Evidence for genetic heterogeneity in D-2-hydroxyglutaric aciduria

  • Hum Mutat. 2010 Mar;31(3):279-83. doi: 10.1002/humu.21186.
Martijn Kranendijk  1 ,  Eduard A Struys ,  K Michael Gibson ,  Wjera V Wickenhagen ,  Jose E Abdenur ,  Jochen Buechner ,  Ernst Christensen ,  Raquel Dodelson de Kremer ,  Abdellatif Errami ,  Paul Gissen ,  Wanda Gradowska ,  Emma Hobson ,  Lily Islam ,  Stanley H Korman ,  Thaddeus Kurczynski ,  Bruno Maranda ,  Concetta Meli ,  Cristiano Rizzo ,  Claude Sansaricq ,  Friedrich K Trefz ,  Rachel Webster ,  Cornelis Jakobs ,  Gajja S Salomons
Affiliations
  • 1. Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands.
PMID: 20020533 DOI: 10.1002/humu.21186
Abstract

We performed molecular, enzyme, and metabolic studies in 50 patients with D-2-hydroxyglutaric aciduria (D-2-HGA) who accumulated D-2-hydroxyglutarate (D-2-HG) in physiological fluids. Presumed pathogenic mutations were detected in 24 of 50 patients in the D-2-hydroxyglutarate dehydrogenase (D2HGDH) gene, which encodes D-2-hydroxyglutarate dehydrogenase (D-2-HGDH). Enzyme assay of D-2-HGDH confirmed that all patients with mutations had impaired enzyme activity, whereas patients with D-2-HGA whose enzyme activity was normal did not have mutations. Significantly lower D-2-HG concentrations in body fluids were observed in mutation-positive D-2-HGA patients than in mutation-negative patients. These results imply that multiple genetic loci may be associated with hyperexcretion of D-2-HG. Accordingly, we suggest a new classification: D-2-HGA Type I associates with D-2-HGDH deficiency, whereas idiopathic D-2-HGA manifests with normal D-2-HGDH activity and higher D-2-HG levels in body fluids compared with Type I patients. It remains possible that several classifications for idiopathic D-2-HGA patients with diverse genetic loci will be revealed in future studies.