Mutations in phenotypically mild D ‐2‐hydroxyglutaric aciduria

D ‐2‐hydroxyglutaric aciduria is a neurometabolic disorder with mild and severe phenotypes. Recently, we reported pathogenic mutations in the D ‐ 2 ‐ hydroxyglutarate dehydrogenase gene as the cause of the severe phenotype of D ‐2‐hydroxyglutaric aciduria in two patients. Here, we report two novel pathogenic mutations in this gene in one patient with a mild presentation and two asymptomatic siblings with D ‐2‐hydroxyglutaric aciduria from two unrelated consanguineous Palestinian families: a splice error (IVS4‐2A→G) and a missense mutation (c.1315A→G;p.Asn439Asp). Overexpression of this mutant protein showed marked reduction of the enzyme activity. Ann Neurol 2005