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Charcot–Marie–Tooth disease

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Charcot–Marie–Tooth disease
File:Charcot-marie-tooth foot.jpg
The foot of a person with Charcot–Marie–Tooth disease. The lack of muscle, a high arch, and claw toes are signs of this genetic disease.
Classification and external resources
ICD-10 G60.0
ICD-9 356.1
OMIM 311860 611566 311070 311850 (X Type 5)
302800 304040 (X Type 1)
DiseasesDB 5815 2343
MedlinePlus 000727
eMedicine orthoped/43 pmr/29
NCI Charcot–Marie–Tooth disease
Patient UK Charcot–Marie–Tooth disease
MeSH D002607

Charcot–Marie–Tooth disease (CMT), also known as Charcot–Marie–Tooth neuropathy, hereditary motor and sensory neuropathy (HMSN) and peroneal muscular atrophy (PMA), is a genetically and clinically heterogeneous group of inherited disorders of the peripheral nervous system characterised by progressive loss of muscle tissue and touch sensation across various parts of the body. Currently incurable, this disease is one of the most common inherited neurological disorders affecting approximately 1 in 2,500 people[1][2] equating to approximately 26,000 people in the United Kingdom and 128,000 people in the United States. CMT was previously classified as a subtype of muscular dystrophy.[1]

Signs and symptoms

Symptoms of CMT usually begin in early childhood or early adulthood, but can begin earlier. Some people do not experience symptoms until their early thirties or forties. Usually, the initial symptom is foot drop 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 a "stork leg" or "inverted champagne bottle" appearance. Weakness in the hands and forearms occurs in many people as the disease progresses.

Loss of touch sensation in the feet, ankles and legs, as well as in the hands, wrists and arms occur with various types of the disease. Early and late onset forms occur with 'on and off' painful spasmodic muscular contractions that can be disabling when the disease activates. High arched feet (pes cavus) or flat arched feet (pes planus) are classically associated with the disorder.[3] Sensory and proprioceptive nerves in the hands and feet are often damaged, while pain nerves are left intact. Overuse of an affected hand or limb can activate symptoms including numbness, spasm, and painful cramping.

Symptoms and progression of the disease can vary. Breathing can be affected in some; so can hearing, vision, as well as the neck and shoulder muscles. Scoliosis is common. Hip sockets can be malformed. Gastrointestinal problems can be part of CMT,[4][5] as can difficulty chewing, swallowing, and speaking (due to atrophy of vocal cords).[6] A tremor can develop as muscles waste. Pregnancy has been known to exacerbate CMT, as well as extreme emotional stress. Patients with CMT must avoid periods of prolonged immobility such as when recovering from a secondary injury as prolonged periods of limited mobility can drastically accelerate symptoms of CMT.[7]

Pain due to postural changes, skeletal deformations, muscular fatigue and cramping is fairly common in people with CMT. It can be mitigated or treated by physical therapies, surgeries, and corrective or assistive devices. Analgesic medications may also be needed if other therapies do not provide relief from pain.[8] Neuropathic pain is often a symptom of CMT, though, like other symptoms of CMT, its presence and severity varies from case to case. For some people, pain can be significant to severe and interfere with daily life activities. However, pain is not experienced by all people with CMT. When neuropathic pain is present as a symptom of CMT, it is comparable to that seen in other peripheral neuropathies, as well as Postherpetic neuralgia and Complex regional pain syndrome, among other diseases.[9]


Charcot–Marie–Tooth disease is caused by mutations that cause defects in neuronal proteins. Nerve signals are conducted by an axon with a myelin sheath wrapped around it. Most mutations in CMT affect the myelin sheath, but some affect the axon.

The most common cause of CMT (70-80% of the cases) is the duplication of a large region on the short arm of chromosome 17 that includes the gene PMP22. Some mutations affect the gene MFN2, which codes for a mitochondrial protein. Cells contain separate sets of genes in their nucleus and in their mitochondria. In nerve cells, the mitochondria travel down the long axons. In some forms of CMT, mutated MFN2 causes the mitochondria to form large clusters, or clots, which are unable to travel down the axon towards the synapses. This prevents the synapses from functioning.[10]

CMT is divided into the primary demyelinating neuropathies (CMT1, CMT3, and CMT4) and the primary axonal neuropathies (CMT2), with frequent overlap. Another cell involved in CMT is the Schwann cell, which creates the myelin sheath, by wrapping its plasma membrane around the axon in a structure that is sometimes compared to a Swiss roll.[11]

Neurons, Schwann cells, and fibroblasts work together to create a nonworking nerve. Schwann cells and neurons exchange molecular signals that regulate survival and differentiation. These signals are disrupted in CMT.[11]

Demyelinating Schwann cells causes abnormal axon structure and function. They may cause axon degeneration, or they may simply cause axons to malfunction.[1]

The myelin sheath allows nerve cells to conduct signals faster. When the myelin sheath is damaged, nerve signals are slower, and this can be measured by a common neurological test, electromyography. When the axon is damaged, on the other hand, this results in a reduced compound muscle action potential (CMAP).[12]


CMT can be diagnosed through symptoms, through measurement of the speed of nerve impulses (nerve conduction studies), through biopsy of the nerve, and through DNA testing. DNA testing can give a definitive diagnosis, but not all the genetic markers for CMT are known. CMT is first noticed when someone develops lower leg weakness, such as foot drop; or foot deformities, including hammertoes and high arches. But signs alone do not lead to diagnosis. Patients must be referred to a physician specialising in neurology or rehabilitation medicine. To see signs of muscle weakness the neurologist will ask patients to walk on their heels or to move part of their leg against an opposing force. In order to identify sensory loss the neurologist will test for deep tendon reflexes, such as the knee jerk, which are reduced or absent in CMT. The doctor will also ask about family history because CMT is hereditary. The lack of family history does not rule out CMT, but it will allow the doctor to rule out other causes of neuropathy such as diabetes or exposure to certain chemicals or drugs.[13]

In 2010, CMT was one of the first diseases where the genetic cause of a particular patient's disease was precisely determined by sequencing the whole genome of an affected individual. This was done by the scientists employed by the Charcot Marie Tooth Association (CMTA) [14][15] Two mutations were identified in a gene, SH3TC2, known to cause CMT. Researchers then compared the affected patient's genome to the genomes of the patient's mother, father, and seven siblings with and without the disease. The mother and father each had one normal and one mutant copy of this gene, and had mild or no symptoms. The offspring that inherited two mutant genes presented fully with the disease. Sequencing the initial patient's whole genome cost $50,000, but researchers estimated that it would soon cost $5,000 and become common.


CMT is a result of genetic mutations in a number of genes. Based on the affected gene, CMT can be categorized into types and subtypes.[15]

Clinical categories

Type Name Incidence Notes
CMT1 Demyelinating type Affects approximately 30% of CMT patients Causes severe demyelination, thereby impairing nerve conduction velocity.
CMT2 Axonal type Affects approximately 20–40% of CMT patients Mainly affects axons. Tends to affect lower extremities more than upper extremities. Clinical symptoms are often less severe than in CMT1. As it is an axonopathy, average nerve conduction velocity is usually not affected (sometimes slightly below normal but mostly above 38 m/s).
CMT3 Dejerine–Sottas disease Very rare Severely impaired nerve conduction velocity.
CMT4 Spinal type
CMT5 Pyramidal type
CMT6 Will cause Deafness and Blindness
CMTDI Dominant intermediate type
CMTRI Recessive intermediate type
CMTX X-linked type Affects approximately 10–20% of CMT patients This type encompasses all CMT forms that are inherited in an X-linked manner. Average NCV: 25–40 m/s.

Genetic subtypes

Type Subtype OMIM Gene Locus Inheritance Notes
CMT1 CMT1A[16] 118220 PMP22 17p11.2 Autosomal dominant The most common form of the disease, 70–80% of Type 1 patients. Average NCV: 20–25 m/s. Allelic with subtype CMT1E. When associated with subtype CMT1B (causing essential tremor and ataxia), it is called Roussy–Lévy syndrome.
CMT1B 118200 MPZ 1q23.3 Autosomal dominant Responsible for 5–10% of Type 1 patients. Average NCV: < 15 m/s
CMT1C 601098 LITAF 16p13.13 Autosomal dominant Usually shows up in infancy. Average NCV: 26–42 m/s. Symptoms are identical to CMT1A.
CMT1D 607678 EGR2 10q21.3 Autosomal dominant Average NCV: 15–20 m/s
CMT1E 118300 PMP22 17p11.2 Autosomal dominant Characterised by demyelination and loss of hearing; allelic with subtype CMT1A
CMT1F 607734 NEFL 8p21.2 Autosomal dominant
CMT2 CMT2A1 118210 KIF1B 1p36.22 Autosomal dominant
CMT2A2 609260 MFN2 1p36.22 Autosomal dominant
CMT2B 600882 RAB7A
3q21.3 Autosomal dominant
CMT2B1 605588 LMNA 1q22 Autosomal recessive A laminopathy
CMT2B2 605589 MED25 19q13.33 Autosomal dominant
CMT2C 606071 TRPV4 12q24.11 Autosomal dominant May cause vocal cord, diaphragm, and distal weakness
CMT2D 601472 GARS 7p14.3 Autosomal dominant Symptoms are more severe in the upper extremities (hands), which is atypical for CMT
CMT2E 607684 NEFL 8p21.2 Autosomal dominant
CMT2F 606595 HSPB1 7q11.23 Autosomal dominant
CMT2G 608591  ? 12q12–q13.3 Autosomal dominant
CMT2H 607731 GDAP1 8q21.11 Autosomal dominant Allelic with subtype CMT2K
CMT2I 607677 MPZ 1q23.3 Autosomal dominant Allelic with subtype CMT2J and forms of CMT3
CMT2J 607736 MPZ 1q23.3 Autosomal dominant Allelic with subtype CMT2I and forms of CMT3
CMT2K 607831 GDAP1 8q21.11 Autosomal dominant Allelic with subtype CMT2H
CMT2L 608673 HSPB8 12q24.23 Autosomal dominant Allelic with Autosomal dominant distal spinal muscular atrophy
CMT2M 606482 DNM2 19p13.2 Autosomal dominant Full name: CMT2M, included; more commonly classified as subtype CMTDIB
CMT2N 613287 AARS 16q22.1 Autosomal dominant
CMT2O 614228 DYNC1H1 14q32.31 Autosomal dominant Allelic with spinal muscular atrophy with lower extremity predominance
CMT2P 614436 LRSAM1 9q33.3 Autosomal dominant
Autosomal recessive
Juvenile or adult onset, slowly progressive
CMT2Q 615025 DHTKD1 10p14 Autosomal dominant
CMT2R 615490 TRIM2 4q31.3 Autosomal recessive
CMT2S 616155 IGHMBP2 11q13.3 Autosomal recessive
CMT2T 616233 DNAJB2 2q35 Autosomal recessive
CMT2U 616280 MARS 12q13.3 Autosomal dominant
CMT3 CMT3 145900 MPZ
Autosomal dominant
Autosomal recessive
More commonly known as Dejerine–Sottas disease; subtype CMT4F sometimes included here
CMT4 CMT4A 214400 GDAP1 8q21.11 Autosomal recessive Allelic with subtype CMTRIA
CMT4B1 601382 MTMR2 11q21 Autosomal recessive
CMT4B2 604563 SBF2 11p15.4 Autosomal recessive
CMT4B3 615284 SBF1 22q13.33 Autosomal recessive
CMT4C 601596 SH3TC2 5q32 Autosomal recessive May lead to respiratory compromise
CMT4D 601455 NDRG1 8q24.3 Autosomal recessive Characterised by demyelination and loss of hearing
CMT4E 605253 MPZ
Autosomal recessive Also known as congenital hypomyelinating neuropathy; phenotype largely overlapping with subtype CMT4F
CMT4F 145900 PRX 19q13.2 Autosomal recessive Phenotype largely overlapping with subtype CMT4E; may be the same as CMT3
CMT4G 605285 HK1 10q22.1 Autosomal recessive Also known as Russe-type hereditary motor and sensory neuropathy (HMSNR); second most common cause of CMT in the Spanish Roma population
CMT4H 609311 FGD4 12p11.21 Autosomal recessive
CMT4J 611228 FIG4 6q21 Autosomal recessive Allelic to amyotrophic lateral sclerosis type 11
CMT5 CMT5 600361  ? 4q34.3–q35.2 Autosomal dominant Also known as CMT with pyramidal features; onset in 2nd decade of life with distal muscle wasting, particularly in legs
CMT6 CMT6 601152 MFN2 1p36.22 Autosomal dominant Characterised by optic atrophy, hence known also as CMT with optic atrophy
CMTDI CMTDIA 606483  ? 10q24.1–q25.1 Autosomal dominant
CMTDIB 606482 DNM2 19p13.2 Autosomal dominant Also classified as subtype CMT2M
CMTDIC 608323 YARS 1p35.1 Autosomal dominant
CMTDID 607791 MPZ 1q23.3 Autosomal dominant
CMTDIE 614455 INF2 14q32.33 Autosomal dominant
CMTRI CMTRIA 608340 GDAP1 8q21.11 Autosomal recessive Allelic with subtype CMT4A
CMTRIB 613641 KARS 16q23.1 Autosomal recessive
CMTX CMTX1 302800 GJB1 Xq13.1 X-linked dominant Responsible for approximately 90% of CMTX patients; some studies put this number significantly higher.[17][18] Note that different mutations of GJB1 may produce markedly different forms of Charcot–Marie–Tooth disease.
CMTX2 302801 CMTX2 Xq22.2 X-linked recessive
CMTX3 302802 CMTX3 Xq26 X-linked recessive
CMTX4 310490 NAMSD Xq24–q26.1 X-linked recessive Also known as Cowchock syndrome
CMTX5 311070 PRPS1 Xq22.3 X-linked recessive Also known as Rosenberg–Chutorian syndrome; signs include optic atrophy, polyneuropathy and deafness
Type Subtype OMIM Gene Locus Inheritance Notes

It has to be kept in mind that sometimes a particular patient diagnosed with CMT can exhibit a combination of any of the above gene mutations; thus, in these cases precise classification can be a little arbitrary.


Although there is no current standard treatment, the use of ascorbic acid has been proposed, and has shown some benefit in animal models.[19] A clinical trial to determine the effectiveness of high doses of ascorbic acid (vitamin C) in treating humans with CMT type 1A has been conducted.[20] The results of the trial upon children have shown that a high dosage intake of ascorbic acid is safe [but] did not demonstrate effectiveness.[21]

Often the most important goal for patients with CMT is to maintain movement, muscle strength, and flexibility. Therefore, physical therapy and moderate activity are usually recommended, but overexertion should be avoided. A physiotherapist should be involved in designing an exercise program that fits a patient’s personal strengths and flexibility. Orthoses (bracing) can also be used to correct problems caused by CMT. An orthotist may address gait abnormalities by prescribing the use of ankle-foot orthoses (AFOs). These orthoses help control foot drop and ankle instability and often provide a better sense of balance for patients. Appropriate footwear is also very important for people with CMT, but they often have difficulty finding well-fitting shoes because of their high arched feet and hammer toes. Due to the lack of good sensory reception in the feet, CMT patients may also need to see a podiatrist for help in trimming nails or removing calluses that develop on the pads of the feet. A final decision a patient can make is to have surgery. Using a podiatrist or an orthopedic surgeon, patients can choose to stabilize their feet or correct progressive problems. These procedures include straightening and pinning the toes, lowering the arch, and sometimes, fusing the ankle joint to provide stability.[7] CMT patients must take extra care to avoid falling because fractures take longer to heal in someone with an underlying disease process. Additionally, the resulting inactivity may cause the CMT to worsen.[7]

The Charcot-Marie-Tooth Association classifies the chemotherapy drug vincristine as a "definite high risk" and states that "vincristine has been proven hazardous and should be avoided by all CMT patients, including those with no symptoms."[22]

There are also several corrective surgical procedures that can be done to improve physical condition.


The disease is named after those who classically described it: Jean-Martin Charcot (1825–1893), 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) 6: 97–138. 1886. ), and Howard Henry Tooth (1856–1925) ("The peroneal type of progressive muscular atrophy", dissertation, London, 1886.)


There is a documentary titled "Bernadette" that follows a young woman battling the disease. It was made in 2012 and is currently sold online and shown for free to American viewers on[23]

See also


  1. 1.0 1.1 1.2 Krajewski, K. M. (2000). "Neurological dysfunction and axonal degeneration in Charcot-Marie-Tooth disease type 1A". Brain 123 (7): 1516–27. PMID 10869062. doi:10.1093/brain/123.7.1516. 
  2. Physical Medicine and Rehabilitation for Charcot-Marie-Tooth Disease. Medscape. Retrieved March 20th, 2012.
  3. Le, Tao; Bhushan, Vikas (6 January 2014). First Aid for the USMLE Step 1 2014. McGraw-Hill Education. ISBN 9780071831420. Retrieved 4 September 2014. Typically autosomal dominant inheritance pattern associated with scoliosis and foot deformities (high or flat arches). 
  4.[full citation needed]
  5. Soykan I, McCallum RW (January 1997). "Gastrointestinal involvement in neurologic disorders: Stiff-man and Charcot-Marie-Tooth syndromes". The American Journal of the Medical Sciences 313 (1): 70–3. PMID 9001170. doi:10.1097/00000441-199701000-00012. 
  6.[full citation needed]
  7. 7.0 7.1 7.2 "Treatment and Management of CMT" (Press release). Charcot-Marie-Tooth Association. October 6, 2010. Retrieved August 26, 2011. 
  9. Carter, Gregory T.; Jensen, Mark P.; Galer, Bradley S.; Kraft, George H.; Crabtree, Linda D.; Beardsley, Ruth M.; Abresch, Richard T.; Bird, Thomas D. (1998). "Neuropathic pain in Charcot-Marie-tooth disease". Archives of Physical Medicine and Rehabilitation 79 (12): 1560–4. PMID 9862301. doi:10.1016/S0003-9993(98)90421-X. 
  10. 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): 422–30. PMID 17215403. doi:10.1523/JNEUROSCI.4798-06.2007. 
  11. 11.0 11.1 Berger, Philipp; Young, Peter; Suter, Ueli (2002). "Molecular cell biology of Charcot-Marie-Tooth disease". Neurogenetics 4 (1): 1–15. PMID 12030326. doi:10.1007/s10048-002-0130-z. 
  12. Yiu, Eppie M.; Burns, Joshua; Ryan, Monique M.; Ouvrier, Robert A. (2008). "Neurophysiologic abnormalities in children with Charcot-Marie-Tooth disease type 1A". Journal of the Peripheral Nervous System 13 (3): 236–241. PMID 18844790. doi:10.1111/j.1529-8027.2008.00182.x. 
  13.[full citation needed]
  14. Wade, Nicholas (2010-03-10). "Disease Cause Is Pinpointed With Genome". New York Times. 
  15. 15.0 15.1 Lupski, James R.; Reid, Jeffrey G.; Gonzaga-Jauregui, Claudia; Rio Deiros, David; Chen, David C.Y.; Nazareth, Lynne; Bainbridge, Matthew; Dinh, Huyen et al. (2010). "Whole-Genome Sequencing in a Patient with Charcot–Marie–Tooth Neuropathy". New England Journal of Medicine 362 (13): 1181–91. PMID 20220177. doi:10.1056/NEJMoa0908094. 
  16. Inoue, K; Dewar, K; Katsanis, N; Reiter, LT; Lander, ES; Devon, KL; Wyman, DW; Lupski, JR; Birren, B (June 2001). "The 1.4-Mb CMT1A duplication/HNPP deletion genomic region reveals unique genome architectural features and provides insights into the recent evolution of new genes.". Genome research 11 (6): 1018–33. PMC 311111. PMID 11381029. doi:10.1101/gr.180401. 
  17. Latour, Philippe; Fabreguette, Anne; Ressot, Catherine; Blanquet-Grossard, FranÇOise; Antoine, Jean-Christophe; Calvas, Patrick; Chapon, FranÇOise; Corbillon, Emmanuel et al. (1997). "New Mutations in the X-Linked Form of Charcot-Marie-Tooth Disease". European Neurology 37 (1): 38–42. PMID 9018031. doi:10.1159/000117403. 
  18. Abrams, Charles K.; Rash, John E. (2009). "Connexins in the Nervous System". In Harris, Andrew; Locke, Darren. Connexins. New York: Springer. pp. 323–57. ISBN 978-1-934115-46-6. doi:10.1007/978-1-59745-489-6_15. 
  19. Passage, Edith; Norreel, Jean Chrétien; Noack-Fraissignes, Pauline; Sanguedolce, Véronique; Pizant, Josette; Thirion, Xavier; Robaglia-Schlupp, Andrée; Pellissier, Jean François; Fontés, Michel (2004). "Ascorbic acid treatment corrects the phenotype of a mouse model of Charcot-Marie-Tooth disease". Nature Medicine 10 (4): 396–401. PMID 15034573. doi:10.1038/nm1023. 
  20. "Neuromuscular Trial/Study". Clinical Trials. Muscular Dystrophy Association. 2007-07-18. Retrieved 2008-05-28. 
  21. Burns, Joshua; Ouvrier, Robert A; Yiu, Eppie M; Joseph, Pathma D; Kornberg, Andrew J; Fahey, Michael C; Ryan, Monique M (2009). "Ascorbic acid for Charcot–Marie–Tooth disease type 1A in children: A randomised, double-blind, placebo-controlled, safety and efficacy trial". Lancet Neurology 8 (6): 537–44. PMID 19427269. doi:10.1016/S1474-4422(09)70108-5. 
  22. CMT Association: Medical Alert
  23. Bernadette at the Internet Movie Database

External links