Charcot–Marie–Tooth disease

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For other diseases, see Charcot disease.
It has been suggested that this article or section be merged with Hereditary motor and sensory neuropathy. (Discuss) Proposed since

June 2012.

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 (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 systemcharacterised 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 theUnited Kingdom and 125,000 people in the USA. CMT was previously classified as a subtype of muscular dystrophy.[1]

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. Some people do not experience symptoms until their early thirties or forties. However. spasm. Hip sockets can be malformed. pain is not experienced by all people with CMT. where the toes are always curled. it is comparable to that seen in other peripheral neuropathies. its presence and severity varies from case to case. as well as in the hands. like other symptoms of CMT. Wasting of muscle tissue of the lower parts of the legs may give rise to a "stork leg" or "inverted bottle" appearance. and speaking (as vocal cords atrophy). as well as Postherpetic neuralgia and Complex regional pain syndrome. as can chewing. Overuse of an affected hand or limb can activate symptoms including numbness. so can hearing. swallowing. Symptoms and progression of the disease can vary. Weakness in the hands and forearms occurs in many people later in life as the disease progresses. Early and late onset forms occur with 'on and off' painful spasmodic muscular contractions that can be disabling when the disease activates. When pain is present as a symptom of CMT. This can also cause claw toe.[4] . Loss of touch sensation in the feet. the initial symptom is foot drop early in the course of the disease. ankles and legs. while pain nerves are left intact. though. High arched feet (pes cavus) are classically associated with the disorder. Breathing can be affected in some. and painful cramping. among other diseases.Contents [hide]          1 Signs and symptoms 2 Causes 3 Diagnosis 4 Classification 5 Management 6 History 7 See also 8 References 9 External links [edit]Signs and symptoms Symptoms of CMT usually begin in late childhood or early adulthood. Sensory and proprioceptive nerves in the hands and feet are often damaged. A tremor can develop as muscles waste. vision. Pregnancy has been known to exacerbate CMT. Scoliosis is common. Gastrointestinal problems can be part of CMT. Usually. as well as the neck and shoulder muscles. For some people. pain can be significant to severe and interfere with daily life activities. as well as extreme emotional stress.[3] Neuropathic pain is often a symptom of CMT. wrists and arms is characteristic in various types of the disease.

and this can be measured by a common neurological test. and through DNA testing. hammertoes and high arches. Nerve signals are conducted by an axon with a myelin sheath wrapped around it. In nerve cells. this results in a reduced compound muscle action potential (CMAP). CMT3. through biopsy of the nerve. Some mutations affect the gene MFN2. DNA testing can give a definitive diagnosis.[1] The myelin sheath allows nerve cells to conduct signals faster. Patients must be referred to a physician specialising in neurology or rehabilitation medicine. such as the knee jerk. which creates the myelin sheath. with frequent overlap. but some affect the axon. or they may simply cause axons to malfunction. This prevents the synapses from functioning. The doctor will also ask about family history because CMT is hereditary. which are unable to travel down the axon towards the synapses. Schwann cells. nerve signals are slower.electromyography. or clots. but it will allow the doctor to rule out other causes of neuropathy such as diabetes or exposure to certain chemicals or drugs.[6] Neurons. When the myelin sheath is damaged. and fibroblasts work together to create a working nerve. These signals are disrupted in CMT. and CMT4) and the primary axonal neuropathies (CMT2).[8] .[5] CMT is divided into the primary demyelinating neuropathies (CMT1. which are reduced or absent in CMT. which codes for a mitochondrial protein. In order to identify sensory loss the neurologist will test for deep tendon reflexes. Schwann cells and neurons exchange molecular signals that regulate survival and differentiation.[7] [edit]Diagnosis CMT can be diagnosed through symptoms. They may cause axon degeneration. through measurement of the speed of nerve impulses (electromyography). But signs alone do not lead to diagnosis. Most mutations in CMT affect the myelin sheath. mutated MFN2 causes the mitochondria to form large clusters. Another cell involved in CMT is theSchwann cell. the mitochondria travel down the long axons. on the other hand.CMT is first noticed when someone develops lower leg weakness and foot deformities such as foot drop. In some forms of CMT. by wrapping its plasma membrane around the axon in a structure that is sometimes compared to a Swiss roll.[6] Demyelinating Schwann cells causes abnormal axon structure and function. but not all the genetic markers for CMT are known. 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. When the axon is damaged. Cells contain separate sets of genes in their nucleus and in their mitochondria.[edit]Causes Charcot–Marie–Tooth disease is caused by mutations that cause defects in neuronal proteins. The lack of family history does not rule out CMT. 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.

Clinical symptoms are often less severe than in CMT1. The mother and father each had one normal and one mutant copy of this gene. 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.000. As it is an axonopathy. Sequencing the initial patient's whole genome cost $50. Based on the affected gene. known to cause CMT. Researchers then compared the affected patient's genome to the genomes of the patient's mother. This was done by the scientists employed by the Charcot Marie Tooth Association (CMTA) [9][10] Two mutations were identified in a gene. but researchers estimated that it would soon cost $5.In 2010. [edit]Classification CMT is a result of genetic mutations in a number of genes. CMT4 Spinal type CMT5 Pyramidal type CMT6 CMTDI Dominant intermediate type CMTRI Recessive intermediate type . thereby impairing nerve conduction velocity. CMT3 Dejerine-Sottas disease Very rare Does not impair nerve conduction velocity. father. and seven siblings with and without the disease. and had mild or no symptoms. SH3TC2.[10] Clinical categories Type Name Incidence Notes CMT1 Demyelinating type Affects approximately 30% of CMT patients Causes severe demyelination.000 and become common. average nerve conduction velocity is usually not affected (sometimes slightly below normal but mostly above 38 m/s). CMT can be categorized into types and subtypes. Tends to affect lower extremities more than upper extremities. The offspring that inherited two mutant genes presented fully with the disease. CMT2 Axonal type Affects approximately 20–40% of CMT patients Mainly affects axons.

33 Autosomal dominant CMT2C 606071 TRPV4 12q24. Average NCV: 26– 42 m/s. Average NCV: < 15 m/s CMT1 CMT1C 601098 LITAF 16p13. CMT1D 607678 EGR2 10q21.2 Autosomal dominant CMT2A1 118210 KIF1B 1p36.3 Autosomal dominant Symptoms are more severe in the upper extremities (hands).22 Autosomal dominant CMT2A2 609260 MFN2 1p36. CMT1B 118200 MPZ 1q23.3 Autosomal dominant Responsible for 5–10% of Type 1 patients. Allelic with subtype CMT1E. 70–80% of Type 1 patients.3 Autosomal dominant CMT2 CMT2B1 605588 LMNA 1q22 Autosomal recessive A laminopathy CMT2B2 605589 MED25 19q13.22 Autosomal dominant CMT2B 600882 RAB7A RAB7B 3q21.11 Autosomal dominant May cause vocal cord.2 Autosomal dominant Characterised by demyelination and loss of hearing. it is called Roussy–Lévy syndrome. Genetic subtypes Type Subtype OMIM Gene Locus Inheritance Notes CMT1A 118220 PMP22 17p11. diaphragm. which is atypical for CMT .13 Autosomal dominant Usually shows up in infancy. When associated with subtype CMT1B (causing essential tremor and ataxia). allelic with subtype CMT1A CMT1F 607734 NEFL 8p21.2 Autosomal dominant The most common form of the disease. Average NCV: 25–40 m/s. and distal weakness CMT2D 601472 GARS 7p14.3 Autosomal dominant Average NCV: 15–20 m/s CMT1E 118300 PMP22 17p11. Symptoms are identical to CMT1A. Average NCV: 20–25 m/s.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.

phenotype largely overlapping with subtype CMT4F CMT4F 145900 PRX 19q13. included.2 Autosomal dominant Full name: CMT2M.3 Autosomal dominant CMT2H 607731 GDAP1 8q21.3 17p12 19q13.23 Autosomal dominant CMT2G 608591 ? 12q12–q13.3 Autosomal recessive Characterised by demyelination and loss of hearing CMT4E 605253 MPZ EGR2 1q23.3 Autosomal dominant Allelic with subtype CMT2J and forms of CMT3 CMT2J 607736 MPZ 1q23. more commonly classified as subtype CMTDIB CMT3 CMT3 145900 MPZ EGR2 PMP22 PRX 1q23.3 10q21.23 Autosomal dominant CMT2M 606482 DNM2 19p13.11 Autosomal dominant Allelic with subtype CMT2K CMT2I 607677 MPZ 1q23.2 Autosomal dominant CMT2F 606595 HSPB1 7q11.4 Autosomal recessive CMT4C CMT4 601596 SH3TC2 5q32 Autosomal recessive May lead to respiratory compromise CMT4D 601455 NDRG1 8q24. may be the same as CMT3 .2 Autosomal recessive Phenotype largely overlapping with subtype CMT4E.3 Autosomal dominant Allelic with subtype CMT2I and forms of CMT3 CMT2K 607831 GDAP1 8q21. subtype CMT4F sometimes included here CMT4A 214400 GDAP1 8q21.CMT2E 607684 NEFL 8p21.11 Autosomal dominant Allelic with subtype CMT2H CMT2L 608673 HSPB8 12q24.2 Autosomal dominant Autosomal recessive More comonly known as Dejerine–Sottas disease.11 Autosomal recessive Allelic with subtype CMTRIA CMT4B1 601382 MTMR2 11q21 Autosomal recessive CMT4B2 604563 SBF2 11p15.3 Autosomal recessive Also known as congenital hypomyelinating neuropathy.3 10q21.

[11][12] CMTX2 302801 CMTX2 Xq22. onset in 2nd decade of life with distal muscle wasting.1 Autosomal recessive CMTX1 302800 GJB1 Xq13.3–q35. polyneuropathy and deafness .3 X-linked recessive Also known as Rosenberg–Chutorian syndrome. some studies put this number significantly higher. hence known also as CMT with optic atrophy CMTDIA 606483 ? 10q24.2 Autosomal recessive Also known as Russe-type hereditary motor and sensory neuropathy (HMSNR) CMT4H 609311 FGD4 12p11.1–q25.21 Autosomal recessive CMT4J 611228 FIG4 6q21 Autosomal recessive Allelic to amyotrophic lateral sclerosis type 11 CMT5 CMT5 600361 ? 4q34. signs include optic atrophy.2 X-linked recessive CMTX CMTX3 302802 CMTX3 Xq26 X-linked recessive CMTX4 310490 NAMSD Xq24–q26. particularly in legs CMT6 CMT6 601152 MFN2 1p36.33 Autosomal dominant CMTRIA 608340 GDAP1 CMTRI CMTRIB 613641 KARS 8q21.1 Autosomal dominant CMTDIB 606482 DNM2 19p13.1 X-linked recessive Also known as Cowchock syndrome CMTX5 311070 PRPS1 Xq22.22 Autosomal dominant Characterised by optic atrophy.2 Autosomal dominant Also classified as subtype CMT2M CMTDI CMTDIC 608323 YARS 1p35.1 Autosomal dominant CMTDID 607791 MPZ 1q23.CMT4G 605285 NMSR 10q23.2 Autosomal dominant Also known as CMT with pyramidal features.1 X-linked dominant Responsible for approximately 90% of CMTX patients.11 Autosomal recessive Allelic with subtype CMT4A 16q23.3 Autosomal dominant CMTDIE 614455 INF2 14q32.

and sometimes. . [edit]Management Although there is no current standard treatment.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. Revue médicale. Using a podiatrist or an orthopedic surgeon. Bracing can also be used to correct problems caused by CMT. muscle strength. including those with no symptoms. Due to the lack of good sensory reception in the feet. the use of ascorbic acid has been proposed.[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. physical therapy and moderate activity are recommended but overexertion should be avoided."[19] There are also several corrective surgical procedures that can be done to improve physical condition. lowering the arch.[17] CMT patients must take extra care to avoid falling because fractures take longer to heal in someone with an underlying disease process. and flexibility they have. Therefore. and has shown some benefit in animal models.[15] In 2010. Paris. the resulting inactivity may cause the CMT to worsen. a study published in the Journal Science indicated that scientists had identified those proteins that control the thickness of myelin sheath. in these cases precise classification can be a little arbitrary. A physiotherapist should be involved in designing an exercise program that fits a patient’s personal strengths and flexibility. braces called AFOs (ankle-foot orthoses). souvent familiale débutant par les pieds et les jambes et atteignant plus tard les mains".[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. 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. [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. Gait abnormalities can be corrected by the use of either articulated (hinged) or unarticulated. [edit]History The disease is named after those who classically described it: Jean-Martin Charcot (1825–1893). Appropriate footwear is also very important for people with CMT. thus. This discovery is expected to open the avenue to new treatments in the coming years. These procedures include straightening and pinning the toes.[16] The most important activity for patients with CMT is to maintain what movement. patients can choose to stabilize their feet or correct progressive problems. his pupil Pierre Marie (1853–1940) ("Sur une forme particulière d'atrophie musculaire progressive. Additionally. but they often have difficulty finding well-fitting shoes because of their high arched feet and hammer toes. These braces help control foot drop and ankle instability and often provide a better sense of balance for patients. A final decision a patient can make is to have surgery. fusing the ankle joint to provide stability.

2010. Beardsley.1529-8027. Schmidt. (2000). ^ Yiu. New England Journal of Medicine362 (13): 1181– 91.2008. dissertation. Bird. Corbillon.1093/brain/123. Véronique. George H. Mark P. Young.charcot-marie-tooth. 7. doi:10. ^ "Treatment and Management of CMT" (Press release). Retrieved 2008-05-28. Charcot-Marie-Tooth Association. Rash. Xavier.Neuromuscular Trial/Study".2007. doi:10. In Harris. .1111/j. Bradley S. Charles K. Pauline. ^ Carter. Gregory T.. 5. Philippe. 2007-07-18. Brain 123 (7): 1516– 27. "Connexins in the Nervous System". 14. 13.1056/NEJMoa0908094. Pestronk. Patrick. "Ascorbic acid treatment corrects the phenotype of a mouse model of Charcot-Marie-Tooth disease". H. 9. 4. pp. Burns.PMID 20220177. "Disease Cause Is Pinpointed With Genome".doi:10. Noack-Fraissignes.. Nature Medicine 10 (4): 396–401.1516. Ryan.Y. Catherine. 6. doi:10. doi:10. R.. Pellissier.. Jean François et al. 12.7. 3. Fabreguette. European Neurology 37 (1): 38– 42. London. Norreel.1016/S00039993(98)90421-X. doi:10. Chen. PMID 9018031.. Thomas D. Linda D. 8.1886.. Retrieved August 26. 323–57. 2012. Joshua. ^ http://www. Dinh. 11. James R.. ^ Baloh. Retrieved March 20th. "Neurophysiologic abnormalities in children with Charcot-Marie-Tooth disease type 1A".1007/s10048-002-0130-z. 1886. R. Claudia. ISBN 978-1-934115-46-6. Andrew. PMID 15034573.. Jean Chrétien. (1997) Nazareth.. Ouvrier. FranÇOise. Ueli (2002). Jean-Christophe. PMID 12030326.doi:10.Connexins. K.. "Altered Axonal Mitochondrial Transport in the Pathogenesis of Charcot-Marie-Tooth Disease from Mitofusin 2 Mutations". Antoine. ^ a b c Krajewski.4798-06. Milbrandt. Eppie M. ^ "Clinical Trials . Richard T. Josette. Robaglia-Schlupp. David.. Blanquet-Grossard. (2004).1038/nm1023. Darren. David C. Ressot. Calvas. Archives of Physical Medicine and Rehabilitation 79 (12): 1560–4.. "Neuropathic pain in Charcot-Marie-tooth disease". John E. Ruth M. ^ Physical Medicine and Rehabilitation for Charcot-Marie-Tooth Disease. Nicholas (2010-03-10). E. 6: 97-138. (2007). "Molecular cell biology of Charcot-Marie-Tooth disease". doi:10. Reid. Journal of Neuroscience 27 (2): 422–30. Crabtree. Locke.1007/978-1-59745-489-6_15. M. October 6. PMID 9862301. (2009). Philipp. "Whole-Genome Sequencing in a Patient with Charcot–Marie–Tooth Neuropathy".1159/000117403. Jeffrey G. Andrée. Thirion. Robert A. Monique M. and Howard Henry Tooth (1856–1925) ("The peroneal type of progressive muscular atrophy".). ^ Latour. New York: Springer. 10. Medscape. ^ a b Berger. Peter.PMID 18844790. Lynne. ^ Abrams. ^ Passage. Jensen.doi:10. Bainbridge. 2011. New York Times.00182. Emmanuel et al.. 2.) [edit]See also    Palmoplantar keratoderma and spastic paraplegia Hereditary motor and sensory neuropathies Hereditary motor neuropathies [edit]References 1. "New Mutations in the X-Linked Form of Charcot-Marie-Tooth Disease". Anne. Edith. Gonzaga-Jauregui.PMID 17215403. Abresch.. Pizant.. Suter. FranÇOise. (2008). (2010). J. Journal of the Peripheral Nervous System 13 (3): 236–241. (1998). A.x. Kraft. Huyen et al. Chapon. Galer.1523/JNEUROSCI. ^ a b Lupski.php ^ Wade. Rio Deiros.Neurogenetics 4 (1): 1– 15. "Neurological dysfunction and axonal degeneration in Charcot-Marie-Tooth disease type 1A". Matthew. Sanguedolce.

Fahey. Ouvrier. double-blind. placebo-controlled.15. ^ "Treatment and Management of CMT". Yiu. Joshua. ^ Burns. Pathma D. ^ CMT Association: Medical Alert [edit]External links . Kornberg. Monique M (2009). doi:10. Michael C. May 18. 16. Robert A. 19. 18. Andrew J. 17. The Lancet Neurology 8 (6): 537–44. "Ascorbic acid for Charcot–Marie–Tooth disease type 1A in children: A randomised. ^ "Nerves Under Control: Potential Treatment for Charcot-Marie-Tooth Disease". Joseph. Eppie M. ^ "Treatment and Management of CMT". 2010. safety and efficacy trial". Science Daily.1016/S1474-4422(09)70108-5. Ryan.

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