D-2-hydroxyglutaric aciduria: Biochemical marker or clinical disease entity?

D-2-Hydroxyglutaric aciduria has been observed in patients with extremely v ariable clinical symptoms, creating doubt about the existence of a disease entity related to the biochemical finding. An international survey of patie nts with D-2-hydroxyglutaric aciduria was initiated to solve this issue. Th e clinical history, neuroimaging, and biochemical findings of 17 patients w ere studied. Ten of the patients had a severe early-infantile-onset encepha lopathy characterized by epilepsy, hypotonia, cerebral visual failure, and little development. Five of these patients had a cardiomyopathy. In neuroim aging, all patients had a mild ventriculomegaly, often enlarged frontal sub arachnoid spaces and subdural effusions, and always signs of delayed cerebr al maturation. In all patients who underwent neuroimaging before 6 months, subependymal cysts over the head or corpus of the caudate nucleus were note d Seven patients had a much milder and variable clinical picture, most ofte n characterized by mental retardation, hypotonia, and macrocephaly, but som etimes no related clinical problems. Neuroimaging findings in 3 patients va riably showed delayed cerebral maturation, ventriculomegaly, or subependyma l cysts. Biochemical findings included elevations of D-2-hydroxyglutaric ac id in urine, plasma, and cerebrospinal fluid in both groups. Cerebrospinal fluid gamma-aminobutyric acid was elevated in almost all patients investiga ted. Urinary citric acid cycle intermediates were variably elevated. The co nclusion of the study is that D-2-hydroxyglutaric aciduria is a distinct ne urometabolic disorder with at least two phenotypes.