Investigations by mass isotopomer analysis of the formation of D-2-hydroxyglutarate by cultured lymphoblasts from two patients with D-2-hydroxyglutaric aciduria.

D-2-Hydroxyglutaric aciduria is an inborn error of metabolism first described in 1980. To date, more than 40 patients have been diagnosed with this disease. To identify the metabolic precursor of D-2-hydroxyglutarate (D-2-HG), cultured human lymphoblasts from two patients with D-2-HG aciduria were grown in culture medium supplemented with [U-(13)C(6)]glucose or [(2)H(5)]glutamate. Mass isotopomer distribution measurements of D-2-HG, 2-ketoglutarate (2-KG) and citrate were performed by gas chromatography-mass spectrometry. The mass isotopomer distributions in D-2-HG, 2-KG and citrate, following [U-(13)C(6)]glucose and [(2)H(5)]glutamate incubations, revealed that 2-KG interconverts rapidly to D-2-HG and that D-2-HG is formed within the mitochondria.