title: Management of a patient with holocarboxylase synthetase deficiency.
abstract: We investigated in a patient with holocarboxylase synthetase deficiency, the relation between the biochemical and genetic factors of the mutant protein with the pharmacokinetic factors of successful biotin treatment. A girl exhibited abnormal skin at birth, and developed in the first days of life neonatal respiratory distress syndrome and metabolic abnormalities diagnostic of multiple carboxylase deficiency. Enzyme assays showed low carboxylase activities. Fibroblast analysis showed poor incorporation of biotin into the carboxylases, and low transfer of biotin by the holocarboxylase synthetase enzyme. Kinetic studies identified an increased Km but a preserved Vmax. Mutation analysis showed the child to be a compound heterozygote for a new nonsense mutation Q379X and for a novel missense mutation Y663H. This mutation affects a conserved amino acid, which is located the most 3' of all recorded missense mutations thus far described, and extends the region of functional biotin interaction. Treatment with biotin 100mg/day gradually improved the biochemical abnormalities in blood and in cerebrospinal fluid (CSF), corrected the carboxylase enzyme activities, and provided clinical stability and a normal neurodevelopmental outcome. Plasma concentrations of biotin were increased to more than 500 nM, thus exceeding the increased Km of the mutant enzyme. At these pharmacological concentrations, the CSF biotin concentration was half the concentration in blood. Measuring these pharmacokinetic variables can aid in optimizing treatment, as individual tailoring of dosing to the needs of the mutation may be required.
authors.affiliation: Department of Pediatrics, University of Colorado at Denver, CO, USA. johan.vanhove@uchsc.edu
authors.forename: Johan L K
authors.initials: JL
authors.lastname: Van Hove
authors.forename: Sagi
authors.initials: S
authors.lastname: Josefsberg
authors.forename: Cynthia
authors.initials: C
authors.lastname: Freehauf
authors.forename: Janet A
authors.initials: JA
authors.lastname: Thomas
authors.forename: Le Phuc
authors.initials: le P
authors.lastname: Thuy
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Barshop
authors.forename: Michael
authors.initials: M
authors.lastname: Woontner
authors.forename: Donald M
authors.initials: DM
authors.lastname: Mock
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Chiang
authors.forename: Elaine
authors.initials: E
authors.lastname: Spector
authors.forename: Iván
authors.initials: I
authors.lastname: Meneses-Morales
authors.forename: Rafael
authors.initials: R
authors.lastname: Cervantes-Roldán
authors.forename: Alfonso
authors.initials: A
authors.lastname: León-Del-Río
mesh_terms: D000595:Amino Acid Sequence; D001710:Biotin / Q000008:administration & dosage* / Q000378:metabolism; D019731:Carbon-Nitrogen Ligases / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics; D002478:Cells, Cultured; D005260:Female; D028922:Holocarboxylase Synthetase Deficiency / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D007700:Kinetics; D008969:Molecular Sequence Data; D009154:Mutation; D016415:Sequence Alignment
chemical_list: D001710:Biotin; D019731:Carbon-Nitrogen Ligases; C023312:holocarboxylase synthetases