• Online Features  This Article  • Full text  • PDF  • Reply to article  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on Web of Science (11)  • Contact me when this article is cited  Related Content  • Related article  • Similar articles in this journal  Topic Collections  • Neurology  • Neurogenetics  • Neuromuscular diseases  • Neurology, Other  • Genetic Disorders  • Alert me on articles by topic  Social Bookmarking   What's this?

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

Arch Neurol. 2009;66(12):1511-1516.

Background  Mutations in the gene encoding mitofusin 2 (MFN2) cause Charcot-Marie-Tooth disease type 2 (CMT2), with heterogeneity concerning severity and associated clinical features.

Objective  To describe MFN2 mutations and associated phenotypes in patients with hereditary motor and sensory neuropathy (HMSN).

Design  Direct sequencing of the MFN2 gene and clinical investigations of patients with MFN2 mutations.

Setting  Molecular genetics laboratory of a university hospital and the Limoges National Referral Center for Rare Peripheral Neuropathies.

Patients  One hundred fifty index patients with HMSN and a median motor nerve conduction velocity of 25 m/s or greater and without mutations in the genes encoding connexin 32 and myelin protein zero.

Main Outcome Measures  Results of genetic analyses 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 conduction 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 heterozygous mutations. Phenotypes varied from mild forms to early-onset severe forms. Additional features were encountered in 8 patients (32%). Six patients underwent 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.

Author Affiliations: Service de neurologie (Drs Calvo, Funalot, Ghorab, Magy, and Vallat), Centre de référence "neuropathies périphériques rares" (Drs Calvo, Funalot, Ghorab, Magy and Vallat), and Service de biochimie et génétique moléculaire (Drs Funalot, Sturtz, and Magdelaine), Centre Hospitalier Universitaire (CHU) de Limoges, Limoges, France; Institute for Neuromuscular Research, The Children's Hospital at Westmead, Westmead, Australia (Dr Ouvrier); Département de médecine de l’enfant et de l’adolescent, CHU de Rennes, Rennes, France (Dr Lazaro); Service de génétique, CHU de Tours, Tours, France (Dr Toutain); Consultation de génétique, Clinique Saint-Jean-Languedoc, Toulouse, France (Dr De Mas); Département de neurophysiologie clinique, groupe hospitalier Pitié-Salpêtrière, Paris, France (Dr Bouche); Services de génétique médicale (Dr Gilbert-Dussardier) and rééducation fonctionnelle (Dr Guillou), CHU de Poitiers, Poitiers, France; Services de neurologie et explorations fonctionnelles du système nerveux (Dr Arne-Bes) and neurologie pédiatrique (Dr Carrière), CHU de Toulouse, Toulouse; Consultation de génétique médicale, CH Bretagne-Atlantique, Vannes, France (Dr Journel); and Cabinet de neurologie, Rennes (Dr Minot-Myhie). Dr Calvo is now with Instituto de Neurolgìa, Hospital de Clìnicas de la Facultad de Medicina, Universidad de la Repùblica, Montevideo, Uruguay.

CiteULike    Connotea    Delicious    Digg    Facebook    Reddit    Technorati    Twitter     What's this?

RELATED ARTICLE

This Month in Archives of Neurology
Arch Neurol. 2009;66(12):1442-1444.
FULL TEXT  

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Large Kindred Evaluation of Mitofusin 2 Novel Mutation, Extremes of Neurologic Presentations, and Preserved Nerve Mitochondria
Klein et al.
Arch Neurol 2011;68:1295-1302.
ABSTRACT | FULL TEXT  

Recessive axonal Charcot-Marie-Tooth disease due to compound heterozygous mitofusin 2 mutations
Polke et al.
Neurology 2011;77:168-173.
ABSTRACT | FULL TEXT  

MFN2 mutations cause severe phenotypes in most patients with CMT2A
Feely et al.
Neurology 2011;76:1690-1696.
ABSTRACT | FULL TEXT  

The GST domain of GDAP1 is a frequent target of mutations in the dominant form of axonal Charcot Marie Tooth type 2K
Crimella et al.
J. Med. Genet. 2010;47:712-716.
ABSTRACT | FULL TEXT