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

BACKGROUND

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.

METHODS AND

RESULTS

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.

CONCLUSIONS

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.