Charcot-Marie-Tooth disease type 2A with an autosomal-recessive inheritance: the first report of an adult-onset disease

J Hum Genet. 2018 Jan;63(1):89-92. doi: 10.1038/s10038-017-0353-3. Epub 2017 Nov 13.


Axonal Charcot-Marie-Tooth disease (CMT) is most frequently caused by mutations in the MFN2 gene (CMT2A) that can lead to various clinical phenotypes. The age at disease onset varies, but most cases occur before adolescence. We report two Japanese sisters who presented with middle-age-onset peripheral neuropathy with distinct clinical features. In the affected sisters, a homozygous missense mutation, c.1894C>T, p.R632W, corresponding to the transmembrane domain of MFN2 was identified; this mutation was heterozygous in another non-affected sibling, demonstrating co-segregation of the genotype and phenotype. The patients developed adult-onset slowly progressive muscle weakness that was predominant in the calf muscles and sensory disturbance. Magnetic resonance imaging revealed diffuse atrophy of the spinal cord, especially in the thoracic segment, and mild atrophy of the parietal lobe and the cerebellum in both patients. Electron microscopy of the sural nerve revealed clusters of round and swollen mitochondria. This is the first case report of adult-onset CMT2A with an autosomal-recessive inheritance pattern. The phenotype caused by the MFN2 mutation in these cases is very mild, considering that the mutation causes middle-aged-onset Charcot-Marie-Tooth even in the homozygous state. The mechanism of MFN2 mutation-induced toxicity is an interesting theme that awaits further investigations.

Publication types

  • Case Reports

MeSH terms

  • Adult
  • Age of Onset
  • Charcot-Marie-Tooth Disease / genetics*
  • Charcot-Marie-Tooth Disease / pathology
  • Female
  • GTP Phosphohydrolases / genetics*
  • Genes, Recessive*
  • Humans
  • Mitochondrial Proteins / genetics*
  • Mutation, Missense*


  • Mitochondrial Proteins
  • GTP Phosphohydrolases
  • MFN2 protein, human