MFN2 – Charcot-Marie-Tooth disease type 2A2

Charcot-Marie-Tooth disease type 2A2 (CMT2A2) is an autosomal dominant axonal neuropathy characterized by distal muscle weakness, gait disturbance, vocal cord paralysis, and optic atrophy. It results from heterozygous mutations in the mitofusin 2 gene (MFN2), which encodes a mitochondrial GTPase essential for outer‐membrane fusion. Clinical reports describe classic and atypical features including early central nervous system involvement and drug‐induced exacerbations.

Multiple independent cohorts have identified >30 unrelated probands with pathogenic MFN2 variants. Three early‐onset patients harboring R94W, R364W, and Trp740Arg variants were reported in Chinese families ([PMID:22762946]). A single patient with c.669T>G (p.Phe223Leu) developed accelerated vocal cord paralysis and optic atrophy after ethambutol exposure ([PMID:23733358]). A pediatric case with c.314C>T (p.Pro105Leu) demonstrated CNS white matter changes inherited from an affected mother ([PMID:38183043]). In a Spanish series, nine MFN2 mutations were found in 24 patients from 14 families ([PMID:19889647]). Segregation across multiple pedigrees further supports pathogenicity.

The variant spectrum is dominated by missense changes within the conserved GTPase domain; hotspots include c.280C>T (p.Arg94Trp), c.1090C>T (p.Arg364Trp), and c.2218T>C (p.Trp740Arg). Additional in‐frame and splice‐site mutations have been reported, with de novo occurrence in ~28% of CMT2A2 families. Loss‐of‐function alleles are rare and not clearly associated with disease unless in compound heterozygosity.

Functional assays in patient fibroblasts and murine/yeast models demonstrate that disease variants impair mitochondrial fusion, alter complex II/V activity, and provoke dominant‐negative effects. Homooligomeric mutant MFN2 fails to mediate fusion but is complemented by wild-type MFN1 in vitro ([PMID:17296794]). Knock-in mice expressing R94W recapitulate fragmentation and neuropathy, with rescue by MFN1 overexpression in neurons ([PMID:24862862]; [PMID:30882371]).

One variant, c.2113G>A (p.Val705Ile), does not segregate with disease and is present in controls, indicating a benign polymorphism ([PMID:26316991]). No robust conflicting disease associations have been described.

Integration of robust genetic, segregation, and functional data across >30 families and multiple models yields a Definitive gene–disease association. Clinically, MFN2 mutation testing enables accurate diagnosis, informs prognosis, and guides potential mitochondrial‐targeted therapies.

Key Take-home: Pathogenic MFN2 variants cause autosomal dominant CMT2A2 through dominant-negative disruption of mitochondrial fusion, making MFN2 sequencing high‐value for diagnosis and therapeutic stratification.

References

• Muscle & nerve • 2013 • Ethambutol toxicity exacerbating the phenotype of CMT2A2. PMID:23733358
• BMC pediatrics • 2024 • A case report of peroneal muscle atrophy type 2A2 with central nervous system involvement as initial presentation. PMID:38183043
• Clinical neuropathology • 2013 • Mitofusin 2 gene mutation causing early-onset CMT2A with different progressive courses. PMID:22762946
• Journal of medical genetics • 2010 • Phenotypic spectrum of MFN2 mutations in the Spanish population. PMID:19889647
• Clinical genetics • 2007 • Mitochondrial GTPase mitofusin 2 mutations in Korean patients with Charcot-Marie-Tooth neuropathy type 2. PMID:17309650
• The Journal of cell biology • 2007 • Complementation between mouse Mfn1 and Mfn2 protects mitochondrial fusion defects caused by CMT2A disease mutations. PMID:17296794
• Journal of neurodegenerative diseases • 2013 • The MFN2 V705I Variant Is Not a Disease-Causing Mutation: A Segregation Analysis in a CMT2 Family. PMID:26316991

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