title: Clinical and biochemical characterization of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency that causes Leigh-like disease and ketoacidosis.
abstract: 3-Hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency is an autosomal recessive disorder characterized by episodes of ketoacidosis and a Leigh-like basal ganglia disease, without high concentrations of pyruvate and lactate in the cerebrospinal fluid. Only 4 cases of HIBCH deficiency have been reported. However, clinical-biochemical correlation in HIBCH deficiency by determining the detailed residual enzyme activities has not yet been elucidated. Here, we report a case of two Japanese siblings with HIBCH deficiency carrying a new homozygous missense mutation (c.287C > A, [p.A96D]) at the substrate-binding site. A transfection study using HIBCH expression vectors harboring wild type or 4 reported mutations, including the newly identified mutation (p.A96D, p.Y122C, p.G317E, and p.K74Lfs*13), revealed a correlation between residual HIBCH activities and the severity of the disease. All HIBCH mutants, except p.K74Lfs*13, showed residual enzyme activity and only the patient with p.K74Lfs*13 had congenital anomalies. p.G317E showed only low enzyme activity (~ 3%) of that of wild-type HIBCH. Although p.A96D had approximately 7 times higher enzyme activity than p.G317E, patients with p.A96D died during childhood. These findings are essential for clinical management, genetic counseling, and specific meal and concomitant drug considerations as part of the treatment for patients with HIBCH deficiency.
authors.affiliation: Department of Genetics, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors.forename: Misako
authors.initials: M
authors.lastname: Naiki
authors.affiliation: Department of Pediatrics, Kasugai Municipal Hospital, Kasugai, Aichi, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Hoshino
authors.affiliation: Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Aichi, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Kitaura
authors.affiliation: Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Aichi, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kondo
authors.affiliation: Department of Genetics, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Nomura
authors.affiliation: Department of Genetics, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Kimura
authors.affiliation: Department of Genetics, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Fukushi
authors.affiliation: Department of Genetics, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, Japan.
authors.forename: Yasukazu
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Division of Genomics Research, Life Science Research Center, Gifu University, Gifu, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Shimozawa
authors.affiliation: Department of Pediatrics, Shimane University, Faculty of Medicine, Izumo, Shimane, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Yamaguchi
authors.affiliation: Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Aichi, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Shimomura
authors.affiliation: Division of Developmental Disabilities Medicine, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors.forename: Kiyokuni
authors.initials: K
authors.lastname: Miura
authors.affiliation: Department of Genetics, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Wakamatsu
keywords: HIBCH; Ketoacidosis; Leigh-like disease; Valine catabolic pathway