We have generated a novel mouse model of D2HGA type II, a rare neurometabolic disorder caused by germline gain-of-function mutations in IDH2. Our Idh2R140Q KI model displays dramatically elevated 2HG levels in plasma, bone marrow, heart, spleen, and brain compared with Idh2wt littermates, which is associated with early onset cardiomyopathy, brain abnormalities, shortened life span, and in some mice, periodic seizures, runting, and face/head abnormalities. Here, IDH2 is linked to cardiomyopathy.