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Genotype-Phenotype Correlations in Charcot-Marie-Tooth Disease Type 2 Caused by Mitofusin 2 Mutations

Abstract : Background: Mutations in the gene encoding mito- fusin 2 (MFN2) cause Charcot-Marie-Tooth disease type 2 (CMT2), with heterogeneity concerning severity and associated clinical features. Objective: To describe MFN2 mutations and associ- ated phenotypes in patients with hereditary motor and sensory neuropathy (HMSN). Design: Direct sequencing of the MFN2 gene and clini- cal investigations of patients with MFN2 mutations. Setting: Molecular genetics laboratory of a university hospital and the LimogesNational Referral Center for Rare Peripheral Neuropathies. Patients: One hundred fifty index patients with HMSN and amedianmotor nerve conduction velocity of 25m/s or greater and without mutations in the genes encoding connexin 32 and myelin protein zero. Main Outcome Measures: Results of genetic analy- ses and phenotypic observations. Results: Twenty different missense mutations were identified in 20 index patients. Mutation frequency was 19 of 107 (17.8%) in patients with CMT2 and 1 of 43 (2.3%) in patients with a median motor nerve conduc- tion velocity less than 38 m/s. Four patients had proven de novo mutations, 8 families had autosomal dominant inheritance, and 3 had autosomal recessive inheritance. The remaining 5 patients were sporadic cases with het- erozygous mutations. Phenotypes varied from mild forms to early-onset severe forms. Additional features were encountered in 8 patients (32%). Six patients un- derwent sural nerve biopsy: electronic microscopy showed prominent mitochondrial abnormalities on longitudinal sections. Conclusions: MFN2 mutations are a frequent cause of CMT2, with variable severity and either dominant or recessive inheritance. MFN2 gene testing must be a first-line analysis in axonal HMSN irrespective of the mode of inheritance or the severity of the peripheral neuropathy.
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Contributeur : Franck Sturtz <>
Soumis le : mardi 4 octobre 2011 - 14:25:58
Dernière modification le : jeudi 20 août 2020 - 03:05:12

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  • HAL Id : hal-00628883, version 1

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Judith Calvo, Benoît Funalot, Robert A. Ouvrier, Leila Lazaro, Annick Toutain, et al.. Genotype-Phenotype Correlations in Charcot-Marie-Tooth Disease Type 2 Caused by Mitofusin 2 Mutations. Archives of Neurology -Chigago-, American Medical Association, 2009, 66 (12), pp.1511-1516. ⟨hal-00628883⟩

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