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

M. S. Van Der Knaap, C. Jakobs, G. F. Hoffmann, W. L. Nyhan, W. O. Renier, J. A.M. Smeitink, C. E. Catsman-Berrevoets, O. Hjalmarson, H. Vallance, K. Sugita, C. M. Bowe, J. T. Herrin, W. J. Craigen, N. R.M. Buist, D. S.K. Brookfield, R. A. Chalmers

Research output: Contribution to journalArticleAcademicpeer-review


D-2-Hydroxyglutaric aciduria has been observed in patients with extremely variable clinical symptoms, creating doubt about the existence of a disease entity related to the biochemical finding. An international survey of patients with D-2-hydroxyglutaric aciduria was initiated to solve this issue. The clinical history, neuroimaging, and biochemical findings of 17 patients were studied. Ten of the patients had a severe early-infantile-onset encephalopathy characterized by epilepsy, hypotonia, cerebral visual failure, and little development. Five of these patients had a cardiomyopathy. In neuroimaging, all patients had a mild ventriculomegaly, often enlarged frontal subarachnoid spaces and subdural effusions, and always signs of delayed cerebral maturation. In all patients who underwent neuroimaging before 6 months, subependymal cysts over the head or corpus of the caudate nucleus were noted. Seven patients had a much milder and variable clinical picture, most often characterized by mental retardation, hypotonia, and macrocephaly, but sometimes no related clinical problems. Neuroimaging findings in 3 patients variably showed delayed cerebral maturation, ventriculomegaly, or subependymal cysts. Biochemical findings included elevations of D-2-hydroxyglutaric acid in urine, plasma, and cerebrospinal fluid in both groups. Cerebrospinal fluid γ-aminobutyric acid was elevated in almost all patients investigated. Urinary citric acid cycle intermediates were variably elevated. The conclusion of the study is that D-2- hydroxyglutaric aciduria is a distinct neurometabolic disorder with at least two phenotypes.

Original languageEnglish
Pages (from-to)111-119
Number of pages9
JournalAnnals of Neurology
Issue number1
Publication statusPublished - 1999

Cite this