Clinical and electrophysiologic features of CMT2A with mutations in the mitofusin 2 gene

Background: Axonal neuropathy linked to the CMT2A locus was originally associated with a mutation in the KIF1B gene. However, mutations in this gene have not been described associated with any other CMT2A families. Recently, mutations in the MFN2 gene, encoding the mitochondrial GTPase mitofusin 2 (Mfn2), have been identified as causative of CMT2A in seven families. The authors report three additional CMT2A families associated with novel mutations in highly conserved regions of the Mfn2 GTPase domain. Methods: The authors performed a standardized neuromuscular and nerve conduction examination, genotyped known CMT loci, and analyzed the MFN2 gene by direct sequencing in three pedigrees and 10 additional probands affected by axonal CMT. Results: Sequencing of the MFN2 gene revealed a novel mutation in each family (c. 818T > G, c. 638T > C, and c. 314C > T). The largest family demonstrated an age-independent variable expression such that approximately one quarter of individuals with the mutation presented with features mild enough as to remain occult even with electrophysiologic evaluation. Conclusion: These results confirm that the majority of cases of CMT linked to the CMT2A locus are due to MFN2 mutations. The phenotype is largely indistinguishable from KIF1B-related CMT and from CMT2E and CMT2F. At least in some families, as many as 25% of individuals with MFN2 mutations may be asymptomatic and have a normal electrophysiologic examination, although a detailed neuromuscular examination may suggest the trait. Given the frequency of MFN2 mutations among CMT2 probands ( 3/13, or 23%), genetic testing of CMT2 patients should begin with a screen of the MFN2 gene.