Novel variants and rare clinical presentations in MFN2-related Charcot-Marie-Tooth disease: Insights from 10 families

Charcot-Marie-Tooth disease (CMT) is a genetically heterogeneous group of inherited neuropathies, and MFN2-related CMT is a common CMT subtype. In this study, we described 13 affected individuals from 10 unrelated Iranian families harboring MFN2 variants.

A total of 10 families (13 individuals) affected with MFN2-related CMT were recruited from a large CMT cohort, after whole exome sequencing and subsequent co-segregation analysis. We identified 10 missense variants, including five novel ones: p.Arg364Leu, p.Arg663His, p.Thr130Asn, p.Arg476Gly, and p.Glu744Asp. Patients showed a wide range of features, with age at onset varying from 1 to 69 years. Typical CMT features such as distal limb weakness, foot deformities, and sensory impairments were accompanied by rare clinical findings including erectile dysfunction (3/8 males), cognitive dysfunction, and central nervous system (CNS) abnormalities apparent on brain magnetic resonance imaging (MRI). Notably, two individuals carried biallelic MFN2 variants displaying AR MFN2-related CMT: one compound heterozygote individual who presented with diaphragmatic weakness and vocal cord involvement, and another homozygote individual who manifested a relatively mild phenotype. Intrafamilial variability and reduced penetrance were also noted, with some heterozygote individuals remaining asymptomatic throughout their lives.

Our findings not only expand the mutational spectrum of MFN2-related CMT, but also highlight its broader phenotypic heterogeneity. This study also underscores that rare manifestations such as cognitive impairment and autonomic symptoms may be under-recognized features.