L2-hydroxyglutaric aciduria presenting with learning disability and cerebellar signs: A case report
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.
- Balaji P, Viswanathan V, Chellathurai A, Panigrahi D. An interesting case of metabolic dystonia: L-2 hydroxyglutaric aciduria. Ann Indian Acad Neurol. 2014;17(1):97-99. doi: 10.4103/0972-2327.128565
- Duran M, Kamerling JP, Bakker HD, van Gennip AH, Wadman SK. L-2-hydroxyglutaric aciduria: An inborn error of metabolism? J Inherit Metab Dis. 1980;3(1): 109-112. doi: 10.1007/BF02312543
- Spatz MA. Genetics home reference. J Med Libr Assoc. 2004;92:282-283.
- Aghili M, Zahedi F, Rafiee E. Hydroxyglutaric aciduria and malignant brain tumor: A case report and literature review. J Neurooncol. 2009;91(2):233-236. doi: 10.1007/s11060-008-9706-2
- Zafeiriou DI, Ververi A, Salomons GS, et al. L-2- Hydroxyglutaric aciduria presenting with severe autistic features. Brain Dev. 2008;30(4):305-307. doi: 10.1016/j.braindev.2007.09.005
- Muhlhausen C, Salomons GS, Lukacs Z, et al. Combined D2-/L2-hydroxyglutaric aciduria (SLC25A1 deficiency): Clinical course and effects of citrate treatment. J Inherit Metab Dis. 2014;37(5):775-781. doi: 10.1007/s10545-014-9702-y
- Kwong Y, Smith H, Sharma R. L-2-Hydroxyglutaric Aciduria; 2012. Available from: https://www.radiopaedia.org [Last accessed: July 22, 2024] doi: 10.53347/rID-20917
- Nagy A, Bley AE, Eichler F. Canavan disease. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, et al., editors. GeneReviewsR. Seattle, WA: University of Washington; 1993-2024.
- Steenweg ME, Jakobs C, Errami A, et al. An overview of L‐2‐hydroxyglutarate dehydrogenase gene (L2HGDH) variants: A genotype-phenotype study. Hum Mutat. 2010;31(4):380-390. doi: 10.1002/humu.21197
- Topcu M, Jobard F, Halliez S, et al. L-2-Hydroxyglutaric aciduria: Identification of a mutant gene C14orf160, localized on chromosome 14q22.1. Hum Mol Genet. 2004;13(22):2803-2811. doi: 10.1093/hmg/ddh300