**Background:** L-2-hydroxyglutaric aciduria (L2HGA) is an autosomal recessive inherited metabolic disorder caused by pathogenic variants in the L2HGDH gene (14q22.1), encoding mitochondrial 2-hydroxyglutarate dehydrogenase. First described by Duran et al. in 1980, the estimated prevalence is less than 1/1,000,000 births. The disorder typically manifests in the first year of life with a slowly progressive course of cerebellar ataxia, dysarthria, and neurological deterioration. Seizures, macrocephaly, pyramidal and extrapyramidal signs, and growth stunting may also be present. No specific treatment exists; management is mainly supportive, with some reports suggesting benefit from riboflavin (FAD) and L-carnitine supplementation. The biochemical hallmark is increased concentration of L-2-hydroxyglutaric acid in body fluids, with chiral separation required to distinguish L2HGA from D2HGA and other disorders. Brain MRI shows characteristic T2 hyperintensities in anterior subcortical white matter and basal ganglia with centripetal extension sparing the brainstem and corpus callosum.
**Methods:** The authors report two sisters from Pakistan born to consanguineous parents, with 4 years of follow-up. They also conducted a literature search of Google Scholar using terms 'L-2-HGA', 'L2HGA', and 'L-2-hydroxyglutaric aciduria' without date or language restrictions. The search yielded 20 articles with 155 cases. Six cases lacking enantiomeric or molecular analysis were excluded. Clinical outcomes were compared with 45 reported patients with L2HGA for whom treatment and outcome data were available. Urine organic acid analysis was performed by gas chromatography mass spectrometry. Chiral differentiation of 2-hydroxyglutaric acid enantiomers was performed using liquid chromatography mass spectrometry analysis of diacetyl-L-tartrate derivatized 2-HG enantiomers in plasma on an AB Sciex 5500 QTRAP system. Targeted L2HGDH sequencing was performed.
**Key Results:** Patient 1 (15-year-old girl) presented with psychomotor delay, seizures, ataxia, intentional tremors, and dysarthria. Early motor milestones were delayed (neck control at 5 months, sitting at 8 months, walking after 15 months). First seizure occurred at 7 years. Examination revealed scanning speech, dysdiadochokinesia, intentional tremors, past pointing, wide-based ataxic gait, exaggerated deep tendon reflexes, and bilateral sustained ankle clonus. Brain MRI showed diffuse confluent subcortical white matter T2/FLAIR hyperintense signals, predominantly frontal with centripetal distribution, diffusion restriction, and globus pallidus involvement. Urine organic acids showed marked excretion of 2-hydroxyglutaric acid. Chiral analysis confirmed L-2-HG as the dominant enantiomer. Targeted sequencing identified a homozygous pathogenic variant c.829C>T (p.Arg227*) in L2HGDH. After 1.5 years of treatment with riboflavin 100 mg twice daily and L-carnitine 1500 mg twice daily, speech improved with minimal scanning quality, she could drink without straws, comb hair, and brush teeth. Gait became more stable, though exaggerated reflexes and ankle clonus persisted. She had one brief seizure episode. Patient 2 (17-year-old sister) had similar presentation with delayed milestones (neck control at 4 months, sitting at 8 months, walking after 16 months, first word after 2 years). First seizure at 8 years. Examination findings were identical to her sister. Same homozygous variant was identified. Both parents and a brother were heterozygous carriers. After 1.5 years of the same treatment, speech, tremors, and ataxia improved; she no longer needed straws to drink. Exaggerated reflexes and ankle clonus persisted. Literature review of 45 treated cases showed consanguinity in 21 (47%), age of diagnosis from 4 months to 43 years, and one death (2.2%). Common presentations included seizures (26%, n=39), ataxia (26%, n=39), intellectual deficit (22%, n=33), dysarthria (11.5%, n=17), and delayed walking (11%, n=16). Among 12 cases treated with riboflavin and/or carnitine, 10 showed improvement or stabilization, one expired, and one deteriorated.
**Clinical Implications:** L2HGA should be suspected in patients with psychomotor retardation, cerebellar ataxia, seizures, and characteristic MRI findings of centripetal subcortical leukoencephalopathy with basal ganglia and dentate nuclei involvement. Chiral separation of 2-HG enantiomers is essential for accurate diagnosis. Treatment with riboflavin and L-carnitine may improve symptoms including speech, tremors, and ataxia, even when initiated late in the disease course. Early diagnosis and treatment initiation could potentially modify the clinical course. The paper reinforces that neuroradiological features are rather specific to L2HGA and should prompt biochemical and genetic testing.