Mutations in the Gene Encoding 3-Hydroxyisobutyryl-CoA Hydrolase Results in Progressive Infantile Neurodegeneration

• Published in: American journal of human genetics Vol. 80; no. 1; pp. 195 - 199
• Main Authors: Loupatty, Ference J., Clayton, Peter T., Ruiter, Jos P.N., Ofman, Rob, IJlst, Lodewijk, Brown, Garry K., Thorburn, David R., Harris, Robert A., Duran, Marinus, DeSousa, Carlos, Krywawych, Steve, Heales, Simon J.R., Wanders, Ronald J.A.
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01-01-2007; University of Chicago Press; Cell Press; The American Society of Human Genetics
• Subjects: Base Sequence; Biological and medical sciences; Brain - abnormalities; Cell culture; Cells, Cultured; Fibroblasts - enzymology; Fundamental and applied biological sciences. Psychology; Gene expression; General aspects. Genetic counseling; Genetic Predisposition to Disease; Genetics of eukaryotes. Biological and molecular evolution; Humans; Infant; Medical genetics; Medical sciences; Molecular and cellular biology; Molecular Sequence Data; Molecular structure; Mutation; Nerve Degeneration - genetics; Nerve Degeneration - pathology; Thiolester Hydrolases - genetics; Thiolester Hydrolases - metabolism; Human; Progressive; Gene; Enzyme; Genetics; Hydrolases; Mutation; Child
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/510725

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-C
4-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.