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 journalArticle

1 Citation (Scopus)

Abstract

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
Volume86
Issue number1
DOIs
StatePublished - Jul 1 2019

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Inborn Urea Cycle Disorder
Cognition
Therapeutics
Intellectual Disability
Liver Transplantation
Argininosuccinic Aciduria
Citrullinemia
Argininosuccinate Synthase
Sodium Benzoate
Newborn Infant
Ornithine Carbamoyltransferase
Developmental Disabilities
Ammonium Compounds
Multicenter Studies
Observational Studies
Nitrogen

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

for the Urea Cycle Disorders Consortium and the European Registry and Network for Intoxication Type Metabolic Diseases Consortia Study Group (2019). Impact of Diagnosis and Therapy on Cognitive Function in Urea Cycle Disorders. Annals of Neurology, 86(1), 116-128. https://doi.org/10.1002/ana.25492

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.

In: Annals of Neurology, Vol. 86, No. 1, 01.07.2019, p. 116-128.

Research output: Contribution to journalArticle

for the Urea Cycle Disorders Consortium and the European Registry and Network for Intoxication Type Metabolic Diseases Consortia Study Group 2019, 'Impact of Diagnosis and Therapy on Cognitive Function in Urea Cycle Disorders', Annals of Neurology, vol. 86, no. 1, pp. 116-128. https://doi.org/10.1002/ana.25492
for the Urea Cycle Disorders Consortium and the European Registry and Network for Intoxication Type Metabolic Diseases Consortia Study Group. Impact of Diagnosis and Therapy on Cognitive Function in Urea Cycle Disorders. Annals of Neurology. 2019 Jul 1;86(1):116-128. https://doi.org/10.1002/ana.25492
for the Urea Cycle Disorders Consortium and the European Registry and Network for Intoxication Type Metabolic Diseases Consortia Study Group. / Impact of Diagnosis and Therapy on Cognitive Function in Urea Cycle Disorders. In: Annals of Neurology. 2019 ; Vol. 86, No. 1. pp. 116-128.
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AU - for the Urea Cycle Disorders Consortium and the European Registry and Network for Intoxication Type Metabolic Diseases Consortia Study Group

AU - Posset, Roland

AU - Gropman, Andrea L.

AU - Nagamani, Sandesh C.S.

AU - Burrage, Lindsay C.

AU - Bedoyan, Jirair K.

AU - Wong, Derek

AU - Berry, Gerard T.

AU - Baumgartner, Matthias R.

AU - Yudkoff, Marc

AU - Zielonka, Matthias

AU - Hoffmann, Georg F.

AU - Burgard, Peter

AU - Schulze, Andreas

AU - McCandless, Shawn E.

AU - Garcia-Cazorla, Angeles

AU - Seminara, Jennifer

AU - Garbade, Sven F.

AU - Kölker, Stefan

AU - Lee, Brendan

AU - Harding, Cary

AU - Coughlin, Curtis R.

AU - Le Mons, Cynthia

AU - Dobbelaere, Dries

AU - Leão Teles, Elisa

AU - Cortès-Saladelafont, Elisenda

AU - Gleich, Florian

AU - Eyskens, Francois

AU - Enns, Gregory

AU - Wilkening, Greta N.

AU - Barić, Ivo

AU - Lawrence Merritt, J.

AU - Heringer, Jana

AU - Blasco-Alonso, Javier

AU - Zeman, Jiri

AU - Häberle, Johannes

AU - Sykut-Cegielska, Jolanta

AU - Djordjevic, Maja

AU - Batshaw, Mark L.

AU - Summar, Marshall

AU - Freisinger, Peter

AU - Gallagher, Renata C.

AU - Berry, Susan A.

AU - Waisbren, Susan

AU - Stricker, Tamar

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AB - 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.

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