DUPLICATION OF THE PMP22 GENE IN 17P PARTIAL TRISOMY PATIENTS WITH CHARCOT-MARIE-TOOTH TYPE-1A NEUROPATHY

Autosomal dominant Charcot-Marie-Tooth type-1A neuropathy (CMT1A) is a demyelinating peripheral nerve disorder that is commonly associated w ith a submicroscopic tandem DNA duplication of a 1.5-Mb region of 17p1 1.2p12 that contains the peripheral myelin gene PMP22. Clinical featur es of CMT1A include progressive distal muscle atrophy and weakness, fo ot and hand deformities, gait abnormalities, absent reflexes, and the completely penetrant electrophysiologic phenotype of symmetric reducti ons in motor nerve conduction velocities (NCVs). Molecular and fluores cence in situ hybridization (FISH) analyses were performed to determin e the duplication status of the PMP22 gene in four patients with rare cytogenetic duplications of 17p. Neuropathologic features of CMT1A wer e seen in two of these four patients, in addition to the complex pheno type associated with 17p partial trisomy. Our findings show that the C MT1A phenotype of reduced NCV is specifically associated with PMP22 ge ne duplication, thus providing further support for the PMP22 gene dosa ge mechanism for CMT1A.