Mutations in the gene encoding 3-hydroxyisobutyryl-CoA hydrolase results in progressive infantile neurodegeneration

Ference J. Loupatty, Peter T. Clayton, Jos P.N. Ruiter, Rob Ofman, Lodewijk Ijlst, Garry K. Brown, David R. Thorburn, Robert A. Harris, Marinus Duran, Carlos DeSousa, Steve Krywawych, Simon J.R. Heales, Ronald J.A. Wanders

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

Only a single patient with 3-hydroxyisobutyryl-CoA hydrolase deficiency has been described in the literature, and the molecular basis of this inborn error of valine catabolism has remained unknown until now. Here, we present a second patient with 3-hydroxyisobutyryl-CoA hydrolase deficiency, who was identified through blood spot acylcarnitine analysis showing persistently increased levels of hydroxy-C4-carnitine. Both patients manifested hypotonia, poor feeding, motor delay, and subsequent neurological regression in infancy. Additional features in the newly identified patient included episodes of ketoacidosis and Leigh-like changes in the basal ganglia on a magnetic resonance imaging scan. In cultured skin fibroblasts from both patients, the 3-hydroxyisobutyryl-CoA hydrolase activity was deficient, and virtually no 3-hydroxyisobutyryl-CoA hydrolase protein could be detected by western blotting. Molecular analysis in both patients uncovered mutations in the HIBCH gene, including one missense mutation in a conserved part of the protein and two mutations affecting splicing. A carefully interpreted acylcarnitine profile will allow more patients with 3-hydroxyisobutyryl-CoA hydrolase deficiency to be diagnosed.

Original languageEnglish (US)
Pages (from-to)195-199
Number of pages5
JournalAmerican Journal of Human Genetics
Volume80
Issue number1
DOIs
StatePublished - Jan 2007

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Loupatty, F. J., Clayton, P. T., Ruiter, J. P. N., Ofman, R., Ijlst, L., Brown, G. K., Thorburn, D. R., Harris, R. A., Duran, M., DeSousa, C., Krywawych, S., Heales, S. J. R., & Wanders, R. J. A. (2007). Mutations in the gene encoding 3-hydroxyisobutyryl-CoA hydrolase results in progressive infantile neurodegeneration. American Journal of Human Genetics, 80(1), 195-199. https://doi.org/10.1086/510725