MT-ND6 – MELAS Syndrome

A limited body of evidence links MT-ND6 variants to mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). A single adult patient presented with acute psychosis and seizures and was found to carry a heteroplasmic c.14453G>A variant in MT-ND6, leading to a revised diagnosis of MELAS (PMID:32552696). Maternal transmission was suggested by pedigree analysis, but no additional unrelated probands have been described.

Genetic Evidence

The index case exhibited psychosis (HP:0000709) and seizure (HP:0001250) and harbored a heteroplasmic m.14453G>A variant in MT-ND6, with high mutant load in muscle and blood. Maternal inheritance was supported by co-segregation in a single maternal relative (n=1).

Functional Evidence

No dedicated functional assays have been reported for the m.14453G>A MT-ND6 variant in MELAS. However, complex I dysfunction is a known disease mechanism in MELAS, and MT-ND6 encodes a critical subunit of complex I.

Integrated Assessment

Overall, the association between MT-ND6 and MELAS is classified as Limited based on single-family evidence and lack of multiple unrelated cases. Additional probands and functional studies are required to strengthen causality. Key Take-home: MT-ND6 sequencing should be considered in adult-onset MELAS presentations when common tRNA mutations are absent, with maternal segregation analysis to support pathogenicity.

References

• BMC neurology • 2020 • Late-onset MELAS syndrome with mtDNA 14453G→A mutation masquerading as an acute encephalitis: a case report. PMID:32552696

Evidence Based Scoring (AI generated)