title: Clinical, biochemical, and molecular findings in three patients with 3-hydroxyisobutyric aciduria.
abstract: 3-Hydroxyisobutyric aciduria is a rare entity and affected individuals display a range of clinical manifestations including dysmorphic features and neurodevelopmental problems in the majority of patients. Here, we present two novel patients with 3-hydroxyisobutyric aciduria. To our knowledge, these are the 11th and 12th cases of 3-hydroxyisobutyic aciduria reported. It is believed that a deficiency in 3-hydroxyisobutyrate dehydrogenase is the most likely cause of this disorder. Measurement of 3-hydroxyisobutyrate dehydrogenase activity in fibroblasts homogenates of the two newly identified patients and a previously reported patient, however, revealed similar activities as in control fibroblasts. Since other enzymes with overlapping substrate specificity could conceal abnormal 3-hydroxyisobutyrate dehydrogenase activity, we cloned a candidate human cDNA for 3-hydroxyisobutyrate dehydrogenase (HIBADH). By heterologous expression in Escherichia coli, we showed that the product of the HIBADH gene indeed displays 3-hydroxyisobutyrate dehydrogenase activity. Mutation analysis of the corresponding gene in the patients suffering from 3-hydroxyisobutyric aciduria revealed no mutations. We conclude that HIBADH is not the causative gene in 3-hydroxyisobutyric aciduria.
authors.affiliation: Department of Clinical Chemistry and Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Ference J
authors.initials: FJ
authors.lastname: Loupatty
authors.forename: Annemarie
authors.initials: A
authors.lastname: van der Steen
authors.forename: Lodewijk
authors.initials: L
authors.lastname: Ijlst
authors.forename: Jos P N
authors.initials: JP
authors.lastname: Ruiter
authors.forename: Rob
authors.initials: R
authors.lastname: Ofman
authors.forename: Matthias R
authors.initials: MR
authors.lastname: Baumgartner
authors.forename: Diana
authors.initials: D
authors.lastname: Ballhausen
authors.forename: Seiji
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Marinus
authors.initials: M
authors.lastname: Duran
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
mesh_terms: D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002675:Child, Preschool; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D006885:Hydroxybutyrates / Q000737:chemistry / Q000378:metabolism / Q000652:urine*; D008297:Male; D008661:Metabolism, Inborn Errors / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism* / Q000652:urine; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014633:Valine / Q000378:metabolism
chemical_list: D006885:Hydroxybutyrates; D011993:Recombinant Fusion Proteins; D004247:DNA; D000429:Alcohol Oxidoreductases; C021398:3-hydroxyisobutyrate dehydrogenase; D014633:Valine