title: Genotype-phenotype correlations in Charcot-Marie-Tooth disease type 2 caused by mitofusin 2 mutations.
abstract: 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).
  
  
  METHODS
  Direct sequencing of the MFN2 gene and clinical investigations of patients with MFN2 mutations.
  
  
  METHODS
  Molecular genetics laboratory of a university hospital and the Limoges National Referral Center for Rare Peripheral Neuropathies.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
authors.affiliation: Service de neurologie, Centre Hospitalier Universitaire (CHU) de Limoges, Limoges, France.
authors.forename: Judith
authors.initials: J
authors.lastname: Calvo
authors.forename: Benoît
authors.initials: B
authors.lastname: Funalot
authors.forename: Robert A
authors.initials: RA
authors.lastname: Ouvrier
authors.forename: Leila
authors.initials: L
authors.lastname: Lazaro
authors.forename: Annick
authors.initials: A
authors.lastname: Toutain
authors.forename: Philippe
authors.initials: P
authors.lastname: De Mas
authors.forename: Pierre
authors.initials: P
authors.lastname: Bouche
authors.forename: Brigitte
authors.initials: B
authors.lastname: Gilbert-Dussardier
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Arne-Bes
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Carrière
authors.forename: Hubert
authors.initials: H
authors.lastname: Journel
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Minot-Myhie
authors.forename: Claire
authors.initials: C
authors.lastname: Guillou
authors.forename: Karima
authors.initials: K
authors.lastname: Ghorab
authors.forename: Laurent
authors.initials: L
authors.lastname: Magy
authors.forename: Franck
authors.initials: F
authors.lastname: Sturtz
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Vallat
authors.forename: Corinne
authors.initials: C
authors.lastname: Magdelaine
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002607:Charcot-Marie-Tooth Disease / Q000145:classification / Q000235:genetics* / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D005260:Female; D020558:GTP Phosphohydrolases; D005799:Genes, Dominant; D005808:Genes, Recessive; D005819:Genetic Markers / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics*; D010641:Phenotype; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: D005819:Genetic Markers; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human