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Ann Neurol. 2019 Apr 24. doi: 10.1002/ana.25492. [Epub ahead of print]

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

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Center for Pediatric and Adolescent Medicine, Division of Pediatric Neurology and Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany.
Children's National Health System and George Washington School of Medicine, Washington, DC.
Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX.
Center for Human Genetics and Department of Genetics and Genome Sciences, University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH.
David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA.
Harvard Medical School and Boston Children's Hospital, Boston, MA.
University Children's Hospital Zurich and Children's Research Center, Zurich, Switzerland.
University of Pennsylvania School of Medicine and Children's Hospital of Philadelphia, Philadelphia, PA.
Heidelberg Research Center for Molecular Medicine, Heidelberg, Germany.
Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.
Children's Hospital Colorado and University of Colorado, School of Medicine, Aurora, CO.
Hospital San Joan de Deu, Institut Pediàtric de Recerca. Servicio de Neurologia and CIBERER, ISCIII, Barcelona, Spain.



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.


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.


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.


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.


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