genetic and classification of charcot – marie – tooth (cmt) disease

according to the well-known classification of dyck, inherited peripheral neuropathies can be categorized as hereditary motor and sensory neuropathies (hmsn) or charcot – marie – tooth (cmt) disease, hereditary motor neuropathies (hmn), and hereditary sensory neuropathies (hsn). cmt is a clinically and genetically heterogeneous group of motor and sensory neuropathies, and is the most common inherited neuromuscular disorder, with an estimated overall prevalence of 17-40/10000. cmt is clinically characterized by distal limb muscle wasting and weakness, usually with skeletal deformities ,distal sensory loss, abnormalities of deep tendon reflexes and a progressive course. they are currently classified according to mode of inheritance, electrophysiological characteristics and molecular data. the mode of inheritance may be autosomal dominant, autosomal recessive or x-linked. electrophysiological features distinguish demyelinating from axonal forms. the median motor nerve conduction velocity (mncv) is generally chosen to define: 1) demyelinating cmt (cmt1) with median mncvs below 30 m/s 2) intermediate cmt with median mncvs between 30 and 40 m/s 3) axonal cmt (cmt2) with median mncvs above 40 m/s. autosomal dominant demyelinating cmt or cmt1 is due in 70% of the cases to a 1.5 mb duplication of the chromosomal 17p11.2 region (cmtia) containing the pmp22 gene.this gene encodes the peripheral myelin protein of 22 kd (pmp22), a transmembrane glycoprotein that represents 5% of the proteins of the peripheral nervous system. the phenotype in cmt1a patients results from a gene dosage effect due to the presence of 3 copies of the pmp22 gene instead of 2. the age at onset is highly variable, ranging from infancy to the eighth decade. electroneuromyographic testing shows a diffuse and homogeneous slowing of nerve conduction. the findings are identical in asymptomatic carriers, making median mncv a reliable tool for screening affected at-risk individuals. secondary axonal loss is always observed, and is correlated with neurological dysfunction and disease progression. nerve biopsies are no longer used for the diagnosis of cmt1a, since the 17p11.2 duplication is routinely detected by molecular biology but would show a characteristic demyelinating neuropathy with presence of onion bulb formations, associated with a secondary loss of myelinated fibres, especially those of large diameter. some rare mutations in the pmp22 gene have been associated with cmt1 and seem to cause a more severe phenotype than the 17p11.2 duplication, known as dejerine-sottas disease or congenital hypomyelinating neuropathy. about 4% of cmt1 patients have mutations in the mpz (myelin protein zero) gene (cmt1b), encoding a major protein of compact myelin. three others genes have been identified in cmt1: litaf/simple (lipopolysaccharideinduced tumor necrosis factor- α)(cmtic), egr2 (early growth response 2 gene) (cmt1d), and nefl (neurofilament light chain) (cmt1f). mutations in these genes are infrequent mpz and nefl mutations may also produce an axonal phenotype. the second most common cause of demyelinating cmt in patients without the 17p11.2 duplication are mutations in the connexin-32 (cx32) gene, responsible for x-linked cmt (cmtx). the cx32 protein is localized in noncompacted domains of the myelin, such as paranodal loops and schmidt-lantermann incisures. it forms reflexive intracellular channels in schwann cells and provides a radial pathway through the myelin sheath that connects the perinuclar and adaxonal cytoplasmic region. cmtx is characterized genetically by the absence of father to son transmission in pedigrees and clinically by a more severe course of the disease in men than in women. cx32 mutations are more frequent in intermediate cmt, where they account for more than 40% of the families. in such cases, nerve biopsies show features of both axonal and demyelinating processes, reflecting the key role of cx32 protein in axon-schwann cell interactions. autosomal recessive demyelinating cmt, or cmt4, are also very heterogeneous. most genes have been identified in consanguineous families originating from north africa or the middle east. they are usually characterized by 1) an early age at onset, 2) involvement of distal limbs progressing to proximal limbs, which may be responsible for the loss of ambulation, 3) associated signs such as vocal cord paresis, bulbar and facial weakness, sensorineural deafness, glaucoma, scoliosis…, 4) severe secondary axonal loss leading to absence of measurable mncvs, 5) particular features of the myelin sheaths on nerve biopsies. seven genes and an additional locus have been identified: gdap1(ganglioside-induced differentiation-associated protein1), mtmr2 (myotubularin-related protein2), mtmr13, kiaa1985, ndrg1 (nmyc downstream-regulated gene 1), egr2, periaxin and hmsn-russe at chromosome 10q23. the cmt4a and cmt4c, caused by gdap1 and kiaa1985 mutations, respectively, seem to be frequent causes of cmt4. the functions of the corresponding protein are still largely unknown. treatment is currently supportive and a therapy that fundamentally alters the course of cmt neuropathy is still lacking but recent studies in animal models show promising results. a better understanding of the molecular architecture of the peripheral nerve, the functional pathways, the myelination process, and the complex interaction between the myelinating schwann cells, the axon, and muscle is crucial to identify targets for therapeutic interventions. the identification of loci, genes, and disease-causing mutations involved toward inherited peripheral neuropathies is the first step toward this understanding, and in the mean time provide tools for molecular genetic diagnosis.