The enzymatic defect causing this
progressive neurometabolic disorder has not been found. d-2-Hydroxyglutaric acid is a stereoisomer of l-2-hydroxyglutaric acid and an intermediate in glutamate,
5-aminolevulinic acid, and gamma-aminobutyric acid (GABA)
metabolism. Elevated levels of GABA were found in the cerebrospinal
fluid of some patients with d-2-hydroxyglutaric aciduria. A
mild and a severe phenotype have been reported, with a more variable
clinical picture and less consistency seen on MRI findings of the
mild phenotype. Regardless of the phenotype, progressive psychomotor
degeneration with macrocephaly, epilepsy (hypsarrhythmia),
hypotonia, cerebral and/or cerebellar atrophy with cerebellar
ataxia, and mental and motor developmental delay can be found. The
most consistent MRI findings are enlargement of the lateral
ventricles, subependymal cysts, and signs of delayed cerebral
maturation. Nonneurologic manifestations include prenatal and
postnatal growth retardation, cardiomyopathy, facial anomalies, and
episodic vomiting. Inspiratory stridor and apnea were the reasons
for tracheotomy in one patient at age 4 months.