How has the classification of Charcot-Marie-Tooth (CMT) disease evolved?

Updated: May 22, 2018
  • Author: Timothy C Parsons, MD; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
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As more heterogeneity and overlap in clinical appearance, pathological features, and forms of inheritance were recognized in the following decades, an improved classification system was needed to avoid confusion. Starting in the 1950s, the clinical use of nerve conduction studies combined with pathological information allowed patients to be divided into 2 major groups.

  • Group 1 was characterized by slow nerve conduction velocities and evidence of hypertrophic demyelinating neuropathy.

  • Group 2 was characterized by relatively normal nerve conduction velocities and axonal degeneration.

Most of the families demonstrated autosomal dominant inheritance, and affected relatives in each family could all be categorized in the same group. [4, 5, 6]

In 1975, Dyck expanded the classification system of what was now known as hereditary motor and sensory neuropathy (HMSN) to include forms with additional features. [7]

  • HMSN types 1A and 1B (dominantly inherited hypertrophic demyelinating neuropathies)

  • HMSN type 2 (dominantly inherited neuronal neuropathies)

  • HMSN type 3 (hypertrophic neuropathy of infancy [Dejerine-Sottas])

  • HMSN type 4 (hypertrophic neuropathy [Refsum] associated with phytanic acid excess)

  • HMSN type 5 (associated with spastic paraplegia)

  • HMSN type 6 (with optic atrophy)

  • HMSN type 7 (with retinitis pigmentosa)

In the 1980s it became clear that this revised classification system, based on clinical and electrophysiologic characteristics, was inadequate to describe the genetic heterogeneity within each of these categories. Linkage studies revealed Charcot-Marie-Tooth type 1 loci on both chromosome 1 [8] and chromosome 17 [9] , and X-linked and recessively inherited forms were increasingly recognized.

In 1991, 2 groups showed that the most common form of CMT1, known as CMT1A, was associated with a duplication within chromosome 17p11.2. [10, 11] This duplication is believed to be in the peripheral myelin protein 22kD (PMP22) gene, and overexpression of the gene product appears to be causative, since a gene dosage effect has been demonstrated. [12] It is estimated that this duplication is responsible for about 70% of CMT1 cases [13] and the vast majority of CMT1A cases, with rare exceptions such as partial 17p trisomy. [12, 14]

Other Charcot-Marie-Tooth genes were discovered in the 1990s. The second most common form of CMT1 (CMT1B) and some cases of Déjerine-Sottas syndrome were found to be associated with mutations in the myelin protein zero (MPZ) gene on chromosome 1. [15, 16, 17] The most common form of CMTX (CMTX1), was found to be due to mutations in the gap junction protein beta 1/connexin 32 (Cx32) on chromosome Xq13.1. [18] Interestingly, hereditary neuropathy with liability to pressure palsies (HNPP) was found to be associated with a deletion in the PMP22 gene [19] , but this syndrome will not be reviewed here.

The difficulty classifying Charcot-Marie-Tooth subtypes is made more evident by the fact that mutations of each of these genes have been associated with multiple, overlapping phenotypes. For instance, myelin protein zero mutations are associated CMT1B, Déjerine-Sottas syndrome, and the axonal CMT2 phenotype. [20, 21, 22] Déjerine-Sottas syndrome has been associated with mutations or deletions in PMP22, myelin protein zero, and early growth response 2 (EGR2) genes. [15, 23, 24]

In addition, the boundaries between even the major types of CMT are not always as clear as the original series suggested. In the mid 1970s, Bradley, Davis, and Madrid performed a similar study to those performed by Dyck and Lambert, Thomas and Calne, and Buchthal and Behse, and proposed a CMT classification that included an intermediate group characterized by median motor nerve conduction velocities of 25-45 m/sec and intermediate pathological changes. [25, 26, 27] A study performed by Brust, Lovelace, and Devi suggested a bimodality in nerve conduction velocities among type 1 patients, again raising the possibility of an intermediate form [28] , but these were considered exceptions and were never incorporated into the major classification systems. In 1985, a large kinship with an intermediate form was described.

In 1998, sequencing of the PMP22 and MPZ genes in this kinship did not reveal mutations, underscoring that it is a distinct entity. [29, 30] Several associated mutations have been discovered since, and as with other forms of CMT, these studies have demonstrated genetic heterogeneity.

Given what is now known about clinical and genetic heterogeneity, a system that takes both clinical and genetic characteristics into account is not possible. This review will use the following system:

  • CMT1 is a dominantly inherited, hypertrophic, predominantly demyelinating form.

  • CMT2 is a dominantly inherited predominantly axonal form.

  • Dejerine-Sottas is a severe form with onset in infancy.

  • CMTX is inherited in an X-linked manner.

  • CMT4 includes the various demyelinating autosomal recessive forms of Charcot-Marie-Tooth disease.

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