Research Publications

Browse scientific publications from the NIH-funded RDCRN network and its 20 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.

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.

Lingor P, Weber M, Camu W, et al. ROCK-ALS: Protocol for a Randomized, Placebo-Controlled, Double- Blind Phase IIa Trial of Safety, Tolerability and Efficacy of the Rho Kinase (ROCK) Inhibitor Fasudil in Amyotrophic Lateral Sclerosis. Front Neurol. 2019; 10: 293. PMCID: PMC6446974, PMID: 30972018.

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.

Nicolas A, Kenna KP, Renton AE, Ticozzi N, Faghri F, Chia R, Dominov JA, Kenna BJ, Nalls MA, Keagle P, Rivera AM, van Rheenen W, Murphy NA, van Vugt JJFA, Geiger JT, Van der Spek RA, Pliner HA, Shankaracharya, Smith BN, Marangi G, Topp SD, Abramzon Y, Gkazi AS, Eicher JD, Kenna A; ITALSGEN Consortium, Mora G, Calvo A, Mazzini L, Riva N, Mandrioli J, Caponnetto C, Battistini S, Volanti P, La Bella V, Conforti FL, Borghero G, Messina S, Simone IL, Trojsi F, Salvi F, Logullo FO, D'Alfonso S, Corrado L, Capasso M, Ferrucci L; Genomic Translation for ALS Care (GTAC) Consortium, Moreno CAM, Kamalakaran S, Goldstein DB; ALS Sequencing Consortium, Gitler AD, Harris T, Myers RM; NYGC ALS Consortium, Phatnani H, Musunuri RL, Evani US, Abhyankar A, Zody MC; Answer ALS Foundation, Kaye J, Finkbeiner S, Wyman SK, LeNail A, Lima L, Fraenkel E, Svendsen CN, Thompson LM, Van Eyk JE, Berry JD, Miller TM, Kolb SJ, Cudkowicz M, Baxi E; Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium, Benatar M, Taylor JP, Rampersaud E, Wu G, Wuu J; SLAGEN Consortium, Lauria G, Verde F, Fogh I, Tiloca C, Comi GP, Sorarù G, Cereda C; French ALS Consortium, Corcia P, Laaksovirta H, Myllykangas L, Jansson L, Valori M, Ealing J, Hamdalla H, Rollinson S, Pickering-Brown S, Orrell RW, et al. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. Neuron. 2018 Mar 21;97(6):1267-1288. doi: 10.1016/j.neuron.2018.02.027. PMID: 29566793; PMCID: PMC5867896.

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.

Simone R, Balendra R, Moens TG, et al. G-quadruplex-binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo. EMBO Mol Med. 2018 Jan;10(1):22-31. doi: 10.15252/emmm.201707850. PMID: 29113975; PMCID: PMC5760849.

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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.

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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.

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Liu BM. Epidemiological and clinical overview of the 2024 Oropouche virus disease outbreaks, an emerging/re-emerging neurotropic arboviral disease and global public health threat. J Med Virol. 2024 Sep;96(9):e29897. doi: 10.1002/jmv.29897.

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.

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.

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.

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.

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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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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Wechsler JB, Hirano I. Biological therapies for eosinophilic gastrointestinal diseases. J Allergy Clin Immunol. 2018 Jul;142(1):24-31.e2. doi: 10.1016/j.jaci.2018.05.018. Epub 2018 May 31.

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Jensen ET, Dellon ES. Environmental factors and eosinophilic esophagitis. J Allergy Clin Immunol. 2018 Jul;142(1):32-40. doi: 10.1016/j.jaci.2018.04.015. Epub 2018 May 2.

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Azouz NP, Ynga-Durand MA, Caldwell JM, Jain A, Rochman M, Fischesser DM, Ray LM, Bedard MC, Mingler MK, Forney C, Eilerman M, Kuhl JT, He H, Biagini Myers JM, Mukkada VA, Putnam PE, Khurana Hershey GK, Kottyan LC, Wen T, Martin LJ, Rothenberg ME. The antiprotease SPINK7 serves as an inhibitory checkpoint for esophageal epithelial inflammatory responses. Sci Transl Med. 2018 Jun 6;10(444):eaap9736. doi: 10.1126/scitranslmed.aap9736.

Pesek RD, Gupta SK. Emerging drugs for eosinophilic esophagitis. Expert Opin Emerg Drugs. 2018 Jun;23(2):173-183. doi: 10.1080/14728214.2018.1483335. Epub 2018 Jun 8.

Hiremath G, Vaezi MF, Gupta SK, Acra S, Dellon ES. Management of Esophageal Food Impaction Varies Among Gastroenterologists and Affects Identification of Eosinophilic Esophagitis. Dig Dis Sci. 2018 Jun;63(6):1428-1437. doi: 10.1007/s10620-018-4972-0. Epub 2018 Feb 20.

Mark J, Fernando SD, Masterson JC, Pan Z, Capocelli KE, Furuta GT, de Zoeten EF. Clinical Implications of Pediatric Colonic Eosinophilia. J Pediatr Gastroenterol Nutr. 2018 May;66(5):760-766. doi: 10.1097/MPG.0000000000001784.

Martin LJ, He H, Collins MH, Abonia JP, Biagini Myers JM, Eby M, Johansson H, Kottyan LC, Khurana Hershey GK, Rothenberg ME. Eosinophilic esophagitis (EoE) genetic susceptibility is mediated by synergistic interactions between EoE-specific and general atopic disease loci. J Allergy Clin Immunol. 2018 May;141(5):1690-1698. doi: 10.1016/j.jaci.2017.09.046. Epub 2017 Nov 10.

Wright BL, Nguyen N, Shim KP, Masterson JC, Jacobsen EA, Ochkur SI, Lee JJ, Furuta GT. Increased GATA-3 and T-bet expression in eosinophilic esophagitis versus gastroesophageal reflux disease. J Allergy Clin Immunol. 2018 May;141(5):1919-1921.e5. doi: 10.1016/j.jaci.2017.12.993. Epub 2018 Jan 31.

Philpott H, Dellon E. Histologic improvement after 6 weeks of dietary elimination for eosinophilic esophagitis may be insufficient to determine efficacy. Asia Pac Allergy. 2018 Apr 25;8(2):e20. doi: 10.5415/apallergy.2018.8.e20. eCollection 2018 Apr.

Fahey LM, Chandramouleeswaran PM, Guan S, Benitez AJ, Furuta GT, Aceves SS, Wang ML, Liacouras CA, Muir AB, Sleiman PM, Hakonarson H, Spergel JM, Cianferoni A. Food allergen triggers are increased in children with the TSLP risk allele and eosinophilic esophagitis. Clin Transl Gastroenterol. 2018 Mar 6;9(3):139. doi: 10.1038/s41424-018-0003-x.

Ruffner MA, Brown-Whitehorn TF, Verma R, Cianferoni A, Gober L, Shuker M, Muir AB, Liacouras CA, Spergel JM. Clinical tolerance in eosinophilic esophagitis. J Allergy Clin Immunol Pract. 2018 Mar-Apr;6(2):661-663. doi: 10.1016/j.jaip.2017.06.035. Epub 2017 Aug 12.

Patel RV, Hirano I. New Developments in the Diagnosis, Therapy, and Monitoring of Eosinophilic Esophagitis. Curr Treat Options Gastroenterol. 2018 Mar;16(1):15-26. doi: 10.1007/s11938-018-0167-1.

Nguyen N, Fernando SD, Biette KA, Hammer JA, Capocelli KE, Kitzenberg DA, Glover LE, Colgan SP, Furuta GT, Masterson JC. TGF-β1 alters esophageal epithelial barrier function by attenuation of claudin-7 in eosinophilic esophagitis. Mucosal Immunol. 2018 Mar;11(2):415-426. doi: 10.1038/mi.2017.72. Epub 2017 Aug 23.

Atkins D. The Occasional Ebb and Flow between Eosinophilic Esophagitis and IgE-Mediated Food Allergy. J Allergy Clin Immunol Pract. 2018 Mar-Apr;6(2):651-652. doi: 10.1016/j.jaip.2017.11.011.

Hill DA, Spergel JM. Is eosinophilic esophagitis a member of the atopic march?. Ann Allergy Asthma Immunol. 2018 Feb;120(2):113-114. doi: 10.1016/j.anai.2017.10.003.

Hill DA, Spergel JM. The atopic march: Critical evidence and clinical relevance. Ann Allergy Asthma Immunol. 2018 Feb;120(2):131-137. doi: 10.1016/j.anai.2017.10.037.

Philpott H, Dellon ES. The role of maintenance therapy in eosinophilic esophagitis: who, why, and how?. J Gastroenterol. 2018 Feb;53(2):165-171. doi: 10.1007/s00535-017-1397-z. Epub 2017 Oct 10.

Whelan KA, Muir AB, Nakagawa H. Esophageal 3D Culture Systems as Modeling Tools in Esophageal Epithelial Pathobiology and Personalized Medicine. Cell Mol Gastroenterol Hepatol. 2018 Jan 31;5(4):461-478. doi: 10.1016/j.jcmgh.2018.01.011. eCollection 2018.

Kasagi Y, Chandramouleeswaran PM, Whelan KA, Tanaka K, Giroux V, Sharma M, Wang J, Benitez AJ, DeMarshall M, Tobias JW, Hamilton KE, Falk GW, Spergel JM, Klein-Szanto AJ, Rustgi AK, Muir AB, Nakagawa H. The Esophageal Organoid System Reveals Functional Interplay Between Notch and Cytokines in Reactive Epithelial Changes. Cell Mol Gastroenterol Hepatol. 2018 Jan 3;5(3):333-352. doi: 10.1016/j.jcmgh.2017.12.013. eCollection 2018 Mar.

Collins MH, Capocelli K, Yang GY. Eosinophilic Gastrointestinal Disorders Pathology. Front Med (Lausanne). 2018 Jan 15;4:261. doi: 10.3389/fmed.2017.00261. eCollection 2017.

Dellon ES, Hirano I. Epidemiology and Natural History of Eosinophilic Esophagitis. Gastroenterology. 2018 Jan;154(2):319-332.e3. doi: 10.1053/j.gastro.2017.06.067. Epub 2017 Aug 1.

Safroneeva E, Straumann A, Schoepfer AM. Latest Insights on the Relationship Between Symptoms and Biologic Findings in Adults with Eosinophilic Esophagitis. Gastrointest Endosc Clin N Am. 2018 Jan;28(1):35-45. doi: 10.1016/j.giec.2017.08.001.

O'Shea KM, Aceves SS, Dellon ES, Gupta SK, Spergel JM, Furuta GT, Rothenberg ME. Pathophysiology of Eosinophilic Esophagitis. Gastroenterology. 2018 Jan;154(2):333-345. doi: 10.1053/j.gastro.2017.06.065. Epub 2017 Jul 27.

Cheng K, Gupta SK, Kantor S, Kuhl JT, Aceves SS, Bonis PA, Capocelli KE, Carpenter C, Chehade M, Collins MH, Dellon ES, Falk GW, Gopal-Srivastava R, Gonsalves N, Hirano I, King EC, Leung J, Krischer JP, Mukkada VA, Schoepfer A, Spergel JM, Straumann A, Yang GY, Furuta GT, Rothenberg ME. Creating a multi-center rare disease consortium - the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR). Transl Sci Rare Dis. 2017 Dec 18;2(3-4):141-155. doi: 10.3233/TRD-170016.

Eluri S, Dellon ES. Toward More Efficient Dietary Elimination Therapy for Eosinophilic Esophagitis: The Fantastic 4?. Clin Gastroenterol Hepatol. 2017 Nov;15(11):1668-1670. doi: 10.1016/j.cgh.2017.07.022. Epub 2017 Jul 26.

Caldwell JM, Paul M, Rothenberg ME. Novel immunologic mechanisms in eosinophilic esophagitis. Curr Opin Immunol. 2017 Oct;48:114-121. doi: 10.1016/j.coi.2017.08.006. Epub 2017 Sep 29.

Case C, Furuta GT, Atkins D, Pan Z, Robinson J. Diet and Stress in Pediatric Eosinophilic Esophagitis. J Pediatr Gastroenterol Nutr. 2017 Sep;65(3):281-284. doi: 10.1097/MPG.0000000000001481.

Menard-Katcher C, Benitez AJ, Pan Z, Ahmed FN, Wilkins BJ, Capocelli KE, Liacouras CA, Verma R, Spergel JM, Furuta GT, Muir AB. Influence of Age and Eosinophilic Esophagitis on Esophageal Distensibility in a Pediatric Cohort. Am J Gastroenterol. 2017 Sep;112(9):1466-1473. doi: 10.1038/ajg.2017.131. Epub 2017 May 16.

Pesek RD, Rettiganti M, O'Brien E, Beckwith S, Daniel C, Luo C, Scurlock AM, Chandler P, Levy RA, Perry TT, Kennedy JL, Chervinskiy S, Vonlanthen M, Casteel H, Fiedorek SC, Gibbons T, Jones SM. Effects of allergen sensitization on response to therapy in children with eosinophilic esophagitis. Ann Allergy Asthma Immunol. 2017 Aug;119(2):177-183. doi: 10.1016/j.anai.2017.06.006. Epub 2017 Jul 1.

Abonia JP, Spergel JM, Cianferoni A. Eosinophilic Esophagitis: A Primary Disease of the Esophageal Mucosa. J Allergy Clin Immunol Pract. 2017 Jul-Aug;5(4):951-955. doi: 10.1016/j.jaip.2017.02.004. Epub 2017 Mar 28.

Dellon ES. Management of refractory eosinophilic oesophagitis. Nat Rev Gastroenterol Hepatol. 2017 Aug;14(8):479-490. doi: 10.1038/nrgastro.2017.56. Epub 2017 May 24.

Hirano I, Spechler S, Furuta G, Dellon ES. White Paper AGA: Drug Development for Eosinophilic Esophagitis. Clin Gastroenterol Hepatol. 2017 Aug;15(8):1173-1183. doi: 10.1016/j.cgh.2017.03.016. Epub 2017 Mar 22.

Wen T, Rothenberg ME. Clinical Applications of the Eosinophilic Esophagitis Diagnostic Panel. Front Med (Lausanne). 2017 Jul 14;4:108. doi: 10.3389/fmed.2017.00108. eCollection 2017.

Whelan KA, Merves JF, Giroux V, Tanaka K, Guo A, Chandramouleeswaran PM, Benitez AJ, Dods K, Que J, Masterson JC, Fernando SD, Godwin BC, Klein-Szanto AJ, Chikwava K, Ruchelli ED, Hamilton KE, Muir AB, Wang ML, Furuta GT, Falk GW, Spergel JM, Nakagawa H. Autophagy mediates epithelial cytoprotection in eosinophilic oesophagitis. Gut. 2017 Jul;66(7):1197-1207. doi: 10.1136/gutjnl-2015-310341. Epub 2016 Feb 16.

Eluri S, Book WM, Kodroff E, Strobel MJ, Gebhart JH, Jones PD, Menard-Katcher P, Ferris ME, Dellon ES. Lack of Knowledge and Low Readiness for Health Care Transition in Eosinophilic Esophagitis and Eosinophilic Gastroenteritis. J Pediatr Gastroenterol Nutr. 2017 Jul;65(1):53-57. doi: 10.1097/MPG.0000000000001415.

Molina-Infante J, Hirano I, Spechler SJ; PPI-REE Task Force of the European Society of Eosinophilic Oesophagitis (EUREOS). Clarifying misunderstandings and misinterpretations about proton pump inhibitor-responsive oesophageal eosinophilia. Gut. 2017 Jun;66(6):1173-1174. doi: 10.1136/gutjnl-2016-312851. Epub 2016 Sep 13.

Atkins D, Furuta GT, Liacouras CA, Spergel JM. Eosinophilic esophagitis phenotypes: Ready for prime time?. Pediatr Allergy Immunol. 2017 Jun;28(4):312-319. doi: 10.1111/pai.12715. Epub 2017 May 4.

Menard-Katcher C, Furuta GT, Kramer RE. Dilation of Pediatric Eosinophilic Esophagitis: Adverse Events and Short-term Outcomes. J Pediatr Gastroenterol Nutr. 2017 May;64(5):701-706. doi: 10.1097/MPG.0000000000001336.

Muir AB, Wang ML, Metz D, Falk G, Markowitz J, Spergel JM, Liacouras CA. Proton pump inhibitor-responsive oesophageal eosinophilia: too early to change clinical practice. Gut. 2017 May;66(5):979-980. doi: 10.1136/gutjnl-2016-312601. Epub 2016 Jul 26.

Mehta P, Sundaram SS, Furuta GT, Pan Z, Atkins D, Markowitz S. Propofol Use in Pediatric Patients With Food Allergy and Eosinophilic Esophagitis. J Pediatr Gastroenterol Nutr. 2017 Apr;64(4):546-549. doi: 10.1097/MPG.0000000000001291.

Furuta GT, Aceves SS. The National Biome Initiative: An allergy perspective. J Allergy Clin Immunol. 2017 Apr;139(4):1131-1134. doi: 10.1016/j.jaci.2017.02.008. Epub 2017 Feb 28.

Hill DA, Dudley JW, Spergel JM. The Prevalence of Eosinophilic Esophagitis in Pediatric Patients with IgE-Mediated Food Allergy. J Allergy Clin Immunol Pract. 2017 Mar-Apr;5(2):369-375. doi: 10.1016/j.jaip.2016.11.020. Epub 2016 Dec 30.

Collins MH, Martin LJ, Alexander ES, Boyd JT, Sheridan R, He H, Pentiuk S, Putnam PE, Abonia JP, Mukkada VA, Franciosi JP, Rothenberg ME. Newly developed and validated eosinophilic esophagitis histology scoring system and evidence that it outperforms peak eosinophil count for disease diagnosis and monitoring. Dis Esophagus. 2017 Feb 1;30(3):1-8. doi: 10.1111/dote.12470.

Nguyen N, Furuta GT, Menard-Katcher C. Sticky Steroids: In Search of an Approved Treatment for Eosinophilic Esophagitis. J Pediatr Gastroenterol Nutr. 2017 Feb;64(2):172-173. doi: 10.1097/MPG.0000000000001326.

Atkins D. Aeroallergens in Eosinophilic Esophagitis: Significant Triggers or Noise in the System?. J Pediatr Gastroenterol Nutr. 2017 Jan;64(1):1-2. doi: 10.1097/MPG.0000000000001268.

Dellon ES, Collins MH, Bonis PA, Leung J, Capocelli KE, Dohil R, Falk GW, Furuta GT, Menard-Katcher C, Gupta SK, Hirano I, Hiremath GS, Kagalwalla AF, Wershil BK, Liacouras CA, Muir AB, Mukkada VA, Putnam PE, Schoepfer AM, Straumann A, Wo JM, Yang GY, Rothenberg ME, Gonsalves N. Substantial Variability in Biopsy Practice Patterns Among Gastroenterologists for Suspected Eosinophilic Gastrointestinal Disorders. Clin Gastroenterol Hepatol. 2016 Dec;14(12):1842-1844. doi: 10.1016/j.cgh.2016.04.025. Epub 2016 Apr 22.

Venter C, Fleischer DM. Diets for diagnosis and management of food allergy: The role of the dietitian in eosinophilic esophagitis in adults and children. Ann Allergy Asthma Immunol. 2016 Nov;117(5):468-471. doi: 10.1016/j.anai.2016.08.003. Epub 2016 Aug 31.

Rosenberg HF, Masterson JC, Furuta GT. Eosinophils, probiotics, and the microbiome. J Leukoc Biol. 2016 Nov;100(5):881-888. doi: 10.1189/jlb.3RI0416-202R. Epub 2016 Aug 22.

Ruffner MA, Spergel JM. Non-IgE-mediated food allergy syndromes. Ann Allergy Asthma Immunol. 2016 Nov;117(5):452-454. doi: 10.1016/j.anai.2016.04.014. Epub 2016 Oct 24.

Wen T, Rothenberg ME. The Regulatory Function of Eosinophils. Microbiol Spectr. 2016 Oct;4(5):10.1128/microbiolspec.MCHD-0020-2015. doi: 10.1128/microbiolspec.MCHD-0020-2015.

Morris DW, Stucke EM, Martin LJ, Abonia JP, Mukkada VA, Putnam PE, Rothenberg ME, Fulkerson PC. Eosinophil progenitor levels are increased in patients with active pediatric eosinophilic esophagitis. J Allergy Clin Immunol. 2016 Sep;138(3):915-918.e5. doi: 10.1016/j.jaci.2016.03.027. Epub 2016 May 16.

Muir AB, Benitez AJ, Dods K, Spergel JM, Fillon SA. Microbiome and its impact on gastrointestinal atopy. Allergy. 2016 Sep;71(9):1256-63. doi: 10.1111/all.12943. Epub 2016 Jun 23.

Rawson R, Yang T, Newbury RO, Aquino M, Doshi A, Bell B, Broide DH, Dohil R, Kurten R, Aceves SS. TGF-β1-induced PAI-1 contributes to a profibrotic network in patients with eosinophilic esophagitis. J Allergy Clin Immunol. 2016 Sep;138(3):791-800.e4. doi: 10.1016/j.jaci.2016.02.028. Epub 2016 Apr 8.

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.

Muir AB, Dods K, Henry SJ, Benitez AJ, Lee D, Whelan KA, DeMarshall M, Hammer DA, Falk G, Wells RG, Spergel J, Nakagawa H, Wang ML. Eosinophilic Esophagitis-Associated Chemical and Mechanical Microenvironment Shapes Esophageal Fibroblast Behavior. J Pediatr Gastroenterol Nutr. 2016 Aug;63(2):200-9. doi: 10.1097/MPG.0000000000001100.

Imam T, Gupta SK. Topical glucocorticoid vs. diet therapy in eosinophilic esophagitis: the need for better treatment options. Expert Rev Clin Immunol. 2016 Aug;12(8):797-9. doi: 10.1080/1744666X.2016.1191947. Epub 2016 Jun 13.

Kia L, Hirano I. Advances in the endoscopic evaluation of eosinophilic esophagitis. Curr Opin Gastroenterol. 2016 Jul;32(4):325-31. doi: 10.1097/MOG.0000000000000278.

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.

Carlson DA, Hirano I. Narrow-caliber esophagus of eosinophilic esophagitis: difficult to define, resistant to remedy. Gastrointest Endosc. 2016 Jun;83(6):1149-50. doi: 10.1016/j.gie.2016.01.034.

Davis BP, Rothenberg ME. Mechanisms of Disease of Eosinophilic Esophagitis. Annu Rev Pathol. 2016 May 23;11:365-93. doi: 10.1146/annurev-pathol-012615-044241. Epub 2016 Feb 24.

Tkachenko E, Rawson R, La E, Doherty TA, Baum R, Cavagnero K, Miyanohara A, Dohil R, Kurten RC, Aceves SS. Rigid substrate induces esophageal smooth muscle hypertrophy and eosinophilic esophagitis fibrotic gene expression. J Allergy Clin Immunol. 2016 Apr;137(4):1270-1272.e1. doi: 10.1016/j.jaci.2015.09.020. Epub 2015 Nov 2.

Kliewer KL, Venter C, Cassin AM, Abonia JP, Aceves SS, Bonis PA, Dellon ES, Falk GW, Furuta GT, Gonsalves N, Gupta SK, Hirano I, Kagalwalla A, Leung J, Mukkada VA, Spergel JM, Rothenberg ME. Should wheat, barley, rye, and/or gluten be avoided in a 6-food elimination diet?. J Allergy Clin Immunol. 2016 Apr;137(4):1011-1014. doi: 10.1016/j.jaci.2015.10.040. Epub 2015 Dec 24.

Chandramouleeswaran PM, Shen D, Lee AJ, Benitez A, Dods K, Gambanga F, Wilkins BJ, Merves J, Noah Y, Toltzis S, Yearley JH, Spergel JM, Nakagawa H, Malefyt Rd, Muir AB, Wang ML. Preferential Secretion of Thymic Stromal Lymphopoietin (TSLP) by Terminally Differentiated Esophageal Epithelial Cells: Relevance to Eosinophilic Esophagitis (EoE). PLoS One. 2016 Mar 18;11(3):e0150968. doi: 10.1371/journal.pone.0150968. eCollection 2016.

Molina-Infante J, Bredenoord AJ, Cheng E, Dellon ES, Furuta GT, Gupta SK, Hirano I, Katzka DA, Moawad FJ, Rothenberg ME, Schoepfer A, Spechler SJ, Wen T, Straumann A, Lucendo AJ; PPI-REE Task Force of the European Society of Eosinophilic Oesophagitis (EUREOS). Proton pump inhibitor-responsive oesophageal eosinophilia: an entity challenging current diagnostic criteria for eosinophilic oesophagitis. Gut. 2016 Mar;65(3):524-31. doi: 10.1136/gutjnl-2015-310991. Epub 2015 Dec 18.

Watts A, Alexander JA, Gupta SK. Eosinophilic esophagitis: search for noninvasive techniques for long-term monitoring. Gastrointest Endosc. 2016 Feb;83(2):307-8. doi: 10.1016/j.gie.2015.07.006.

Hill DA, Spergel JM. The Immunologic Mechanisms of Eosinophilic Esophagitis. Curr Allergy Asthma Rep. 2016 Feb;16(2):9. doi: 10.1007/s11882-015-0592-3.

Gonsalves N, Furuta GT, Atkins D. Eosinophilic Gastrointestinal Disorders Affect More Than Just the Esophagus. J Pediatr Gastroenterol Nutr. 2016 Jan;62(1):1-2. doi: 10.1097/MPG.0000000000000993.

Rajan J, Newbury RO, Anilkumar A, Dohil R, Broide DH, Aceves SS. Long-term assessment of esophageal remodeling in patients with pediatric eosinophilic esophagitis treated with topical corticosteroids. J Allergy Clin Immunol. 2016 Jan;137(1):147-156.e8. doi: 10.1016/j.jaci.2015.05.045. Epub 2015 Jul 30.

Rawson R, Anilkumar A, Newbury RO, Bafna V, Aquino M, Palmquist J, Hoffman HM, Mueller JL, Dohil R, Broide DH, Aceves SS. The TGFβ1 Promoter SNP C-509T and Food Sensitization Promote Esophageal Remodeling in Pediatric Eosinophilic Esophagitis. PLoS One. 2015 Dec 14;10(12):e0144651. doi: 10.1371/journal.pone.0144651. eCollection 2015.

Furuta GT, Katzka DA. Eosinophilic Esophagitis. N Engl J Med. 2015 Oct 22;373(17):1640-8. doi: 10.1056/NEJMra1502863.

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.

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.

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.

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.

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.

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.