Biochemical markers and neuropsychological functioning in distal urea cycle disorders

Members of the Urea Cycle Disorders Consortium

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Urea cycle disorders often present as devastating metabolic conditions, resulting in high mortality and significant neuropsychological damage, despite treatment. The Urea Cycle Disorders Longitudinal Study is a natural history study that collects data from regular clinical follow-up and neuropsychological testing. This report examines links between biochemical markers (ammonia, glutamine, arginine, citrulline) and primary neuropsychological endpoints in three distal disorders, argininosuccinic acid synthetase deficiency (ASD or citrullinemia type I), argininosuccinic acid lyase deficiency (ASA or ALD), and arginase deficiency (ARGD). Laboratory results and test scores from neuropsychological evaluations were assessed in 145 study participants, ages 3 years and older, with ASD (n = 64), ASA (n = 65) and ARGD (n = 16). Mean full scale IQ was below the population mean of 100 ± 15 for all groups: (ASD = 79 ± 24; ASA = 71 ± 21; ARGD = 65 ± 19). The greatest deficits were noted in visual performance and motor skills for all groups. While ammonia levels remain prominent as prognostic biomarkers, other biomarkers may be equally valuable as correlates of neuropsychological functioning. Cumulative exposure to the biomarkers included in the study proved to be highly sensitive indicators of neuropsychological outcomes, even when below the cut-off levels generally considered toxic. Blood levels of biomarkers obtained on the day of neuropsychological evaluations were not correlated with measures of functioning for any disorder in any domain. The importance of cumulative exposure supports early identification and confirms the need for well-controlled management of all biochemical abnormalities (and not just ammonia) that occur in urea cycle disorders.

Original languageEnglish (US)
Pages (from-to)657-667
Number of pages11
JournalJournal of Inherited Metabolic Disease
Volume41
Issue number4
DOIs
StatePublished - Jul 1 2018

Bibliographical note

Funding Information:
Funding The Urea Cycle Disorders Consortium (UCDC) is part of the Rare Diseases Clinical Research Network (RDCRN), and is supported jointly by the National Center for Advancing Translational Science’s Office of Rare Diseases Research and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD061221). The Urea Cycle Disorders Consortium is also supported by the O’Malley Foundation, the Rotenberg Family Fund, the Dietmar-Hopp Foundation, and the Kettering Fund. In addition, support for neuropsychological testing is provided by an NIH grant for Intellectual and Developmental Disability Research Centers (U54HD090257).

Funding Information:
The authors gratefully acknowledge the support of our sponsors. We thank all the members of the Urea Cycle Consortium, including physicians, coordinators, psychologists, other support staff and especially Jennifer Seminara. We are extremely grateful to the participants in this study who generously volunteered their time and provided us with invaluable information. Members of the Urea Cycle Disorders Consortium: Nicholas Ah Mew, Mark L. Batshaw, Matthias R. Baumgartner, Susan A. Berry, Curtis Coughlin, Stephen Cederbaum, George A. Diaz, Annette Feigenbaum, Renata C. Gallagher, Benjamin Goodlett, Andrea Gropman, Cary O. Harding, Georg Hoffmann, Douglas S. Kerr, Brendan Lee, Cynthia Le Mons, Uta Lichter-Konecki, Shawn E. McCandless, J. Lawrence Merritt II, Sandesh CS Nagamani, Andreas Schulze, Margretta R. Seashore, Tamar Stricker, Marshall L. Summar, Mendel Tuchman, Susan Waisbren, James Weisfeld-Adams, Derek Wong, and Marc Yudkoff. Susan Waisbren consults for Dimension Therapeutics. Dr. Cederbaum consults for Aeglea Biotherapeutics. David Cuthbertson, Peter Burgard, Robert McCarter and Amy Holbert have nothing to declare. The Urea Cycle Disorders Consortium (UCDC) is part of the Rare Diseases Clinical Research Network (RDCRN), and is supported jointly by the National Center for Advancing Translational Science?s Office of Rare Diseases Research and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD061221). The Urea Cycle Disorders Consortium is also supported by the O?Malley Foundation, the Rotenberg Family Fund, the Dietmar-Hopp Foundation, and the Kettering Fund. In addition, support for neuropsychological testing is provided by an NIH grant for Intellectual and Developmental Disability Research Centers (U54HD090257).

Funding Information:
The Urea Cycle Disorders Consortium (UCDC) is part of the Rare Diseases Clinical Research Network (RDCRN) and is supported jointly by the National Center for Advancing Translational Science, Office of Rare Diseases Research and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD061221). The goals of the RDCRN are to perform natural history studies of rare diseases and to hasten the bringing to market of orphan products to treat rare disorders (Batshaw et al 2014; Seminara et al 2010). Philanthropic support supplements these research activities, as well. The UCDC Longitudinal Study, now in its 11th year, collects medical and neuropsychological information on the eight different urea cycle disorders. This paper focuses on three distal disorders, argininosuccinate synthetase deficiency (ASD or citrullinemia type I) (OMIM 215700), argininosuccinic acid lyase deficiency (ASA or ALD) (OMIM 207900), and arginase deficiency (ARGD) (OMM 207800), with the aim of characterizing the associations between biochemical markers (ammonia, glutamine, citrulline, and arginine) and neuropsychological outcomes. A better understanding of these biochemical markers and their relationships to specific functional domains has the potential to guide treatment and contribute to the design of clinical drug trials.

Funding Information:
Acknowledgements The authors gratefully acknowledge the support of our sponsors. We thank all the members of the Urea Cycle Consortium, including physicians, coordinators, psychologists, other support staff and especially Jennifer Seminara. We are extremely grateful to the participants in this study who generously volunteered their time and provided us with invaluable information. Members of the Urea Cycle Disorders Consortium: Nicholas Ah Mew, Mark L. Batshaw, Matthias R. Baumgartner, Susan A. Berry, Curtis Coughlin, Stephen Cederbaum, George A. Diaz, Annette Feigenbaum, Renata C. Gallagher, Benjamin Goodlett, Andrea Gropman, Cary O. Harding, Georg Hoffmann, Douglas S. Kerr, Brendan Lee, Cynthia Le Mons, Uta Lichter-Konecki, Shawn E. McCandless, J. Lawrence Merritt II, Sandesh CS Nagamani, Andreas Schulze, Margretta R. Seashore, Tamar Stricker, Marshall L. Summar, Mendel Tuchman, Susan Waisbren, James Weisfeld-Adams, Derek Wong, and Marc Yudkoff.

Publisher Copyright:
© 2018, SSIEM.

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