Clinical, biochemical, and molecular findings in three patients with 3-hydroxyisobutyric aciduria

Mol Genet Metab. 2006 Mar;87(3):243-8. doi: 10.1016/j.ymgme.2005.09.019. Epub 2006 Feb 8.

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.

Publication types

  • Case Reports

MeSH terms

  • Alcohol Oxidoreductases / genetics
  • Alcohol Oxidoreductases / metabolism
  • Cells, Cultured
  • Child, Preschool
  • DNA / genetics
  • DNA Mutational Analysis
  • Genome, Human / genetics
  • Humans
  • Hydroxybutyrates / chemistry
  • Hydroxybutyrates / metabolism
  • Hydroxybutyrates / urine*
  • Male
  • Metabolism, Inborn Errors / enzymology
  • Metabolism, Inborn Errors / genetics*
  • Metabolism, Inborn Errors / metabolism*
  • Metabolism, Inborn Errors / urine
  • Recombinant Fusion Proteins / metabolism
  • Valine / metabolism

Substances

  • Hydroxybutyrates
  • Recombinant Fusion Proteins
  • DNA
  • Alcohol Oxidoreductases
  • 3-hydroxyisobutyrate dehydrogenase
  • Valine