013 Apr 1.

Marmursztejn J, Guillevin L, Trebossen R, Cohen P, Guilpain P, Pagnoux C, Mouthon L, Legmann P, Vignaux O, Duboc D. Churg-Strauss syndrome cardiac involvement evaluated by cardiac magnetic resonance imaging and positron-emission tomography: a prospective study on 20 patients. Rheumatology (Oxford). 2013 Apr;52(4):642-50. doi: 10.1093/rheumatology/kes155. Epub 2012 Jul 5.

Monach PA. IgG4-related Disease: 2013 Update. Curr Treat Options Cardiovasc Med. 2013 Apr;15(2):214-23. doi: 10.1007/s11936-013-0232-y.

Pagnoux C, de Boysson H. L38. How to treat primary vasculitis of the central nervous system. Presse Med. 2013 Apr;42(4 Pt 2):605-7. doi: 10.1016/j.lpm.2013.01.038. Epub 2013 Mar 1.

Rothschild PR, Pagnoux C, Seror R, Brézin AP, Delair E, Guillevin L. Ophthalmologic manifestations of systemic necrotizing vasculitides at diagnosis: a retrospective study of 1286 patients and review of the literature. Semin Arthritis Rheum. 2013 Apr;42(5):507-14. doi: 10.1016/j.semarthrit.2012.08.003. Epub 2012 Dec 24.

Walsh M, Merkel PA, Peh CA, Szpirt W, Guillevin L, Pusey CD, De Zoysa J, Ives N, Clark WF, Quillen K, Winters JL, Wheatley K, Jayne D; PEXIVAS Investigators. Plasma exchange and glucocorticoid dosing in the treatment of anti-neutrophil cytoplasm antibody associated vasculitis (PEXIVAS): protocol for a randomized controlled trial. Trials. 2013 Mar 14;14:73. doi: 10.1186/1745-6215-14-73.

Terrier B, Carrat F, Krastinova E, Marie I, Launay D, Lacraz A, Belenotti P, de Saint Martin L, Quemeneur T, Huart A, Bonnet F, Le Guenno G, Kahn JE, Hinschberger O, Rullier P, Hummel A, Diot E, Pagnoux C, Lzaro E, Bridoux F, Zenone T, Hermine O, Leger JM, Mariette X, Senet P, Plaisier E, Cacoub P. Prognostic factors of survival in patients with non-infectious mixed cryoglobulinaemia vasculitis: data from 242 cases included in the CryoVas survey. Ann Rheum Dis. 2013 Mar;72(3):374-80. doi: 10.1136/annrheumdis-2012-201405. Epub 2012 May 14.

Pagnoux C, Mahendira D, Laskin CA. Fertility and pregnancy in vasculitis. Best Pract Res Clin Rheumatol. 2013 Feb;27(1):79-94. doi: 10.1016/j.berh.2013.02.002.

Tomasson G. Quality of life and outcome measures in vasculitis. Best Pract Res Clin Rheumatol. 2013 Feb;27(1):69-77. doi: 10.1016/j.berh.2013.01.003.

Pagnoux C, Saadoun D. Virus-Associated Vasculitides: An Update. An Update. Current Immunology Reviews. 2013 Feb. Volume 9, Number 1, February 2013, pp. 2-12(11).

Kermani TA, Warrington KJ. Polymyalgia rheumatica. Lancet. 2013 Jan 5;381(9860):63-72. doi: 10.1016/S0140-6736(12)60680-1. Epub 2012 Oct 8.

Comarmond C, Pagnoux C, Khellaf M, Cordier JF, Hamidou M, Viallard JF, Maurier F, Jouneau S, Bienvenu B, Puéchal X, Aumaître O, Le Guenno G, Le Quellec A, Cevallos R, Fain O, Godeau B, Seror R, Dunogué B, Mahr A, Guilpain P, Cohen P, Aouba A, Mouthon L, Guillevin L; French Vasculitis Study Group. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): clinical characteristics and long-term followup of the 383 patients enrolled in the French Vasculitis Study Group cohort. Arthritis Rheum. 2013 Jan;65(1):270-81. doi: 10.1002/art.37721.

Pugnet G, Pagnoux C, Bézanahary H, Ly KH, Vidal E, Guillevin L. Progressive multifocal encephalopathy after cyclophosphamide in granulomatosis with polyangiitis (Wegener) patients: case report and review of literature. Clin Exp Rheumatol. 2013 Jan-Feb;31(1 Suppl 75):S62-4. Epub 2013 Apr 22.

Néel A, Masseau A, Hervier B, Bossard C, Cacoub P, Pagnoux C, Hamidou MA. Life-threatening hepatitis C virus-associated polyarteritis nodosa successfully treated by rituximab. J Clin Rheumatol. 2011 Dec;17(8):439-41. doi: 10.1097/RHU.0b013e31823a58d7.

Cartin-Ceba R, Peikert T, Specks U. Pathogenesis of ANCA-associated vasculitis. Curr Rheumatol Rep. 2012 Dec;14(6):481-93. doi: 10.1007/s11926-012-0286-y.

Chung SA, Xie G, Roshandel D, Sherva R, Edberg JC, Kravitz M, Dellaripa PF, Hoffman GS, Mahr AD, Seo P, Specks U, Spiera RF, St Clair EW, Stone JH, Plenge RM, Siminovitch KA, Merkel PA, Monach PA. Meta-analysis of genetic polymorphisms in granulomatosis with polyangiitis (Wegener's) reveals shared susceptibility loci with rheumatoid arthritis. Arthritis Rheum. 2012 Oct;64(10):3463-71. doi: 10.1002/art.34496.

Kermani TA, Ham EK, Camilleri MJ, Warrington KJ. Polyarteritis nodosa-like vasculitis in association with minocycline use: a single-center case series. Semin Arthritis Rheum. 2012 Oct;42(2):213-21. doi: 10.1016/j.semarthrit.2012.03.006. Epub 2012 Jun 15.

Grayson PC, Maksimowicz-McKinnon K, Clark TM, Tomasson G, Cuthbertson D, Carette S, Khalidi NA, Langford CA, Monach PA, Seo P, Warrington KJ, Ytterberg SR, Hoffman GS, Merkel PA; Vasculitis Clinical Research Consortium. Distribution of arterial lesions in Takayasu's arteritis and giant cell arteritis. Ann Rheum Dis. 2012 Aug;71(8):1329-34. doi: 10.1136/annrheumdis-2011-200795. Epub 2012 Feb 10.

Richesson RL, Sutphen R, Shereff D, Krischer JP. The Rare Diseases Clinical Research Network Contact Registry update: features and functionality. Contemp Clin Trials. 2012 Jul;33(4):647-56. doi: 10.1016/j.cct.2012.02.012. Epub 2012 Mar 2.

Dunogué B, Pagnoux C, Guillevin L. Churg-strauss syndrome: clinical symptoms, complementary investigations, prognosis and outcome, and treatment. Semin Respir Crit Care Med. 2011 Jun;32(3):298-309. doi: 10.1055/s-0031-1279826. Epub 2011 Jun 14.

Kermani TA, Schmidt J, Crowson CS, Ytterberg SR, Hunder GG, Matteson EL, Warrington KJ. Utility of erythrocyte sedimentation rate and C-reactive protein for the diagnosis of giant cell arteritis. Semin Arthritis Rheum. 2012 Jun;41(6):866-71. doi: 10.1016/j.semarthrit.2011.10.005. Epub 2011 Nov 25.

Néel A, Pagnoux C, Guillevin L, Hamidou M. [Central nervous system vasculitides: an update]. Rev Med Interne. 2012 Jul;33(7):381-9. doi: 10.1016/j.revmed.2011.11.020. Epub 2012 Jun 7.

Néel A, Auffray-Calvier E, Guillon B, Fontenoy AM, Loussouarn D, Pagnoux C, Hamidou MA. Challenging the diagnosis of primary angiitis of the central nervous system: a single-center retrospective study. J Rheumatol. 2012 May;39(5):1026-34. doi: 10.3899/jrheum.110707. Epub 2012 Apr 1.

Zhu W, Hou J, Chen YP. Exploiting multi-layered information to iteratively predict protein functions. Math Biosci. 2012 Apr;236(2):108-16. doi: 10.1016/j.mbs.2012.02.004. Epub 2012 Mar 3.

Kermani TA, Warrington KJ. Recent advances in diagnostic strategies for giant cell arteritis. Curr Neurol Neurosci Rep. 2012 Apr;12(2):138-44. doi: 10.1007/s11910-011-0243-6.

Pagnoux C, Wolter NE. Vasculitis of the upper airways. Swiss Med Wkly. 2012 Mar 19;142:w13541. doi: 10.4414/smw.2012.13541. eCollection 2012.

Shahane A, Khasnis A, Hajj Ali R. Three unusual mimics of primary angiitis of the central nervous system. Rheumatol Int. 2012 Mar;32(3):737-42. doi: 10.1007/s00296-010-1679-8. Epub 2010 Dec 16.

Dufour JF, Le Gallou T, Cordier JF, Aumaître O, Pinède L, Aslangul E, Pagnoux C, Marie I, Puéchal X, Decaux O, Dubois A, Agard C, Mahr A, Comoz F, Boutemy J, Broussolle C, Guillevin L, Sève P, Bienvenu B; French Center-East Internists Group and the French Vasculitis Study Group. Urogenital manifestations in Wegener granulomatosis: a study of 11 cases and review of the literature. Medicine (Baltimore). 2012 Mar;91(2):67-74. doi: 10.1097/MD.0b013e318239add6.

Chemouny JM, Pagnoux C, Caudwell V, Karras A, Borie R, Guillevin L, Vrtovsnik F, Daugas E. ANCA-associated diseases and lung carcinomas: a five-case series. Clin Nephrol. 2014 Feb;81(2):132-7. doi: 10.5414/CN107407.

Tomasson G, Boers M, Walsh M, LaValley M, Cuthbertson D, Carette S, Davis JC, Hoffman GS, Khalidi NA, Langford CA, McAlear CA, McCune WJ, Monach PA, Seo P, Specks U, Spiera R, St Clair EW, Stone JH, Ytterberg SR, Merkel PA. Assessment of health-related quality of life as an outcome measure in granulomatosis with polyangiitis (Wegener's). Arthritis Care Res (Hoboken). 2012 Feb;64(2):273-9. doi: 10.1002/acr.20649.

Grayson PC, Tomasson G, Cuthbertson D, Carette S, Hoffman GS, Khalidi NA, Langford CA, McAlear CA, Monach PA, Seo P, Warrington KJ, Ytterberg SR, Merkel PA; Vasculitis Clinical Research Consortium. Association of vascular physical examination findings and arteriographic lesions in large vessel vasculitis. J Rheumatol. 2012 Feb;39(2):303-9. doi: 10.3899/jrheum.110652. Epub 2011 Dec 15.

Kostianovsky A, Hauser T, Pagnoux C, Cohen P, Daugas E, Mouthon L, Miossec P, Cordier JF, Guillevin L; French Vasculitis Study Group (FVSG). Alveolar haemorrhage in ANCA-associated vasculitides: 80 patients' features and prognostic factors. Clin Exp Rheumatol. 2012 Jan-Feb;30(1 Suppl 70):S77-82. Epub 2012 May 11.

Kostianovsky A, Charles P, Alves JF, Goulet M, Pagnoux C, Le Guern V, Mouthon L, Krivine A, Villiger P, Launay O, Guillevin L; French Vasculitis Study Group. Immunogenicity and safety of seasonal and 2009 pandemic A/H1N1 influenza vaccines for patients with autoimmune diseases: a prospective, monocentre trial on 199 patients. Clin Exp Rheumatol. 2012 Jan-Feb;30(1 Suppl 70):S83-9. Epub 2012 May 11.

Roubaud-Baudron C, Pagnoux C, Méaux-Ruault N, Grasland A, Zoulim A, LE Guen J, Prud'homme A, Bienvenu B, de Menthon M, Camps S, LE Guern V, Aouba A, Cohen P, Mouthon L, Guillevin L; French Vasculitis Study Group. Rituximab maintenance therapy for granulomatosis with polyangiitis and microscopic polyangiitis. J Rheumatol. 2012 Jan;39(1):125-30. doi: 10.3899/jrheum.110143. Epub 2011 Nov 15.

Tomasson G, Grayson PC, Mahr AD, Lavalley M, Merkel PA. Value of ANCA measurements during remission to predict a relapse of ANCA-associated vasculitis--a meta-analysis. Rheumatology (Oxford). 2012 Jan;51(1):100-9. doi: 10.1093/rheumatology/ker280. Epub 2011 Oct 29.

Pujol R, Jaraquemada D, Rodríguez-Pla A. Capítulo 5: Tolerancia y Enfermedades Autoinmunitarias (Chapter 5:Tolerance and Autoimmune Disorders). Tratado de Medicina Interna Farreras-Rozman (Internal Medicine Textbook Farreras-Rozman). XVII Edition. 2012; Rozman C, ed. Editorial Elsevier, Spain.

Monach PA, Kümpers P, Lukasz A, Tomasson G, Specks U, Stone JH, Cuthbertson D, Krischer J, Carette S, Ding L, Hoffman GS, Iklé D, Kallenberg CG, Khalidi NA, Langford CA, Seo P, St Clair EW, Spiera R, Tchao N, Ytterberg SR, Haubitz M, Merkel PA. Circulating angiopoietin-2 as a biomarker in ANCA-associated vasculitis. PLoS One. 2012;7(1):e30197. doi: 10.1371/journal.pone.0030197. Epub 2012 Jan 18.

Kelley JM, Monach PA, Ji C, Zhou Y, Wu J, Tanaka S, Mahr AD, Johnson S, McAlear C, Cuthbertson D, Carette S, Davis JC Jr, Dellaripa PF, Hoffman GS, Khalidi N, Langford CA, Seo P, St Clair EW, Specks U, Stone JH, Spiera RF, Ytterberg SR, Merkel PA, Edberg JC, Kimberly RP. IgA and IgG antineutrophil cytoplasmic antibody engagement of Fc receptor genetic variants influences granulomatosis with polyangiitis. Proc Natl Acad Sci U S A. 2011 Dec 20;108(51):20736-41. doi: 10.1073/pnas.1109227109. Epub 2011 Dec 6.

Grayson PC, Sloan JM, Niles JL, Monach PA, Merkel PA. Antineutrophil cytoplasmic antibodies, autoimmune neutropenia, and vasculitis. Semin Arthritis Rheum. 2011 Dec;41(3):424-33. doi: 10.1016/j.semarthrit.2011.02.003. Epub 2011 Apr 19.

Monach PA, Tomasson G, Specks U, Stone JH, Cuthbertson D, Krischer J, Ding L, Fervenza FC, Fessler BJ, Hoffman GS, Ikle D, Kallenberg CG, Langford CA, Mueller M, Seo P, St Clair EW, Spiera R, Tchao N, Ytterberg SR, Gu YZ, Snyder RD, Merkel PA. Circulating markers of vascular injury and angiogenesis in antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2011 Dec;63(12):3988-97. doi: 10.1002/art.30615.

Pagnoux C, Bérezné A, Damade R, Paillot J, Aouizerate J, Le Guern V, Salmon D, Guillevin L. Encrusting cystitis due to Corynebacterium urealyticum in a patient with ANCA-associated vasculitis: case report and review of the literature. Semin Arthritis Rheum. 2011 Oct;41(2):297-300. doi: 10.1016/j.semarthrit.2010.11.004. Epub 2011 Feb 1.

Silva F, Seo P, Schroeder DR, Stone JH, Merkel PA, Hoffman GS, Spiera R, Sebastian JK, Davis JC Jr, St Clair EW, Allen NB, McCune WJ, Ytterberg SR, Specks U; Wegener's Granulomatosis Etanercept Trial Research Group. Solid malignancies among etanercept-treated patients with granulomatosis with polyangiitis (Wegener's): long-term followup of a multicenter longitudinal cohort. Arthritis Rheum. 2011 Aug;63(8):2495-503. doi: 10.1002/art.30394.

Direskeneli H, Aydin SZ, Kermani TA, Matteson EL, Boers M, Herlyn K, Luqmani RA, Neogi T, Seo P, Suppiah R, Tomasson G, Merkel PA. Development of outcome measures for large-vessel vasculitis for use in clinical trials: opportunities, challenges, and research agenda. J Rheumatol. 2011 Jul;38(7):1471-9. doi: 10.3899/jrheum.110275.

Walsh M, Mukhtyar C, Mahr A, Herlyn K, Luqmani R, Merkel PA, Jayne DR. Health-related quality of life in patients with newly diagnosed antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Care Res (Hoboken). 2011 Jul;63(7):1055-61. doi: 10.1002/acr.20471.

Espy C, Morelle W, Kavian N, Grange P, Goulvestre C, Viallon V, Chéreau C, Pagnoux C, Michalski JC, Guillevin L, Weill B, Batteux F, Guilpain P. Sialylation levels of anti-proteinase 3 antibodies are associated with the activity of granulomatosis with polyangiitis (Wegener's). Arthritis Rheum. 2011 Jul;63(7):2105-15. doi: 10.1002/art.30362.

Merkel PA, Aydin SZ, Boers M, Direskeneli H, Herlyn K, Seo P, Suppiah R, Tomasson G, Luqmani RA. The OMERACT core set of outcome measures for use in clinical trials of ANCA-associated vasculitis. J Rheumatol. 2011 Jul;38(7):1480-6. doi: 10.3899/jrheum.110276.

Cao Y, Schmitz JL, Yang J, Hogan SL, Bunch D, Hu Y, Jennette CE, Berg EA, Arnett FC Jr, Jennette JC, Falk RJ, Preston GA. DRB1*15 allele is a risk factor for PR3-ANCA disease in African Americans. J Am Soc Nephrol. 2011 Jun;22(6):1161-7. doi: 10.1681/ASN.2010101058. Epub 2011 May 26.

Marchand-Janssen C, Loulergue P, Mouthon L, Mahr A, Blanche P, Deforges L, Lebon P, Cohen P, Pagnoux C, Le Guern V, Bienvenu B, Aouba A, Guillevin L, Launay O. Patients with systemic inflammatory and autoimmune diseases are at risk of vaccine-preventable illnesses. Rheumatology (Oxford). 2011 Jun;50(6):1099-105. doi: 10.1093/rheumatology/keq422. Epub 2011 Jan 21.

Tomasson G, Lavalley M, Tanriverdi K, Finkielman JD, Davis JC Jr, Hoffman GS, McCune WJ, St Clair EW, Specks U, Spiera R, Stone JH, Freedman JE, Merkel PA; Wegener's Granulomatosis Etanercept Trial (WGET) Research Group. Relationship between markers of platelet activation and inflammation with disease activity in Wegener's granulomatosis. J Rheumatol. 2011 Jun;38(6):1048-54. doi: 10.3899/jrheum.100735. Epub 2011 Mar 16.

Guilpain P, Chéreau C, Goulvestre C, Servettaz A, Montani D, Tamas N, Pagnoux C, Hachulla E, Weill B, Guillevin L, Mouthon L, Batteux F. The oxidation induced by antimyeloperoxidase antibodies triggers fibrosis in microscopic polyangiitis. Eur Respir J. 2011 Jun;37(6):1503-13. doi: 10.1183/09031936.00148409. Epub 2010 Nov 11.

Pagnoux C, Thorne C, Mandelcorn ED, Carette S. CNS involvement in acute posterior multifocal placoid pigment epitheliopathy. Can J Neurol Sci. 2011 May;38(3):526-8. doi: 10.1017/s0317167100012002.

Le Guenno G, Mahr A, Pagnoux C, Dhote R, Guillevin L; French Vasculitis Study Group. Incidence and predictors of urotoxic adverse events in cyclophosphamide-treated patients with systemic necrotizing vasculitides. Arthritis Rheum. 2011 May;63(5):1435-45. doi: 10.1002/art.30296.

Luqmani RA, Suppiah R, Grayson PC, Merkel PA, Watts R. Nomenclature and classification of vasculitis - update on the ACR/EULAR diagnosis and classification of vasculitis study (DCVAS). Clin Exp Immunol. 2011 May;164 Suppl 1(Suppl 1):11-3. doi: 10.1111/j.1365-2249.2011.04358.x.

Kermani TA, Ytterberg SR, Warrington KJ. Pneumocystis jiroveci pneumonia in giant cell arteritis: A case series. Arthritis Care Res (Hoboken). 2011 May;63(5):761-5. doi: 10.1002/acr.20435.

Pagnoux C, Le Guern V, Goffinet F, Diot E, Limal N, Pannier E, Warzocha U, Tsatsaris V, Dhote R, Karras A, Cohen P, Damade R, Mouthon L, Guillevin L. Pregnancies in systemic necrotizing vasculitides: report on 12 women and their 20 pregnancies. Rheumatology (Oxford). 2011 May;50(5):953-61. doi: 10.1093/rheumatology/keq421. Epub 2010 Dec 22.

Suppiah R, Judge A, Batra R, Flossmann O, Harper L, Höglund P, Javaid MK, Jayne D, Mukhtyar C, Westman K, Davis JC Jr, Hoffman GS, McCune WJ, Merkel PA, St Clair EW, Seo P, Spiera R, Stone JH, Luqmani R. A model to predict cardiovascular events in patients with newly diagnosed Wegener's granulomatosis and microscopic polyangiitis. Arthritis Care Res (Hoboken). 2011 Apr;63(4):588-96. doi: 10.1002/acr.20433.

Kermani TA, Crowson CS, Achenbach SJ, Luthra HS. Idiopathic retroperitoneal fibrosis: a retrospective review of clinical presentation, treatment, and outcomes. Mayo Clin Proc. 2011 Apr;86(4):297-303. doi: 10.4065/mcp.2010.0663.

Walsh M, Catapano F, Szpirt W, Thorlund K, Bruchfeld A, Guillevin L, Haubitz M, Merkel PA, Peh CA, Pusey C, Jayne D. Plasma exchange for renal vasculitis and idiopathic rapidly progressive glomerulonephritis: a meta-analysis. Am J Kidney Dis. 2011 Apr;57(4):566-74. doi: 10.1053/j.ajkd.2010.10.049. Epub 2010 Dec 30.

Pagnoux C, Stubbe M, Lifermann F, Decaux O, Pavic M, Bérezné A, Delacroix-Szmania I, Méaux-Ruault N, Bienvenu B, Cabane J, Guillevin L; French Vasculitis Study Group. Wegener's granulomatosis strictly and persistently localized to one organ is rare: assessment of 16 patients from the French Vasculitis Study Group database. J Rheumatol. 2011 Mar;38(3):475-8. doi: 10.3899/jrheum.100518. Epub 2010 Dec 1.

Kermani TA, Warrington KJ, Amin S. Malignancy risk in vasculitis. Ther Adv Musculoskelet Dis. 2011 Feb;3(1):55-63. doi: 10.1177/1759720X10387460.

Direskeneli H, Aydin SZ, Merkel PA. Assessment of disease activity and progression in Takayasu's arteritis. Clin Exp Rheumatol. 2011 Jan-Feb;29(1 Suppl 64):S86-91. Epub 2011 May 11.

Barreto P, Pagnoux C, Luca L, Aouizerate J, Ortigueira I, Cohen P, Muller G, Guillevin L. Dorsal prevertebral lesions in Wegener granulomatosis: report on four cases. Joint Bone Spine. 2011 Jan;78(1):88-91. doi: 10.1016/j.jbspin.2010.07.017. Epub 2010 Sep 18.

de Menthon M, Cohen P, Pagnoux C, Buchler M, Sibilia J, Détrée F, Gayraud M, Khellaf M, Penalba C, Legallicier B, Mouthon L, Guillevin L. Infliximab or rituximab for refractory Wegener's granulomatosis: long-term follow up. A prospective randomised multicentre study on 17 patients. Clin Exp Rheumatol. 2011 Jan-Feb;29(1 Suppl 64):S63-71. Epub 2011 May 11.

Kermani TA, Warrington KJ. Lower extremity vasculitis in polymyalgia rheumatica and giant cell arteritis. Curr Opin Rheumatol. 2011 Jan;23(1):38-42. doi: 10.1097/BOR.0b013e3283410072.

Suppiah R, Flossman O, Mukhtyar C, Alberici F, Baslund B, Brown D, Hasan N, Holle J, Hruskova Z, Jayne D, Judge A, Little MA, Merkel PA, Palmisano A, Seo P, Stegeman C, Tesar V, Vaglio A, Westman K, Luqmani R. Measurement of damage in systemic vasculitis: a comparison of the Vasculitis Damage Index with the Combined Damage Assessment Index. Ann Rheum Dis. 2011 Jan;70(1):80-5. doi: 10.1136/ard.2009.122952. Epub 2010 Aug 24.

Guillevin L, Pagnoux C, Seror R, Mahr A, Mouthon L, Toumelin PL; French Vasculitis Study Group (FVSG). The Five-Factor Score revisited: assessment of prognoses of systemic necrotizing vasculitides based on the French Vasculitis Study Group (FVSG) cohort. Medicine (Baltimore). 2011 Jan;90(1):19-27. doi: 10.1097/MD.0b013e318205a4c6.

Mahr AD, Edberg JC, Stone JH, Hoffman GS, St Clair EW, Specks U, Dellaripa PF, Seo P, Spiera RF, Rouhani FN, Brantly ML, Merkel PA. Alpha₁-antitrypsin deficiency-related alleles Z and S and the risk of Wegener's granulomatosis. Arthritis Rheum. 2010 Dec;62(12):3760-7. doi: 10.1002/art.27742.

Silva F, Hummel AM, Jenne DE, Specks U. Discrimination and variable impact of ANCA binding to different surface epitopes on proteinase 3, the Wegener's autoantigen. J Autoimmun. 2010 Dec;35(4):299-308. doi: 10.1016/j.jaut.2010.06.021.

Seror R, Pagnoux C, Ruivard M, Landru I, Wahl D, Rivière S, Aussant S, Mahr A, Cohen P, Mouthon L, Guillevin L; French Vasculitis Study Group. Treatment strategies and outcome of induction-refractory Wegener's granulomatosis or microscopic polyangiitis: analysis of 32 patients with first-line induction-refractory disease in the WEGENT trial. Ann Rheum Dis. 2010 Dec;69(12):2125-30. doi: 10.1136/ard.2010.131953. Epub 2010 Jul 19.

Dion J, Bachmeyer C, Moguelet P, Lescure FX, Pagnoux C. Livedo reticularis and erythematous macules of the forearms indicating cutaneous microscopic polyangiitis. Am J Med. 2010 Nov;123(11):e5-6. doi: 10.1016/j.amjmed.2010.03.011.

Herlyn K, Hellmich B, Seo P, Merkel PA. Patient-reported outcome assessment in vasculitis may provide important data and a unique perspective. Arthritis Care Res (Hoboken). 2010 Nov;62(11):1639-45. doi: 10.1002/acr.20276. Epub 2010 Jun 15.

Pierrot-Deseilligny Despujol C, Pouchot J, Pagnoux C, Coste J, Guillevin L. Predictors at diagnosis of a first Wegener's granulomatosis relapse after obtaining complete remission. Rheumatology (Oxford). 2010 Nov;49(11):2181-90. doi: 10.1093/rheumatology/keq244. Epub 2010 Jul 31.

Walsh M, Merkel PA, Mahr A, Jayne D. Effects of duration of glucocorticoid therapy on relapse rate in antineutrophil cytoplasmic antibody-associated vasculitis: A meta-analysis. Arthritis Care Res (Hoboken). 2010 Aug;62(8):1166-73. doi: 10.1002/acr.20176.

Flint J, Morgan MD, Savage CO. Pathogenesis of ANCA-associated vasculitis. Rheum Dis Clin North Am. 2010 Aug;36(3):463-77. doi: 10.1016/j.rdc.2010.05.006. Epub 2010 Jun 23.

Pagnoux C, Dechartres A, Giraudeau B, Seror R, Guillevin L, Ravaud P. Reporting of corticosteroid use in systemic disease trials: evidence from a systematic review of the potential impact on treatment effect. Arthritis Care Res (Hoboken). 2010 Jul;62(7):1002-8. doi: 10.1002/acr.20139.

Silva F, Specks U, Kalra S, Hogan MC, Leung N, Sethi S, Fervenza FC. Mycophenolate mofetil for induction and maintenance of remission in microscopic polyangiitis with mild to moderate renal involvement--a prospective, open-label pilot trial. Clin J Am Soc Nephrol. 2010 Mar;5(3):445-53. doi: 10.2215/CJN.06010809. Epub 2010 Jan 21.

Koening CL, Gota CE, Langford CA, Hoffman GS, Natowicz MR. Serum chitotriosidase activity and Wegener's granulomatosis. Clin Biochem. 2010 Mar;43(4-5):512-4. doi: 10.1016/j.clinbiochem.2009.11.015. Epub 2009 Dec 1.

Pagnoux C, Seror R, Henegar C, Mahr A, Cohen P, Le Guern V, Bienvenu B, Mouthon L, Guillevin L; French Vasculitis Study Group. Clinical features and outcomes in 348 patients with polyarteritis nodosa: a systematic retrospective study of patients diagnosed between 1963 and 2005 and entered into the French Vasculitis Study Group Database. Arthritis Rheum. 2010 Feb;62(2):616-26. doi: 10.1002/art.27240.

Rodríguez-Pla A, Martínez-Murillo F, Savino PJ, Eagle RC Jr, Seo P, Soloski MJ. MMP-12, a novel matrix metalloproteinase associated with giant cell arteritis. Rheumatology (Oxford). 2009 Nov;48(11):1460-1. doi: 10.1093/rheumatology/kep271. Epub 2009 Sep 6.

Merkel PA, Herlyn K, Mahr AD, Neogi T, Seo P, Walsh M, Boers M, Luqmani R. Progress towards a core set of outcome measures in small-vessel vasculitis. Report from OMERACT 9. J Rheumatol. 2009 Oct;36(10):2362-8. doi: 10.3899/jrheum.090373.

Silva F, Specks U, Sethi S, Irazabal MV, Fervenza FC. Successful pregnancy and delivery of a healthy newborn despite transplacental transfer of antimyeloperoxidase antibodies from a mother with microscopic polyangiitis. Am J Kidney Dis. 2009 Sep;54(3):542-5. doi: 10.1053/j.ajkd.2009.02.016. Epub 2009 Apr 23.

Seo P, Jayne D, Luqmani R, Merkel PA. Assessment of damage in vasculitis: expert ratings of damage. Rheumatology (Oxford). 2009 Jul;48(7):823-7. doi: 10.1093/rheumatology/kep103. Epub 2009 May 19.

Khasnis A, Langford CA. Update on vasculitis. J Allergy Clin Immunol. 2009 Jun;123(6):1226-36. doi: 10.1016/j.jaci.2009.04.024.

Griggs RC, Batshaw M, Dunkle M, Gopal-Srivastava R, Kaye E, Krischer J, Nguyen T, Paulus K, Merkel PA; Rare Diseases Clinical Research Network. Clinical research for rare disease: opportunities, challenges, and solutions. Mol Genet Metab. 2009 Jan;96(1):20-6. doi: 10.1016/j.ymgme.2008.10.003. Epub 2008 Nov 13.

Merkel PA, Cuthbertson DD, Hellmich B, Hoffman GS, Jayne DR, Kallenberg CG, Krischer JP, Luqmani R, Mahr AD, Matteson EL, Specks U, Stone JH; Vasculitis Clinical Research Consortium. Comparison of disease activity measures for anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis. Ann Rheum Dis. 2009 Jan;68(1):103-6. doi: 10.1136/ard.2008.097758. Epub 2008 Jul 29.

Finkielman JD, Merkel PA, Schroeder D, Hoffman GS, Spiera R, St Clair EW, Davis JC Jr, McCune WJ, Lears A, Ytterberg SR, Hummel AM, Viss MA, Peikert T, Stone JH, Specks U; WGET Research Group. Glycosylation of proteinase 3 (PR3) is not required for its reactivity with antineutrophil cytoplasmic antibodies (ANCA) in Wegener's granulomatosis. Clin Exp Rheumatol. 2009 Jan-Feb;27(1 Suppl 52):S45-52.

Koening CL, Hernández-Rodríguez J, Molloy ES, Clark TM, Hoffman GS. Limited utility of rapamycin in severe, refractory Wegener's granulomatosis. J Rheumatol. 2009 Jan;36(1):116-9. doi: 10.3899/jrheum.080664.

Tomasson G, Monach PA, Merkel PA. Thromboembolic disease in vasculitis. Curr Opin Rheumatol. 2009 Jan;21(1):41-6. doi: 10.1097/BOR.0b013e32831de4e7.

Khasnis A, Molloy ES. Mimics of primary systemic vasculitides. International Journal of Clinical Rheumatology [Internet]. 2009; 4 5:[1-13 pp.]. DOI 10.2217/ijr.09.37.

Hauser T, Mahr A, Metzler C, Coste J, Sommerstein R, Gross WL, Guillevin L, Hellmich B. The leucotriene receptor antagonist montelukast and the risk of Churg-Strauss syndrome: a case-crossover study. Thorax. 2008 Aug;63(8):677-82. doi: 10.1136/thx.2007.087825. Epub 2008 Feb 14.

Mahr AD, Neogi T, Lavalley MP, Davis JC, Hoffman GS, McCune WJ, Specks U, Spiera RF, St Clair EW, Stone JH, Merkel PA; Wegener's Granulomatosis Etanercept Trial Research Group. Assessment of the item selection and weighting in the Birmingham vasculitis activity score for Wegener's granulomatosis. Arthritis Rheum. 2008 Jun 15;59(6):884-91. doi: 10.1002/art.23707.

Rodríguez-Pla A, Beaty TH, Savino PJ, Eagle RC Jr, Seo P, Soloski MJ. Association of a nonsynonymous single-nucleotide polymorphism of matrix metalloproteinase 9 with giant cell arteritis. Arthritis Rheum. 2008 Jun;58(6):1849-53. doi: 10.1002/art.23457.

Wung PK, Anderson T, Fontaine KR, Hoffman GS, Specks U, Merkel PA, Spiera R, Davis JC, St Clair EW, McCune WJ, Stone JH; WEGENER'S GRANULOMATOSIS ETANERCEPT TRIAL RESEARCH GROUP. Effects of glucocorticoids on weight change during the treatment of Wegener's granulomatosis. Arthritis Rheum. 2008 May 15;59(5):746-753. doi: 10.1002/art.23561.

Koening CL, Langford CA. Takayasu's arteritis. Curr Treat Options Cardiovasc Med. 2008 Apr;10(2):164-72. doi: 10.1007/s11936-008-0018-9.

Rodríguez-Pla A. Chapter 40: Polyarteritis Nodosa and other Necrotizing Systemic Vasculitis. Manual de Enfermedades Reumáticas de la Sociedad Española de Reumatología (Handbook of the Spanish Society of Rheumatology).  5ª Edición . 2008; JJ Gomez-Reino et. al., editores.  Editorial Médica Panamericana, S.A.

Silva F, Lynch JP, Fishbein MC, Specks U. Wegener Granulomatosis. In “Interstitial Pulmonary and Bronchiolar Disorders, (Lynch JP III, Ed). InformaUSA, NY. 2008; volume 227; pp 605-642.

Mahr AD, Jover JA, Spiera RF, Hernández-García C, Fernández-Gutiérrez B, Lavalley MP, Merkel PA. Adjunctive methotrexate for treatment of giant cell arteritis: an individual patient data meta-analysis. Arthritis Rheum. 2007 Aug;56(8):2789-97. doi: 10.1002/art.22754.

Seo P, Luqmani RA, Flossmann O, Hellmich B, Herlyn K, Hoffman GS, Jayne D, Kallenberg CG, Langford CA, Mahr A, Matteson EL, Mukhtyar CB, Neogi T, Rutgers A, Specks U, Stone JH, Ytterberg SR, Merkel PA. The future of damage assessment in vasculitis. J Rheumatol. 2007 Jun;34(6):1357-71.

Sebastian JK, Mahr AD, Ahmed SS, Stone JH, Romay-Penabad Z, Davis JC, Hoffman GS, McCune WJ, St Clair EW, Specks U, Spiera R, Pierangeli S, Merkel PA. Antiendothelial cell antibodies in patients with Wegener's granulomatosis: prevalence and correlation with disease activity and manifestations. J Rheumatol. 2007 May;34(5):1027-31. Epub 2007 Apr 15.

Hellmich B, Flossmann O, Gross WL, Bacon P, Cohen-Tervaert JW, Guillevin L, Jayne D, Mahr A, Merkel PA, Raspe H, Scott DG, Witter J, Yazici H, Luqmani RA. EULAR recommendations for conducting clinical studies and/or clinical trials in systemic vasculitis: focus on anti-neutrophil cytoplasm antibody-associated vasculitis. Ann Rheum Dis. 2007 May;66(5):605-17. doi: 10.1136/ard.2006.062711. Epub 2006 Dec 14.

Rodríguez-Pla A, Rosselló-Urgell J, Bosch-Gil JA, Huguet-Redecilla P, Vilardell-Tarres M. Proposal to decrease the number of negative temporal artery biopsies. Scand J Rheumatol. 2007 Mar-Apr;36(2):111-8. doi: 10.1080/03009740600991646.

Richesson RL, Andrews JE, Krischer JP. Use of SNOMED CT to represent clinical research data: a semantic characterization of data items on case report forms in vasculitis research. J Am Med Inform Assoc. 2006 Sep-Oct;13(5):536-46. doi: 10.1197/jamia.M2093. Epub 2006 Jun 23.

Koening CL, Langford CA. Novel therapeutic strategies for large vessel vasculitis. Rheum Dis Clin North Am. 2006 Feb;32(1):173-86, xi. doi: 10.1016/j.rdc.2005.09.006.

Merkel PA, Seo P, Aries P, Neogi T, Villa-Forte A, Boers M, Cuthbertson D, Felson DT, Hellmich B, Hoffman GS, Jayne DR, Kallenberg CG, Krischer J, Mahr A, Matteson EL, Specks U, Luqmani R, Stone J; Vasculitis Clinical Research Consortium; OMERACT 7 Special Interest Group. Current status of outcome measures in vasculitis: focus on Wegener's granulomatosis and microscopic polyangiitis. Report from OMERACT 7. J Rheumatol. 2005 Dec;32(12):2488-95.

Rodríguez-Pla A, Bosch-Gil JA, Rosselló-Urgell J, Huguet-Redecilla P, Stone JH, Vilardell-Tarres M. Metalloproteinase-2 and -9 in giant cell arteritis: involvement in vascular remodeling. Circulation. 2005 Jul 12;112(2):264-9. doi: 10.1161/CIRCULATIONAHA.104.520114. Epub 2005 Jul 5.