X-linked Charcot-Marie-Tooth disease (CMTX1) is the third most common form of inherited neuropathy. Patients develop a progressive distal weakness and atrophy that results from length-dependent axonal loss. CMTX1 is caused by mutations in GJB1, the gene that encodes the gap junction protein connexin32. More than 700 different GJB1 variants have been found, the majority of which result in defective function of the gap junctions formed by connexin32. In addition to the demyelinating neuropathy, many patients have subclinical CNS findings, and a few GJB1 mutations are associated with striking, transient CNS manifestations.
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• Charcot-Marie-Tooth disease type X1 is the second most common form of Charcot-Marie-Tooth disease.
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• Men are more affected than women; women are variably affected.
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• Intermediate conduction slowing (25 to 40 m/sec) is characteristic for men; slowing is typically less pronounced in women.
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• Charcot-Marie-Tooth disease type X is caused by mutations in GJB1, the gene that encodes connexin32.
Historical note and terminology
Shortly after the first descriptions of autosomal dominant kindreds with inherited neuropathy by Charcot, Marie, and Tooth in 1886, Herringham described a family in which males were selectively affected (22). He noted the similarity of the affected men to the individuals described by Charcot, Marie, and Tooth, and was struck by the finding that the women who passed the trait of their fathers to their own sons were themselves unaffected. "This form makes one wonder what inheritance is. That the diseased tissues of a consumptive father should be so represented in his spermatozoon as to cause his child to fall into consumption is remarkable enough. But that the women of this family, themselves even uncommonly buxom and healthy, should be able to select their children, and transmit to the males alone tissues unlike their own, and endowed with a regular form of weakness that they do not themselves possess, is still more marvelous. It seems as if the daughter of a diseased father carried from the beginning of her life ova of 2 sexes, the female healthy, the male containing within it the representation of the father's disease." What makes Herringham's analysis so prescient is that in 1889, Mendel's discovery of autosomal inheritance was unheralded and Morgan's demonstration of X-linked inheritance did not appear until 1910.
Non-syndromic, inherited neuropathies are called Charcot-Marie-Tooth disease (CMT) or hereditary motor and sensory neuropathy (50; 16). Most forms of Charcot-Marie-Tooth disease have slowly progressive, length-dependent weakness, atrophy, and sensory loss, including reduction of deep tendon reflexes. On the basis of the clinical features, nerve conduction velocities, and histopathology, Charcot-Marie-Tooth disease was subdivided into demyelinating (conduction velocities of the motor nerves in the arms less than 35 m/s) and axonal (conduction velocities of the motor nerves in the arms greater than 35 m/s); “intermediate” forms of Charcot-Marie-Tooth disease have also been recognized owing to their intermediate conduction velocities (conduction velocities of the motor nerves in the arms 30 to 40 m/s). Dominant mutations in PMP22, MPZ, LITAF/SIMPLE, EGR2, GJB1, and PMP2 cause CMT1; this list is mostly complete because a few CMT1 patients do not have mutations in these genes (15). All of these genes are expressed by myelinating Schwann cells and are thought to cause disease through their effects in myelinating Schwann cells (48). Although demyelination is the initial effect of these mutations, the severity of all of these neuropathies is directly related to the degree of axonal loss rather than demyelination per se (31).