Evidence for genetic heterogeneity in D-2-hydroxyglutaric aciduria

✍ Scribed by Martijn Kranendijk; 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

• Publisher: John Wiley and Sons
• Year: 2010
• Tongue: English
• Weight: 208 KB
• Volume: 31
• Category: Article
• ISSN: 1059-7794
• DOI: 10.1002/humu.21186

✦ Synopsis

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.