Abstract
The Urea Cycle Disorders Consortium (UCDC) has conducted, beginning in 2006, a longitudinal study (LS) of eight enzyme deficiencies/transporter defects associated with the urea cycle. These include N-acetylglutamate synthase deficiency (NAGSD); Carbamyl phosphate synthetase 1 deficiency (CPS1D); Ornithine transcarbamylase deficiency (OTCD); Argininosuccinate synthetase deficiency (ASSD) (Citrullinemia); Argininosuccinate lyase deficiency (ASLD) (Argininosuccinic aciduria); Arginase deficiency (ARGD, Argininemia); Hyperornithinemia, hyperammonemia, homocitrullinuria (HHH) syndrome (or mitochondrial ornithine transporter 1 deficiency [ORNT1D]); and Citrullinemia type II (mitochondrial aspartate/glutamate carrier deficiency [CITRIN]). There were 678 UCD patients enrolled in 14 sites in the U.S., Canada, and Europe at the writing of this paper. This review summarizes findings of the consortium related to outcome, focusing primarily on neuroimaging findings and neurocognitive function. Neuroimaging studies in late onset OTCD offered evidence that brain injury caused by biochemical dysregulation may impact functional neuroanatomy serving working memory processes, an important component of executive function and regulation. Additionally, there were alteration in white mater microstructure and functional connectivity at rest. Intellectual deficits in OTCD and other urea cycle disorders (UCD) vary. However, when neuropsychological deficits occur, they tend to be more prominent in motor/performance areas on both intelligence tests and other measures. In some disorders, adults performed significantly less well than younger patients. Further longitudinal follow-up will reveal whether this is due to declines throughout life or to improvements in diagnostics (especially newborn screening) and treatments in the younger generation of patients.
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Acknowledgments
The Urea Cycle Disorders Consortium (UCDC; U54HD061221) is a part of the National Institutes of Health (NIH) Rare Disease Clinical Research Network (RDCRN), supported through collaboration between the Office of Rare Diseases Research (ORDR), the National Center for Advancing Translational Science (NCATS and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). The UCDC is also supported by the O’Malley Foundation, the Rotenberg Family Fund, the Dietmar-Hopp Foundation, and the Kettering Fund. The Neuropsychology Network is acknowledged for help with data collection and analyses.
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Mark Batshaw declares that he has no conflict of interest.
Andrea Gropman declares that she has a grant through the Urea Cycle Disorders Consortium funded by NIH.
Susan Waisbren declares that she has a subcontract from the Children’s National Health System through the Urea Cycle Disorders Consortium funded by the NIH.
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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study.
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Communicated by: Johannes Häberle
Members of the Urea Cycle Disorders Consortium: Mendel Tuchman, Marshall L. Summar, Matthias R. Baumgartner, Susan A. Berry, Curtis Coughlin, Stephen Cederbaum, George A. Diaz, Annette Feigenbaum, Renata C. Gallagher, Cary O. Harding, Georg Hoffmann, Douglas S. Kerr, Brendan Lee, Uta Lichter-Konecki, Shawn E. McCandless, Robert McCarter, J. Lawrence Merritt II, Sandesh CS Nagamani, Andreas Schulze, Margretta R. Seashore, Jennifer Seminara, Tamar Stricker, James Weisfeld-Adams, Derek Wong, and Marc Yudkoff.
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Waisbren, S., Gropman, A., Members of the Urea Cycle Disorders Consortium (UCDC). et al. Improving long term outcomes in urea cycle disorders-report from the Urea Cycle Disorders Consortium. J Inherit Metab Dis 39, 573–584 (2016). https://doi.org/10.1007/s10545-016-9942-0
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DOI: https://doi.org/10.1007/s10545-016-9942-0