Kranendijk et al. (2010) phenotypically characterized 17 unrelated patients with D-2-hydroxyglutaric aciduria without mutations in the D2HGDH gene (609186). These individuals had the same phenotypic spectrum associated with D2HGA caused by mutations in the D2HGDH gene (i.e., ranging ... Kranendijk et al. (2010) phenotypically characterized 17 unrelated patients with D-2-hydroxyglutaric aciduria without mutations in the D2HGDH gene (609186). These individuals had the same phenotypic spectrum associated with D2HGA caused by mutations in the D2HGDH gene (i.e., ranging from asymptomatic to developmental delay, epilepsy, hypotonia, cardiomyopathy, and dysmorphic features). Among the 15 patients there were 9 females and 6 males. Those still living ranged in age from 3 to 22 years. The age of death of the 9 remaining patients ranged from a few months to 14 years. The mean urinary D-2-hydroxyglutaric acid in mmol/mol creatinine was 2,153 among 14 individuals, higher than excretion of D-2-hydroxyglutaric acid in D2HGA1, where the mean was 969 among 20 individuals.
Somatic mutation in the IDH1 (147700) or IDH2 genes had been shown to result in the enzyme's abnormal ability to convert 2-ketoglutarate (2-KG) to D-2-hydroxyglutarate (D2HG) (Yan et al., 2009; Ward et al., 2010). For this reason Kranendijk ... Somatic mutation in the IDH1 (147700) or IDH2 genes had been shown to result in the enzyme's abnormal ability to convert 2-ketoglutarate (2-KG) to D-2-hydroxyglutarate (D2HG) (Yan et al., 2009; Ward et al., 2010). For this reason Kranendijk et al. (2010) sought mutations in the IDH1 or IDH2 genes in 17 unrelated patients with D2HGA without mutations in the D2HGDH gene. Kranendijk et al. (2010) found no mutations in the IDH1 gene but identified mutations in the IDH2 gene in 15 of the 17 individuals. Fourteen had a R140Q mutation (147650.0001) and 1 had R140G (147650.0002). Somatic R140Q mutation had been identified in acute myeloid leukemia and shown to lead to abnormal production of D-2-hydroxyglutaric acid (Ward et al., 2010). The higher excretion of D-2-hydroxyglutaric acid in type 2 patients compared to type 1 patients could best be explained by hyperproduction of this metabolite. The involvement of mitochondrial IDH2 is also consistent with the finding that D-2-hydroxyglutaric acid is derived from mitochondrial 2-KG. In 8 of 9 sets of parents the mutation could not be detected, indicating that the heterozygous mutation arose de novo and that D2HGA type 2 is an autosomal dominant trait. In 1 family, however, 3 affected pregnancies were diagnosed with increased D-2-hydroxyglutaric acid levels in amniotic fluid, suggesting germline mosaicism in the mother who herself had normal urinary D-2-hydroxyglutaric acid levels and showed somatic mosaicism in her blood.