Charcot-Marie-Tooth (CMT) disease is the most prevalent peripheral inherited neuropathy (1/2500 to 10 000; 2.8/10 000 in Spain), and the mean age at onset is 16 years (range 2 to 50 years, but presentation in the early infancy and as late as the 80s has been reported). Patients present with motor and sensory polyneuropathic semiology (distal lower limb weakness and atrophy, gait abnormalities and frequent falls) and pes cavus. Apart from the motor nerve related deficits, most patients suffer slight sensory loss in hands and feet. The treatment of the disease is supportive. Life expectancy is not shortened - except in some forms of Déjerine-Sottas and severe forms of CMT-, but disabilities are the rule.
The slow increase in physical disability in adulthood may well be explained by decreased reserves and compensatory mechanisms together with progression of skeletal deformations due to muscle weakness. However this classic concept is controversial, as can be related to CMT1A only: progression of axonal loss definitely occurs in most if not all CMT types and is a cause of progressive wasting and weakness in many patients.
Sometimes CMT disease is associated with moderate to severe chronic extremity pain, that is usually related to bone, joint and muscle involvement, and rarely neuropathic.
CMT is more frequently an autosomal dominant disease (but there is genetic heterogeneity, and more than 30 pathogenic genes have been implicated, X-linked and autosomal recessive forms, eve mitochondrial DNA mutations showing a CMT-like phenotype have been reported). The most common syndrome is CMT1A, which accounts for 55% of all CMT cases and 66.8% of CMT1 cases, and which is usually caused by an allelic trisomy of a region spanning 1.5Mb in 17p11.2, containing the PM P22 gene (causing excessive gene dosage, and overproduction of PMP22 and its accumulation in Schwann cells that is a proposed mechanism resulting in programmed cell death, the ultimate mechanism of CMT development remaining unknown), but the percentages can vary according to different series reported and geographic origin. The 1970s classification from Dyck is valid, but molecular genetics has changed the nosology (see Berciano J, et al. for complete information):
a) type I (CMT1, demyelinating or hypertrophic) with AD or AR inheritance; b) type II (CMT2, neuronal or axonal) with AD or AR inheritance; c) type III (CMT3, usually with de novo heterozygous gene mutations, AR uncommon) reserved for Déjérine-Sottas disease or patients with severe forms of hypomyelinating CMT; d) X-linked forms, and e) complex forms (e.g. associated with pyramidal involvement, optic atrophy, deafness -occurying in several CMT types; pigmentary degeneration of the retina suggest mitochondrial disease). The disease shows the more prevalent phenotypes caused by mutations in the gene encoding peripheral myelinprotein-22 (duplication), dynamin-2 being very rare.
Diagnostic: lineage of affected ancestors, and/or (in the case of negative family survey), onset during childhood; prolonged and slowly progressive clinical course; presence of pes cavus, and - unlike in acquired neuropathies - absence of positive sensory symptoms (paraesthesias or dysaesthesias) despite a clear semiology of sensory deficit. An electrophysiologic examination should follow (CMT1 and CMT2 classification depends on the cuttoff value 38m/s by convention, for the upper limb motor nerves conduction velocity, both median and ulnar nerves), and, in selected cases, neuropathologic criteria (nerve biopsy). Finally genetic testing specifically targeted (molecular diagnosis).