L2hydroxyglutarate

L-2-hydroxyglutarate, commonly abbreviated as L-2HG, is a chiral metabolite of the cellular metabolism that exists as the L enantiomer of 2-hydroxyglutarate (2-HG). In humans, L-2HG is produced at low levels under normal conditions but can accumulate in response to metabolic stress or genetic defects.

Biochemistry and metabolism: L-2HG is generated from the Krebs cycle intermediate 2-oxoglutarate by promiscuous activity of certain dehydrogenases, particularly under conditions such as hypoxia or mitochondrial dysfunction. It is normally detoxified by the mitochondrial enzyme L-2-hydroxyglutarate dehydrogenase (L2HGDH), which converts L-2HG back to 2-oxoglutarate. Mutations in the L2HGDH gene disrupt this repair pathway, leading to elevated levels of L-2HG in tissues and body fluids.

Clinical significance: The accumulation of L-2HG causes L-2-hydroxyglutaric aciduria (L-2-HGA), a rare autosomal recessive neurometabolic disorder. L-2-HGA typically presents in early childhood with developmental delay, hypotonia or motor impairment, seizures, ataxia, and progressive intellectual disability. Neuroimaging often reveals leukoencephalopathy with diffuse white matter changes. Diagnosis is based on elevated L-2HG levels in urine, plasma, or cerebrospinal fluid, detected by mass spectrometry or other sensitive analytical methods, and can be confirmed by genetic testing of L2HGDH.

Role in research and disease mechanism: L-2HG can inhibit α-ketoglutarate–dependent dioxygenases, influencing epigenetic regulation and cellular metabolism. Although its role as an oncometabolite is less well established than that of D-2-hydroxyglutarate, L-2HG–mediated metabolic and epigenetic disturbances are actively studied in neurometabolic disease and certain cancers.

Treatment and prognosis: There is no cure for L-2-HGA, and management is supportive, focusing on seizure control and developmental support. Early diagnosis aids in genetic counseling. Research continues into potential therapeutic strategies targeting the L-2HG repair pathway.