Double trouble in hereditary neuropathy: concomitant mutations in the PMP-22 gene and another gene produce novel phenotypes

Arch Neurol. 2006 Jan;63(1):112-7. doi: 10.1001/archneur.63.1.112.


Background: Mutations in the peripheral myelin protein 22 (PMP-22) gene are the most common cause of Charcot-Marie-Tooth neuropathy and may rarely occur in combination with other neurogenetic diseases.

Objective: To characterize 3 families having a mutation in PMP-22 in addition to another neurogenetic disease mutation.

Design: Clinical, electrophysiologic, and genetic evaluations were made of 3 families with more than 1 genetic neuromuscular disease.

Setting and patients: Family members were evaluated in neurogenetic and muscular dystrophy clinics in a university medical center setting.

Results: Three unusual families were found: (1) 2 young brothers each having a PMP-22 duplication and a missense mutation in the GJB1 (Connexin-32) gene; (2) a 32-year-old woman having a PMP-22 duplication and a 1000-fold CTG repeat expansion in the DMPK gene (DM1 myotonic dystrophy); and (3) a 39-year-old man with a PMP-22 deletion and a missense mutation in the ABCD1 gene (adrenomyeloneuropathy). The mutations were "additive," causing a more severe phenotype than expected with each individual disease and coinciding with the important impact of each gene on peripheral nerve function.

Conclusions: Individuals having 2 separate mutations in neuromuscular disease-related genes may develop unusually severe phenotypes. Neurologists should be alert to this possibility.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Child
  • DNA Mutational Analysis / methods
  • Electromyography / methods
  • Family Health*
  • Female
  • Genetic Carrier Screening
  • Heredodegenerative Disorders, Nervous System / genetics*
  • Heredodegenerative Disorders, Nervous System / physiopathology
  • Humans
  • Male
  • Muscular Diseases / genetics
  • Muscular Diseases / physiopathology
  • Mutation / genetics*
  • Myelin Proteins / genetics*
  • Neural Conduction / physiology
  • Phenotype*


  • Myelin Proteins
  • PMP22 protein, human