D-2-Hydroxyglutaric aciduria: unravelling the biochemical pathway and the genetic defect

J Inherit Metab Dis. 2006 Feb;29(1):21-9. doi: 10.1007/s10545-006-0317-9.


D-2-Hydroxyglutaric aciduria (D-2-HGA) is a neurometabolic inherited disorder first described in 1980. In the following years, it became clear that the clinical phenotype of the disease varies widely from severe neonatal to asymptomatic. However, the sparse biochemical knowledge made D-2-HGA a poorly understood disease. Much progress has been made in the last five years in various studies, revealing two human enzymes that play a role in the metabolism of D-2-hydroxyglutarate (D-2-HG): hydroxyacid-oxoacid transhydrogenase (HOT) and D-2-HG dehydrogenase. HOT is expected to be responsible for the formation of D-2-HG, while D-2-HG dehydrogenase converts D-2-HG into 2-ketoglutarate. We demonstrated pathogenic mutations in the D2HGD gene in patients with D-2-HGA, helping to unravel the primary defect causing D-2-HGA. However, in approximately 50% of the patients with D-2-HGA examined, no pathogenic mutations have yet been found.

Publication types

  • Review

MeSH terms

  • Alcohol Oxidoreductases / metabolism
  • Amino Acid Metabolism, Inborn Errors / diagnosis*
  • Amino Acid Metabolism, Inborn Errors / genetics*
  • Brain Diseases, Metabolic, Inborn / diagnosis
  • Brain Diseases, Metabolic, Inborn / genetics
  • Glutarates / urine*
  • Humans
  • Mitochondrial Proteins
  • Models, Chemical
  • Models, Genetic
  • Mutation
  • Phenotype
  • Stereoisomerism


  • Glutarates
  • Mitochondrial Proteins
  • alpha-hydroxyglutarate
  • Alcohol Oxidoreductases
  • 2-hydroxyacid dehydrogenase
  • hydroxyacid-oxoacid transhydrogenase