Clinical features These are the most common forms of inherited peripheral neuropathy and, indeed, among the most common of all inherited neurologic diseases. The early symptoms of childhood clumsiness and athletic imprecision are listed previously, to which are added foot deformities of high arches and hammer toes. There may have been ankle fractures, foot-drop, medical plantar foot calluses and a need for podiatric treatment at an early age, painless or foot ulcers. In adolescence, an “inverted champagne bottle” appearance of the forelegs may become apparent. The typical case of CMT has its onset during late childhood or adolescence, although neurologists are increasingly aware that some cases, particularly type 2, may not attract attention until middle life. CMT1 cases usually make their appearance during the first decade while the peak age of onset of CMT2 is in the second decade or even later. Both motor and sensory signs are said to be more severe in the first type (Harding and Thomas, 1980). Adult patients have difficulty dating the onset of symptoms, so much so that with milder forms, they may not even be aware of having a neuropathic illness. In some cases, the widespread nerve conduction changes only come to light when this test is performed for the diagnosis of an unrelated problem or when a parent becomes aware of their own neuropathy after their child proves to have the disease. Some types that present in adulthood may even have a subacute or seemingly acute presentation, particularly the myelin protein zero (MPZ) and the PMP22 deletion (hereditary liability to pressure palsies) types.
Because the clinical description was provided in 1886 almost simultaneously by Tooth in England and by Charcot and Marie in France, all of their names have been attached to it, even though similar cases had been recorded earlier by Eulenberg (1856), Friedreich (1873), Ormerod (1884), and Osler (1880). The two important advances in our understanding of this disease since the original descriptions have been the separation of the main subtypes on the basis of their electrophysiologic (EMG) features and the discovery of genetic mutations that cause most of these diseases.
The frequency of the disease cannot be stated with precision because of its clinical heterogeneity, but the usually quoted prevalence is 1 in 2,500 of the population, the most frequent subtype occurring in 1 in 4,000. This class of neuropathies is characterized clinically, as discussed previously, by the pattern of heredity, the speed of motor nerve conduction, and special clinical characteristics including the age of onset of symptoms such as difficulty walking and certain appended neuropathic syndromic findings such as hearing loss. From a genetic perspective, the classification is based on the gene that is affected and the nature of the mutation; deletions and duplications are the most common, but many single nucleotide polymorphisms have also been identified.
As a guide to the frequency of various types, Saporta and colleagues in a study of over 1,000 patients from neuromuscular clinics found that two-thirds of patients had a mutation detected by conventional means. When combined with the mode of inheritance, the most common type was the typical demyelinating variety of Charcot-Marie-Tooth disease (CMT1A, 17p duplication), and fewer than 10 percent each had X-linked CMTX1, hereditary liability to pressure palsies (HNPP), CMT1B, or the main axonal type, CMT2A; together, these implicated only 4 genes and all other forms, derived from about 30 other mutations, accounted for under 1 percent each. This is informative in guiding genetic testing in clinical circumstances. Still, almost one-third of patients with a clear history of heredofamilial neuropathy had none of the currently detectable mutations.