General description

L-2-hydroxyglutaric aciduria (L2HGA) is a rare autosomal recessive neurometabolic disorder characterized by progressive neurodegeneration, distinct neuroimaging patterns, and systemic accumulation of L-2-hydroxyglutaric acid (L2HG). L2HGA arises from biallelic pathogenic variants in the L2HGDH gene (14q22.1), which encodes mitochondrial L-2-hydroxyglutarate dehydrogenase. This enzyme catalyzes the oxidation of L2HG to α-ketoglutarate, a critical step in the mitochondrial NAD+-dependent degradation pathway. Loss of enzymatic activity leads to systemic accumulation of L2HG, with particularly high concentrations in cerebrospinal fluid and urine.

While patients may initially appear asymptomatic, most present in early childhood with developmental delay or seizures. Symptoms include mild to moderate intellectual and motor decline, cerebellar ataxia, and seizures. About two-thirds of patients experience cerebellar ataxia and seizures, while around half show macrocephaly and extrapyramidal signs. Early hypotonia is common, with spasticity developing later in the disease. Diagnosis is confirmed by elevated L-2-hydroxyglutaric acid in urine.

References

1. Steenweg, Marjan E., et al. "L-2-Hydroxyglutaric aciduria: pattern of MR imaging abnormalities in 56 patients." Radiology 251.3 (2009): 856-865.