Charcot-Marie-Tooth disease type X

Steven S Scherer MD PhD (Dr. Scherer of the University of Pennsylvania School of Medicine has no relevant financial relationships to disclose.)
Louis H Weimer MD, editor. (Dr. Weimer of Columbia University has received consulting fees from Roche.)
Originally released August 30, 1999; last updated February 8, 2017; expires February 8, 2020

This article includes discussion of Charcot-Marie-Tooth disease type X, CMT1X, hereditary motor and sensory neuropathy X, hereditary motor and sensory neuropathy type X, X-linked Charcot-Marie-Tooth disease, and X-linked CMT. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

X-linked Charcot-Marie-Tooth disease (CMT1X) is the second most common form of inherited neuropathy. Patients develop a progressive distal weakness and atrophy that results from length-dependent axonal loss. More than 400 different mutations in GJB1, the gene that encodes the gap junction protein connexin32, cause CMT1X. Most mutations result in defective function of the gap junctions formed by Cx32. In addition to the demyelinating neuropathy, many patients have subclinical CNS findings, and a few GJB1 mutations are associated with striking, transient CNS manifestations.

Key points

 

• Charcot-Marie-Tooth disease type X is the second most common form of Charcot-Marie-Tooth disease.

 

• Men are more affected than women; women are variably affected.

 

• Intermediate conduction slowing (25 to 40 m/sec) is characteristic for men; slowing is typically less pronounced in women.

 

• 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 (Herringham 1888). 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.

Dominantly inherited, non-syndromic neuropathies are called Charcot-Marie-Tooth disease (CMT) or hereditary motor and sensory neuropathy (Shy et al 2005; Fridman and Reilly 2015). 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 2 types: type 1 (demyelinating) and type 2 (axonal). Subsequent linkage studies led to the further subdivision of CMT1 into distinct genetic forms: CMT1A (linked to chromosome 17), CMT1B (linked to chromosome 1), CMT1C (linked to chromosome 16), and CMT1X (linked to the X chromosome). Mutations in PMP22, MPZ, LITAF/SIMPLE, EGR2, GJB1, and PMP2 cause CMT1; this list is likely incomplete because a few CMT1 patients do not have mutations in these genes (Fridman et al 2015). All of these genes are expressed by myelinating Schwann cells and are thought to cause disease through their effects in myelinating Schwann cells (Scherer and Wrabetz 2008). 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 (Lewis et al 2003).

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