Charcot–Marie–Tooth Disease and Associated Peripheral Neuropathies

Abstract

Abstract Charcot–Marie–Tooth (CMT) disease, a hereditary motor and sensory neuropathy, is the most frequent inherited neuromuscular disorder. According to electrophysiological and nerve biopsy criteria, CMT is classified into three categories: demyelinating, axonal and intermediate. Mutations in more than 30 genes/loci result in CMT phenotype. The main demyelinating CMT form is a 1.4‐Mb duplication, which affects the PMP22 (70%) gene, followed by mutations in the GJB1 (6%) and MPZ (3–5%) genes. Regarding axonal CMT, the commonest form is due to mutations in the MFN2 (20%) gene. Other neuropathies that share clinical similarities and genetic basis with CMT include Déjérine–Sottas syndrome, congenital hypomyelinating neuropathy and hereditary neuropathy with liability to pressure palsies. During the last decade advances have allowed to get insight of the molecular bases of this group of peripheral neuropathies and in most cases, an accurate genetic diagnosis is possible. Key Concepts: The Charcot–Marie–Tooth (CMT) disease, a hereditary motor sensory neuropathy, is the most frequent inherited neurological disease. According to electrophysiological and histopathological criteria, CMT can be classified into three forms: demyelinating, axonal and intermediate. Genes involved in Déjérine–Sottas syndrome, congenital hypomyelinating neuropathy and hereditary neuropathy with liability to pressure palsies are also associated with CMT. CMT is characterised by a wide genetic heterogeneity because more than 30 genes/loci are related to this disease and also because all the Mendelian patterns can be found in this group of diseases. The duplication of 1.4 Mb which affects the PMP22 gene (CMT1A duplication) is the most prevalent cause of Charcot–Marie–Tooth disease with a percentage of 43% of the total CMT. Once the most frequent genes related to CMT ( PMP22 , MPZ , GJB1 , MFN2 and GDAP1 ) have been ruled out, mutations in the remaining known genes occur in less than 1% of CMT cases. The complexity of CMT genetics makes difficult to identify the disease‐causing mutation in many cases and therefore, the next‐generation sequencing (NGS) technologies facilitate the genetic diagnosis.