L2HGDH

L2HGDH, or L-2-hydroxyglutarate dehydrogenase, is a human gene that encodes a mitochondrial flavin adenine dinucleotide (FAD)-dependent enzyme. The L-2-hydroxyglutarate dehydrogenase protein catalyzes the oxidation of the metabolite L-2-hydroxyglutarate (L-2HG) to 2-oxoglutarate (α-ketoglutarate) within the mitochondrial matrix, contributing to the catabolism of enantiomeric hydroxyglutarates. By metabolizing L-2HG, L2HGDH helps maintain cellular levels of this metabolite and supports normal mitochondrial metabolism.

Genetics and disease relevance: Mutations in L2HGDH cause L-2-hydroxyglutaric aciduria (L-2-HGA), a rare autosomal recessive neurometabolic disorder. Pathogenic variants include missense, nonsense, and splice-site mutations that reduce or abolish enzyme activity. The resulting accumulation of L-2HG in body fluids and tissues is associated with neurological impairment and progressive clinical features.

Clinical presentation and diagnosis: L-2-HGA typically presents in early childhood with developmental delay, hypotonia, and seizures, often followed by progressive ataxia and motor impairment. Neuroimaging frequently shows bilateral subcortical white matter changes with cerebellar involvement and basal ganglia changes. Biochemically, patients exhibit markedly elevated levels of L-2-hydroxyglutarate in urine, plasma, and sometimes cerebrospinal fluid. Definitive diagnosis is established by genetic testing confirming biallelic pathogenic variants in L2HGDH.

Management and prognosis: There is no cure or disease-modifying therapy for L-2-HGA; management is supportive and multidisciplinary, focusing on developmental therapies, seizure control, and monitoring of neurological status. Prognosis varies with the extent of neurological involvement and response to supportive care. See also D-2-hydroxyglutaric aciduria and related metabolic disorders.