Charcot-Marie-Tooth disease
From Wikipedia, the free encyclopedia
| Charcot-Marie-Tooth disease | |
|---|---|
| Classification and external resources | |
 The foot of a person with Charcot-Marie-Tooth. The lack of muscle, a high arch, and hammer toes are signs of the genetic disease. |
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| ICD-10 | G60.0 |
| ICD-9 | 356.1 |
| DiseasesDB | 5815 2343 |
| MedlinePlus | 000727 |
| eMedicine | orthoped/43 pmr/29 |
| MeSH | D002607 |
Charcot-Marie-Tooth disease (CMT), known also as Hereditary Motor and Sensory Neuropathy (HMSN), Hereditary Sensorimotor Neuropathy (HSMN), or Peroneal Muscular Atrophy, is a heterogeneous 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. Presently incurable, this disease is one of the most common inherited neurological disorders, with 37 in 100,000 affected.[1]
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[edit] Description
The disorder is caused by the absence of proteins that are essential for normal function of the nerves due to errors in the gene coding molecules. The absence of these chemical substances gives rise to dysfunction either in the axon or the myelin sheath of the nerve cell. Most of the mutations identified result in disrupted myelin production, however a small proportion of mutations occur in gene MFN2, which doesn't seem to have anything to do with myelin. Instead MFN2 controls behaviour of mitochondria. Recent research showed that the mutated MFN2 causes mitochondria to form large clusters. In nerve cells these large clusters of mitochondria failed to travel down the axon towards the synapses. It is suggested these mitochondria clots make the synapses fail, resulting in CMT disease.[2]
The different classes of this disorder have been divided into the primary demyelinating neuropathies (CMT1, CMT3, and CMT4) and the primary axonal neuropathies (CMT2). Recent studies, however, show that the pathologies of these two classes are frequently intermingled, due to the dependence and close cellular interaction of Schwann cells and neurons. Schwann cells are responsible for myelin formation, enwrapping neural axons with their plasma membranes in a process called “myelination”.[3]
The molecular structure of the nerve depends upon the interactions between neurons, Schwann cells, and fibroblasts. Schwann cells and neurons, in particular, exchange signals that regulate survival and differentiation during development. These signals are important to CMT disease because a disturbed communication between Schwann cells and neurons, resulting from a genetic defect, is observed in this disorder.[3]
It is clear that interaction with demyelinating Schwann cells causes the expression of abnormal axonal structure and function, but we still do not know how these abnormalities result in CMT. One possibility is that the weakness and sensory loss experienced by patients with CMT is a result of axonal degradation. Another possibility is that axonal dysfunction occurs, not degeneration, and that this dysfunction is induced by demyelinating Schwann cells.[1]
Most patients experience demyelinating neuropathies, and this is characterized by a reduction in nerve conduction velocity (NCV), due to a partial or complete loss of the myelin sheath. Axonopathies, on the other hand, are characterized by a reduced compound muscle action potential (CMAP),
[edit] Symptoms
Symptoms usually begin in late childhood or early adulthood. 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 "stork leg" or "inverted bottle" appearance. Weakness in the hands and forearms occurs in many people later in life as the disease progresses.
Symptoms and progression of the disease can vary. Breathing can be affected in some; so can hearing, vision, and 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.
[edit] Diagnosis
A definitive diagnosis for a specific type of CMT is established via genetic testing for most types. However, some genetic markers have not yet been identified, and a diagnosis can also be established via an 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.
[edit] Types
The condition can be broken down into a few major categories, which in turn can be classified further based upon the associated genes.
| Name | Inheritance | Frequency | Notes |
|---|---|---|---|
| CMT Type 1 (CMT1) | Autosomal dominant | Type 1 affects approximately 80% of CMT patients and is the most common type of CMT. The subtypes share clinical symptoms. | Causes demyelination, which can be detected by measuring nerve conduction velocities. |
| CMT Type 2 (CMT2) | Autosomal dominant (except CMT2B1) |
Type 2 affects approximately 20-40% of CMT patients. | Main effect is on the axon. The average nerve conduction velocity is slightly below normal, but generally above 38m/s |
| CMT Type 3 (CMT3) | Autosomal recessive | Type 3 affects very few CMT patients. | |
| CMT Type 4 (CMT4) | Autosomal recessive | Type 4 affects very few CMT patients. | |
| CMT X-Linked (CMTX) | X-linked dominant | CMTX affects approximately 10-20% of CMT patients. | Approx 10% of X-linked CMT patients have some other form than CMTX. However a study published in 1997 indicates that a connexin 32 gene mutation is associated with this form which may be more common than previously thought.[4][5] |
More details on the types are provided in the table below:
| Type | OMIM | Gene | Locus | Description | |
| CMT1A | 118220 | PMP22 | 17p11.2 | The most common form of the disease, 70-80% of Type 1 patients. Average NCV: 20-25m/s when associated with essential tremor and ataxia, called Roussy-Levy Syndrome 180800 | |
| CMT1B | 118200 | MPZ | 1q22 | Caused by mutations in the gene producing protein zero (P0). 5-10% of Type 1 patients. Average NCV: <15m/s | |
| CMT1C | 601098 | LITAF | 16p13.1-p12.3 | Causes severe demyelination, which can be detected by measuring nerve conduction velocities. Usually shows up in infancy. Average NCV: 26-42m/s. Identical symptoms to CMT-1A. | |
| CMT1D | 607678 | EGR2 | 10q21.1-q22.1 | Average NCV: 15-20m/s | |
| CMT1E | 118300 | PMP22 | 17p11.2 | Demyelinating, deafness | |
| CMT2A | 118210 | MFN2 or KIF1B | 1p36 | The cause is likely located on chromosome 1 for the mitofusion 2 protein. Some research has also linked this form of CMT to the protein kinesin 1B. Does not show up on nerve conduction velocity tests, because it is caused by axonopathy. | |
| CMT2B | 600882 | RAB7 (RAB7A, RAB7B) | 3q21. | ||
| CMT2B1 | 605588 | LMNA | 1q22 | axonal CMT, (laminopathy) | |
| CMT2B2 | 605589 | ? | 19q13.3 | ||
| CMT2C | 606071 | 12q23-q24 | May cause vocal cord, diaphragm, and distal weaknesses. | ||
| CMT2D | 601472 | GARS | 7p15 | Patients with mutations in the GARS gene tend to have more severe symptoms in the upper extremities (hands), which is atypical for CMT in general. | |
| CMT2E | 607684 | NEFL | 8p21 | ||
| CMT2F | 606595 | HSPB1 | 7q11-q21 | ||
| CMT2G | 608591 | 12q12-13 | |||
| CMT2H | 607731 | GDAP1 | 8q13-q21.1 | ||
| CMT2J | 607736 | 1q22 | |||
| CMT2K | 607831 | 8q13-q21.1 | |||
| CMT2L | 608673 | 12q24 | |||
| CMT3 | 145900 | varies | varies | Sometimes called Dejerine-Sottas disease. Rarely found. Average NCV: Normal (50-60m/s). This is an old classification. Currently this is referred to as CMT4F.[citation needed] | |
| CMT4A | 214400 | GDAP1 | 8q13-q21.1 | ||
| CMT4B1 | 601382 | MTMR2 | 11q22 | ||
| CMT4B2 | 604563 | CMT4B2 (SBF2) | 11p15 | May be called "SBF2/MTMR13". | |
| CMT4C | 601596 | KIAA1985 (SH3TC2) | 5q32 | May lead to respiratory compromise. | |
| CMT4D | 601455 | NDRG1 | 8q24.3 | Demyelinating, deafness | |
| CMT4E | 605253 | EGR2 | 10q21.1-10q22.1 | "CMT4E" is a tentative name | |
| CMT4F | 145900 | PRX | 19q13.1-19q13.2 | "CMT4F" is a tentative name | |
| CMT4H | 609311 | FGD4 | 12p11.21 | ||
| CMT4J | 611228 | KIAA0274 (FIG4) | 6q21 | ||
| CMTX1 | 302800 | GJB1 | Xq13.1 | Average NCV: 25-40m/s | |
| CMTX2 | 302801 | Xq22.2 | |||
| CMTX3 | 302802 | Unknown, but 11 of 15 eliminated[6] | Xq26 | ||
| CMTX4 | 310490 | Xq24-q26.1 | Known as Cowchock syndrome | ||
| CMTX5 | 311070 | Xq22-q24 | Known as Rosenberg-Chutorian syndrome. Signs include optic atrophy, polyneuropathy and deafness |
[edit] Genetic testing
Genetic testing is available for many of the different types of Charcot-Marie-Tooth. For a listing of test availabilities, see GeneTests.org
[edit] Management and treatment
Although there is no current standard treatment, the use of ascorbic acid has been proposed, and has shown some benefit in animal models.[7] 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.[8] 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.[9]
People who have CMT are advised to maintain a healthy weight, because extra weight can limit mobility and places additional stress on the joints. They are also advised to be moderately physically active, and to pay special attention to the maintenance of their strength and flexibility. Water therapy is particularly beneficial, since the stress put on the joints is minimized.
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."[10]
There are also several corrective surgical procedures that can be done to improve physical condition.
[edit] History
The disease is named for 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.)
[edit] See also
[edit] References
- ^ a b Krajewski KM, Lewis RA, Fuerst DR, et al. (2000). "Neurological dysfunction and axonal degeneration in Charcot-Marie-Tooth disease type 1A". Brain 123 ( Pt 7): 1516–27. doi:. PMID 10869062. http://brain.oxfordjournals.org/cgi/content/full/123/7/1516#SEC4.
- ^ Baloh RH, Schmidt RE, Pestronk A, Milbrandt J (2007). "Altered axonal mitochondrial transport in the pathogenesis of Charcot-Marie-Tooth disease from mitofusin 2 mutations". J. Neurosci. 27 (2): 422–30. doi:. PMID 17215403. http://www.jneurosci.org/cgi/content/abstract/27/2/422.
- ^ a b Berger P, Young P, Suter U (2002). "Molecular cell biology of Charcot-Marie-Tooth disease". Neurogenetics 4 (1): 1–15. doi:. PMID 12030326. http://link.springer.de/link/service/journals/10048/bibs/2004001/20040001.htm.
- ^ Latour P, Fabreguette A, Ressot C, et al. (1997). "New mutations in the X-linked form of Charcot-Marie-Tooth disease". Eur. Neurol. 37 (1): 38–42. doi:. PMID 9018031.
- ^ Andrew L Harris and Darren Locke (2009). Connexins, A Guide. New York: Springer. pp. 574. ISBN 978-1-934115-46-6. http://www.springer.com/978-1-934115-46-6.
- ^ Brewer M, Changi F, Antonellis A, et al. (July 2008). "Evidence of a founder haplotype refines the X-linked Charcot-Marie-Tooth (CMTX3) locus to a 2.5 Mb region". Neurogenetics 9 (3): 191–5. doi:. PMID 18458969.
- ^ Passage E, Norreel JC, Noack-Fraissignes P, et al. (2004). "Ascorbic acid treatment corrects the phenotype of a mouse model of Charcot-Marie-Tooth disease". Nat. Med. 10 (4): 396–401. doi:. PMID 15034573.
- ^ "Clinical Trials - Neuromuscular Trial/Study". 2007-07-18. http://www.mda.org/research/view_ctrial.aspx?id=186. Retrieved 2008-05-28.
- ^ Burns, Joshua; Robert Ouvrier, Eppie Yiu, Pathma Joseph, Andrew Kornberg, Michael Fahey, Monique Ryan (June 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): 537–544. doi:.
- ^ CMT Association: Medical Alert
[edit] External links
- Charcot Marie Tooth Association
- CMT Central - An Insight into CMT - Sourced info on CMT, by and for people with CMT
- Charcot Marie Tooth North American Database - patients with CMT who do not live in North America are also encouraged to join
- Muscular Dystrophy Association - Although CMT is not a form of Muscular Dystrophy, it is one of several non-muscular dystrophy diseases for which the MDA offers support
- Muscular Dystrophy Canada
- Hereditary Neuropathy Foundation
- CMT United Kingdom
- Charcot-Marie-Tooth disease at the Open Directory Project
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