Double Trouble in Hereditary Neuropathy:Concomitant Mutations in the PMP-22 Gene

January 10, 2006

Archives of Neurology Vol. 63 No. 1, January 2006

Double Trouble in Hereditary Neuropathy

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

Novel Phenotypes

A. Hodapp, MD; T. , MD; Hillary P. Lipe, ARNP;

Sara J. Michelson, MS, CGC; H. Kraft, MD; D. Bird, MD

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, , 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.

Recommended Posts