Charcot Marie Tooth Disease

Information and facts about Eponymous diseases.

Charcot-Marie-Tooth disease, also known as Hereditary Motor and Sensory Neuropathy (HSNM) or Peroneal Muscular Atrophy, is an inherited disorder of nerves (neuropathy) that is characterized by loss of muscle tissue and touch sensation, predominantly in the feet and legs but also in the hands and arms in the advanced stages of disease. The disease is presently incurable.

The disorder is caused by the absence of molecules that are essential for normal function of the nerves due to deficiencies in the structure of the genes coding these molecules. The absence of these chemical substances gives rise to dysfunction either in the axon or the myelin sheath of the nerve cell.

Symptoms usually begin in late-childhood or early adulthood. Usually, the initial symptom is foot drop due to involvement of the peroneal nerve, which is responsible for raising the feet, early in the course of the disease. This can also cause hammer toe, where the toes are always curled. Wasting of muscle tissue of the lower parts of the legs may give rise to "stork leg" appearance. Symptoms and progression of the disease can vary. Extreme emotional stress is thought to hasten the progression.

The diagnosis is established by electromyography examination (which shows that the velocity of nerve impulse conduction is decreased and the time required to charge the nerve is increased) and nerve biopsy. Genetic markers have been identified for some, but not all forms of the disease.

The disease is named for those who classically described it: Jean-Martin Charcot (1825-1893) and his pupil Pierre Marie (1853-1940) ("Sur une forme particulière d'atrophie musculaire progressive, souvent familiale débutant par les pieds et les jambes et atteignant plus tard les mains", Revue médicale, Paris, 1886; 6: 97-138.), and Howard Henry Tooth (1856-1925) ("The peroneal type of progressive muscular atrophy", dissertation, London, 1886.)

Types of the disease

CMT Type 1 (CMT1)

Type 1 affects approximately 50% of CMT patients and is the most common type of CMT. The subtypes share clinical symptoms. Autosomal dominant. Causes demyelination, which can be detected by measuring nerve conduction velocities.

CMT type 1A - CMT1A (OMIM 118220

http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=118220)) - The most common form of the disease, caused by mutations in the PMP22 gene (locus 17p11.2). 70-80% of Type 1 patients. Average NCV: 15-20m/s
CMT type 1B - CMT1B (OMIM 118200 (http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=118200)) - Caused by slight mutations in the MPZ gene (1q22) producing protein zero (P0). 5-10% of Type 1 patients. Average NCV: <20m/s
CMT type 1C - CMT1C - Sometimes called Dejerine-Sottas disease - Causes severe demyelination, which can be detected by measuring nerve conduction velocities. Autosomal dominant. Usually shows up in infancy. LITAF Gene (16p13.1-p12.3) Average NCV: 26-42m/s. Identical symptoms to CMT-1A.
CMT type 1D - CMD1D - EGR2 Gene (10q21.1-q22.1) - Average NCV: 15-20m/s
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CMT Type 2 (CMT2)
Type 2 affects approximately 20-40% of CMT patients. Type 2 CMT is Autosomal dominant neuropathy with its main affect on the axon. The average nerve conduction velocity is slightly below normal, but generally above 38m/s

CMT type 2A - CMT2A (OMIM 118210 (http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=118210)) - The cause is likely located on chromosome 1 for the mitofusion 2 (MFN2) protein (locus 1p36). Some research has also linked this form of CMT to the protein kinesin 1B (KIF1B) (1p36.2). Does not show up on nerve condution velocity tests, because it is caused by axonopathy.
CMT type 2B - CMT2B (OMIM 600882 (http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600882)) - RAB7 gene (3q21).
CMT type 2C - CMT2C - (12q23-q24) - May cause vocal cord, diaphragm, and distal weaknesses.
CMT type 2D - CMT2D (OMIM 601472 (http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601472)) - 6ARS gene (7p15).
CMT type 2E - CMT2E - NEFL gene (8p21).
CMT type 2F - CMT2F (OMIM 606595 (http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606595)) - HSPB1 gene (7q11-q21).
CMT type 2G - CMT2G - (12q12-13)
CMT type 2H - CMT2H (OMIM 607731 (http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=607731))
CMT type 2J - CMT2J (OMIM 607736 (http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=607736)) - (1q22)
CMT type 2K - CMT2K (OMIM 607831 (http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=607831)) - (8q13-q21.1)
CMT type 2L - CMT2L (OMIM 608673 (http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=608673)) - (12q24)

CMT Type 3 (CMT3)
Type 3 affects a very few CMT patients.

CMT type 3 - CMT3 - Rarely found. Autosomal recessive. Average NCV: Normal (50-60m/s)

CMT Type 4 (CMT4)
Type 4 affects a very few CMT patients.

CMT type 4A - CMT4A (OMIM 214400 (http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=214400)) - GDAP1 Gene (locus 8q13-q21.1) - Autosomal recessive.
CMT type 4B1 - CMT4B1 (OMIM 601382 (http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601382)) - MTMR2 Gene (11q22) - Autosomal recessive.
CMT type 4B2 - CMT4B2 - CMT4B2 Gene, may be called "SBF2/MTMR13" (11p15) - Autosomal recessive.
CMT type 4C - CMT4C - KIAA1985 Gene (5q32) - May lead to respiratory compromise.
CMT type 4D - CMT4D - NDRG1 Gene (8q24.3)
CMT type 4E - CMT4E - EGR2 (10q21.1-10q22.1) - "CMT4E" is a tentative name
CMT type 4F - CMT4F - PRX (19q13.1-19q13.2) - "CMT4F" is a tentative name

CMT X-Linked (CMTX)
CMTX affects approximately 10-20% of CMT patients and is X-linked dominant.

CMTX (OMIM 302800 (http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=302800)) - GJB1 Gene (locus Xq13.1) - Average NCV: 25-40m/s
Other X-linked forms - Approx 10% of X-linked CMT patients have some other form than CMTX.

Genetic testing

Genetic testing is available for many of the different types of Charcot-Marie-Tooth.

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