Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands.
Hum Mutat. 2010 Mar;31(3):279-83. doi: 10.1002/humu.21186.
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.
我们对 50 名在生理液中积累 D-2-羟戊二酸（D-2-HG）的 D-2-羟戊二酸尿症（D-2-HGA）患者进行了分子、酶和代谢研究。在 D-2-羟戊二酸脱氢酶（D2HGDH）基因中检测到 50 名患者中的 24 名患有推定致病性突变，该基因编码 D-2-羟戊二酸脱氢酶（D-2-HGDH）。D-2-HGDH 的酶测定证实，所有突变患者的酶活性均受损，而酶活性正常的 D-2-HGA 患者则没有突变。突变阳性的 D-2-HGA 患者的体液中 D-2-HG 浓度明显低于突变阴性患者。这些结果表明，多个遗传位点可能与 D-2-HG 的过度排泄有关。因此，我们建议进行新的分类：D-2-HGA 型 I 与 D-2-HGDH 缺乏有关，而特发性 D-2-HGA 则表现为正常的 D-2-HGDH 活性和比 I 型患者更高的体液中 D-2-HG 水平。在未来的研究中，可能会揭示出具有不同遗传位点的特发性 D-2-HGA 患者的几种分类。
