title: Partial response to biotin therapy in a patient with holocarboxylase synthetase deficiency: clinical, biochemical, and molecular genetic aspects.
abstract: We report the clinical course and biochemical findings of a 10-year-old, mentally retarded girl with late-onset holocarboxylase synthetase (HCS, gene symbol HLCS) deficiency and only partial response to biotin. On treatment, even with an unusually high dose of 200mg/day, activities of the biotin-dependent mitochondrial carboxylases in lymphocytes remained below 50% of the mean control values. Not only urinary 3-hydroxyisovaleric acid excretion has been persistently elevated, but also plasma and, with even higher concentrations, cerebrospinal fluid 3-hydroxyisovaleric acid have not normalized. The unusual and insufficient response of this patient to biotin treatment can be explained by the effect of the combination of the common HLCS allele IVS10 +5 g>a on one chromosome and a truncating mutation on the other. This case illustrates mechanisms involved in the genotype-phenotype correlation that unequivocally exists in HCS deficiency.
authors.affiliation: Department of General Pediatrics, University Children's Hospital Kiel, Germany. santer@pediatrics.uni-kiel.de
authors.forename: R
authors.initials: R
authors.lastname: Santer
authors.forename: H
authors.initials: H
authors.lastname: Muhle
authors.forename: T
authors.initials: T
authors.lastname: Suormala
authors.forename: E R
authors.initials: ER
authors.lastname: Baumgartner
authors.forename: M
authors.initials: M
authors.lastname: Duran
authors.forename: X
authors.initials: X
authors.lastname: Yang
authors.forename: Y
authors.initials: Y
authors.lastname: Aoki
authors.forename: Y
authors.initials: Y
authors.lastname: Suzuki
authors.forename: U
authors.initials: U
authors.lastname: Stephani
mesh_terms: D017668:Age of Onset; D001710:Biotin / Q000008:administration & dosage / Q000627:therapeutic use*; D019735:Carbon-Carbon Ligases / Q000378:metabolism; D019731:Carbon-Nitrogen Ligases / Q000172:deficiency / Q000235:genetics*; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D005808:Genes, Recessive; D028922:Holocarboxylase Synthetase Deficiency / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D043586:Methylmalonyl-CoA Decarboxylase / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D011766:Pyruvate Carboxylase / Q000378:metabolism; D012326:RNA Splicing / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014631:Valerates / Q000652:urine
chemical_list: D014631:Valerates; C004961:beta-hydroxyisovaleric acid; D001710:Biotin; D019731:Carbon-Nitrogen Ligases; C023312:holocarboxylase synthetases; D019735:Carbon-Carbon Ligases; D011766:Pyruvate Carboxylase; C021573:methylcrotonoyl-CoA carboxylase; D043586:Methylmalonyl-CoA Decarboxylase