L2hydroxyglutaric

L-2-hydroxyglutaric acid, also called L-2-HG, is a hydroxy derivative of glutaric acid that exists as two enantiomers, L- and D-2-hydroxyglutaric acid. The molecule is a small dicarboxylic acid with a single stereocenter, and the L isomer is the form most closely linked to a human metabolic disorder. In normal metabolism, only trace amounts are present in body fluids; the two enantiomers have distinct origins and biological roles.

Biosynthesis and metabolism occur within central carbon metabolism pathways. L-2-HG is produced endogenously in small amounts from α-ketoglutarate under certain conditions and is normally kept at low levels by the enzyme L-2-hydroxyglutarate dehydrogenase (L2HGDH), which oxidizes L-2-HG back to α-ketoglutarate. Deficiencies or dysfunction in this enzyme lead to accumulation of L-2-HG in tissues and fluids.

Clinical significance centers on L-2-hydroxyglutaric aciduria (L-2HGA), a rare autosomal recessive metabolic disorder caused by mutations in the L2HGDH gene. Patients typically show elevated levels of L-2-HG in urine, plasma, and cerebrospinal fluid, along with progressive neurodevelopmental delay, hypotonia or ataxia, seizures, and varying degrees of intellectual impairment. Neuroimaging may reveal bilateral white matter abnormalities. The condition is diagnosed through enantiomer-specific measurement of 2-hydroxyglutarate in body fluids and confirmatory genetic testing for L2HGDH mutations.

Distinguishing L-2-HG from the D- isomer is clinically important, as the two enantiomers have different disease associations. In oncology, 2-hydroxyglutarate can accumulate in tumors through different mechanisms, most notably D-2-HG produced by mutant IDH enzymes; the role of L-2-HG in cancer is less well defined. There is no widely curative treatment for L-2HGA; management is supportive and multidisciplinary.