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

  1. 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.

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

  2. 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.

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

  3. 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.

  4. 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

  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

  6. Schlegel, C; Edwards, KM; Morgan, T; Welch-Burke, T; Lee, Hye-Seung; Urea Cycle Disorders Consortium; Summar, M. No association of Vaccines and Hyperammonemic Events in Children With Urea Cycle Disorders (UCD) (In press)

  7. 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.

    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.

 

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. Gropman A. Brain imaging in urea cycle disorders. Mol Genet Metab. 2010 Feb 13. [Epub ahead of print]

  3. 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.

  4. 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.

  5. Gropman AL, Summar M, Leonard JV. Neurological implications of urea cycle disorders. J Inherit Metab Dis. 2007 30(6):865-79.

  6. 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.

  7. Gropman AL, Batshaw ML. Cognitive outcome in urea cycle disorders. Mol Genet Metab. 2004 Apr;81 Suppl 1:S58-62.

  8. 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.

  9. 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.

  10. 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.

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

 

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.

 

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.

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

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