title: MFN2 mutations cause severe phenotypes in most patients with CMT2A.
abstract: BACKGROUND
  Charcot-Marie-Tooth disease type 2A (CMT2A), the most common form of CMT2, is caused by mutations in the mitofusin 2 gene (MFN2), a nuclear encoded gene essential for mitochondrial fusion and tethering the endoplasmic reticulum to mitochondria. Published CMT2A phenotypes have differed widely in severity.
  
  
  METHODS
  To determine the prevalence and phenotypes of CMT2A within our clinics we performed genetic testing on 99 patients with CMT2 evaluated at Wayne State University in Detroit and on 27 patients with CMT2 evaluated in the National Hospital for Neurology and Neurosurgery in London. We then preformed a cross-sectional analysis on our patients with CMT2A.
  
  
  RESULTS
  Twenty-one percent of patients had MFN2 mutations. Most of 27 patients evaluated with CMT2A had an earlier onset and more severe impairment than patients without CMT2A. CMT2A accounted for 91% of all our severely impaired patients with CMT2 but only 11% of mildly or moderately impaired patients. Twenty-three of 27 patients with CMT2A were nonambulatory prior to age 20 whereas just one of 78 non-CMT2A patients was nonambulatory after this age. Eleven patients with CMT2A had a pure motor neuropathy while another 5 also had profound proprioception loss. MFN2 mutations were in the GTPase domain, the coiled-coil domains, or the highly conserved R3 domain of the protein.
  
  
  CONCLUSIONS
  We find MFN2 mutations particularly likely to cause severe neuropathy that may be primarily motor or motor accompanied by prominent proprioception loss. Disruption of functional domains of the protein was particularly likely to cause neuropathy.
authors.affiliation: Department of Neurology, Wayne State University, 421 Ea Canfield, Detroit, MI 48201, USA.
authors.forename: S M E
authors.initials: SM
authors.lastname: Feely
authors.forename: M
authors.initials: M
authors.lastname: Laura
authors.forename: C E
authors.initials: CE
authors.lastname: Siskind
authors.forename: S
authors.initials: S
authors.lastname: Sottile
authors.forename: M
authors.initials: M
authors.lastname: Davis
authors.forename: V S
authors.initials: VS
authors.lastname: Gibbons
authors.forename: M M
authors.initials: MM
authors.lastname: Reilly
authors.forename: M E
authors.initials: ME
authors.lastname: Shy
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004247:DNA / Q000235:genetics; D055724:Electrophysiological Phenomena; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics*; D018908:Muscle Weakness / Q000209:etiology / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000503:physiopathology; D009154:Mutation / Q000502:physiology*; D009431:Neural Conduction / Q000502:physiology; D009460:Neurologic Examination; D010523:Peripheral Nervous System Diseases / Q000473:pathology; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D004247:DNA; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human