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Concomitant Mutations in the PMP-22 Gene and Another Gene Produce Novel Phenotypes

Julie A. Hodapp, MD; Gregory T. Carter, MD; Hillary P. Lipe, ARNP; Sara J. Michelson, MS, CGC; George H. Kraft, MD; Thomas D. Bird, MD

Arch Neurol. 2006;63:112-117.

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.

Author Affiliations: Departments of Rehabilitation Medicine (Drs Hodapp, Carter, and Kraft) and Neurology (Ms Michelson and Dr Bird), School of Medicine, University of Washington, and Puget Sound Health Care System, Geriatric Research Education and Clinical Center (Ms Lipe and Dr Bird), Seattle.

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