D-2-hydroxyglutaric aciduria in three patients with proven SSADH deficiency: genetic coincidence or a related biochemical epiphenomenon?

Abstract Succinic semialdehyde dehydrogenase (SSADH) deficiency and d -2-hydroxyglutaric aciduria ( d -2-HGA) are rare inborn errors of metabolism primarily revealed by urinary organic acid screening. Three patients with proven SSADH deficiency excreted, in addition to GHB considerable amounts of d -2-HG. We examined whether these patients suffered from two inborn errors of metabolism by measuring d -2-HG concentrations in the culture medium of cells from these patients. In addition, mutation analysis of the d -2-hydroxyglutarate dehydrogenase gene was performed. Normal concentrations of d -2-HG were measured in the culture media of fibroblasts or lymphoblasts derived from the three patients. In one patient, we found a heterozygous likely pathogenic mutation in the d -2-hydroxyglutarate dehydrogenase gene. These combined results argue against the hypothesis that the patients are affected with “primary” d -2-HGA in combination with their SSADH deficiency. Moderately increased levels of d -2-HG were also found in urine, plasma, and cerebrospinal fluid samples derived from 12 other patients with SSADH deficiency, revealing that d -2-HG is a common metabolite in this disease. The increase of d -2-HG in SSADH deficiency can be explained by the action of hydroxyacid-oxoacid transhydrogenase, a reversible enzyme that oxidases GHB in the presence of 2-ketoglutarate yielding SSA and d -2-HG.