A common mutation is associated with a mild, potentially asymptomatic phenotype in patients with isovaleric acidemia diagnosed by newborn screening

Regina Ensenauer, Jerry Vockley, Jan Marie Willard, Joseph C. Huey, Jörn Oliver Sass, Steven D. Edland, Barbara K. Burton, Susan A. Berry, René Santer, Sarah Grünert, Hans Georg Koch, Iris Marquardt, Piero Rinaldo, Sihoun Hahn, Dietrich Matern

Research output: Contribution to journalArticlepeer-review

99 Scopus citations

Abstract

Isovaleric acidemia (IVA) is an inborn error of leucine metabolism that can cause significant morbidity and mortality. Since the implementation, in many states and countries, of newborn screening (NBS) by tandem mass spectrometry, IVA can now be diagnosed presymptomatically. Molecular genetic analysis of the JVD gene for 19 subjects whose condition was detected through NBS led to the identification of one recurring mutation, 932C→T (A282V), in 47% of mutant alleles. Surprisingly, family studies identified six healthy older siblings with identical genotype and biochemical evidence of IVA. Our findings indicate the frequent occurrence of a novel mild and potentially asymptomatic phenotype of IVA. This has significant consequences for patient management and counseling.

Original languageEnglish (US)
Pages (from-to)1136-1142
Number of pages7
JournalAmerican Journal of Human Genetics
Volume75
Issue number6
DOIs
StatePublished - Dec 2004

Bibliographical note

Funding Information:
Financial support was provided by the Barbara Woodward Lipps fund of the Mayo Foundation (to J.V.) and by Public Health Service grant R01-DK45482 (to J.V.). The funding sources had no involvement in study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication. The authors thank Jennifer L. Winters and W. Edward Highsmith Jr., Ph.D., for assistance with molecular genetic analysis and are grateful to all physicians, genetic counselors, and screening laboratories (Drs. J. Charrow, J. W. Ellison, T. Freese, D. K. Grange, C. Korenke, W. Lehnert, M. Leichsenring, M. Lindner, L. A. Schimmenti, J. P. Schubert, K. O. Schwab, L. Sweetman, D. A. H. Whiteman, and D. A. Pond, M.S.) who provided patient samples and/or data.

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