MTFMT – Leigh syndrome

MTFMT (HGNC:29666) has been robustly implicated in the pathogenesis of Leigh syndrome (MONDO_0009723). Multiple independent case reports and cohort studies have identified biallelic pathogenic variants in MTFMT in patients presenting with early‐onset global developmental delay, ataxia, and spasticity (PMID:26060307).

Genetic evidence is anchored by the recurrent finding of the homozygous c.626C>T (p.Ser209Leu) variant. This variant has been reported in several unrelated probands and is supported by segregation data in multi‐case series, with over 38 patients documented in a recent study (PMID:30911575). Such findings underscore the autosomal recessive inheritance pattern observed in affected families.

Further genetic analyses have uncovered additional MTFMT alleles in patients with Leigh syndrome. One of the defining features in the genetic spectrum is the presence of this specific coding change, which meets stringent HGVS criteria and represents the most common pathogenic allele. The consistency of this variant in multiple independent studies further strengthens the causative link between MTFMT and Leigh syndrome (PMID:28058511).

Functional studies provide corroborative evidence by demonstrating that mutations in MTFMT result in impaired mitochondrial translation. Rescue experiments in patient fibroblasts have shown that re‐expression of wild‐type MTFMT restores mitochondrial protein synthesis, thereby linking the genetic lesion to the observed biochemical deficiency (PMID:30767393).

The convergence of genetic and functional data reinforces a strong gene–disease relationship. Despite the clinical heterogeneity observed across reported cases, the recurrence of the c.626C>T (p.Ser209Leu) variant across multiple ethnically diverse cohorts highlights its diagnostic importance. Moreover, the clear demonstration of loss‐of‐function through functional assays complements the consistent genetic findings.

Key take‑home: The robust, multi‐layered evidence supporting the association between MTFMT mutations, particularly c.626C>T (p.Ser209Leu), and Leigh syndrome not only aids diagnostic decision‑making but also paves the way for targeted therapeutic strategies.

References

• Journal of child neurology • 2016 • MTFMT Deficiency Mimicking Acquired Demyelinating Disease PMID:26060307
• Neurogenetics • 2017 • Identification and functional characterization of a novel MTFMT mutation associated with selective vulnerability of the visual pathway and a mild neurological phenotype PMID:28058511
• Annals of clinical and translational neurology • 2019 • Leigh syndrome caused by mutations in MTFMT is associated with a better prognosis PMID:30911575
• The FEBS journal • 2019 • Msc6p is required for mitochondrial translation initiation in the absence of formylated Met-tRNAfMet PMID:30767393

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