TY - JOUR
T1 - Impact of Diagnosis and Therapy on Cognitive Function in Urea Cycle Disorders
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 O.
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
N1 - Publisher Copyright:
© 2019 American Neurological Association
PY - 2019/7
Y1 - 2019/7
N2 - 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.
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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U2 - 10.1002/ana.25492
DO - 10.1002/ana.25492
M3 - Article
C2 - 31018246
AN - SCOPUS:85065742491
SN - 0364-5134
VL - 86
SP - 116
EP - 128
JO - Annals of Neurology
JF - Annals of Neurology
IS - 1
ER -