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Summary Article: Charcot-Marie-Tooth Disease
from Encyclopedia of Human Genetics and Disease


One of the must common neurological disorders; affects an estimated 350,000 in the United States; worldwide, affects 1 in 2,500 people of all races and ethnic groups

Other Names

Charcot-Marie-Tooth neuropathy; hereditary motor and sensory neuropathy (HMSN); hereditary sensorimotor neuropathy (HSMN); Morbus Charcot-Marie-Tooth; peroneal muscular atrophy

Several researchers have given their names to Charcot-Marie-Tooth disorder. The first description of the condition was in 1884 by the German doctor Friedrich Schultze, who was convinced he was dealing with a muscle disorder. Following soon in 1886 were the classic descriptions published in a French journal by Jean-Martin Charcot and his pupil Pierre Marie. In this article they described five cases of progressive muscular atrophy and assumed it was related to the nervous system. That same year, Howard H. Tooth in London wrote about the peroneal type of progressive muscular atrophy related to neuropathy. Thus, the disorder then was introduced as a neuropathy rather than just a muscle problem and called Charcot-Marie-Tooth disease.

What Is Charcot-Marie-Tooth Disease?

Charcot-Marie-Tooth disease, or CMT, is characterized by slowly progressive wasting and weakness of peripheral muscles of the arms and feet. The peripheral nerves connect the brain and spinal cord to these muscles and also to the sensory cells that detect heat, cold, and touch. The condition usually begins in late childhood or early adolescence, but onset can begin at any time even into late adulthood. The following symptoms of the disease are caused by degeneration of the peripheral nerves, nerve roots, and even the spinal cord:

  • Earliest symptoms involve muscle weakness in the foot, causing extremely high arches or curled toes, called hammer toes.

  • Abnormal feet make it difficult to flex the foot and may cause the person to develop a high step or gait and increase the risk for falls.

  • Lower legs may take on an “inverted champagne bottle” appearance because of the loss of muscle bulk.

  • As the disease progresses, weakness in lower limbs may require the person to use a wheelchair.

  • Muscle loss in the hands may make it impossible to write, fasten buttons, or even open doors.

  • Sensory cells are disturbed, and the person may experience burning or numbing sensation in the feet and hands.

  • Sensitivity to touch, heat, and cold is decreased.

  • In rare cases, there is a loss vision and hearing.

The symptoms of CMT may vary even within a family. Several types of CMT exist, including CMT1, CMT2, CMT3, CMT4, and CMTX. There are subtypes of several of these types.

What Is the Genetic Cause of Charcot-Marie-Tooth Disease?

CMT has a rather complicated system of inheritance depending upon the type and subtype. Following is an outline of the types of CMT and the pattern of inheritance:

  • CMT-1 Type 1: caused by mutations in PMP22 (subtypes 1A and 1E, MZB (subtype 1B), LITF (subtype 1 C), ERG2 (subtype 1D), and NEFL (subtype 1F). CMT1A and CMT1B are inherited in an autosomal dominant pattern. CMT1A results from a duplication on chromosome 17. The gene provides instructions for producing peripheral myelin protein-22, a critical component of the myelin sheath.

  • CMT2: There are many subtypes designated from A to L. The striking feature is abnormalities of the axon of the peripheral nerve rather than the myelin sheath. The gene here is unknown. There has been some connection between this condition and one that codes for kinesins, which are proteins that aid in transporting materials to the cell. The following genes may be involved: MFN2, KIFB, RAB7A, LMNA, BSCL2, GARS, GDAP1, NEFL, HSPB1, MPZ, GDAP1, HSPB8, and DNM2.

  • CMT3: Also known as Dejerine-Sottas disease, this is a severe neuropathy that attacks the myelin sheath beginning in infancy; the newborn will have severe muscle atrophy, weakness, and sensory problems. Mutations in the PMP-22 gene cause this rare disorder.

  • CMT4: This has several subtypes of autosomal recessive genes that cause problems with the myelin and also sensory disorders. Each subtype is related to a different genetic mutation, none of which have been identified. However, the following genes are under investigation: GDAP1, MTMR2, SBF2, SH3TC2, NDRG1, EGR2, PRX, FGD4, and FIG4.

  • CMTX: This is the only one of the CMT types connected to the X chromosome. This condition is inherited in a dominant pattern and related to a point mutation in the connein-32 gene on the X chromosome. Males who inherit this gene develop moderate to severe symptoms.

What Is the Treatment for Charcot-Marie-Tooth Disease?

Although no cure exists for the condition, occupational therapy, physical therapy, braces, and orthopedic devices may help. Pain-killing drugs can be prescribed for those in severe pain. The National Institute of Neurological Disorders and Stroke (NINDS) supports research on CMT and other peripheral neuropathies and is working to treat, prevent, and ultimately cure the disorder. Ongoing research is being conducted to identify gene mutations that cause the various subtypes.

Further Reading
  • Charcot-Marie-Tooth Disease.” 2011. Charcot-Marie-Tooth Association (CMTA). Accessed 5/10/12.
  • Charcot-Marie Tooth Disease.” 2010. Mayo Clinic. Accessed 5/10/12.
  • Charcot-Marie-Tooth Fact Sheet.” 2011. National Institute of Neurological Disorders and Stroke. Accessed 5/10/12.
  • Copyright 2013 by Evelyn B. Kelly

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