Submission Details

MFN2 encodes for GTPases on the outer mitochondrial membranes. The gene was first described as the cause of CMT2 in 14 families in 2004 (PMID: 15064763). A subsequent study screened 323 CMT2 patients and identified significant variants in 29 of them; up to 33% of patients with family history of CMT carried a likely pathogenic MFN2 variant (PMID: 16714318). Chung et al reported 10 pathogenic mutations in 26 patients from 15 families (PMID: 16835246). MFN2 is expressed in the liver and adipose tissues, and is abundantly expressed in the brain. MFN2 is essential for mitochondrial fusion and contact, mitochondrial transport, ER-mitochondrial contact, and is a mediator of cellular autophagy and mitophagy. Two studies have reported semidominant families with axonal motor and sensory neuropathy with pathogenic variants in MFN2 identified through candidate gene sequencing. Phenotype was variable in many studies, even with the same mutation, as some families had optic atrophy, but others did not. Optic atrophy as an additional symptom to CMT2 was first reported in 6 families by Zuchner et al, where three probands carried de novo MFN2 changes (PMID: 16437557). Other phenotypes reported included periventricular and subcortical hyperintense lesions by brain MRI in eight patients, sensorineural hearing loss in three patients, and bilateral extensor plantar responses in two patients. The role of MFN2 with mitochondrial function, shape, mobility and fusion has been supported with experimental functional studies (Baloh et al, 2007, PMID: 17215403; Chen et al, 2003, PMID: 12527753). In summary, MFN2 is DEFINITIVELY associated with semidominant axonal hereditary motor and sensory neuropathy due to the presence of both genetic case level evidence and experimental evidence.