Impact of Diagnosis and Therapy on Cognitive Function in Urea Cycle Disorders
Roland Posset, Andrea L Gropman, Sandesh C S Nagamani, Lindsay C Burrage, Jirair K Bedoyan, Derek Wong, Gerard T Berry, Matthias R Baumgartner, Marc Yudkoff, Matthias Zielonka, Georg F Hoffmann, Peter Burgard, Andreas Schulze, Shawn E McCandless, Angeles Garcia-Cazorla, Jennifer Seminara, Sven F Garbade, Stefan Kölker, Urea Cycle Disorders Consortium and the European Registry and Network for Intoxication Type Metabolic Diseases Consortia Study Group, Brendan Lee, Cary O Harding, Curtis R Coughlin 2nd, Cynthia Le Mons, Dries Dobbelaere, Elisa Leão Teles, Elisenda Cortès-Saladelafont, Florian Gleich, Francois Eyskens, Gregory Enns, Greta N Wilkening, Ivo Barić, J Lawrence Merritt 2nd, Jana Heringer, Javier Blasco-Alonso, Jiri Zeman, Johannes Häberle, Jolanta Sykut-Cegielska, Maja Djordjevic, Mark L Batshaw, Marshall Summar, Peter Freisinger, Renata C Gallagher, Susan A Berry, Susan Waisbren, Tamar Stricker, Roland Posset, Andrea L Gropman, Sandesh C S Nagamani, Lindsay C Burrage, Jirair K Bedoyan, Derek Wong, Gerard T Berry, Matthias R Baumgartner, Marc Yudkoff, Matthias Zielonka, Georg F Hoffmann, Peter Burgard, Andreas Schulze, Shawn E McCandless, Angeles Garcia-Cazorla, Jennifer Seminara, Sven F Garbade, Stefan Kölker, Urea Cycle Disorders Consortium and the European Registry and Network for Intoxication Type Metabolic Diseases Consortia Study Group, Brendan Lee, Cary O Harding, Curtis R Coughlin 2nd, Cynthia Le Mons, Dries Dobbelaere, Elisa Leão Teles, Elisenda Cortès-Saladelafont, Florian Gleich, Francois Eyskens, Gregory Enns, Greta N Wilkening, Ivo Barić, J Lawrence Merritt 2nd, Jana Heringer, Javier Blasco-Alonso, Jiri Zeman, Johannes Häberle, Jolanta Sykut-Cegielska, Maja Djordjevic, Mark L Batshaw, Marshall Summar, Peter Freisinger, Renata C Gallagher, Susan A Berry, Susan Waisbren, Tamar Stricker
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.
Conflict of interest statement
Potential Conflicts of Interest
All other authors declare that they have nothing to report.
© 2019 American Neurological Association.
Figures
Source: PubMed