Impact of Diagnosis and Therapy on Cognitive Function in Urea Cycle Disorders

for the Urea Cycle Disorders Consortium and the European Registry and Network for Intoxication Type Metabolic Diseases Consortia Study Group

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


OBJECTIVE: Individuals with urea cycle disorders (UCDs) often present with intellectual and developmental disabilities. The major aim of this study was to evaluate the impact of diagnostic and therapeutic interventions on cognitive outcomes in UCDs.

METHODS: This prospective, observational, multicenter study includes data from 503 individuals with UCDs who had comprehensive neurocognitive testing with a cumulative follow-up of 702 patient-years.

RESULTS: The mean cognitive standard deviation score (cSDS) was lower in symptomatic than in asymptomatic (p < 0.001, t test) individuals with UCDs. Intellectual disability (intellectual quotient < 70, cSDS < -2.0) was associated with the respective subtype of UCD and early disease onset, whereas height of the initial peak plasma ammonium concentration was inversely associated with neurocognitive outcomes in mitochondrial (proximal) rather than cytosolic (distal) UCDs. In ornithine transcarbamylase and argininosuccinate synthetase 1 deficiencies, we did not find evidence that monoscavenger therapy with sodium or glycerol phenylbutyrate was superior to sodium benzoate in providing cognitive protection. Early liver transplantation appears to be beneficial for UCDs. It is noteworthy that individuals with argininosuccinate synthetase 1 and argininosuccinate lyase deficiencies identified by newborn screening had better neurocognitive outcomes than those diagnosed after the manifestation of first symptoms.

INTERPRETATION: Cognitive function is related to interventional and non-interventional variables. Early detection by newborn screening and early liver transplantation appear to offer greater cognitive protection, but none of the currently used nitrogen scavengers was superior with regard to long-term neurocognitive outcome. Further confirmation could determine these variables as important clinical indicators of neuroprotection for individuals with UCDs. ANN NEUROL 2019.

Original languageEnglish (US)
Pages (from-to)116-128
Number of pages13
JournalAnnals of Neurology
Issue number1
StatePublished - Jul 2019

Bibliographical note

Funding Information:
S.K. receives funding from Horizon Pharma Ireland for the European Post-Authorization Registry for Ravicti (glycerol PBA) oral liquid in partnership with the E-IMD (RRPE; EU PAS Register No. EUPAS17267; http://www.encepp. eu/). A.S. and S.E.M, J.L.M 2nd, R.C.G, and G.E. receive personal or consultant fees from Horizon Pharma Ireland. J.K.B. received honorarium for an Advisory Board Meeting in July 2018 on using Ravicti for newborns under 2 months of age from Horizon Pharma Ireland. COH and SAB received payment for the support of clinical trial(s) from Horizon Pharma Ireland Limited, and SAB is a member of the clinical advisory board of Horizon Pharma Ireland Limited. Horizon Pharma Ireland manufactures a drug that was studied among other scavenger drugs in this analysis regarding the impact of long-term scavenger therapy on cognitive outcome in individuals with UCDs. All other authors declare that they have nothing to report.

Funding Information:
The UCDC (U54HD061221) is a part of the NIH Rare Disease Clinical Research Network, supported through collaboration between the Office of Rare Diseases Research, the National Center for Advancing Translational Science, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The UCDC is also supported by the O’Malley Foundation, the Rotenberg Family Fund, the Dietmar Hopp Foundation, the Kettering Fund, and the National Urea Cycle Disorders Foundation. In addition, support for neuropsychological testing is provided by an NIH grant for Intellectual and Developmental Disability Research Centers (U54HD090257). The E-IMD patient registry has received funding from the European Union (EAHC No. 2010 12 01; coordinator: Stefan Kölker) in the framework of the Health Program. After the end of the EU funding period, the E-IMD patient registry has been sustained by funding from the Kindness-for-Kids Foundation, the Kettering Fund, and the Dietmar Hopp Foundation. S.K., P.B., and G.F.H. receive funding from the Dietmar Hopp Foundation for coordinating the study “Newborn Screening and Metabolic Medicine 2020 (NBS2020),” which included individuals with UCDs. M.Z. was supported by the Physician-Scientist Program at University of Heidelberg and by a Career Development Fellowship provided by the Heidelberg Research Center for Molecular Medicine in the framework of the Excellence Initiative II of the German Research Foundation. M.R.B. and J.H. are supported by radiz–Rare Disease Initiative Zurich, a clinical research priority program of the University of Zurich.

Publisher Copyright:
© 2019 American Neurological Association


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