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

• Published in: Annals of neurology Vol. 45; no. 1; pp. 111 - 119
• Main Authors: Van Der Knaap, M. S., Jakobs, C., Hoffmann, G. F., Nyhan, W. L., Renier, W. O., Smeitink, J. A. M., Catsman-Berrevoets, C. E., Hjalmarson, O., Vallance, H., Sugita, K., Bowe, C. M., Herrin, J. T., Craigen, W. J., Buist, N. R. M., Brookfield, D. S. K., Chalmers, R. A.
• Format: Journal Article
• Language: English
• Published: New York John Wiley & Sons, Inc 01-01-1999; Willey-Liss
• Subjects: Aminoacid disorders; Biological and medical sciences; Biomarkers; Cerebral Ventricles - pathology; Child, Preschool; Chorea - diagnostic imaging; Chorea - pathology; Chorea - urine; Cysts; Ependyma - pathology; Epilepsy - diagnostic imaging; Epilepsy - pathology; Epilepsy - urine; Errors of metabolism; Family Health; Female; gamma-Aminobutyric Acid - cerebrospinal fluid; Glutarates - urine; Humans; Infant; Magnetic Resonance Imaging; Male; Medical sciences; Metabolic diseases; Muscle Hypotonia - diagnostic imaging; Muscle Hypotonia - pathology; Muscle Hypotonia - urine; Phenotype; Tomography, X-Ray Computed; Vision, Low - diagnostic imaging; Vision, Low - pathology; Vision, Low - urine; Human; Nervous system diseases; D stereoisomer; Biochemical analysis; Aciduria; Metabolic diseases; Infant; Enzymopathy; Nuclear magnetic resonance imaging; Genetic disease; Symptomatology; Phenotype; Glutaric acid; Medical imagery; Diagnosis; Child; Aminoacid disorder
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/1531-8249(199901)45:1<111::AID-ART17>3.0.CO;2-N

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. Ann Neurol 1999;45:111–119