title: HIBCH deficiency in a patient with phenotypic characteristics of mitochondrial disorders.
abstract: HIBCH (3-hydroxyisobutyryl-CoA hydrolase) deficiency (MIM #250620) is a rare autosomal recessive inborn error of metabolism, leading to a block in the catabolic pathway of the amino acid valine and presumably to accumulation of toxic valine metabolites in mitochondria. Only three families with HIBCH deficiency and biallelic HIBCH mutations have been described. We report on a further patient, first child of healthy consanguineous parents, with severe developmental delay, seizures, hyperintensities of the basal ganglia on magnetic resonance imaging (MRI), progressive brain atrophy, optic nerve atrophy, repeatedly elevated blood lactate, and respiratory chain complexes I, I + III and cytochrome c oxidase deficiencies with borderline depletion of mitochondrial DNA in muscle tissue. Laboratory findings in blood and skeletal muscle were inconsistent and did not allow a definite diagnosis, but supported the hypothesis of mitochondrial dysfunction. Homozygosity mapping and whole-exome sequencing revealed a homozygous one-base pair insertion in HIBCH. Deficiency of enzyme activity was confirmed in cultured fibroblasts. Although relatively unspecific, the clinical features were similar to those of the previously reported cases. Given the clinical variability and large number of differential diagnoses, the prevalence of HIBCH deficiency is probably underestimated. Next-generation sequencing approaches are an effective tool for identifying the underlying genetic basis in patients suspected of mitochondrial disorders.
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Miriam S
authors.initials: MS
authors.lastname: Reuter
authors.forename: Jörn Oliver
authors.initials: JO
authors.lastname: Sass
authors.forename: Thomas
authors.initials: T
authors.lastname: Leis
authors.forename: Julia
authors.initials: J
authors.lastname: Köhler
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Mayr
authors.forename: René G
authors.initials: RG
authors.lastname: Feichtinger
authors.forename: Manfred
authors.initials: M
authors.lastname: Rauh
authors.forename: Ina
authors.initials: I
authors.lastname: Schanze
authors.forename: Luzy
authors.initials: L
authors.lastname: Bähr
authors.forename: Regina
authors.initials: R
authors.lastname: Trollmann
authors.forename: Steffen
authors.initials: S
authors.lastname: Uebe
authors.forename: Arif B
authors.initials: AB
authors.lastname: Ekici
authors.forename: André
authors.initials: A
authors.lastname: Reis
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology*; D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics* / Q000473:pathology*; D001483:Base Sequence; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D059472:Exome / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008279:Magnetic Resonance Imaging; D028361:Mitochondrial Diseases / Q000235:genetics / Q000473:pathology*; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D017422:Sequence Analysis, DNA / Q000379:methods; D013869:Thiolester Hydrolases / Q000172:deficiency* / Q000235:genetics
chemical_list: D013869:Thiolester Hydrolases
keywords: HIBCH deficiency; Leigh-like hyperintensities; mitochondrial disorders; valine metabolism