Genotype-phenotype correlations in Charcot-Marie-Tooth disease type 2 caused by mitofusin 2 mutations

Mutations in the gene encoding mitofusin 2 (MFN2) cause Charcot-Marie-Tooth disease type 2 (CMT2), with heterogeneity concerning severity and associated clinical features.

To describe MFN2 mutations and associated phenotypes in patients with hereditary motor and sensory neuropathy (HMSN).

Direct sequencing of the MFN2 gene and clinical investigations of patients with MFN2 mutations.

Molecular genetics laboratory of a university hospital and the Limoges National Referral Center for Rare Peripheral Neuropathies.

One hundred fifty index patients with HMSN and a median motor nerve conduction velocity of 25 m/s or greater and without mutations in the genes encoding connexin 32 and myelin protein zero.

Results of genetic analyses and phenotypic observations.

Twenty different missense mutations were identified in 20 index patients. Mutation frequency was 19 of 107 (17.8%) in patients with CMT2 and 1 of 43 (2.3%) in patients with a median motor nerve conduction velocity less than 38 m/s. Four patients had proven de novo mutations, 8 families had autosomal dominant inheritance, and 3 had autosomal recessive inheritance. The remaining 5 patients were sporadic cases with heterozygous mutations. Phenotypes varied from mild forms to early-onset severe forms. Additional features were encountered in 8 patients (32%). Six patients underwent sural nerve biopsy: electronic microscopy showed prominent mitochondrial abnormalities on longitudinal sections.

MFN2 mutations are a frequent cause of CMT2, with variable severity and either dominant or recessive inheritance. MFN2 gene testing must be a first-line analysis in axonal HMSN irrespective of the mode of inheritance or the severity of the peripheral neuropathy.