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

Judith Calvo 1, 2, 3 Benoît Funalot 2, 4, 5, * Robert A. Ouvrier 6 Leila Lazaro 7 Annick Toutain 8 Philippe de Mas 9 Pierre Bouche 10 Brigitte Gilbert-Dussardier 11 Marie-Christine Arné-Bes 12 Jean-Pierre Carrière 13 Hubert Journel 14 Marie-Christine Minot-Myhie Claire Guillou 15 Karima Ghorab 1, 2 Laurent Magy 1, 2, 4 Franck Sturtz 4, 5 Jean-Michel Vallat 1, 2, 4 Corinne Magdelaine 4, 5
* Auteur correspondant
1 Service de Neurologie [CHU Limoges]
2 Centre de référence national neuropathies périphériques rares [CHU Limoges]
3 Intituto de neurologia
4 EA4021 - Biomolécules Thérapies anti-tumorales
5 Service de Biochimie et Génétique Moléculaire [CHU Limoges]
6 Institute of Neuromuscular Research
7 Département de médecine de l'enfant et de l'adolescent
8 Service de génétique [Tours]
9 Consultation de génétique
10 CHU Pitié-Salpêtrière [AP-HP]
11 Service de Genetique medicale
12 Neurologie et Explorations Fonctionnelles du Système Nerveux [Toulouse]
13 Service de neurologie pédiatrique
14 Génétique Médicale
15 Service de rééducation fonctionnelle
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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https://hal-unilim.archives-ouvertes.fr/hal-00628883
Contributeur : Franck Sturtz <>
Soumis le : mardi 4 octobre 2011 - 14:25:58
Dernière modification le : vendredi 11 décembre 2020 - 03:18:36

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  • HAL Id : hal-00628883, version 1

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EA6309 | UNILIM | GEIST | CNRS | LCSN | PEIRENE | UNIV-TLSE3 | SORBONNE-UNIVERSITE

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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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