Charcot-Marie-Tooth Disease Type 1A – Association with a Spontaneous Point Mutation in the PMP22 Gene

Background: Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy. CMT type 1A is associated with a 1.5-megabase (Mb) DNA duplication in region p11.2-p12 of chromosome 17 in most patients. An increased dosage of a gene within the duplicated segment appears to cause the disease. The PMP22 gene, which encodes a myelin protein, has been mapped within the duplication and proposed as a candidate gene for CMT type 1A. Methods: We analyzed DNA samples from a cohort of 32 unrelated patients with CMT type 1 who did not have the 1.5-Mb tandem duplication in 17p11.2-p12 for mutations within the PMP22 coding region. Molecular techniques included the polymerase chain reaction (PCR), heteroduplex analysis to detect point mutations, and direct nucleotide-sequence determination of amplified PCR products. Results: A 10-year-old boy was identified with a point mutation in PMP22, which resulted in the substitution of cysteine for serine in a putative transmembrane domain of PMP22. Analysis of family members revealed that the PMP22 point mutation arose spontaneously and segregated with the CMT type 1 phenotype in an autosomal dominant pattern. The patients with the PMP22 point mutation had clinical and electrophysiologic phenotypes that were similar to those of patients with the 1.5-Mb duplication. Conclusions: The PMP22 gene has a causative role in CMT type 1. Either a point mutation in PMP22 or a duplication of the region including the PMP22 gene can result in the disease phenotype., Charcot-Marie-Tooth disease (CMT)¹,² is the most common inherited peripheral neuropathy, with a frequency of 1 in 2500,³ and is one of the most prevalent autosomal dominant diseases⁴. It is a clinically heterogeneous disorder of the peripheral nerves characterized by slowly progressive atrophy of the distal muscles, predominantly those innervated by the peroneal nerve⁴,⁵. Progressive weakness of varying intensity and atrophy of the muscles of the feet, hands, and legs, leading to pes cavus deformity, clawhand, and stork-leg appearance, usually begin in the second or third decade of life⁴,⁵. Enlarged greater auricular nerves may be…