ABSTRACT
D-2-hydroxyglutaric aciduria is an organic aciduria in which the clinical phenotypic spectrum is quite broad. The clinical phenotype was set out by van der Knaap and associates in an international survey of 25 patients with documented D-2-hydroxyglutaric aciduria. Patients with combined D2- and L-2 hydroxyglutaric aciduria have displayed little evidence of developmental progress. The biochemical hallmark of these diseases is the accumulation of D-2-hydroxyglutaric acid in body fluids. The pathophysiology of the disease is thought to represent a developmental neurotoxicity of D-2-hydroxyglutaric acid. D-2-Hydroxyglutaric acid inhibited creatine kinase in brain and in skeletal and cardiac muscle, and cytochrome c oxidase activity in fibroblasts in vitro, but electron transport chain activity in the fibroblasts of patients was normal. Patients with combined D-2 and L-2-hydroxyglutaric aciduria urine excrete increased quantities of citric acid cycle intermediates, 2-ketoglutarate, malate, fumarate and succinate.
