Advertisement

Journal of Inherited Metabolic Disease

, Volume 41, Issue 4, pp 657–667 | Cite as

Biochemical markers and neuropsychological functioning in distal urea cycle disorders

  • Susan E. WaisbrenEmail author
  • David Cuthbertson
  • Peter Burgard
  • Amy Holbert
  • Robert McCarter
  • Stephen Cederbaum
  • Members of the Urea Cycle Disorders Consortium
Original Article

Abstract

Urea cycle disorders often present as devastating metabolic conditions, resulting in high mortality and significant neuropsychological damage, despite treatment. The Urea Cycle Disorders Longitudinal Study is a natural history study that collects data from regular clinical follow-up and neuropsychological testing. This report examines links between biochemical markers (ammonia, glutamine, arginine, citrulline) and primary neuropsychological endpoints in three distal disorders, argininosuccinic acid synthetase deficiency (ASD or citrullinemia type I), argininosuccinic acid lyase deficiency (ASA or ALD), and arginase deficiency (ARGD). Laboratory results and test scores from neuropsychological evaluations were assessed in 145 study participants, ages 3 years and older, with ASD (n = 64), ASA (n = 65) and ARGD (n = 16). Mean full scale IQ was below the population mean of 100 ± 15 for all groups: (ASD = 79 ± 24; ASA = 71 ± 21; ARGD = 65 ± 19). The greatest deficits were noted in visual performance and motor skills for all groups. While ammonia levels remain prominent as prognostic biomarkers, other biomarkers may be equally valuable as correlates of neuropsychological functioning. Cumulative exposure to the biomarkers included in the study proved to be highly sensitive indicators of neuropsychological outcomes, even when below the cut-off levels generally considered toxic. Blood levels of biomarkers obtained on the day of neuropsychological evaluations were not correlated with measures of functioning for any disorder in any domain. The importance of cumulative exposure supports early identification and confirms the need for well-controlled management of all biochemical abnormalities (and not just ammonia) that occur in urea cycle disorders.

Notes

Acknowledgements

The authors gratefully acknowledge the support of our sponsors. We thank all the members of the Urea Cycle Consortium, including physicians, coordinators, psychologists, other support staff and especially Jennifer Seminara. We are extremely grateful to the participants in this study who generously volunteered their time and provided us with invaluable information.

Members of the Urea Cycle Disorders Consortium:

Nicholas Ah Mew, Mark L. Batshaw, Matthias R. Baumgartner, Susan A. Berry, Curtis Coughlin, Stephen Cederbaum, George A. Diaz, Annette Feigenbaum, Renata C. Gallagher, Benjamin Goodlett, Andrea Gropman, Cary O. Harding, Georg Hoffmann, Douglas S. Kerr, Brendan Lee, Cynthia Le Mons, Uta Lichter-Konecki, Shawn E. McCandless, J. Lawrence Merritt II, Sandesh CS Nagamani, Andreas Schulze, Margretta R. Seashore, Tamar Stricker, Marshall L. Summar, Mendel Tuchman, Susan Waisbren, James Weisfeld-Adams, Derek Wong, and Marc Yudkoff.

Funding

The Urea Cycle Disorders Consortium (UCDC) is part of the Rare Diseases Clinical Research Network (RDCRN), and is supported jointly by the National Center for Advancing Translational Science’s Office of Rare Diseases Research and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD061221). The Urea Cycle Disorders Consortium is also supported by the O’Malley Foundation, the Rotenberg Family Fund, the Dietmar-Hopp Foundation, and the Kettering Fund. In addition, support for neuropsychological testing is provided by an NIH grant for Intellectual and Developmental Disability Research Centers (U54HD090257).

The authors confirm independence from the sponsors; the content of the article has not been influenced by the sponsor.

Compliance with ethical standards

Conflict of interest

Susan Waisbren consults for Dimension Therapeutics.

Dr. Cederbaum consults for Aeglea Biotherapeutics.

David Cuthbertson, Peter Burgard, Robert McCarter and Amy Holbert have nothing to declare.

The Urea Cycle Disorders Consortium (UCDC) is part of the Rare Diseases Clinical Research Network (RDCRN), and is supported jointly by the National Center for Advancing Translational Science’s Office of Rare Diseases Research and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD061221). The Urea Cycle Disorders Consortium is also supported by the O’Malley Foundation, the Rotenberg Family Fund, the Dietmar-Hopp Foundation, and the Kettering Fund. In addition, support for neuropsychological testing is provided by an NIH grant for Intellectual and Developmental Disability Research Centers (U54HD090257).

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. Proof that informed consent was obtained is available upon request.

Human rights

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). This study was approved at each of the study sites through local Institutional Review Boards or Reliance Agreements from Children’s National Health Center, Washington, DC. Written Informed consent was obtained from all participants in this study or from parents/guardians when appropriate.

References

  1. Achenbach T, Rescorla L (2000) Child behavior checklist. ASEBA, BurlingtonCrossRefGoogle Scholar
  2. Adams W, Sheslow D (1995) Wide range assessment of visual motor abilities. Pearson, BloomingtonGoogle Scholar
  3. Baruteau J, Jameson E, Morris AA et al (2017) Expanding the phenotype in argininosuccinic aciduria: need for new therapies. J Inherit Metab Dis.  https://doi.org/10.1007/s10545-017-0022-x
  4. Batshaw ML, Brusilow SW (1980) Treatment of hyperammonemic coma caused by inborn errors of urea synthesis. J Pediatr 97(6):893–900CrossRefPubMedGoogle Scholar
  5. Batshaw ML, Tuchman M, Summar M, Seminara J (2014) Members of the urea cycle disorders consortium. A longitudinal study of urea cycle disorders. Mol Genet Metab 113(1–2):127–130.  https://doi.org/10.1016/j.ymgme.2014.08.001. CrossRefPubMedPubMedCentralGoogle Scholar
  6. Beery KE, Beery NA (2010) Beery-Buktenica developmental test of visual-motor integration. Pearson, BloomingtonGoogle Scholar
  7. Delis DC, Kramer JH, Kaplan E, Ober BA (2000) California Verbal Learning Test. Psychological Corporation, San AntonioGoogle Scholar
  8. Delis DC, Kaplan E, Kramer JH (2001) Delis-Kaplan Executive Function System. Psychological Corporation, San AntonioGoogle Scholar
  9. Enns GM (2008) Neurologic damage and neurocognitive dysfunction in urea cycle disorders. Semin Pediatr Neurol 15(3):132–139.  https://doi.org/10.1016/j.spen.2008.05.007. CrossRefPubMedGoogle Scholar
  10. Gunz AC, Choong K, Potter M, Miller E (2013) Magnetic resonance imaging findings and neurodevelopmental outcomes in neonates with urea-cycle defects. Int Med Case Rep J 6:41–48.  https://doi.org/10.2147/IMCRJ.S43513 CrossRefPubMedPubMedCentralGoogle Scholar
  11. Harrison PL, Oakland T (2003) Adaptive behavior assessment system, 2nd edn. Psychological Corporation, San AntonioGoogle Scholar
  12. Hood A, Antenor-Dorsey JA, Rutlin J et al (2015) Prolonged exposure to high and variable phenylalanine levels over the lifetime predicts brain white matter integrity in children with phenylketonuria. Mol Genet Metab 114(1):19–24.  https://doi.org/10.1016/j.ymgme.2014.11.007 CrossRefPubMedGoogle Scholar
  13. Kölker S, Garcia-Cazorla A, Valayannopoulos V et al, (2015) The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation. J Inherit Metab Dis. 38(6):1041-57.  https://doi.org/10.1007/s10545-015-9839-3
  14. Korkman M, Kirk U, Kemp S (2007) Nepsy-ii. Psychological Corporation, San AntonioGoogle Scholar
  15. Lafayette Grooved Pegboard, Model 32025, Lafayette Instrument Company, Lafayette, INGoogle Scholar
  16. Lafayette Hand Dynamometer, Model 78010, Lafayette Instrument Company, Lafayette, INGoogle Scholar
  17. Lee B, Diaz GA, Rhead W et al (2016) Gultamine and hyperammonemic crises in patients with urea cycle disorders. Mol Genet Metab 117(1):27–32.  https://doi.org/10.1016/j.ymgme.2015.11.005 CrossRefPubMedGoogle Scholar
  18. Meyers JE, Meyers KR (1995) Rey complex figure test and recognition trial. Psychological Assessment Resources, Inc., LutzGoogle Scholar
  19. Posset R, Garcia-Cazorla A, Valayannopoulos V et al (2016) Age at disease onset and peak ammonium level rather than interventional variables predict the neurological outcome in urea cycle disorders. J Inherit Metab Dis 39(5):661–672.  https://doi.org/10.1007/s10545-016-9938-9 CrossRefPubMedGoogle Scholar
  20. Roth RM, Isquith PK, Gioia GA (2005) Behavior rating inventory of executive function. Psychological Assessment Resources, Inc., LutzGoogle Scholar
  21. Seminara J, Tuchman M, Krivitsky L et al (2010) Establishing a consortium for the study of rare diseases: the urea cycle disorders consortium. Mol Genet Metab 100(Suppl 1):S97–105CrossRefPubMedPubMedCentralGoogle Scholar
  22. Shapiro E, Bernstein J, Adams HR et al (2016) Neurocognitive clinical outcome assessments for inborn errors of metabolism and other rare conditions. Mol Genet Metab 118:659CrossRefGoogle Scholar
  23. Summar M, Tuchman M (2001) Proceedings of a consensus conference for the management of patients with urea cycle disorders. J Pediatr 138(1 Suppl):S6–10CrossRefPubMedGoogle Scholar
  24. Waisbren SE, Gropman AL, Members of the Urea Cycle Disorders Consortium (UCDC), Batshaw ML (2016) Improving long term outcomes in urea cycle disorders-report from the urea cycle disorders consortium. J Inherit Metab Dis 39:573–584CrossRefPubMedPubMedCentralGoogle Scholar
  25. Wechsler D (2011) Wechsler abbreviated scale of intelligence, vol 1999. Psychological Corporation, San AntonioGoogle Scholar
  26. Wechsler D (2002) Wechsler preschool and primary scale of intelligence, 3rd edn. Psychological Corporation, San AntonioGoogle Scholar

Copyright information

© SSIEM 2018

Authors and Affiliations

  1. 1.Division of Genetics and GenomicsBoston Children’s Hospital and Department of Medicine, Harvard Medical SchoolBostonUSA
  2. 2.Health Informatics Institute, University of South FloridaTampaUSA
  3. 3.Centre for Child and Adolescent Medicine, Division of Neuropediatrics and Inherited Metabolic DiseasesUniversity Hospital HeidelbergHeidelbergGermany
  4. 4.Children’s National Health CenterWashingtonUSA
  5. 5.Children’s Hospital of Los AngelesLos AngelesUSA

Personalised recommendations