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


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


METHODS
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.
Hodapp
Julie A
JA
Department of Rehabilitation Medicine, School of Medicine, University of Washington, Seattle, USA.
Carter
Gregory T
GT
Lipe
Hillary P
HP
Michelson
Sara J
SJ
Kraft
George H
GH
Bird
Thomas D
TD
D000328:Adult; D002648:Child; D004252:DNA Mutational Analysis / Q000379:methods; D004576:Electromyography / Q000379:methods; D005192:Family Health; D005260:Female; D006580:Genetic Carrier Screening; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D008297:Male; D009135:Muscular Diseases / Q000235:genetics / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D009185:Myelin Proteins / Q000235:genetics*; D009431:Neural Conduction / Q000502:physiology; D010641:Phenotype
D009185:Myelin Proteins; C073687:PMP22 protein, human