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

[adrenomyeloneuropathy]

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 .To characterize 3 families having a mutation in PMP -22 in addition to another neurogenetic disease mutation .Clinical , electrophysiologic , and genetic evaluations were made of 3 families with more than 1 genetic neuromuscular disease .Family members were evaluated in neurogenetic and muscular dystrophy clinics in a university medical center setting .Three unusual families were found : (1 ) 2 young brothers each having a PMP -22 duplication and a missense mutation in the GJB 1 (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 (DM 1 myotonic dystrophy ); and (3 ) a 39 -year -old man with a PMP -22 deletion and a missense mutation in the ABCD 1 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 .Individuals having 2 separate mutations in neuromuscular disease-related genes may develop unusually severe phenotypes . Neurologists should be alert to this possibility .