Charcot–Marie–Tooth disease

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Charcot–Marie–Tooth disease
Classification and external resources

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.
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Charcot–Marie–Tooth disease
Classification and external resources

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.
DiseasesDB5815 2343
eMedicineorthoped/43 pmr/29

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 23,000 people in the United Kingdom and 125,000 people in the USA.

CMT was previously classified as a subtype of muscular dystrophy.[1]


Signs and symptoms

Symptoms of CMT usually begin in late childhood or early adulthood. 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 claw 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 bottle" appearance. Weakness in the hands and forearms occurs in many people later in life as the disease progresses.

Loss of touch sensation in the feet, ankles and legs, as well as in the hands, wrists and arms is characteristic in 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) are classically associated with the disorder. 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, as can chewing, swallowing, and speaking (as vocal cords atrophy). 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.[3]

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 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.[4]


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 in chromosome 17p12 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.[5]

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.[6]

Neurons, Schwann cells, and fibroblasts work together to create a working nerve. Schwann cells and neurons exchange molecular signals that regulate survival and differentiation. These signals are disrupted in CMT.[6]

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).[7]


CMT can be diagnosed through symptoms, through measurement of the speed of nerve impulses (electromyography), 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 and foot deformities such as foot drop, 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.[8]

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) [9][10] 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.[10]

Clinical categories

CMT1Demyelinating typeAffects approximately 30% of CMT patientsCauses severe demyelination, thereby impairing nerve conduction velocity.
CMT2Axonal typeAffects approximately 20–40% of CMT patientsMainly 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).
CMT3Dejerine-Sottas diseaseVery rareDoes not impair nerve conduction velocity.
CMT4Spinal type
CMT5Pyramidal type
CMTDIDominant intermediate type
CMTRIRecessive intermediate type
CMTXX-linked typeAffects approximately 10–20% of CMT patientsThis type encompasses all CMT forms that are inherited in an X-linked manner. Average NCV: 25–40 m/s.

Genetic subtypes

CMT1CMT1A118220PMP2217p11.2Autosomal dominantThe 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.
CMT1B118200MPZ1q23.3Autosomal dominantResponsible for 5–10% of Type 1 patients. Average NCV: < 15 m/s
CMT1C601098LITAF16p13.13Autosomal dominantUsually shows up in infancy. Average NCV: 26–42 m/s. Symptoms are identical to CMT1A.
CMT1D607678EGR210q21.3Autosomal dominantAverage NCV: 15–20 m/s
CMT1E118300PMP2217p11.2Autosomal dominantCharacterised by demyelination and loss of hearing; allelic with subtype CMT1A
CMT1F607734NEFL8p21.2Autosomal dominant
CMT2CMT2A1118210KIF1B1p36.22Autosomal dominant
CMT2A2609260MFN21p36.22Autosomal dominant
3q21.3Autosomal dominant
CMT2B1605588LMNA1q22Autosomal recessiveA laminopathy
CMT2B2605589MED2519q13.33Autosomal dominant
CMT2C606071TRPV412q24.11Autosomal dominantMay cause vocal cord, diaphragm, and distal weakness
CMT2D601472GARS7p14.3Autosomal dominantSymptoms are more severe in the upper extremities (hands), which is atypical for CMT
CMT2E607684NEFL8p21.2Autosomal dominant
CMT2F606595HSPB17q11.23Autosomal dominant
CMT2G608591 ?12q12–q13.3Autosomal dominant
CMT2H607731GDAP18q21.11Autosomal dominantAllelic with subtype CMT2K
CMT2I607677MPZ1q23.3Autosomal dominantAllelic with subtype CMT2J and forms of CMT3
CMT2J607736MPZ1q23.3Autosomal dominantAllelic with subtype CMT2I and forms of CMT3
CMT2K607831GDAP18q21.11Autosomal dominantAllelic with subtype CMT2H
CMT2L608673HSPB812q24.23Autosomal dominant
CMT2M606482DNM219p13.2Autosomal dominantFull name: CMT2M, included; more commonly classified as subtype CMTDIB
Autosomal dominant
Autosomal recessive
More comonly known as Dejerine–Sottas disease; subtype CMT4F sometimes included here
CMT4CMT4A214400GDAP18q21.11Autosomal recessiveAllelic with subtype CMTRIA
CMT4B1601382MTMR211q21Autosomal recessive
CMT4B2604563SBF211p15.4Autosomal recessive
CMT4C601596SH3TC25q32Autosomal recessiveMay lead to respiratory compromise
CMT4D601455NDRG18q24.3Autosomal recessiveCharacterised by demyelination and loss of hearing
Autosomal recessiveAlso known as congenital hypomyelinating neuropathy; phenotype largely overlapping with subtype CMT4F
CMT4F145900PRX19q13.2Autosomal recessivePhenotype largely overlapping with subtype CMT4E; may be the same as CMT3
CMT4G605285NMSR10q23.2Autosomal recessiveAlso known as Russe-type hereditary motor and sensory neuropathy (HMSNR)
CMT4H609311FGD412p11.21Autosomal recessive
CMT4J611228FIG46q21Autosomal recessiveAllelic to amyotrophic lateral sclerosis type 11
CMT5CMT5600361 ?4q34.3–q35.2Autosomal dominantAlso known as CMT with pyramidal features; onset in 2nd decade of life with distal muscle wasting, particularly in legs
CMT6CMT6601152MFN21p36.22Autosomal dominantCharacterised by optic atrophy, hence known also as CMT with optic atrophy
CMTDICMTDIA606483 ?10q24.1–q25.1Autosomal dominant
CMTDIB606482DNM219p13.2Autosomal dominantAlso classified as subtype CMT2M
CMTDIC608323YARS1p35.1Autosomal dominant
CMTDID607791MPZ1q23.3Autosomal dominant
CMTDIE614455INF214q32.33Autosomal dominant
CMTRICMTRIA608340GDAP18q21.11Autosomal recessiveAllelic with subtype CMT4A
CMTRIB613641KARS16q23.1Autosomal recessive
CMTXCMTX1302800GJB1Xq13.1X-linked dominantResponsible for approximately 90% of CMTX patients; some studies put this number significantly higher.[11][12]
CMTX2302801CMTX2Xq22.2X-linked recessive
CMTX3302802CMTX3Xq26X-linked recessive
CMTX4310490NAMSDXq24–q26.1X-linked recessiveAlso known as Cowchock syndrome
CMTX5311070PRPS1Xq22.3X-linked recessiveAlso known as Rosenberg–Chutorian syndrome; signs include optic atrophy, polyneuropathy and deafness

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.[13] 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.[14] The results of the trial upon children have shown that a high dosage intake of ascorbic acid is safe but the efficacy endpoints expected were not met.[15] In 2010, a study published in the Journal Science indicated that scientists had identified those proteins that control the thickness of myelin sheath. This discovery is expected to open the avenue to new treatments in the coming years.[16]

The most important activity for patients with CMT is to maintain what movement, muscle strength, and flexibility they have. Therefore, physical therapy and moderate activity are 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. Bracing can also be used to correct problems caused by CMT. Gait abnormalities can be corrected by the use of either articulated (hinged) or unarticulated, braces called AFOs (ankle-foot orthoses). These braces 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.[17] 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.[18]

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."[19]

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, 1886; 6: 97-138.), and Howard Henry Tooth (1856–1925) ("The peroneal type of progressive muscular atrophy", dissertation, London, 1886.)

See also


  1. ^ a b c Krajewski, K. M. (2000). "Neurological dysfunction and axonal degeneration in Charcot-Marie-Tooth disease type 1A". Brain 123 (7): 1516–27. doi:10.1093/brain/123.7.1516. 
  2. ^ Physical Medicine and Rehabilitation for Charcot-Marie-Tooth Disease. Medscape. Retrieved March 20th, 2012.
  3. ^ "Treatment and Management of CMT" (Press release). Charcot-Marie-Tooth Association. October 6, 2010. Retrieved August 26, 2011. 
  4. ^ 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. doi:10.1016/S0003-9993(98)90421-X. PMID 9862301. 
  5. ^ 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. doi:10.1523/JNEUROSCI.4798-06.2007. PMID 17215403. 
  6. ^ a b Berger, Philipp; Young, Peter; Suter, Ueli (2002). "Molecular cell biology of Charcot-Marie-Tooth disease". Neurogenetics 4 (1): 1–15. doi:10.1007/s10048-002-0130-z. PMID 12030326. 
  7. ^ 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. doi:10.1111/j.1529-8027.2008.00182.x. PMID 18844790. 
  8. ^
  9. ^ Wade, Nicholas (2010-03-10). "Disease Cause Is Pinpointed With Genome". New York Times. 
  10. ^ a b 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. doi:10.1056/NEJMoa0908094. PMID 20220177. 
  11. ^ 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. doi:10.1159/000117403. PMID 9018031. 
  12. ^ Abrams, Charles K.; Rash, John E. (2009). "Connexins in the Nervous System". In Harris, Andrew; Locke, Darren. Connexins. New York: Springer. pp. 323–57. doi:10.1007/978-1-59745-489-6_15. ISBN 978-1-934115-46-6. 
  13. ^ Passage, Edith; Norreel, Jean Chrétien; Noack-Fraissignes, Pauline; Sanguedolce, Véronique; Pizant, Josette; Thirion, Xavier; Robaglia-Schlupp, Andrée; Pellissier, Jean François et al. (2004). "Ascorbic acid treatment corrects the phenotype of a mouse model of Charcot-Marie-Tooth disease". Nature Medicine 10 (4): 396–401. doi:10.1038/nm1023. PMID 15034573. 
  14. ^ "Clinical Trials - Neuromuscular Trial/Study". 2007-07-18. Retrieved 2008-05-28. 
  15. ^ 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". The Lancet Neurology 8 (6): 537–44. doi:10.1016/S1474-4422(09)70108-5. 
  16. ^ "Nerves Under Control: Potential Treatment for Charcot-Marie-Tooth Disease". Science Daily. May 18, 2010. 
  17. ^ "Treatment and Management of CMT". 
  18. ^ "Treatment and Management of CMT". 
  19. ^ CMT Association: Medical Alert

External links