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

Judith Calvo; Benoît Funalot; Robert A. Ouvrier; Leila Lazaro; Annick Toutain; Philippe de Mas; Pierre Bouche; Brigitte Gilbert-Dussardier; Marie-Christine Arné-Bes; Jean-Pierre Carrière; Hubert Journel; Marie-Christine Minot-Myhie; Claire Guillou; Karima Ghorab; Laurent Magy; Franck Sturtz; Jean-Michel Vallat; Corinne Magdelaine

Article dans une revue

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.

Type de document :

Article dans une revue

Domaine :

Sciences du Vivant [q-bio] / Génétique

Sciences du Vivant [q-bio] / Génétique / Génétique humaine

Sciences du Vivant [q-bio] / Biochimie, Biologie Moléculaire / Biologie moléculaire

Sciences du Vivant [q-bio] / Biochimie, Biologie Moléculaire / Génomique, Transcriptomique et Protéomique [q-bio.GN]

Sciences du Vivant [q-bio] / Neurosciences [q-bio.NC]

Sciences du Vivant [q-bio] / Neurosciences [q-bio.NC] / Neurobiologie

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https://hal-unilim.archives-ouvertes.fr/hal-00628883
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Soumis le : mardi 4 octobre 2011 - 14:25:58
Dernière modification le : jeudi 27 janvier 2022 - 03:25:51

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

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