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5101: Longitudinal Study of Urea Cycle Disorders [view study]

  1. Ah Mew N, Krivitzky L, McCarter R, Batshaw M, Tuchman M; Urea Cycle Disorders Consortium of the Rare Diseases Clinical Research Network. Clinical Outcomes of Neonatal Onset Proximal Versus Distal Urea Cycle Disorders Do Not Differ. Journal of Pediatrics. 2013 Feb;162(2):324-9. Epub 2012 Aug 15. PMID: 22901741
  2. The objective of this study was to compare the clinical course and outcome of patients diagnosed with one of 4 neonatal-onset urea cycle disorders (UCDs): deficiency of carbamyl phosphate synthase 1 (CPSD), ornithine transcarbamylase (OTCD), argininosuccinate synthase (ASD), or argininosuccinate lyase (ALD).  Clinical, biochemical, and neuropsychological data from 103 subjects with neonatal-onset UCDs were derived from the Longitudinal Study of Urea Cycle Disorders, an observational protocol of the Urea Cycle Disorders Consortium, one of the Rare Disease Clinical Research Networks.  Some 88% of the subjects presented clinically by age 7 days. Peak ammonia level was 963 μM in patients with proximal UCDs (CPSD or OTCD), compared with 589 μM in ASD and 573 μM in ALD. Roughly 25% of subjects with CPSD or OTCD, 18% of those with ASD, and 67% of those with ALD had a "honeymoon period," defined as the time interval from discharge from initial admission to subsequent admission for hyperammonemia, greater than 1 year. The proportion of patients with a poor outcome (IQ/Developmental Quotient <70) was greatest in ALD (68%), followed by ASD (54%) and CPSD/OTCD (47%). This trend was not significant, but was observed in both patients aged <4 years and those aged ≥ 4 years. Poor cognitive outcome was not correlated with peak ammonia level or duration of initial admission.  Analysis shows that neurocognitive outcomes do not differ between patients with proximal UCDs and those with distal UCDs. Factors other than hyperammonemia may contribute to poor neurocognitive outcome in the distal UCDs.

    Available at: http://www.ncbi.nlm.nih.gov/pubmed/22901741

  3. Wilson JM, Shchelochkov OA, Gallagher RC, Batshaw ML. Hepatocellular carcinoma in a research subject with ornithine transcarbamylase deficiency. Mol. Genet. Metab. Feb 2012;105(2):263-265.

    A 66 year old woman who is a manifesting heterozygote for ornithine transcarbamylase deficiency (OTCD) presented with hepatocellular carcinoma (HCC). Fourteen years prior to this presentation she participated in a phase I gene therapy study which used an adenoviral vector, thought to be non-oncogenic, to deliver a normal OTC gene to hepatocytes [1]. A recent review of data collected through a national longitudinal study of individuals with urea cycle defects [2,3] suggests that early urea cycle disorders (UCDs) are associated with hepatocellular damage and liver dysfunction in many cases. This may predispose an affected individual to a substantially increased risk of developing HCC, as has been observed in certain other inborn errors of metabolism. We speculate that the underlying urea cycle defect may be the cause of HCC in this individual.

    Available at: http://www.ncbi.nlm.nih.gov/pubmed/22129577

  1. Morgan TM, Schlegel C, Edwards KM, et al. Vaccines are not associated with metabolic events in children with urea cycle disorders. Pediatrics. May 2011;127(5):e1147-1153.

    Background: Despite the success of childhood immunizations in prevention of infectious diseases, questions remain about the safety of vaccines in medically fragile children with inborn errors of metabolism such as urea cycle disorders (UCDs). Patients with UCDs are subject to hyperammonemic episodes (HAEs) after infection, fever, or other stressors. Onjective: We sought to assess the risk of HAEs that required urgent care or hospitalization after routine vaccinations in pediatric patients with underlying UCDs. Methods: This was a retrospective investigation of vaccine safety in children with UCDs within the longitudinal Rare Diseases Clinical Research Consortium for UCD. Postvaccination exposure periods were defined as 7 or 21 days after any immunization. The association of vaccines and HAEs was modeled by using conditional Poisson regression, adjusting for age, and using a self-controlled case series method including all patients with >/=1 HAE and with any vaccine exposure. Results: The study enrolled 169 children younger than 18 years. Of these children, 74 had records of at least 1 HAE and at least 1 vaccination. With adjustment for age, there was no increase in relative incidence of HAEs in either the 7-day (1.31 [95% confidence interval (CI): 0.80-2.13]) or 21-day (1.05 [95% CI: 0.74-1.47]) exposure period after vaccination compared with HAEs outside of the vaccination periods. No vaccine type was associated with significantly more HAEs. Conclusions: We found no statistically significant association between childhood immunizations and HAEs in children with UCDs. The results support the safety of immunization in this medically vulnerable population.

    Available at: http://www.ncbi.nlm.nih.gov/pubmed/21482610

  2. Krivitzky LS, Babikian T, Lee HS, Thomas NH, Burke-Paull KL, Batshaw ML. Intellectual, Adaptive, and Behavioral Functioning in Children with Urea Cycle Disorders, Pediatric Research. 2009 Jul;66(1):96-101. PIMD: 19287347

    Inborn errors of urea synthesis lead to an accumulation of ammonia in blood and brain and result in high rates of mortality and neurodevelopmental disability. This study seeks to characterize the cognitive, adaptive, and emotional/behavioral functioning of children with urea cycle disorders (UCDs). These domains were measured through testing and parent questionnaires in 92 children with UCDs [33 neonatal onset (NO), 59 late onset (LO)]. Results indicate that children who present with NO have poorer outcome than those who present later in childhood. Approximately half of the children with NO performed in the range of intellectual disability (ID), including a substantial number ( approximately 30%) who were severely impaired. In comparison, only a quarter of the LO group was in the range of ID. There is also evidence that the UCD group has difficulties in aspects of emotional/behavioral and executive skills domains. In conclusion, children with UCDs present with a wide spectrum of cognitive outcomes. Children with NO disease have a much higher likelihood of having an ID, which becomes even more evident with increasing age. However, even children with LO UCDs demonstrate evidence of neurocognitive and behavioral impairment, particularly in aspects of attention and executive functioning.

    Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19287347/?tool=pubmed

  3. Patrick TB, Richesson RL, Andrews JE, Folk LC. SNOMED CT Coding Variation and Grouping for “other findings” in a Longitudinal Study on Urea Cycle Disorders. AMIA Annu Symp Proc. 2008 Nov 6:11-5. PIMD: 18998949
  4. Semantic interoperability requires consistent use of controlled terminologies. However, non-terminology experts (although perhaps experts in a particular domain) are prone to produce variant coding. We examine this problem by investigating SNOMED CT coding variation for other findings reported on case report forms from a clinical research study on urea cycle disorders. The natural language findings from the forms were normalized, and the associated SNOMED CT concept descriptions were compared. The subset of normalized strings associated with two different concept descriptions were further compared to determine the relationship among the associated SNOMED CT concepts. We found 45% of the concept description pairs were associated with two hierarchically related concepts or with the same concept, while 55% were associated with two unrelated concepts. Clearer guidelines for use of SNOMED CT in particular contexts, or structured data entry tools tailored to the needs of non-expert coders, are needed to better manage coding variation.

    Available at: http://www.ncbi.nlm.nih.gov/pubmed/?term=18998949

  5. Richesson RL, Lee HS, Cuthbertson D, Lloyd J, Young K, Krischer JP. An automated communication system in a contact registry for persons with rare diseases: Scalable tools for identifying and recruiting clinical research participants. Contemp Clin Trials. 2009 Jan;30(1):55-62. Epub 2008 Sep 7. PIMD: 18804556

    OBJECTIVES: Strategies for study recruitment are useful in clinical research network settings. We describe a registry of individuals who have self-identified with one of a multiplicity of rare diseases, and who express a willingness to be contacted regarding possible enrollment in clinical research studies. We evaluate this registry and supporting tools in terms of registry enrollment and impact on participation rates in advertised clinical research studies. METHODS: A web-based automated system generates periodic and customized communications to notify registrants of relevant studies in the NIH Rare Diseases Clinical Research Network (RDCRN). The majority of these communications are sent by email. We compare the characteristics of those enrolled in the registry to the characteristics of participants enrolled in sampled RDCRN studies in order to estimate the impact of the registry on study participation in the network. RESULTS: The registry currently contains over 4000 registrants, representing 40 rare diseases. Estimates of study participation range from 6-27% for all enrollees. Study participation rates for some disease areas are over 40% when considering only contact registry enrollees who live within 100 mi of a clinical research study site. CONCLUSIONS: Automated notifications can facilitate consistent, customized, and timely communication of relevant protocol information to potential research subjects. Our registry and supporting communication tools demonstrate a significant positive impact on study participation rates in our network. The use of the internet and automated notifications make the system scalable to support many protocols and registrants.

    Available at: http://www.ncbi.nlm.nih.gov/pubmed/?term=18804556

  6. Seminara J, Tuchman M, Krivitzky L, et al. Establishing a consortium for the study of rare diseases: The Urea Cycle Disorders Consortium. Mol. Genet. Metab. 2010;100 Suppl 1:S97-105.
  7. The Urea Cycle Disorders Consortium (UCDC) was created as part of a larger network established by the National Institutes of Health to study rare diseases. This paper reviews the UCDC's accomplishments over the first 6years, including how the Consortium was developed and organized, clinical research studies initiated, and the importance of creating partnerships with patient advocacy groups, philanthropic foundations and biotech and pharmaceutical companies.

    Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20188616/?tool=pubmed.

  8. Tuchman M, Lee B, Lichter-Konecki U, Summar ML, Yudkoff M, Cederba um SD, Kerr DS, Diaz GA, Seashore MR, Lee HS, Krischer JP, Batshaw ML and the Urea Cycle Disorders Consortium of the Rare Diseases Clinical Research Network. Cross-sectional multi-center study of patients with urea cycle disorders in the United States. Mol Genet Metab 2008; 94:397-402.

    Inherited urea cycle disorders comprise eight disorders (UCD), each caused by a deficiency of one of the proteins that is essential for ureagenesis. We report on a cross-sectional investigation to determine clinical and laboratory characteristics of patients with UCD in the United States. The data used for the analysis was collected at the time of enrollment of individuals with inherited UCD into a longitudinal observation study. The study has been conducted by the Urea Cycle Disorders Consortium within the Rare Diseases Clinical Research Network (RDCRN) funded by the National Institutes of Health. One-hundred eighty-three patients were enrolled into the study. Ornithine transcarbamylase (OTC) deficiency was the most frequent disorder (55%), followed by argininosuccinic aciduria (16%) and citrullinemia (14%). Seventy-nine percent of the participants were white (16% Latinos), and 6% were African American. Intellectual and developmental disabilities were reported in 39% with learning disabilities (35%) and half had abnormal neurological examination. Sixty-three percent were on a protein restricted diet, 37% were on Na-phenylbutyrate and 5% were on Na-benzoate. Forty-five percent of OTC deficient patients were on L-citrulline, while most patients with citrullinemia (58%) and argininosuccinic aciduria (79%) were on L-arginine. Plasma levels of branched-chain amino acids were reduced in patients treated with ammonia scavenger drugs. Plasma glutamine levels were higher in proximal UCD and in neonatal type disease. The RDCRN allows comprehensive analyses of rare inherited UCD, their frequencies and current medical practices.

    Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2640937/?tool=pubmed.

 

5102: A Randomized, Double-Blind, Crossover Study of Sodium Phenylbutyrate (BuphenylT) and Low-Dose Arginine (100 mg/kg/day) Compared to High-Dose Arginine (500mg/kg/day) Alone on Liver Function, Ureagenesis and Subsequent Nitric Oxide Production in Patients with Argininosuccinic Aciduria (ASA) ) [view study]

  1. Nagamani SC, Shchelochkov OA, Mullins MA, Carter S, Lanpher BC, Sun Q, Kleppe S, Erez A, O'Brian Smith E, Marini JC; Members of the Urea Cycle Disorders Consortium, Lee B. A Randomized Controlled Trial to Evaluate the Effects of High-Dose Versus Low-Dose of Arginine Therapy on Liver Function Tests in Argininosuccinic Aciduria. Mol Genet Metab. 2012 Nov;107(3):315-21. Epub 2012 Sep 17. PMID: 23040521

    This study compares the effects of combinatorial therapy with low-dose arginine and a nitrogen scavenging agent (sodium phenylbutyrate) vs. monotherapy with high-dose arginine on liver function tests in patients with argininosuccinic aciduria (ASA).Twelve patients with ASA were enrolled in a double-blind, placebo-controlled, cross-over study design. Subjects were randomized to receive either a low-dose of arginine therapy (100 mg · kg(-1) · d(-1)) combined with sodium phenylbutyrate (500 mg · kg(-1) · d(-1)) (LDA arm) or a high-dose of arginine alone (500 mg · kg(-1) · d(-1)) (HDA arm) for one week. At the end of one week of therapy, liver function tests were assessed and metabolite fluxes were measured using a multi-tracer stable isotope protocol. Plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT), and measures of synthetic functions of the liver were the primary outcomes. Subjects had significantly increased levels of argininosuccinate (P<0.03) and AST levels (P<0.01) after treatment with high-dose arginine. In the subset of subjects with elevated AST or ALT, treatment with high-dose of arginine was associated with further increases in plasma levels of both aminotransferases. Whereas subjects had increased arginine and citrulline flux with high-dose arginine therapy, the glutamine flux was not different between the two treatment arms. The synthetic liver functions as assessed by prothrombin time, INR, and coagulation factor levels were not different between the HDA and LDA arms. This study demonstrates that dministering higher doses of arginine in subjects with ASA results in increases in AST and ALT levels, especially in the subset of patients with elevated baseline aminotransferases. Hence, low-dose arginine sufficient to normalize arginine levels in plasma combined with nitrogen scavenging therapy should be considered as a therapeutic option for treatment of ASA in patients with elevations of hepatic aminotransferases.

    Available at: http://www.ncbi.nlm.nih.gov/pubmed/23040521

 

5104: Assessing Neural Mechanisms of injury in inborn errors of urea metabolism using Structural MRI, Functional MRI, and Magnetic Resonance Spectroscopy [view study]

  1. Gropman AL, Gertz B, Shattuck K, Kahn IL, Seltzer R, Krivitsky L, Van Meter J (2010). "Diffusion Tensor Imaging Detects areas of abnormal white matter microstructure in patients with partial Ornithine Transcarbamylase Deficiency (OTCD)" [accepted for publication in the AJNR].
  2. BACKGROUND AND PURPOSE: OTCD, an X-linked disorder, is the most common of the UCDs. Neonatal onset is associated with uniformly poor outcome. Males with late-onset OTCD show deficits in executive function, motor planning, and working memory. A broad phenotype is observed in heterozygous females. A specific neurobehavioral phenotype with white matter dysfunction and impaired attention and working memory has been described. The extent to which the deficits involve specific pathways in the brain is unknown. We hypothesized that DTI would disclose white matter microstructure in OTCD correlating with cognitive deficits. MATERIALS AND METHODS: Nineteen adults with partial OTCD and 18 adult control subjects ages 19-59 years participated. MR imaging was performed by using a 3T whole-body scanner. Anisotropy was calculated from the eigenvalues of the diffusion tensor by using the FA metric and was compared between the study and control groups. RESULTS: FA of the frontal white matter was significantly decreased in subjects, indicating changes in white matter microstructure. There was an inverse relationship between FA and disease severity, but not with age. CONCLUSIONS: Findings of MR imaging in OTCD are often normal in patients with late-onset disease, heterozygotes, or in those not in hyperammonemic crisis. DTI was more sensitive than FSE T2-weighted imaging for detecting abnormalities in normal-appearing white matter. The extent of abnormality correlated with cognitive deficits. The location of the deficits in the frontal white matter is important because this area connects fibers that are vital to executive function, attention, and working memory.

    Available at: http://www.ncbi.nlm.nih.gov/pubmed/20488904

  3. Gropman A. Brain imaging in urea cycle disorders. Mol Genet Metab. 2010 Feb 13. [Epub ahead of print]
  4. Urea cycle disorders (UCD) represent a group of rare inborn errors of metabolism that carry a high risk of mortality and neurological morbidity resulting from the effects of accumulation of ammonia and other biochemical intermediates. These disorders result from single gene defects involved in the detoxification pathway of ammonia to urea. UCD include deficiencies in any of the six enzymes and two membrane transporters involved in urea biosynthesis. It has previously been reported that approximately half of infants who present with hyperammonemic coma in the newborn period die of cerebral edema; and those who survive 3days or more of coma invariably have intellectual disability [1]. In children with partial defects there is an association between the number and severity of recurrent hyperammonemic (HA) episodes (i.e. with or without coma) and subsequent cognitive and neurologic deficits [2]. However, the effects of milder or subclinical HA episodes on the brain are largely unknown. This review discusses the results of neuroimaging studies performed as part of the NIH funded Rare Diseases Clinical Research Center in Urea Cycle Disorders and focuses on biomarkers of brain injury in ornithine transcarbamylase deficiency (OTCD). We used anatomic imaging, functional magnetic resonance imaging (fMRI), diffusion-tensor imaging (DTI), and (1)H/(13)C magnetic resonance spectroscopy (MRS) to study clinically stable adults with partial OTCD. This allowed us to determine alterations in brain biochemistry associated with changes in cell volume and osmolarity and permitted us to identify brain biomarkers of HA. We found that white matter tracts underlying specific pathways involved in working memory and executive function are altered in subjects with OTCD (as measured by DTI), including those heterozygous women who were previously considered asymptomatic. An understanding of the pathogenesis of brain injury in UCD is likely to advance our knowledge of more common disorders of liver dysfunction.

    Available at : http://www.ncbi.nlm.nih.gov/pubmed/20207564

  5. Gropman AL, Fricke ST, Seltzer RR, Hailu A, Adeyemo A, Sawyer A, van Meter J, Gaillard WD, McCarter R, Tuchman M, Batshaw M; Urea Cycle Disorders Consortium. 1H MRS identifies symptomatic and asymptomatic subjects with partial ornithine transcarbamylase deficiency. Mol Genet Metab. 2008 95(1-2):21-30.
  6. We used (1)H MRS to evaluate brain metabolic differences in sisters with partial ornithine transcarbamylase deficiency (OTCD) who had discordant clinical symptoms and urea synthetic capabilities to assess whether a brain biomarker of partial OTCD correlated with urea synthetic ability and clinical severity. We performed single voxel 3.0T (1)H MRS in two adult sisters with partial OTCD, one symptomatic and one asymptomatic, in a stable medical state and compared it to one age matched adult control, as well as data collected on an additional 13 subjects with partial OTCD and 12 controls. Data from voxels placed in frontal and parietal white matter (FWM, PWM), posterior cingulate gray matter (PCGM), and thalamus (tha), were corrected for partial volume and analyzed using "LCModel". All three subjects as well as the symptomatic mother of the two sisters, had neurocognitive testing, plasma ammonia levels, plasma amino acid, and urine organic acid analysis. Previous urea synthetic capabilities had been measured by stable isotope analysis. We found IQ scores to be inversely related to symptoms. Decreased myoinositol (mI) identified OTCD subjects, even the sister who is asymptomatic, in the posterior parietal white matter and frontal white matter. Brain metabolism is impaired in partial OTCD. Abnormal metabolism in apparently asymptomatic OTCD females may provide an explanation for neurocognitive impairments previously reported. The concentration of mI seen on (1)H MRS in PWM and FWM in this family could be used to deduce clinical symptomatology and may serve as a non-invasive marker of brain liability in OTCD.

    Available at: http://www.ncbi.nlm.nih.gov/pubmed/18262815

  7. Gropman AL, Seltzer RR, Yudkoff M, Sawyer A, VanMeter J, Fricke ST. 1H MRS allows brain phenotype differentiation in sisters with late onset ornithine transcarbamylase deficiency (OTCD) and discordant clinical presentations. Mol Genet Metab. 2008 94(1):52-60.
  8. OBJECTIVE: To evaluate brain metabolism in subjects with partial ornithine transcarbamylase deficiency (OTCD) utilizing (1)H MRS. METHODS: Single-voxel (1)H MRS was performed on 25 medically-stable adults with partial OTCD, and 22 similarly aged controls. Metabolite concentrations from frontal and parietal white matter (FWM, PWM), frontal gray matter (FGM), posterior cingulate gray matter (PCGM), and thalamus (tha) were compared with controls and IQ, plasma ammonia, glutamine, and disease severity. RESULTS: Cases ranged from 19 to 59 years; average 34 years; controls ranged from 18 to 59 years; average 33 years. IQ scores were lower in cases (full scale 111 vs. 126; performance IQ 106 vs. 117). Decreased myoinositol (mI) in FWM (p=0.005), PWM (p<0.001), PCGM (p=0.003), and tha (p=0.004), identified subjects with OTCD, including asymptomatic heterozygotes. Glutamine (gln) was increased in FWM (p<0.001), PWM (p<0.001), FGM (p=0.002), and PCGM (p=0.001). Disease severity was inversely correlated with [mI] in PWM (r=-0.403; p=0.046) and directly correlated with [gln] in PCGM (r=0.548; p=0.005). N-Acetylaspartate (NAA) was elevated in PWM (p=0.002); choline was decreased in FWM (p=0.001) and tha (p=0.002). There was an inverse relationship between [mI] and [gln] in cases only. Total buffering capacity (measured by [mI/mI+gln] ratio, a measure of total osmolar capacity) was inversely correlated with disease severity in FWM (r=-0.479; p=0.018), PWM (r=-0.458; p=0.021), PCGM (r=-0.567; p=0.003), and tha (r=-0.345; p=0.037). CONCLUSION: Brain metabolism is impaired in partial OTCD. Depletion of mI and total buffering capacity are inversely correlated with disease severity, and serve as biomarkers.

    Available at: http://www.ncbi.nlm.nih.gov/pubmed/18662894

  9. Gropman AL, Summar M, Leonard JV. Neurological implications of urea cycle disorders. J Inherit Metab Dis. 2007 30(6):865-79.
  10. The urea cycle disorders constitute a group of rare congenital disorders caused by a deficiency of the enzymes or transport proteins required to remove ammonia from the body. Via a series of biochemical steps, nitrogen, the waste product of protein metabolism, is removed from the blood and converted into urea. A consequence of these disorders is hyperammonaemia, resulting in central nervous system dysfunction with mental status changes, brain oedema, seizures, coma, and potentially death. Both acute and chronic hyperammonaemia result in alterations of neurotransmitter systems. In acute hyperammonaemia, activation of the NMDA receptor leads to excitotoxic cell death, changes in energy metabolism and alterations in protein expression of the astrocyte that affect volume regulation and contribute to oedema. Neuropathological evaluation demonstrates alterations in the astrocyte morphology. Imaging studies, in particular (1)H MRS, can reveal markers of impaired metabolism such as elevations of glutamine and reduction of myoinositol. In contrast, chronic hyperammonaemia leads to adaptive responses in the NMDA receptor and impairments in the glutamate-nitric oxide-cGMP pathway, leading to alterations in cognition and learning. Therapy of acute hyperammonaemia has relied on ammonia-lowering agents but in recent years there has been considerable interest in neuroprotective strategies. Recent studies have suggested restoration of learning abilities by pharmacological manipulation of brain cGMP with phosphodiesterase inhibitors. Thus, both strategies are intriguing areas for potential investigation in human urea cycle disorders.

    Available at: http://www.ncbi.nlm.nih.gov/pubmed/18038189

  11. Gropman AL. Expanding the diagnostic and research toolbox for inborn errors of metabolism: the role of magnetic resonance spectroscopy. Mol Genet Metab. 2005 86(1-2):2-9.
  12. Available at http://www.ncbi.nlm.nih.gov/pubmed/?term=16276565

  13. Gropman AL, Batshaw ML. Cognitive outcome in urea cycle disorders. Mol Genet Metab. 2004 Apr;81 Suppl 1:S58-62.
  14. Despite treatment, cognitive and motor deficits are common in individuals with inherited urea cycle disorders. However, the extent to which the deficits involve specific cognitive or sensorimotor domains is unknown. Furthermore, little is known about the neurochemical basis of cognitive impairment in these disorders. This paper reviews studies of cognitive and motor dysfunction in urea cycle disorders, and discusses potential venues for investigation of the underlying neural basis that may elucidate these defects. Such methods of investigation may serve as a model for studying the relationship between genes, biochemical markers, brain function, and behavior in other metabolic diseases.

    Available at http://www.ncbi.nlm.nih.gov/pubmed/?term=15050975

  15. Gropman AL, Sailasuta N, Harris KC, Abulseoud O, Ross BD. Ornithine transcarbamylase deficiency with persistent abnormality in cerebral glutamate metabolism in adults. Radiology. 2009 252(3):833-41.
  16. PURPOSE: To determine cerebral glutamate turnover rate in partial-ornithine transcarbamylase deficiency (OTCD) patients by using carbon 13 ((13)C) magnetic resonance (MR) spectroscopy. MATERIALS AND METHODS: The study was performed with approval of the institutional review board, in compliance with HIPAA regulations, and with written informed consent of the subjects. MR imaging, hydrogen 1 ((1)H) MR spectroscopy, and (13)C MR spectroscopy were performed at 1.5 T in 10 subjects, six patients with OTCD and four healthy control subjects, who were in stable condition. Each received intravenous (13)C-glucose (0.2 g/kg), C1 or C2 position, as a 15-minute bolus. Cerebral metabolites were determined with proton decoupling in a parieto-occipital region (n = 9) and without proton decoupling in a frontal region (n = 1) during 60-120 minutes. RESULTS: Uptake and removal of cerebral glucose ([1-(13)C]-glucose or [2-(13)C]-glucose) were comparable in healthy control subjects and subjects with OTCD (P = .1). Glucose C1 was metabolized to glutamate C4 and glucose C2 was metabolized to glutamate C5 at comparable rates, both of which were significantly reduced in OTCD (combined, P = .04). No significant differences in glutamine formation were found in subjects with OTCD (P = .1). [2-(13)C]-glucose and its metabolic products were observed in anterior cingulate gyrus without proton decoupling in one subject with OTCD. CONCLUSION: Treatments that improve cerebral glucose metabolism and glutamate neurotransmission may improve neurologic outcome in patients with OTCD, in whom prevention and treatment of hyperammonemic episodes appear to be insufficient.

    Available at: http://www.ncbi.nlm.nih.gov/pubmed/19567648

  17. Oldham MS, VanMeter JW, Shattuck KF, Cederbaum SD, Gropman AL (2010). Diffusion tensor imaging in arginase deficiency reveals damage to corticospinal tracts. Pediatr Neurol 42(1):49-52.
  18. Individuals with a proximal urea cycle disorder, such as carbamoyl phosphate synthetase deficiency 1 or ornithine transcarbamylase deficiency, may present with encephalopathy resulting from hyperammonemia. The clinical presentation of arginase deficiency is considerably different, characterized by progressive spasticity involving the lower extremities and usually dementia. Diagnosis may be delayed, and patients are often thought to have cerebral palsy. The true etiology of brain injury in arginase deficiency is unknown, but is not thought to be due to hyperammonemia and brain swelling, the mechanism of injury recognized in ornithine transcarbamylase deficiency. Elevated arginine could augment nitric oxide synthesis, leading to oxidative damage. The hypothesis for the present study was that specific brain vulnerability in arginase deficiency would involve microstructural alterations in corticospinal tracts and that this finding, as measured by diffusion tensor imaging, would differ from age-matched control subjects and those with ornithine transcarbamylase deficiency. Diffusion tensor imaging data were compared for a 17-year-old male patient with arginase deficiency, age-matched normal control subjects, and age-matched individuals with ornithine transcarbamylase deficiency. Significant differences were found in suspected areas of interest, specifically in the corticospinal tracts. This finding confirms the hypothesis that the mechanism of injury in arginase deficiency, although still unknown, is unlikely to be similar to that causing ornithine transcarbamylase deficiency.

    http://www.ncbi.nlm.nih.gov/pubmed/20004862

  19. Sailasuta N, Robertson LW, Harris KC, Gropman AL, Allen PS, Ross BD (2008). Clinical NOE (13) C MRS for neuropsychiatric disorders of the frontal lobe. J Magn Reson. 195(2):219-225.

    In this communication, a scheme is described whereby in vivo (13)C MRS can safely be performed in the frontal lobe, a human brain region hitherto precluded on grounds of SAR, but important in being the seat of impaired cognitive function in many neuropsychiatric and developmental disorders. By combining two well known features of (13)C NMR-the use of low power NOE and the focus on (13)C carbon atoms which are only minimally coupled to protons, we are able to overcome the obstacle of SAR and develop means of monitoring the (13)C fluxes of critically important metabolic pathways in frontal brain structures of normal volunteers and patients. Using a combination of low-power WALTZ decoupling, variants of random noise for nuclear overhauser effect enhancement it was possible to reduce power deposition to 20% of the advised maximum specific absorption rate (SAR). In model solutions (13)C signal enhancement achieved with this scheme were comparable to that obtained with WALTZ-4. In human brain, the low power procedure effectively determined glutamine, glutamate and bicarbonate in the posterior parietal brain after [1-(13)C] glucose infusion. The same (13)C enriched metabolites were defined in frontal brain of human volunteers after administration of [1-(13)C] acetate, a recognized probe of glial metabolism. Time courses of incorporation of (13)C into cerebral glutamate, glutamine and bicarbonate were constructed. The results suggest efficacy for measurement of in vivo cerebral metabolic rates of the glutamate-glutamine and tricarboxylic acid cycles in 20 min MR scans in previously inaccessible brain regions in humans at 1.5 T. We predict these will be clinically useful biomarkers in many human neuropsychiatric and genetic conditions.

    Available at: http://www.ncbi.nlm.nih.gov/pubmed/18829354

  20. Gropman AL & Rigas A. Neurometabolic disorders: urea-cycle disorder, outcomes, development and treatment. Pediatric Health 2008, 2 (6): 701-713

    Available at: http://go.galegroup.com/ps/i.do?id=GALE%7CA225220972&v
    =2.1&u=tamp59176&it=r&p=ITOF&sw=w
    .

 

5105: N-carbamylglutamate (NCLG) Effect on ureagenesis in N-acetylglutamate synthase (NAGS) deficiency

  1. Marc Yudkoff, MD, Nicholas Ah Mew, Irma Payan, CRNP, Yevgeny Daikhin, MD, Ilana Nissim, Itzhak Nissim, PhD, and Mendel Tuchman, MD. Effects of a single dose of N-carbamylglutamate on the rate of ureagenesis. Mol. Genet. Metab. Dec 2009;98(4):325-330.

    We studied the effect on ureagenesis of a single dose of N-carbamylglutamate (NCG) in healthy young adults who received a constant infusion (300 min) of NaH(13)CO(3). Isotope ratio-mass spectrometry was used to measure the appearance of label in [(13)C]urea. At 90 min after initiating the H(13)CO3-infusion each subject took a single dose of NCG (50 mg/kg). In 5/6 studies the administration of NCG increased the formation of [(13)C]urea. Treatment with NCG significantly diminished the concentration of blood alanine, but not that of glutamine or arginine. The blood glucose concentration was unaffected by NCG administration. No untoward side effects were observed. The data indicate that treatment with NCG stimulates ureagenesis and could be useful in clinical settings of acute hyperammonemia of various etiologies.

    Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19660971/?tool=pubmed

 

5107: Investigation of Brain Nitrogen Metabolism in Partial Ornithine Transcarbamylase Deficiency (OTCD) Using 1H MRS, DTI, and fMRI [View Study]

  1. Gropman AL, Shattuck K, Prust MJ, et al. Altered neural activation in ornithine transcarbamylase deficiency during executive cognition: An fMRI study. Hum. Brain Mapp. Nov 23 2011.

    Background: Ornithine transcarbamylase deficiency (OTCD) is an X-linked urea cycle disorder characterized by hyperammonemia resulting in white matter injury and impairments in working memory and executive cognition. Objective: To test for differences in BOLD signal activation between subjects with OTCD and healthy controls during a working memory task. Design, setting and patients: Nineteen subjects with OTCD and 21 healthy controls participated in a case-control, IRB-approved study at Georgetown University Medical Center. Intervention: An N-back working memory task was performed in a block design using 3T functional magnetic resonance imaging. Results: In subjects with OTCD we observed increased BOLD signal in the right dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) relative to healthy age matched controls. Conclusions: Increased neuronal activation in OTCD subjects despite equivalent task performance points to sub-optimal activation of the working memory network in these subjects, most likely reflecting damage caused by hyperammonemic events. These increases directly relate to our previous finding of reduced frontal white matter integrity in the superior extents of the corpus callosum; key hemispheric connections for these areas. Future studies using higher cognitive load are required to further characterize these effects. Hum Brain Mapp, 2011. (c) 2011 Wiley Periodicals, Inc.

    This article is not yet publically available. Please contact UCDC Program Manager Jennifer Seminara (jseminar@childrensnational.org) for a copy of this article.

  2. Gropman AL, Fricke ST, Seltzer RR, Hailu A, Adeyemo A, Sawyer A, van Meter J, Gaillard WD, McCarter R, Tuchman M, Batshaw M; Urea Cycle Disorders Consortium.  1H MRS Identifies Symptomatic and Asymptomatic Subjects with Partial Ornithine Transcarbamylase Deficiency.  Journal of Molecular Genetics and Metabolism. 2008 Sep-Oct;95(1-2):21-30. doi: 10.1016/j.ymgme.2008.06.003. Epub 2008 Jul 26. PMID: 18662894
  3. This study evaluates brain metabolism in subjects with partial ornithine transcarbamylase deficiency (OTCD) utilizing (1)H MRS.  Single-voxel (1)H MRS was performed on 25 medically-stable adults with partial OTCD, and 22 similarly aged controls. Metabolite concentrations from frontal and parietal white matter (FWM, PWM), frontal gray matter (FGM), posterior cingulate gray matter (PCGM), and thalamus (tha) were compared with controls and IQ, plasma ammonia, glutamine, and disease severity.  Cases ranged from 19 to 59 years; average 34 years; controls ranged from 18 to 59 years; average 33 years. IQ scores were lower in cases (full scale 111 vs. 126; performance IQ 106 vs. 117). Decreased myoinositol (mI) in FWM (p=0.005), PWM (p<0.001), PCGM (p=0.003), and tha (p=0.004), identified subjects with OTCD, including asymptomatic heterozygotes. Glutamine (gln) was increased in FWM (p<0.001), PWM (p<0.001), FGM (p=0.002), and PCGM (p=0.001). Disease severity was inversely correlated with [mI] in PWM (r=-0.403; p=0.046) and directly correlated with [gln] in PCGM (r=0.548; p=0.005). N-Acetylaspartate (NAA) was elevated in PWM (p=0.002); choline was decreased in FWM (p=0.001) and tha (p=0.002). There was an inverse relationship between [mI] and [gln] in cases only. Total buffering capacity (measured by [mI/mI+gln] ratio, a measure of total osmolar capacity) was inversely correlated with disease severity in FWM (r=-0.479; p=0.018), PWM (r=-0.458; p=0.021), PCGM (r=-0.567; p=0.003), and tha (r=-0.345; p=0.037).  Results show that brain metabolism is impaired in partial OTCD. Depletion of mI and total buffering capacity are inversely correlated with disease severity, and serve as biomarkers.

    Available at: http://www.ncbi.nlm.nih.gov/pubmed/18662894

  4. Gropman AL, Gertz B, Shattuck K, Kahn IL, Seltzer R, Krivitsky L, Van Meter J. Diffusion Tensor Imaging Detects Areas of Abnormal White Matter Microstructure in Patients with Partial Ornithine Transcarbamylase Deficiency. American Journal of Neuroradiology. 2010 Oct;31(9):1719-23. doi: 10.3174/ajnr.A2122. PMID:20488904
  5. OTCD, an X-linked disorder, is the most common of the UCDs. Neonatal onset is associated with uniformly poor outcome. Males with late-onset OTCD show deficits in executive function, motor planning, and working memory. A broad phenotype is observed in heterozygous females. A specific neurobehavioral phenotype with white matter dysfunction and impaired attention and working memory has been described. The extent to which the deficits involve specific pathways in the brain is unknown. We hypothesized that DTI would disclose white matter microstructure in OTCD correlating with cognitive deficits.  Nineteen adults with partial OTCD and 18 adult control subjects ages 19-59 years participated. MR imaging was performed by using a 3T whole-body scanner. Anisotropy was calculated from the eigenvalues of the diffusion tensor by using the FA metric and was compared between the study and control groups.  FA of the frontal white matter was significantly decreased in subjects, indicating changes in white matter microstructure. There was an inverse relationship between FA and disease severity, but not with age.  Findings of MR imaging in OTCD are often normal in patients with late-onset disease, heterozygotes, or in those not in hyperammonemic crisis. DTI was more sensitive than FSE T2-weighted imaging for detecting abnormalities in normal-appearing white matter. The extent of abnormality correlated with cognitive deficits. The location of the deficits in the frontal white matter is important because this area connects fibers that are vital to executive function, attention, and working memory.

    Available at: http://www.ncbi.nlm.nih.gov/pubmed/20488904

  6. Gropman AL, Shattuck K, Prust MJ, et al. Altered neural activation in ornithine transcarbamylase deficiency during executive cognition: An fMRI study. Human Brain Mapping. 2013 Apr;34(4):753-61. doi: 10.1002/hbm.21470. Epub 2011 Nov 23. PMID: 22110002

    Background: Ornithine transcarbamylase deficiency (OTCD) is an X-linked urea cycle disorder characterized by hyperammonemia resulting in white matter injury and impairments in working memory and executive cognition. Objective: To test for differences in BOLD signal activation between subjects with OTCD and healthy controls during a working memory task. Design, setting and patients: Nineteen subjects with OTCD and 21 healthy controls participated in a case-control, IRB-approved study at Georgetown University Medical Center. Intervention: An N-back working memory task was performed in a block design using 3T functional magnetic resonance imaging. Results: In subjects with OTCD we observed increased BOLD signal in the right dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) relative to healthy age matched controls. Conclusions: Increased neuronal activation in OTCD subjects despite equivalent task performance points to sub-optimal activation of the working memory network in these subjects, most likely reflecting damage caused by hyperammonemic events. These increases directly relate to our previous finding of reduced frontal white matter integrity in the superior extents of the corpus callosum; key hemispheric connections for these areas. Future studies using higher cognitive load are required to further characterize these effects. Hum Brain Mapp, 2011. (c) 2011 Wiley Periodicals, Inc.

    Available at: http://www.ncbi.nlm.nih.gov/pubmed/22110002

 

UCDC Publications

  1. Seminara J, Tuchman M, Krivitzky L, et al. Establishing a consortium for the study of rare diseases: The Urea Cycle Disorders Consortium. Mol. Genet. Metab. 2010;100 Suppl 1:S97-105.

    The Urea Cycle Disorders Consortium (UCDC) was created as part of a larger network established by the National Institutes of Health to study rare diseases. This paper reviews the UCDC's accomplishments over the first 6years, including how the Consortium was developed and organized, clinical research studies initiated, and the importance of creating partnerships with patient advocacy groups, philanthropic foundations and biotech and pharmaceutical companies.

 

Related Publications

  1. Jain-Ghai S, Nagamani SC, Blaser S, Siriwardena K, Feigenbaum A. Arginase I deficiency: severe infantile presentation with hyperammonemia: more common than reported? Mol. Genet. Metab. Sep-Oct 2011;104(1-2):107-111.

    Enzyme defects of the urea cycle typically present with significant hyperammonemia and its associated toxicity, in the first few months of life. However, arginase I (ARG1) deficiency, a rare autosomal recessive disorder, has classically been the exception. ARG1 deficiency usually presents later in life with spasticity, seizures, failure to thrive and developmental regression. Neonatal and early infantile presentation of ARG1 deficiency with severe hyperammonemia remains rare and only six such cases have been described. We report a severely affected infant with ARG1 deficiency who presented at 6 weeks of age with lethargy, poor feeding and severe encephalopathy caused by hyperammonemia. The clinical and biochemical features of the proband and six other previously reported cases with neonatal or infantile-onset presentation of ARG1 deficiency with hyperammonemia are reviewed. In addition, the clinical spectrum of seven previously unpublished patients with later onset ARG1 deficiency, who also experienced recurrent hyperammonemia, is presented. Several biochemical abnormalities have been postulated to play a role in the pathogenesis of the neurological changes in ARG1 deficiency including hyperargininemia, elevated guanidino compounds and elevated glutamine levels, as well as the hyperammonemia. The index case demonstrated many of these. The cases reviewed here suggest a genotype/phenotype correlation and advocate for the addition of arginine as a primary target in newborn screening programs.

    Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3171515/

  2. Lichter-Konecki U, Diaz GA, Merritt JL 2nd, Feigenbaum A, Jomphe C, Marier JF, Beliveau M, Mauney J, Dickinson K, Martinez A, Mokhtarani M, Scharschmidt B, Rhead W. Ammonia control in children with urea cycle disorders (UCDs); phase 2 comparison of sodium phenylbutyrate and glycerol phenylbutyrate. Journal of Molecular Genetics and Metabolism. 2011 Aug;103(4):323-9. doi: 10.1016/j.ymgme.2011.04.013. Epub 2011 May 5. PMID:21612962
  3. Twenty four hour ammonia profiles and correlates of drug effect were examined in a phase 2 comparison of sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB or HPN-100), an investigational drug being developed for urea cycle disorders (UCDs).  Protocol HPN-100-005 involved open label fixed-sequence switch-over from the prescribed NaPBA dose to a PBA-equimolar GPB dose with controlled diet. After 7 days on NaPBA or GPB, subjects underwent 24-hour blood sampling for ammonia and drug metabolite levels as well as measurement of 24-hour urinary phenyacetylglutamine (PAGN). Adverse events (AEs), safety labs and triplicate ECGs were monitored.  Eleven subjects (9 OTC, 1 ASS, 1 ASL) enrolled and completed the switch-over from NaPBA (mean dose=12.4 g/d or 322 mg/kg/d; range=198-476 mg/kg/d) to GPB (mean dose=10.8 mL or 0.284 mL/kg/d or 313 mg/kg/d; range=192-449 mg/kg/d). Possibly-related AEs were reported in 2 subjects on NaPBA and 4 subjects on GPB. All were mild, except for one moderate AE of vomiting on GPB related to an intercurrent illness. No clinically significant laboratory or ECG changes were observed. Ammonia was lowest after overnight fast, peaked postprandially in the afternoon to early evening and varied widely over 24h with occasional values >100 μmol/L without symptoms. Ammonia values were ~25% lower on GPB vs. NaPBA (p≥0.1 for ITT and p<0.05 for per protocol population). The upper 95% confidence interval for the difference between ammonia on GPB vs. NaPBA in the ITT population (95% CI 0.575, 1.061; p=0.102) was less than the predefined non-inferiority margin of 1.25 and less than 1.0 in the pre-defined per-protocol population (95% CI 0.516, 0.958; p<0.05). No statistically significant differences were observed in plasma phenylacetic acid and PAGN exposure during dosing with GPB vs. NaPBA, and the percentage of orally administered PBA excreted as PAGN (66% for GPB vs. 69% for NaPBA) was very similar. GPB and NaPBA dose correlated best with urinary-PAGN.  These findings suggest that GPB is at least equivalent to NaPBA in terms of ammonia control, has potential utility in pediatric UCD patients and that U-PAGN is a clinically useful biomarker for dose selection and monitoring.

    Available at: http://www.ncbi.nlm.nih.gov/pubmed/21612962

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