ORPHA: 79315; DO: 0111352;
Location | Phenotype | Phenotype MIM number |
Inheritance | Phenotype mapping key |
Gene/Locus | Gene/Locus MIM number |
---|---|---|---|---|---|---|
15q26.1 | D-2-hydroxyglutaric aciduria 2 | 613657 | 3 | IDH2 | 147650 |
A number sign (#) is used with this entry because of evidence that D-2-hydroxyglutaric aciduria-2 (D2HGA2) is caused by heterozygous mutations in the mitochondrial isocitrate dehydrogenase-2 (IDH2; 147650) gene on chromosome 15q26.
For a general phenotypic description and a discussion of genetic heterogeneity of D-2-hydroxyglutaric aciduria, see D2HGA1 (600721).
Kranendijk et al. (2010) phenotypically characterized 17 unrelated patients with D-2-hydroxyglutaric aciduria who did not have a mutation in the D2HGDH gene (609186). These individuals had the same phenotypic spectrum associated with D2HGA (600721) caused by mutations in the D2HGDH gene (i.e., ranging from asymptomatic to developmental delay, epilepsy, hypotonia, cardiomyopathy, and dysmorphic features). Fifteen patients (9 females and 6 males) were found to have a mutation in the IDH gene (see MOLECULAR GENETICS). Nine patients had died between the ages of a few months to 14 years. Those still living ranged in age from 3 to 22 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.
The transmission pattern of D-2-hydroxyglutaric aciduria-2 in the families reported by Kranendijk et al. (2010) was consistent with autosomal dominant inheritance.
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) searched for 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 an R140Q mutation (147650.0001) and 1 had an R140G mutation (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.
Kranendijk et al. (2010) suggested that although the D2HGDH enzyme functions normally in patients with IDH2 mutations, the active D2HGDH protein appears to lack the catalytic capacity to oxidize all D-2-hydroxyglutaric acid formed by IDH2 containing an R140 mutation. Thus, Kranendijk et al. (2010) denoted the disorder in these patients D2HGA type 2.
Kranendijk, M., Struys, E. A., van Schaftingen, E., Gibson, K. M., Kanhai, W. A., van der Knapp, M. S., Amiel, J., Buist, N. R., Das, A. M., de Klerk, J. B., Feigenbaum, A. S., Grange, D. K., and 11 others. IDH2 mutations in patients with D-2-hydroxyglutaric aciduria. Science 330: 336 only, 2010. [PubMed: 20847235] [Full Text: https://doi.org/10.1126/science.1192632]
Ward, P. S., Patel, J., Wise, D. R., Abdel-Wahab, O., Bennett, B. D., Coller, H. A., Cross, J. R., Fantin, V. R., Hedvat, C. V., Perl, A. E., Rabinowitz, J. D., Carroll, M., Su, S. M., Sharp, K. A., Levine, R. L., Thompson, C. B. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17: 225-234, 2010. [PubMed: 20171147] [Full Text: https://doi.org/10.1016/j.ccr.2010.01.020]
Yan, H., Parsons, D. W., Jin, G., McLendon, R., Rasheed, B. A., Yuan, W., Kos, I., Batinic-Haberle, I., Jones, S., Riggins, G. J., Friedman, H., Friedman, A., Reardon, D., Herndon, J., Kinzler, K. W., Velculescu, V. E., Vogelstein, B., Bigner, D. D. IDH1 and IDH2 mutations in gliomas. New Eng. J. Med. 360: 765-773, 2009. [PubMed: 19228619] [Full Text: https://doi.org/10.1056/NEJMoa0808710]