D-2-hydroxyglutaric aciduria (D2HGA) type 1 [OMIM #600721] and type 2 [OMIM#613657] are rare neurometabolic diseases associated with accumulation of D-2-hydroxyglutaric aciduria (D-2-HG) in urine. The cardinal clinical manifestations in both D2HGA subtypes are developmental delay, hypotonia and seizures. Age of onset is similar for both subtypes, typically occurring at 0-6 months of age in D2HGA type 1, and 0-2 years of age in D2HGA type 2. Additional clinical features described in some patients with D2HGA include macrocephaly, dysmorphic features and cerebral visual abnormalities. 47% of D2HGA type 2 patients have cardiomyopathy (primarily dilated). Brain MRI findings in D2HGA patients include enlargement of lateral ventricles, enlarged subarachnoid spaces, subdural effusions, subependymal psuedocysts, signs of delayed cerebral maturation and multifocal cerebral white matter abnormalities. Differences between MRI findings patients with D2HGA type 1 compared to type 2 have not been delineated to date.
Mutations in the D2HGDH [OMIM #609186] gene are associate with D2HGA type 1, and mutations in the IDH2 gene [OMIM #147650] gene are associated with D2HGA type 2. Mutations in either gene are associated with accumulation of D-2-HG in the urine and cerebral spinal fluid. Conventional urine organic acid screening with gas chromatography mass spectrometry (GC-MS) can detect increased 2-HG (2-hydroxyglutaric acid), but does not differentiate between enantiomeric D-2-HG and L-2-HG. D2HGDH encodes D-2-hydroglutarate dehydrogenase, which converts D-2-HG to 2-ketoglutaric acid. Loss of function mutations in D2HGDH lead to an accumulation of D-2-HG. To date, missense, nonsense, splice site and frameshift mutations in D2HGDH have been described. IDH2 encodes isocitrate dehydrogenase-2, which normally converts isocitrate to 2-ketoglutaric aciduria. Mutations in IDH2 associated with D2HGA are gain-of-function missense mutations, which give isocitrate dehydrogenase-2 the ability to convert 2-ketoglutaric aciduria to D-2-HG. This causes D-2-HG to accumulate. D-2-HG has no known physiological function, however its accumulation appears to lead to the clinical manifestations seen in D2HGA.