L2-hydroxyglutaric aciduria presenting with learning disability and cerebellar signs: A case report

Abstract

L-2-hydroxyglutaric aciduria (L2HGA) is a rare, autosomal recessive neurometabolic disorder due to variants in the L2HGDH gene, which encodes L-2-hydroxyglutarate dehydrogenase (L2HGDH), an enzyme involved in tricarboxylic acid cycle. Deficiency of L2HGDH causes leukoencephalopathy predominantly affecting the cerebellum. This case presents L2HGA in a 12-year-old Sri Lankan boy born to third-degree consanguineous parents, who also showed learning disability and bilateral cerebellar signs. Magnetic resonance imaging (MRI) of the brain revealed T2/FLAIR hyperintensities in bilateral symmetrical subcortical white matter involving the cerebellum. A diagnosis of 2-hydroxyglutaric aciduria was made after a massive peak of 2-hydroxyglutaric acid (2HG) was observed in the analysis of urine organic acids (UOA) using gas chromatography/mass spectrometry. Genetic variant analysis revealed two heterozygous pathogenic variants in the L2HGDH gene, confirming the genetic diagnosis of autosomal recessive L2HGA. Parental genetic testing confirmed the trans phase of the variants in the index patient and their carrier status of a pathogenic L2HGDH variant. Despite typical clinical features and classical MRI findings, initial clues toward the diagnosis are mainly derived from the UOA analysis. In conclusion, this case underscores the paramount importance of analyzing the UOA profile in the process of identifying rare metabolic causes, such as L2HGA, that contribute to learning disability with neurological involvement in children.