2-hydroxyglutaric aciduria

2-Hydroxyglutaric aciduria (2-HGA) is a group of rare inherited neurometabolic disorders characterized by the abnormal accumulation of 2-hydroxyglutaric acid in the body, particularly in the brain and cerebrospinal fluid. There are three main forms: L-2-hydroxyglutaric aciduria (L-2-HGA), D-2-hydroxyglutaric aciduria (D-2-HGA), and combined D,L-2-hydroxyglutaric aciduria. L-2-HGA, caused by mutations in the L2HGDH gene, is the most common form and typically presents in childhood with progressive cerebellar ataxia, psychomotor retardation, epilepsy, and subcortical leukoencephalopathy visible on brain MRI. D-2-HGA exists in two types: type I, caused by mutations in D2HGDH, is generally milder, while type II, caused by gain-of-function mutations in IDH2, tends to be more severe with neonatal-onset epilepsy, cardiomyopathy, and early death. Combined D,L-2-HGA, caused by mutations in SLC25A1, is the most severe form, presenting in the neonatal period with severe epileptic encephalopathy and early lethality. The primary body systems affected include the central nervous system, with progressive white matter abnormalities, cerebellar dysfunction, and cognitive decline being hallmark features across all forms. In D-2-HGA type II, the cardiovascular system may also be significantly affected, with dilated cardiomyopathy being a prominent feature. Diagnosis is established through organic acid analysis in urine showing elevated 2-hydroxyglutaric acid levels, followed by chiral differentiation to distinguish the L- and D-enantiomers, and confirmed by molecular genetic testing. Currently, there is no curative treatment for any form of 2-hydroxyglutaric aciduria. Management is supportive and symptomatic, including antiepileptic medications for seizure control, physical and occupational therapy for motor difficulties, and speech therapy. Riboflavin (vitamin B2) supplementation has been tried in some patients with L-2-HGA, but evidence of efficacy remains limited. Genetic counseling is recommended for affected families.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

Common questions about 2-hydroxyglutaric aciduria