Nationwide Characterization of MFN2-Related CMT in 176 Japanese Patients: Clinical and Genetic Insights

Mitofusin 2 (MFN2) is a major causative gene for axonal Charcot - Marie - Tooth disease type 2A (CMT2A), with a wide phenotypic spectrum. Comprehensive large - scale genotype - phenotype association studies are essential for understanding disease pathogenesis and improved clinical management.

We conducted a nationwide retrospective study of 176 Japanese patients with genetically confirmed pathogenic or likely pathogenic MFN2 variants encompassing clinical, electrophysiological, and genetic characterization.

MFN2 was the second most frequent causative gene among 1211 genetically diagnosed inherited peripheral neuropathy cases in Japan. A total of 76 MFN2 variants were identified, including nine novel likely pathogenic variants. Disease onset occurred at a mean age of 11.1 years, with distal motor weakness and tibialis anterior involvement as prominent features. Sensory symptoms were present in ~60% of patients and were more common in cases with longer disease duration. Central and systemic features, including pyramidal signs, optic atrophy, and vocal cord paralysis, were also observed. Electrophysiological studies revealed a predominantly axonal sensorimotor pattern, with relatively preserved upper limb conduction and marked lower limb abnormalities. Importantly, 24 patients (16%) were non-ambulatory, with earlier onset and greater weakness. Domain-based analysis further revealed that variant location may influence age at onset.

This large-scale study highlights the genetic and clinical diversity of MFN2-related CMT in Japan. Our findings confirm a motor-dominant, length-dependent axonal neuropathy with additional sensory and systemic features in some cases. These results emphasize the importance of early diagnosis, genotype-informed care, and long-term follow-up in managing MFN2-related CMT.