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Exact prevalence and incidence of this disorder are not known but about 80 cases have been reported to date. No geographical predominance has been found for this disorder.

D-2-hydroxyglutaric aciduria has extremely variable clinical manifestations. Severe cases are characterized by neonatal or early infantile-onset epileptic encephalopathy. Marked hypotonia, cerebral visual failure, developmental delay, seizures, involuntary movements, and cardiomyopathy are common in these cases. Facial dysmorphic features have been reported frequently and include a flat face with a broad nasal bridge, and external ear anomalies. In mild cases, the clinical picture is more variable. Developmental delay and hypotonia are the most common findings. No correlation between D-2-HG levels and clinical symptoms has been found. Some patients with elevated D-2-HG levels are asymptomatic. In general, D-2-hydroxygluratic aciduria caused by heterozygous IDH2 mutations, has a more severe clinical course than D-2-hydroxygluratic aciduria caused by mutations in the D2HGDH gene.

Mutations in the D2HGDH gene (2p25.3) encoding mitochondrial D-2-hydroxyglutarate dehydrogenase have been identified in approximately 50% of patients with this disorder. Others were found to harbor a pathogenic heterozygous mutation in the IDH2 gene (15q21-qter) encoding mitochondrial isocitrate dehydrogenase.

Diagnosis is established on the basis of excess D-2-hydroxyglutaric acid in the urine and MRI findings: subependymal cysts, delayed cerebral maturation, and periventricular white-matter abnormalities in severe cases.

Urinary organic acid screening does not allow differentiation between L-2-hydroxygluratic acid and D-2-hydroxyglutaric acid. Therefore, this differentiation has to be performed subsequently by a specialized laboratory.

Prenatal diagnosis can be performed by mutational analysis and detection of increased levels of D-2-hydroxyglutaric acid in amniotic fluid.

D-2-HGA caused by mutations in the D2HGDH gene follows an autosomal recessive pattern of inheritance. Genetic counseling is complicated due to the extremely wide clinical picture and poor understanding of the genetic etiology and underlying mechanisms. In contrast, D-2-HGA caused by a de novo heterozygous mutation in the IDH2 gene, is an autosomal dominant trait, with the exception for one reported family.

There is no specific treatment for D-2-hydroxyglutaric aciduria. Management mainly involves control of seizures when they are present.

The prognosis is entirely dependent on the severity of the clinical picture and course of the disease.