MT-ND4 – MELAS syndrome

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is most frequently associated with the m.3243A>G mutation in MT-TL1; however, a pathogenic role for MT-ND4 variants has been proposed. A single case report described a 25-year-old woman presenting with dysexecutive syndrome, continuous headache, muscular fatigue, and two stroke-like episodes with hemiparesis and epileptic seizures. Genetic testing revealed a heteroplasmic MT-ND4 c.12015T>C (p.Leu419Pro) variant at 12% in blood and 15% in muscle tissue (PMID:30949164). In silico simulations yielded conflicting predictions, and no functional assays specific to this variant have been reported.

Considering only one proband and absence of segregation or replication, the evidence for MT-ND4 in MELAS remains limited. Further unrelated cases, detailed segregation analysis, and experimental studies are required to establish causality. Key take-home: MT-ND4 c.12015T>C (p.Leu419Pro) is a novel candidate for MELAS but currently holds limited clinical validity and requires additional validation.

References

• Frontiers in immunology • 2019 • New Variant of MELAS Syndrome With Executive Dysfunction, Heteroplasmic Point Mutation in the MT-ND4 Gene (m.12015T>C; p.Leu419Pro) and Comorbid Polyglandular Autoimmune Syndrome Type 2. PMID:30949164

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