Specific gain of function mutations in IDH2 cause D2-hydroxyglutaric aciduria, a disorder with severe effects on the central nervous system including infantile encephalopathy, seizures, and white matter abnormalities. Cardiomyopathy is also an important feature of this disorder.
Akbay et al. (Genes Dev. 2014 Mar 1;28(5):479-90. doi: 10.1101/gad.231233.113.) recently published a paper in which they described a conditional mouse model of IDH2 activation, and showed that induction of the mutant IDH2 expression in adult mice leads to dilated cardiomyopathy and white matter abnormalities in the brain. In addition, in utero activation of the mutant IDH2 resulted in a more severe phenotype. Notably, when the mutant gene is silenced, the cardiac abnormalities are improved. These findings provide evidence that inhibitors of mutant IDH2, such as are in development for cancer therapy, may have a role in the treatment of D2-hydroxyglutaric aciduria.
Hilary Vernon, MD PhD