title: Mutations in the gene encoding 3-hydroxyisobutyryl-CoA hydrolase results in progressive infantile neurodegeneration.
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-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.
authors.affiliation: Department of Clinical Chemistry and Pediatrics, Emma Children's Hospital, Amsterdam, The Netherlands.
authors.forename: Ference J
authors.initials: FJ
authors.lastname: Loupatty
authors.forename: Peter T
authors.initials: PT
authors.lastname: Clayton
authors.forename: Jos P N
authors.initials: JP
authors.lastname: Ruiter
authors.forename: Rob
authors.initials: R
authors.lastname: Ofman
authors.forename: Lodewijk
authors.initials: L
authors.lastname: Ijlst
authors.forename: Garry K
authors.initials: GK
authors.lastname: Brown
authors.forename: David R
authors.initials: DR
authors.lastname: Thorburn
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harris
authors.forename: Marinus
authors.initials: M
authors.lastname: Duran
authors.forename: Carlos
authors.initials: C
authors.lastname: Desousa
authors.forename: Steve
authors.initials: S
authors.lastname: Krywawych
authors.forename: Simon J R
authors.initials: SJ
authors.lastname: Heales
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
mesh_terms: D001483:Base Sequence; D001921:Brain / Q000002:abnormalities; D002478:Cells, Cultured; D005347:Fibroblasts / Q000201:enzymology; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D008969:Molecular Sequence Data; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology; D013869:Thiolester Hydrolases / Q000235:genetics* / Q000378:metabolism
chemical_list: D013869:Thiolester Hydrolases; C035908:3-hydroxyisobutyryl-CoA hydrolase