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 [(13)C6]glucose and [(2)H5]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 [(13)C6]glucose was identical for all end-products. Incubations with [(2)H5]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.