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.