Mutations in the gene encoding 3-hydroxyisobutyryl-CoA hydrolase results in progressive infantile neurodegeneration.
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.
Loupatty
Ference J
FJ
Department of Clinical Chemistry and Pediatrics, Emma Children's Hospital, Amsterdam, The Netherlands.
Clayton
Peter T
PT
Ruiter
Jos P N
JP
Ofman
Rob
R
Ijlst
Lodewijk
L
Brown
Garry K
GK
Thorburn
David R
DR
Harris
Robert A
RA
Duran
Marinus
M
Desousa
Carlos
C
Krywawych
Steve
S
Heales
Simon J R
SJ
Wanders
Ronald J A
RJ
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
D013869:Thiolester Hydrolases; C035908:3-hydroxyisobutyryl-CoA hydrolase