clinical features of charcot-marie-tooth (cmt) disease

cmt disease is the most common inherited neuromuscular disorder, with its estimated prevalence being 17–40:100,000. although it is genetically a highly heterogeneous disorder, the clinical phenotype is relatively homogeneous. this is characterized by wasting and weakness of distal limb muscles, involving especially the peroneal compartment (hence the old term of peroneal muscular atrophy), usually associated with distal sensory loss, skeletal deformities, and decrease or absence of deep tendon reflexes. the clinical phenotype is similar for cmt disease caused by mutations in many different genes involved in very diverse functions, coding for structural myelin proteins, gap-junction forming proteins, cytoskeleton elements, enzymes, transcription factors, and so on. dysfunction of all these proteins, even when primarily affecting myelin, eventually leads to an axonal degeneration that is length-dependent. therefore, longer fibers are affected first and more severely, thus producing distal impairment of limb functions, which progressively involves feet and legs and later hands and distal thighs, and results in the typical inverted champagne bottle appearance of the legs. at the same time, sensory loss involves first the feet and then spreads to the legs and later to the hands, and deep tendon reflexes are usually lost also with a length-dependent pattern. exceptions to this general rule in cmt are rare and may point to specific underlying gene mutations. this is also the reason why the different forms of cmt are usually clinically indistinguishable in a single patient, and the precise cmt subtype diagnosis requires a complex approach, based also on inheritance pattern and electrophysiological examination. disease severity is highly variable, even within the same kinship. some individuals may show minimal signs and are unaware of being affected, whereas others may be significantly disabled. however severe impairment and loss of autonomy is infrequent in cmt. marked difference in disease severity has been reported in identical twins with cmt1a.the reasons for such variability of disease expression for cmt caused by the same mutation are unknown and the search for modifier factors is ongoing. disease onset usually occurs during the first decades of life and the course is very slowly progressive over decades. rarely, cmt arises in early infancy with hypotonia, or delay in motor milestones onset may occur in infancy with toe walking. on the other extreme, there are patients and families in which cmt has a late onset. however, the most common heralding symptoms are walking difficulties with steppage gait in a child or adolescent with pes cavus. skeletal deformities are typically found in cmt, being present in more than 66% of all patients, and in 70–95% of cmt1 patients, and they are mainly characterized by pes cavus with hammer toes, whereas scoliosis is less common. in this article i will discuss different clinical presentation of the cmt and compare their relation with electrophysiologic and genetical subgroups of disease.