Charcot-marie-tooth Disease: Insights from Skin Biospy

Inherited neuropathies, collectively known as Charcot-Marie-Tooth disease (CMT), are a group of genetically and phenotypically heterogeneous peripheral neuropathies associated with mutations or copy number variations in over 80 distinct genes. 1 Named after the three neurologists who first described the condition in 1886, CMT is the most common inherited neuromuscular disease. 2 CMT is a motor and sensory neuropathy (HMSN) that is closely related to two other rarer inherited neuropathies: distal hereditary motor neuropathy (dHMN), which has predominantly motor involvement, and hereditary sensory/autonomic neuropathy (HSN or HSAN), which involves only or predominantly sensory and autonomic nerves. These three disorders represent a continuum and are often collectively termed CMT and related disorders. 3 CMT is divided into different forms based on the pattern of inheritance and neurophysiological studies. Autosomal dominant forms are subdivided into demyelinating (CMT1) and axonal (CMT2) forms. CMT4 and CMTX designate the autosomal recessive and X-linked forms, respectively. 4 The term Dejerine-Sottas neuropathy (DSN) is currently used primarily to denote severe early-onset clinical phenotypes regardless of the inheritance pattern. 5 The classification of CMT has been divided further into subtypes, identified by letters, as defined by the mutated gene (Table 1). Epidemiology The prevalence of CMT is about 1 in 2500 people, with a global distribution and no ethnic predisposition. CMT1A, associated with 17p11.2 duplication in the region containing the peripheral myelin protein 22 gene (PMP22), is the most common form of CMT and accounts for 60 to 70% of demyelinating CMT patients (around 50% of all CMT cases). Mutations in the gap junction beta 1 gene (GJB1) causing CMTX result in approximately 10 to 20% of CMT cases and CMT1B associated with mutations in the myelin protein zero gene (MPZ) accounts for less than 5%. Patients with CMT2 are about 20% of all cases. The prevalence of hereditary neuropathy with liability to pressure palsies (HNPP) is not known, but about 85% of patients with clinical evidence of 3 this syndrome have a chromosome 17p11.2 deletion. 6 Although there are many genes associated with CMT, mutations in only four genes (PMP22 duplication/deletion, GJB1, MPZ plus MFN2 in Northern Europe and American populations or GDAP1 in Mediterranean populations) account for over 90% of CMT cases. 6-10 Mutations in the ganglioside-induced differentiation-associated protein 1 gene (GDAP1) lead to both recessive (CMT4A/AR-CMT2K) and dominant (CMT2K) form of CMT. Rarer forms include CMT2E due to mutations in the neurofilament light chain gene …