Neurol Sci. 2026 Feb 16;47(3):264. doi: 10.1007/s10072-026-08875-y.
ABSTRACT
BACKGROUND: Mitochondrial disorders are a group of heterogeneous diseases marked by deficiencies in oxidative phosphorylation (OXPHOS). A common subtype, MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes [SLEs]), is primarily linked to variants in mitochondrial transfer RNA (mt-tRNA) genes, yet the molecular mechanisms underlying many of these variants remain poorly understood.
METHODS: We performed a comprehensive assessment of a 14-year-old male patient, including clinical evaluation, genetic testing, histopathology, and functional biochemical analyses of muscle tissue. A systematic literature review was conducted to compare previously reported MT-TS2 variants and their associated phenotypes.
RESULTS: We identified a rare m.12244G > A variant in the tRNASer(AGY) gene associated with classical MELAS phenotype. Functional analysis demonstrated impaired mitochondrial translation and OXPHOS dysfunction. Histological findings revealed COX-negative and ragged red fibers, while western blotting indicated downregulation of key mitochondrial proteins. Literature review showed that MT-TS2 variants are associated with variable phenotypes including encephalopathy, myopathy, deafness, diabetes, and retinopathy.
CONCLUSION: Our study provides the first experimental validation of the pathogenicity of the m.12244G > A variant, confirming its deleterious impact on mitochondrial function. This finding expands the genotype spectrum of MELAS and highlights the importance of functional validation for rare mtDNA variants.
PMID:41692888 | DOI:10.1007/s10072-026-08875-y