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Definition: Charcot–Marie–Tooth disease(CMT disease) from Dictionary of DNA and Genome Technology

Any of a group of heterogeneous inherited neuropathies which include both demyelinating and axonal types; autosomal dominant, autosomal recessive and X-linked cases are recognized.

Type 1A demyelinating CMT is associated with abnormality of the gene encoding peripheral myelin protein-22 located at 17p11.2, while type 1B demyelinating disease is associated with mutation in the gene for myelin protein zero at 1q22. X-linked CMT disease (CMTX) is reported to exhibit features of both the demyelinating and axonal types.

The type 2A disease is linked to mutations in the mitofusin 2 gene (MFN2) [BMC Med Genet (2006) 7:53].

Summary Article: Charçot–Marie–Tooth Disease
From The Encyclopedia of Neuropsychological Disorders

Charçot–Marie–Tooth (CMT) disease is a genetically heterogeneous disorder involving gradually progressive muscular atrophy and sensory neuropathy. A typical feature of CMT is known as “foot drop” resulting from weakness in the lower leg and foot. As a result of muscular degeneration and loss of sensation in limbs, lessened manual dexterity, weakness, gait problems, and loss of balance occur as the disease progresses. Other common features of CMT disease include loss of sensation in hands and feet, and muscle cramps and pain (Arnold, McEntagart, & Younger, 2005) that worsen at variable rates over time.

Primarily affecting distal body parts, the disease causes muscle atrophy that may result in debilitating deformities of extremities. Physical manifestations of the disease include high-arched feet or flat feet, claw-hand deformities, and, in more severe cases, scoliosis or kyphosis and vocal cord paralysis may exist (Arnold et al., 2005; Scriver, Beaudet, Sly, & Valle, 2001). It is the most common hereditary peripheral neuropathy and usually presents in adolescence or early adulthood with mild initial symptoms such as clumsiness and numbness. CMT is not life threatening, although age of onset, rate of progression, and severity of the disease are variable and unpredictable even among family members, making prognosis difficult.


Pathological mechanisms of CMT disease involve inherited mutated autosomal dominant genes most commonly but may also involve mutated autosomal recessive or X-linked dominant genes (Arnold et al., 2005). There are four subtypes of CMT that have been distinguished based upon the disease pathophysiology: CMT1, CMT2, CMT3, and CMT4. CMT1 is characterized by demyelination and motor nerve conduction velocities below 35 m/s (Stojkovic et al., 2003). Unlike CMT2, nerve biopsies of patients with CMT1 reveal an “onion bulb” formation (Arnold et al., 2005). CMT1A is the most common CMT1 subcategory and has been linked to a duplication on the peripheral myelin protein PMP22 gene, whereas CMT1B is associated with mutations in the myelin protein zero (MPZ) gene and motor nerve conduction velocities of below 25 m/s (Stojkovic et al., 2003).

CMT2 involves axonal dysfunction and motor nerve conduction velocities that fall within normal limits. The mutated genes discovered in CMT2 are responsible for the integrity of the axon, and axonal degeneration occurs when these genes malfunction. Degeneration of the axons in CMT2 is associated with mutations in the mitochondrial fusion protein mitofusin 2 (MFN2) (Baloh, Schmidt, Pestronk, & Milbrandt, 2007). Axonal mitochondrial transport is disrupted in CMT2 and a lack of energy due to an insufficient supply of mitochondria in peripheral axons exists, leading to neuronal dysfunction in distal regions of the body (Baloh et al., 2007).

CMT3, also known as Dejerine–Sottas's disease, begins in infancy and involves severe sensory abnormalities and muscle degeneration. Mutations in the PO gene or the PMP22 gene are believed to be responsible for CMT3 pathology. CMT4 encompasses an array of demyelinating subcategories, each of which cause motor and sensory abnormalities involving leg weakness that progresses to paralysis by adolescence.

CMTX, the X-linked form of CMT, is linked to a mutation in the gene encoding connexin 32, a gap junction protein having multiple roles in the Schwann cell and present in various tissues throughout the body (Abrams et al., 2003). The pathology of CMTX includes axonal loss, partially failed regeneration, and myelin abnormalities (Abrams et al., 2003; Hahn, Ainsworth, Bolton, Bilbao, & Vallat, 2001). Mutations in the connexin 32 gene may explain the variable pattern of muscular abnormalities across patients.


Involvement of cranial nerves is rare and cognitive changes are usually not related to the disease itself, although they may occur secondary to psychological distress. For example, fatigue is common in CMT and associated with slowed mental processing. Psychological aspects of CMT are usually related to decreased mobility. As the disease progresses, the patient becomes increasingly dependent on others to assist them with simple tasks that they no longer are able to accomplish independently given muscle and sensory dysfunction (i.e., buttoning a shirt, walking on uneven surfaces).

The CMT patient may react to increasingly demanding daily activities with altered perceptions of self-efficacy and feelings of inferiority, guilt, and fear. A significant deterioration in quality of life is found in patients with CMT, particularly in older, unemployed women (Padua et al., 2006) who typically report most of the symptoms. Feelings of shame and embarrassment may result from the need to ask others for assistance with simple physical tasks, frequent tripping, unusually shaped feet or hands, and/or awkward gait. Body image, self-esteem, and self-worth are also greatly impacted by the altered physical appearance that accompanies muscle atrophy and the use of orthopedic devices (Arnold et al., 2005).

CMT patients may display anger toward their disability and frustration that they are no longer able to perform simple tasks as efficiently as they once did. CMT patients have a sense of emotional loss that accompanies physical degeneration that may lead to hopelessness and depression. Anxiety is a common psychological feature of the disease based upon the patient's perceived dependence, worry regarding disease progression, and concern about the potential for genetic transmission to offspring. Given the progressive nature of the disease, patients are often uncertain of the future and apprehensive toward goal-making for fear of failure due to physical limitations imposed by CMT disease.

Patients with CMT disease also experience prejudices related to the stigma of having a disability. They may be viewed as less attractive, incompetent, or clumsy. Patients may attempt to hide their disability for fear of job jeopardy or social rejection. Slowed job performance, social isolation, and medical expenses contribute to emotional distress in CMT patients. Adequate resources, social support, and personal beliefs are influential in determining patients' levels of adjustment to their disability (Arnold et al., 2005; Marshak, Seligman, & Prezant, 1999). CMT patients often choose to cope with their illness by modifying their environment to the level of their disability (i.e., replacing staircases with ramps, buying shoes with Velcro rather than laces) in order to maintain a relative amount of independence.


Sensory and motor neuropathy is a common feature of various diseases with multiple causes. CMT disease may mimic acquired neuropathies such as alcoholism and vitamin B12 deficiency, other genetic neuropathies (i.e., amyloid neuropathy), or occur in association with chronic illnesses (i.e., diabetic neuropathy) (Arnold et al., 2005). It is important to distinguish CMT from other neuropathies by its defining clinical features. For the diagnosis of CMT disease, patients undergo a physical examination, electromyography and nerve conduction velocity testing, nerve biopsy, and a comprehensive family and medical history is gathered (Bird, 2004; De Jonghe et al., 1999). MRI and CT are frequently used to diagnose CMT disease by identifying nerve root enlargement within the lumbosacral portion of the spine (Aho, Wallace, Pitt, & Sivakumar, 2004).


Patients with CMT disease should receive social support to assist them in dealing with strong emotions such as depression and anxiety, which commonly accompany the diagnosis of disabling diseases such as CMT. Cognitive restructuring regarding their perception of the level and extent of their disability may improve self-efficacy and the ability to cope effectively. Psychiatric medications such as antidepressants may be necessary in addition to therapy to improve the patient's psychological well-being. Access to resources such as specialty devices and medications to assist with physical discomfort will improve their ability to function motorically, foster independence, and aid in job security. Orthopedic braces and other devices for hands, legs, and feet provide alternate ways of functioning in order to increase independence and efficiency during everyday activities. These devices can be molded to the individual needs of the patient and modified as the disease progresses. Some patients may elect to have reconstructive surgery to correct deformities caused by muscular degeneration and may require rehabilitation and occupational therapy to regain usage of the affected limb.

Patients with CMT disease will benefit from a variety of medical professions including geneticists, neurologists, social workers, psychiatrists, neurological rehabilitation specialists, occupational therapists, orthopedists, and support groups to assist them in adjusting physically and emotionally to their level of disability (Arnold et al., 2005). Patients themselves may contribute to the treatment of CMT and receive free medical resources while increasing their sense of self-worth by becoming research participants in the search for a cure for CMT. Genetic information and testing is available for patients who wish to be informed of the likelihood of passing on CMT to offspring. Education regarding the disease and the transmission of CMT to offspring will help reduce the patient's anxiety and assist them in making informed decisions regarding treatment and future planning.

  • Abrams, C. K.; Freidin, M.; Bukauskas, F.; Dobrenis, K.; Bargiello, T. A.; Verselis, V. K., et al. (2003). Pathogenesis of X-linked Charcot-Marie-Tooth disease: Differential effects of two mutations in connexin 32. Journal of Neuroscience, 23(33), 10548-10558.
  • Aho, T. R.; Wallace, R. C.; Pitt, A. M.; Sivakumar, K. (2004). Charcot-Marie-Tooth disease: Extensive cranial nerve involvement on CT and MR Imaging. American Journal of Neuroradiology, 25, 494-497.
  • Arnold, A.; McEntagart, M.; Younger, D. S. (2005). Psychosocial issues that face patients with Charcot-Marie-Tooth disease: The role of genetic counseling. Journal of Genetic Counseling, 14(4).
  • Baloh, R. H.; Schmidt, R. E.; Pestronk, A.; Milbrandt, J. (2007). Altered axonal mitochondrial transport in the pathogenesis of Charcot-Marie-Tooth disease from mitofusin 2 mutations. Journal of Neuroscience, 27(2), 422-430.
  • Bird, T. D. (2004). Charcot-Marie-Tooth hereditary neuropathy overview. In GeneReviews at GeneTests-GeneClinics: Medical genetics information resource [database online]. Copyright, University of Washington, Seattle. 1997-2001. Available from or
  • De Jonghe, P.; Nelis, E.; Timmerman, V.; Lofgren, A.; Martin, J. J.; Van Broeckhoven, C. (1999). Molecular diagnostic testing in Charcot-Marie-Tooth disease and related disorders. Approaches and results. Annals of the New York Academy of Sciences, 883, 389-396.
  • Hahn, A. F.; Ainsworth, P. J.; Bolton, C. F.; Bilbao, J. M.; Vallat, J. M. (2001). Pathological findings in the x-linked form of Charcot-Marie-Tooth disease: A morphometric and ultrastructural analysis. Acta Neuropathologica (Berlin), 101, 129-139.
  • Marshak, L. E.; Seligman, M.; Prezant, F. (1999). Chapter 1: Families coping with disability. Foundational and conceptual issues. In S. McDaniel; J. Hepworth; W. F. Doherty (Eds.), Disability and the family life cycle (pp. 1-37). Book News Portland, OR.
  • Padua, L.; Aprile, I.; Cavallaro, T.; Commodari, I.; La Torre, G.; Pareyson, D., et al. (2006). Variables influencing quality of life and disability in Charcot Marie Tooth (CMT) patients: Italian multicentre study. Journal of the Neurological Sciences, 27, 417-423.
  • Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (2001). Charcot-Marie-Tooth peripheral neuropathies and related disorders. In C. R. Scriver; A. L. Beaudet; W. S. Sly; D. Valle (Eds.), Metabolic and molecular bases of inherited disease (8th ed., Vol. 4, pp. 63-38). McGraw-Hill New York.
  • Stojkovic, T.; de Seze, J.; Dubourg, O.; Arne-Bes, M. C.; Tardieu, S.; Hache, J. C., et al., (2003). Autonomic and respiratory dysfunction in Charcot-Marie-Tooth disease due to Thr124Met mutation in the myelin protein zero gene. Clinical Neurophysiology, 114, 1609-1614.
  • Stephanie Lei Santiso
    Charles Golden
    Copyright © 2011 Springer Publishing Company

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