From Clinical Presentation to Genetic Confirmation: A Case of L2HGDH-Related Leukodystrophy in an 11-Year-Old

Background: Leukodystrophy describes a diverse range of rare and severe neurological disorders characterized by progressive degeneration of the central nervous system (CNS) and a heterogeneous genetic basis. Leukodystrophies cause a progressive loss of neurological function in infants, children, and sometimes adults. Each type of leukodystrophy is rare and causes different symptoms, such as seizures, balance and mobility problems, behavioral and learning disabilities, developmental delays, hearing, speech, and vision problems.Case Presentation: An 11-year-old female was referred to the Children's Department of Shahid Sadoughi Hospital in Yazd, Iran. She had been diagnosed with leukodystrophy, confirmed by MRI findings and urinary organic acid profiling, indicating abnormalities in the central nervous system (CNS). The disease onset occurred when she was three years old and was initially characterized by seizures, followed by developmental regression. The patient exhibited developmental delay, seizures, encephalopathy, cerebellar ataxia, and other clinical neurological deficits.Methods: In the present study, we ascertained the identity of a patient through clinical studies, including MRI findings and biochemical tests. Whole-exome sequencing (WES) was then conducted to investigate various variants associated with leukodystrophy and determine the specific type present in the patient. The analysis revealed a mutation in L2HGDH (L-2-hydroxyglutarate dehydrogenase), which is associated with a specific type of leukodystrophy. To confirm this, Sanger sequencing was performed on twelve members of the patient's family, all diagnosed with autosomal recessive neurodevelopmental disorders. In silico studies, including protein structural modeling and docking analyses, were conducted using Phyre-2 tools to further investigate the molecular consequences of the mutation in L2HGDH.Result: After the filtration the data obtained from Whole exome sequencing of the patient identified a homozygous missense mutation (c.751C>T; p. Arg251Ter) in L2HGDH gene. Sanger sequencing performed in twelve extended relatives and confirmed the presence of this homozygous variant in one patient and one affected sibling from their respective families. Our computational analysis revealed that this variant is conserved regions observed in various species, and they are likely to impact protein stability.Conclusion: In conclusion, our findings provide evidence supporting the correlation between genotype and MRI findings, as well as the pathogenicity of the identified variant in these patients. This study expands our understanding of potential mutations involved in this heterogeneous disease.