| 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 claw 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 Morbus Charcot-Marie-Tooth, Charcot-Marie-Tooth neuropathy, hereditary motor and sensory neuropathy (HMSN), hereditary sensorimotor neuropathy (HSMN), or peroneal muscular atrophy, is an inherited disorder of nerves (neuropathy) that takes different forms. It is predominantly characterized by loss of muscle tissue and touch sensation, in the feet, ankles and legs as it progresses over time, but also in the hands, wrists and arms 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 'Cavus Feet' are associated with the disorder. Sensory and positioning 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 ranging from numbness, to spasm, to very painful cramping. Currently incurable, this disease is one of the most common inherited neurological disorders, and was considered a type of Muscular Dystrophy for years. [1]
Estimates of incidence vary widely from 1 in 380,000 people affected [1] to 1 in 2,500 people affected [1]. This larger figure might equate to approximately 23,000 people in the UK and 125,000 people in the USA.
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Symptoms of CMT usually begin in late childhood or early adulthood. Some people don't 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 "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, 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.[2]
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.[3]
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. 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.[4]
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.[5]
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.[5]
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).[6]
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 neurologist or a physical medicine and rehabilitation physician (physiatrist). 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.[7]
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.[8][9] 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.
As of early 2010, mutations in 39 genes have been identified as causes of CMT.[8] CMT can be categorized first into major clinical categories, and then into subtypes according to those mutations. Type 1 primarily affects the myelin sheath, and is either dominant, recessive or X-linked. Type 2 primarily affects the axon, and is either dominant or recessive. Other types are mixed.[9]
Clinical categories
| Name | Inheritance | Frequency | Notes |
|---|---|---|---|
| CMT Type 1 (CMT1) | Autosomal dominant | Type 1 affects approximately one-third 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. (anatomic changes directly affect the myelin sheath, with secondary axonal changes. In areas of focal demyelination, impulse conduction is slowed. The prolongation slows conduction velocity along the nerve segment.) |
| 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 The type-2 form of Charcot-Marie-Tooth disease (CMT2) tends to affect the lower extremities more than the upper extremities. CMT2 is often a clinically less severe disease than CMT1. |
| 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 (only CMTX1) |
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.[10][11] |
Genetic subtypes
| 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 |
| CMT1F | 607734 | NEFL | 8p21 | |
| 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 | MED25 | 19q13.3 | |
| CMT2C | 606071 | 'TRPV4 | 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 | MPZ | 1q22 | |
| CMT2K | 607831 | GDAP1 | 8q13-q21.1 | |
| CMT2L | 608673 | HSPB8 | 12q24 | |
| CMT3 | 145900 | varies | varies | Sometimes called Dejerine-Sottas disease. Rarely found. Average NCV: Normal (50–60 m/s). This is an old classification. Currently this is referred to as CMT4F. |
| 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[12] | 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 |
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 a 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]
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."[18]
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.)
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