Novel variants and rare clinical presentations in MFN2-related Charcot-Marie-Tooth disease: Insights from 10 families - 04/06/26

Doi : 10.1016/j.neurol.2026.04.008

H. Gharebaghian ^a,^b, M. Ravanbod ^c, A. Ghasemi ^a, A. Asghar Okhovat ^a,^d, S. Nafissi ^a,^d,^⁎ , A. Alavi ^c,⁎

^a Neuromuscular Research Center, Tehran University of Medical Sciences, Tehran, Iran

^b Department of Neurology, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran

^c Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran

^d Neurology Department, Tehran University of Medical Sciences, Shariati Hospital, Tehran, Iran

^⁎ Corresponding author . ^⁎⁎ Corresponding author .

Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Thursday 04 June 2026

Highlights

•	Pathogenic monoallelic and biallelic variants in the MFN2 gene lead to AD and AR MFN2 -related CMT, respectively. With the later exhibiting a more severe phenotype and an earlier age at onset.
•	We characterize genetic data and clinical features 13 individuals from 10 Iranian families affected with MFN2 -related Charcot-Marie-Tooth disease.
•	With reporting of 10 MFN2 variants including five novel ones, we expanded the genetic spectrum of MFN2 -related CMT.
•	By documenting rare clinical and paraclinical features including erectile dysfunction, learning difficulties, optic atrophy, elevated serum creatine kinase levels and central nervous system abnormalities, we significantly expand the known spectrum of this disorder.

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Abstract

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.

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Keywords : MFN2 gene , Charcot-Marie-Tooth, Whole exome sequencing, Phenotypic heterogeneity