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{{SK}} Hereditary motor and sensory neuropathy; peroneal muscular atrophy
{{SK}} Hereditary motor and sensory neuropathy; peroneal muscular atrophy
==[[Charcot-Marie-Tooth disease overview|Overview]]==
==[[Charcot-Marie-Tooth disease overview|Overview]]==
==[[Charcot-Marie-Tooth disease historical perspective|Historical Perspective]]==
==[[Charcot-Marie-Tooth disease classification|Classification]]==
==[[Charcot-Marie-Tooth disease pathophysiology|Pathophysiology]]==


==[[Charcot-Marie-Tooth disease epidemiology and demographics|Epidemiology and Demographics]]==
==[[Charcot-Marie-Tooth disease epidemiology and demographics|Epidemiology and Demographics]]==
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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), while NCV is normal or only slightly reduced.<ref name="Berger">Berger, P., Young, P. and U. Suter (2002) Neurogenetics 4:1-15. http://www.springerlink.com/, accessed 060220</ref>
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), while NCV is normal or only slightly reduced.<ref name="Berger">Berger, P., Young, P. and U. Suter (2002) Neurogenetics 4:1-15. http://www.springerlink.com/, accessed 060220</ref>
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.)
==Symptoms==
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" 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. About the [[chemotherapy]] drug [[vincristine]], the Charcot-Marie-Tooth Association classifies the drug 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.''<ref>[http://www.charcot-marie-tooth.org/med_alert.php CMT Association: Medical Alert]</ref>


==Diagnosis==
==Diagnosis==
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==Types of the disease==
==Types of the disease==
* CMT Type 1 (CMT1): Type 1 affects approximately 80% 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 2 (CMT2): Type 2 affects approximately 20-40% of CMT patients. Type 2 CMT is [[Autosomal dominant]] neuropathy  with its main effect on the axon. The average [[nerve conduction velocity]] is slightly below normal, but generally above 38 m/s
* CMT Type 3 (CMT3): Type 3 affects a very few CMT patients.
* CMT Type 4 (CMT4): Type 4 affects a very few CMT patients.
* CMT X-Linked (CMTX): CMTX affects approximately 10-20% of CMT patients and is [[Dominant gene|X-linked dominant]]. Approx 10% of X-linked CMT patients have some other form than CMTX.
More details on the types are provided in the table below:
{| class="wikitable"
| '''Type''' || '''[[OMIM]]''' || '''Gene ''' || '''[[Locus (genetics)|Locus]]'''  || '''Description'''
|-
|  CMT1A  || {{OMIM2|118220}} || {{Gene|PMP22}}  || 17p11.2  ||  The most common form of the disease, 70-80% of Type 1 patients.  Average [[Nerve conduction velocity|NCV]]: 15-20 m/s  when associated with essential [[tremor]] and [[ataxia]], called [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=180800 Roussy-Levy Syndrome]
|-
|  CMT1B || {{OMIM2|118200}}  || {{Gene|MPZ}}  || 1q22  ||  Caused by mutations in the gene producing protein zero (P0). 5-10% of Type 1 patients. Average [[Nerve conduction velocity|NCV]]: <20 m/s
|-
|  CMT1C  ||  || {{Gene|LITAF}}  || 16p13.1-p12.3  ||  Causes severe [[myelin|demyelination]], which can be detected by measuring nerve conduction velocities.  [[Autosomal dominant]]. Usually shows up in infancy. Average [[Nerve conduction velocity|NCV]]: 26-42 m/s. Identical symptoms to CMT-1A.
|-
|  CMD1D  ||  || {{Gene|EGR2}}  || 10q21.1-q22.1  ||  Average [[NCV]]: 15-20 m/s
|-
|  CMT2A || {{OMIM2|118210}} || {{Gene|MFN2}} or {{Gene|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 || {{OMIM2|600882}} || RAB7 ({{Gene|RAB7A}}, {{Gene|RAB7B}})  || 3q21.  ||
|-
|  CMT2B1 ||  || {{Gene|LMNA}}  ||  1q22 || [[Autosomal recessive]] axonal CMT, ([[Laminopathies|laminopathy]])
|-
|  CMT2C  || {{OMIM2|606071}}  ||  || 12q23-q24  ||  May cause vocal cord, [[diaphragm]], and distal [[weakness]]es.
|-
|  CMT2D || {{OMIM2|601472}}  || {{Gene|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  ||  || {{Gene|NEFL}}  || 8p21  ||
|-
|  CMT2F || {{OMIM2|606595}}  || {{Gene|HSPB1}}  || 7q11-q21  ||
|-
|  CMT2G  || {{OMIM2|608591}}  ||  || 12q12-13  ||
|-
|  CMT2H || {{OMIM2|607731}}  || {{Gene|GDAP1}}  ||  8q13-q21.1 ||
|-
|  CMT2J || {{OMIM2|607736}}  ||  || 1q22  ||
|-
|  CMT2K || {{OMIM2|607831}}  ||  || 8q13-q21.1  ||
|-
|  CMT2L || {{OMIM2|608673}}  ||  || 12q24  ||
|-
|  CMT3  || {{OMIM2|145900}}  ||  varies || varies  ||  Sometimes called [[Dejerine-Sottas disease]]. Rarely found. [[Autosomal recessive]]. Average [[Nerve conduction velocity|NCV]]: Normal (50-60m/s)
|-
|  CMT4A || {{OMIM2|214400}}  || {{Gene|GDAP1}}  || 8q13-q21.1  || [[Autosomal recessive]].
|-
|  CMT4B1 || {{OMIM2|601382}}  || {{Gene|MTMR2}}  || 11q22  || [[Autosomal recessive]].
|-
|  CMT4B2  ||  ||  CMT4B2 ({{Gene|SBF2}}) || 11p15  || May be called "SBF2/MTMR13". [[Autosomal recessive]].
|-
|  CMT4C  ||  ||  KIAA1985 ({{Gene|SH3TC2}}) || 5q32  ||  May lead to respiratory compromise.
|-
|  CMT4D  || {{OMIM2|601455}} ||  {{Gene|NDRG1}}  || 8q24.3  || [[Autosomal recessive]], [[demyelinating]], [[deafness]]
|-
|  CMT1E  || {{OMIM2|118300}}  || {{Gene|PMP22}}  || 17p11.2  || [[Autosomal dominant]], [[demyelinating]], [[deafness]]
|-
|  CMT4E  ||  ||  {{Gene|EGR2}}  || 10q21.1-10q22.1  ||  "CMT4E" is a tentative name
|-
|  CMT4F  ||  ||  {{Gene|PRX}}  || 19q13.1-19q13.2  ||  "CMT4F" is a tentative name
|-
|  CMT4J  || {{OMIM2|611228}}  || KIAA0274 ({{Gene|FIG4}}) || 6q21  ||  [[Autosomal recessive]]
|-
|  CMTX1  || {{OMIM2|302800}}  || {{Gene|GJB1}}  || Xq13.1  ||  Average [[Nerve conduction velocity|NCV]]: 25-40 m/s
|-
|  CMTX2  || {{OMIM2|302801}}  ||  || Xq22.2  || 
|-
|  CMTX3  || {{OMIM2|302802}}  ||  || Xq26  ||
|-
|  CMT  || {{OMIM2|118301}}  ||  || || with [[Ptosis]] and [[Parkinsonism]]
|-
|  CMT  || {{OMIM2|302803}}  ||  || || type 1 [[aplasia]] cutis congenita


|}


==Genetic testing==
==Genetic testing==

Revision as of 17:38, 22 August 2012

Charcot-Marie-Tooth disease
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.
ICD-10 G60.0
ICD-9 356.1
DiseasesDB 5815 Template:DiseasesDB2
MedlinePlus 000727
MeSH D002607

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Synonyms and keywords: Hereditary motor and sensory neuropathy; peroneal muscular atrophy

Overview

Historical Perspective

Classification

Pathophysiology

Epidemiology and Demographics

Description

The disorder is caused by the absence of molecules that are essential for normal function of the nerves due to errors in 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. Most of the mutations identified result in disrupted myelin production, however the most common 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.[1]

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”.[2]

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.[2]

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.[3]

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), while NCV is normal or only slightly reduced.[2]

Diagnosis

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.

Types of the disease

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

External links

References

  1. ↑ Baloh, R., Schmidt, R., Pestronk, A. and Milbrandt, J. (2007) The Journal of Neuroscience 27(2):422-430, http://www.jneurosci.org/cgi/content/abstract/27/2/422 accessed 070122
  2. ↑ 2.0 2.1 2.2 Berger, P., Young, P. and U. Suter (2002) Neurogenetics 4:1-15. http://www.springerlink.com/, accessed 060220
  3. ↑ Krajewski, K.M., Lewis, R.A., Fuerst, D.R., Turansky, C., Hinderer, S.R., Gerbern, J., Kamholz, J. and M.E. Shy (2000) Brain 123:1516-1527 accessed 060220

Template:Muscular Dystrophy Template:PNS diseases of the nervous system


ca:Malaltia de Charcot-Marie-Tooth de:Morbus Charcot-Marie-Tooth it:Malattia di Charcot-Marie-Tooth nl:Hereditaire Motorische en Sensorische Neuropathieën no:Charcot-Marie-Tooths sykdom sv:Charcot-Marie-Tooths sjukdom

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