Anticipation in a unique family with Charcot-Marie-Tooth syndrome and deafness: delineation of the clinical features and review of the literature

Am J Med Genet. 2002 Apr 1;108(4):295-303. doi: 10.1002/ajmg.10223.


Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous group of polyneuropathies characterized by degeneration of peripheral nerves, resulting in distal muscle atrophy, sensory loss, and deformities of hands and feet. We have studied 34 individuals in a large 84-member four-generation central Illinois family with autosomal dominant Charcot-Marie-Tooth and deafness. Nerve conduction velocities are consistent with type 1 CMT. Audiological evaluation revealed both auditory neuropathy and cochlear involvement in affected individuals. There is increasing clinical severity and younger age of onset of CMT and deafness with each progressive generation, suggestive of anticipation (P < 0.05). The proband, a female diagnosed at birth with hypotonia, bilateral vocal cord palsy, swallowing incoordination, and hearing impairment, died at age 18 months. Another individual died at the age of 3 months from hypotonia later attributed to CMT. Genetic analysis indicated that affected individuals in this family do not have the common 1.4 Mb duplication associated with type 1A CMT; however, all affected individuals have a unique G to C transversion at position 248 in coding exon 3 of the peripheral myelin PMP22 gene located on chromosome 17p11.2-p12. This mutation is predicted to cause an Ala67Pro substitution in the second transmembrane domain of PMP22, consistent with the molecular cause of the CMT phenotype. However, it does not explain the cochlear component of the deafness, the clinical observation of anticipation, and other features in this family.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Adolescent
  • Adult
  • Charcot-Marie-Tooth Disease / genetics
  • Charcot-Marie-Tooth Disease / pathology*
  • Child
  • Child, Preschool
  • DNA / chemistry
  • DNA / genetics
  • DNA Mutational Analysis
  • Deafness / genetics
  • Deafness / pathology*
  • Family Health
  • Fatal Outcome
  • Female
  • Hearing Tests
  • Humans
  • Infant
  • Male
  • Middle Aged
  • Mutation
  • Myelin Proteins / genetics
  • Pedigree
  • Sural Nerve / pathology
  • Sural Nerve / ultrastructure
  • Trinucleotide Repeats / genetics


  • Myelin Proteins
  • PMP22 protein, human
  • DNA