MFN2 – Hereditary Motor and Sensory Neuropathy Type VI

Hereditary motor and sensory neuropathy type VI (MONDO:0019551) is an autosomal dominant peripheral axonal neuropathy variably complicated by optic atrophy and caused by heterozygous variants in MFN2 (PMID:25258575).

Multiple independent case series have identified MFN2 pathogenic variants in HMSN VI. In a cohort of 62 unrelated CMT2 families, two families with early onset optic atrophy carried the c.1090C>T (p.Arg364Trp) variant (PMID:16835246). An additional six HMSN VI families harbor unique heterozygous MFN2 mutations, with de novo occurrence in three and vertical transmission in two families (PMID:16437557).

The variant spectrum in HMSN VI is dominated by missense changes within the GTPase domain, exemplified by c.1090C>T (p.Arg364Trp), which disrupts GTP binding and oligomerization. These eight probands across independent pedigrees and segregation in two families support a strong genetic association.

Cellular and animal models corroborate the pathogenic mechanism. Disease‐linked MFN2 mutants fail to support mitochondrial fusion, leading to fragmented mitochondria and axonal degeneration. Wild-type MFN1 restores fusion when co-expressed with mutant MFN2 in vitro (PMID:17296794), and a knock-in mouse expressing Mfn2 R94W recapitulates neuropathy and bioenergetic defects (PMID:24862862).

Mechanistic studies indicate a dominant-negative effect of pathogenic MFN2 variants on GTPase-dependent assembly rather than haploinsufficiency. The p.Val705Ile change was shown to be a common non-pathogenic polymorphism that does not segregate with disease (PMID:26316991).

Overall, de novo occurrences, segregation, recurrent missense variants, and concordant functional data establish a Strong clinical validity for MFN2 in HMSN VI. MFN2 testing facilitates precise diagnosis, informs genetic counseling, and underpins therapeutic approaches aimed at restoring mitochondrial fusion.

References

• Experimental neurobiology • 2014 • Hereditary Motor and Sensory Neuropathy Type VI with Bilateral Middle Cerebellar Peduncle Involvement. PMID:25258575
• Brain • 2006 • Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations. PMID:16835246
• Annals of neurology • 2006 • Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2. PMID:16437557
• 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 the peripheral nervous system • 2014 • Characterization of the mitofusin 2 R94W mutation in a knock-in mouse model. PMID:24862862
• 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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