Novel insights into L-2-hydroxyglutaric aciduria: Mass isotopomer studies reveal 2-oxoglutaric acid as the metabolic precursor of L-2-hydroxyglutaric acid

Employing lymphoblasts derived from two non related patients with l-2-HG aciduria, we examined the origin of L-2-hydroxyglutaric acid (L-2-HG) through incubation with [C-13(6)]glucose and [H-2(5)]glutamic acid. Formation of labelled 2-ketoglutaric acid (2-KG), citric acid and L-2-HG was determined by GC-MS. The quantitative and qualitative isotopomer pattern following incubation with [C-13(6)]glucose was identical for all end-products. Incubations with [H-2(5)]glutamic acid as precursor revealed the formation of identical isotopomers for 2-KG and L-2-HG. Our data indicate that 2-KG is the metabolic precursor of L-2-HG, adding to previous studies which revealed that 2-KG is the metabolic precursor of d-2-HG. These data suggest that 2-KG has a pathophysiological role in combined d/L-2-HG aciduria.