Skip to main content
SpringerLink
Log in

Improving long term outcomes in urea cycle disorders-report from the Urea Cycle Disorders Consortium

  • SSIEM 2015
  • Published:
Journal of Inherited Metabolic Disease

Abstract

The Urea Cycle Disorders Consortium (UCDC) has conducted, beginning in 2006, a longitudinal study (LS) of eight enzyme deficiencies/transporter defects associated with the urea cycle. These include N-acetylglutamate synthase deficiency (NAGSD); Carbamyl phosphate synthetase 1 deficiency (CPS1D); Ornithine transcarbamylase deficiency (OTCD); Argininosuccinate synthetase deficiency (ASSD) (Citrullinemia); Argininosuccinate lyase deficiency (ASLD) (Argininosuccinic aciduria); Arginase deficiency (ARGD, Argininemia); Hyperornithinemia, hyperammonemia, homocitrullinuria (HHH) syndrome (or mitochondrial ornithine transporter 1 deficiency [ORNT1D]); and Citrullinemia type II (mitochondrial aspartate/glutamate carrier deficiency [CITRIN]). There were 678 UCD patients enrolled in 14 sites in the U.S., Canada, and Europe at the writing of this paper. This review summarizes findings of the consortium related to outcome, focusing primarily on neuroimaging findings and neurocognitive function. Neuroimaging studies in late onset OTCD offered evidence that brain injury caused by biochemical dysregulation may impact functional neuroanatomy serving working memory processes, an important component of executive function and regulation. Additionally, there were alteration in white mater microstructure and functional connectivity at rest. Intellectual deficits in OTCD and other urea cycle disorders (UCD) vary. However, when neuropsychological deficits occur, they tend to be more prominent in motor/performance areas on both intelligence tests and other measures. In some disorders, adults performed significantly less well than younger patients. Further longitudinal follow-up will reveal whether this is due to declines throughout life or to improvements in diagnostics (especially newborn screening) and treatments in the younger generation of patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Albrecht J, Zielińska M, Norenberg MD (2010) Glutamine as a mediator of ammonia neurotoxicity: a critical appraisal. Biochem Pharmacol 80:1303–1308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Batshaw ML, Brusilow SW, Waber L et al (1982) Treatment of inborn errors of urea synthesis: activation of alternate pathways of waste nitrogen synthesis and excretion. N Engl J Med 306:1387–1392

    Article  CAS  PubMed  Google Scholar 

  • Batshaw ML, Msall M, Beaudet AL, Trojak J (1986) Risk of serious illness in heterozygotes for ornithine transcarbamylase deficiency. J Pediatr 108(2):236–241

    Article  CAS  PubMed  Google Scholar 

  • Batshaw ML, MacArthur RB, Tuchman M (2001) Alternative pathway therapy for urea cycle disorders: twenty years later. J Pediatr 138:S46–S55

    Article  CAS  PubMed  Google Scholar 

  • Batshaw ML, Tuchman M, Summar M, Seminara J, Members of the Urea Cycle Disorders Consortium (2014) A longitudinal study of urea cycle disorders. Mol Genet Metab 113(1-2):127–130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brusilow SW, Batshaw ML, Valle D (1979) New pathways of waste nitrogen excretion in inborn errors of urea synthesis. Lancet 2:452–454

    Article  CAS  PubMed  Google Scholar 

  • Campeau PM, Pivalizza PJ, Miller G, McBride K, Karpen S, Goss J, Lee BH (2010) Early orthotopic liver transplantation in urea cycle defects: follow up of a developmental outcome study. Mol Genet Metab 100(Suppl 1):S84–S87

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gropman AL, Fricke ST, Seltzer RR et al (2008) 1H MRS identifies symptomatic and asymptomatic subjects with partial ornithine transcarbamylase deficiency. Mol Genet Metab 95:21–30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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. AJNR 31:1719–1723

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gropman AL, Shattuck K, Prust MJ et al (2013) Altered neural activation in ornithine transcarbamylase deficiency during executive cognition: an fMRI study. Hum Brain Mapp 34:753–761

    Article  PubMed  Google Scholar 

  • Gyato K, Wray J, Huang ZJ, Yudkoff M, Batshaw ML (2004) Metabolic and neuropsychological phenotype in women heterozygous for ornithine transcarbamylase deficiency. Ann Neurol 55:80–86

    Article  PubMed  Google Scholar 

  • Krivitzky L, Babikian T, Lee HS, Thomas NH, Burk-Paull KL, Batshaw ML (2009) Intellectual, adaptive, and behavioral functioning in children with urea cycle disorders. Pediatr Res 66(1):96–101

  • Msall M, Batshaw ML, Suss R, Brusilow SW, Mellits ED (1984) Neurologic outcome in children with inborn errors of urea synthesis. N Engl J Med 310:1500–1505

    Article  CAS  PubMed  Google Scholar 

  • Msall M, Monahan PS, Chapanis N, Batshaw ML (1988) Cognitive development in children with inborn errors of urea synthesis. Acta Paediatr Jpn 30:435–441

    Article  CAS  PubMed  Google Scholar 

  • Pacheco-Colón I, Washington SD, Sprouse C, Helman G, Gropman AL, VanMeter JW (2015) Reduced functional connectivity of default mode and set-maintenance networks in ornithine transcarbamylase deficiency. PLoS One 10(6):e0129595

  • Perito ER, Rhee S, Roberts JP, Rosenthal P (2014) Pediatric liver transplantation for urea cycle disorders and organic acidemias: united network for organ sharing data for 2002–2012. Liver Transpl 20(1):89–99

    Article  PubMed  Google Scholar 

  • Seminara J, Tuchman M, Krivitzky L et al (2010) Establishing a consortium for the study of rare diseases: the urea cycle disorders consortium. Mol Genet Metab 100(Suppl 1):S97–S105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sprouse C, King J, Helman G et al (2014) Investigating neurological deficits in carriers and affected patients with ornithine transcarbamylase deficiency. Mol Genet Metab 113(1-2):136–141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Summar ML, Koelker S, Freedenberg D, Le Mons C, Haberle J, Lee HS, Kirmse B (2013) European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD). Electronic address: http://www.e-imd.org/en/index.phtml; Members of the Urea Cycle Disorders Consortium (UCDC). Electronic address: http://rarediseasesnetwork.epi.usf.edu/ucdc/. The incidence of urea cycle disorders. Mol Genet Metab 110(1–2):179–180. doi:10.1016/j.ymgme.2013.07.008

Download references

Acknowledgments

The Urea Cycle Disorders Consortium (UCDC; U54HD061221) is a part of the National Institutes of Health (NIH) Rare Disease Clinical Research Network (RDCRN), supported through collaboration between the Office of Rare Diseases Research (ORDR), the National Center for Advancing Translational Science (NCATS and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). The UCDC is also supported by the O’Malley Foundation, the Rotenberg Family Fund, the Dietmar-Hopp Foundation, and the Kettering Fund. The Neuropsychology Network is acknowledged for help with data collection and analyses. 

Author information

Authors and Affiliations

  1. Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    Susan E. Waisbren

  2. Children’s Research Institute, Children’s National Health System, Washington, DC, USA

    Andrea L. Gropman

  3. Departments of Pediatrics and Neurology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA

    Mark L. Batshaw

Authors
  1. Susan E. Waisbren
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrea L. Gropman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mark L. Batshaw
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

Members of the Urea Cycle Disorders Consortium (UCDC)

Corresponding author

Correspondence to Mark L. Batshaw.

Ethics declarations

Conflict of interest

Mark Batshaw declares that he has no conflict of interest.

Andrea Gropman declares that she has a grant through the Urea Cycle Disorders Consortium funded by NIH.

Susan Waisbren declares that she has a subcontract from the Children’s National Health System through the Urea Cycle Disorders Consortium funded by the NIH.

Informed consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study.

Animal rights

This article does not contain any studies with animal subjects performed by the any of the authors.

Additional information

Communicated by: Johannes Häberle

Members of the Urea Cycle Disorders Consortium: Mendel Tuchman, Marshall L. Summar, Matthias R. Baumgartner, Susan A. Berry, Curtis Coughlin, Stephen Cederbaum, George A. Diaz, Annette Feigenbaum, Renata C. Gallagher, Cary O. Harding, Georg Hoffmann, Douglas S. Kerr, Brendan Lee, Uta Lichter-Konecki, Shawn E. McCandless, Robert McCarter, J. Lawrence Merritt II, Sandesh CS Nagamani, Andreas Schulze, Margretta R. Seashore, Jennifer Seminara, Tamar Stricker, James Weisfeld-Adams, Derek Wong, and Marc Yudkoff.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Waisbren, S., Gropman, A., Members of the Urea Cycle Disorders Consortium (UCDC). et al. Improving long term outcomes in urea cycle disorders-report from the Urea Cycle Disorders Consortium. J Inherit Metab Dis 39, 573–584 (2016). https://doi.org/10.1007/s10545-016-9942-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10545-016-9942-0

Keywords

Search

Navigation