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

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.