Disease-Related Metabolites in Culture Medium of Fibroblasts from Patients with D-2-Hydroxyglutaric Aciduria, L-2-Hydroxyglutaric Aciduria, And Combined D/L-2-Hydroxyglutaric Aciduria (Endocrinology and Metabolism‪)‬

Among the organic acidurias, the basic defects in d-2hydroxyglutaric aciduria (D-2-HGA), [1] l-2-hydroxyglutaric aciduria (L-2-HGA), and the combined d/l-2-hydroxyglutaric aciduria (D/L-2-HGA) remain mysteries. Despite the fact that the first patients with D-2-HGA (1) and L-2-HGA (2) were described in 1980, no major progress has been made since then in revealing the primary cause of these disorders. Clinical and biochemical findings of 25 patients with D-2-HGA have been described, supporting evidence for the existence of severe and mild clinical phenotypes of this disorder (3, 4). Biochemically, these two variants cannot be distinguished. Frequent clinical findings in D-2-HGA include developmental delay, epilepsy, and hypotonia. Movement disorders and cardiomyopathy are also common among patients with D-2-HGA. In 1995, Wanders and Mooyer (5) published the finding of a FAD-dependent d-2-hydroxyglutarate (D-2-HG) dehydrogenase localized in human mitochondria. The involvement of this enzyme in D-2HGA has not been demonstrated. In 1993, the clinical and biochemical findings in 12 patients with L-2-HGA were described (6). The clinical phenotype includes white matter disease and mental retardation and appears specific for L-2-HGA. In all seven individuals in whom the cerebrospinal fluid (CSF) and plasma concentrations of l-2-hydroxyglutarate (L-2-HG) had been measured, the CSF/plasma ratio was 1, indicating that L-2-HGA is a neurometabolic disorder. In the same report, in vitro experiments performed with [sup.14]C-labeled 2-ketoglutarate revealed the existence of a [NAD.sup.+]-dependent L-2-HG dehydrogenase in human liver, but the involvement of this enzyme in L-2-HGA has not been demonstrated. To date, we know of 75 individual cases of L-2-HGA.