Charcot-Marie-Tooth disease(CMT)

Alternative Names::Morbus Charcot-Marie-Tooth, Charcot-Marie-Tooth neuropathy, hereditary motor and sensory neuropathy (HMSN), hereditary sensorimotor neuropathy (HSMN), or peroneal muscular atrophy.

Definition:
Charcot–Marie–Tooth disease (CMT) is  an inherited disorder of nerves (neuropathy) that takes different forms. It 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. Currently incurable, this disease is one of the most common inherited neurological disorders, with 36 in 100,000 affected.

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In 1886, Professor Jean Martin Charcot of France (1825-1893) and his student Pierre Marie (1853-1940) published the first description of distal muscle weakness and wasting beginning in the legs, calling it peroneal muscular atrophy.

Howard Henry Tooth (1856-1926) described the same disease in his Cambridge dissertation in 1886, calling the condition peroneal progressive muscular atrophy. Tooth was the first to attribute symptoms correctly to neuropathy rather than to myelopathy, as physicians previously had done.

In 1912, Hoffman identified a case of peroneal muscular atrophy with thickened nerves. This disease was referred to as Hoffman disease and later was known as Charcot-Marie-Tooth-Hoffman disease.

In 1968, CMT disease was subdivided into 2 types, CMT 1 and CMT 2, based on pathologic and physiologic criteria. CMT disease has been subdivided further based on the genetic cause of the disease.

•In CMT type 1, the peripheral nerves’ axons – the part of the nerve cell that transmits electrical signals to the muscles – lose their protective outer coverings, their myelin sheaths. This disrupts the axons’ function.

•In CMT type 2, the axons’ responses are diminished due to a defect within the axons themselves. CMT type 2, the less common of the two classes, can be further separated into at least six subtypes, caused by defects in different genes.

Symptoms:
Symptoms of the 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.

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English: The foot of a person with Charcot-Mar...
English: The foot of a person with Charcot-Marie-Tooth. The lack of muscle, high arch, and hammer toes are signs of the genetic disease. This patient was diagnosed with CMT-1A. Deutsch: atrophischer Hohlfuß bei hereditärer motosensibler Neuropathie I (Charcot-Marie-Tooth) (Photo credit: Wikipedia)

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.

Neuropathic pain is often a symptom of CMT though, like other symptoms of CMT, it’s 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

The most common symptoms of Charcot-Marie-Tooth disease may include:

*Weakness in your legs, ankles and feet
*Loss of muscle bulk in legs and feet
*High foot arches
*Curled toes (hammertoes)
*Decreased ability to run
*Difficulty lifting your foot at the ankle (footdrop)
*Awkward or higher than normal step (gait)
*Frequent tripping or falling
*Decreased sensation in your legs and feet
*Numbness in the legs and feet

As Charcot-Marie-Tooth disease progresses, symptoms may not be limited to the feet and legs but may also involve the thighs, hands and arms. Charcot-Marie-Tooth disease generally doesn’t cause pain.

Causes:
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.

Risk Factors:
Charcot-Marie-Tooth disease is hereditary, so you’re at higher risk of developing the disorder if anyone in your immediate family has had the disease. Other causes of neuropathies, such as diabetes, may cause symptoms of or worsen Charcot-Marie-Tooth disease.

 

Complecations:
Complications of Charcot-Marie-Tooth disease vary in severity from person to person, with foot abnormalities and difficulty walking generally being the most serious problems. Muscle weakness may also increase, and injury to areas of the body with decreased sensation may occur.

Diagnosis:
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.

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. 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.

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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.

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.

Demyelinating Schwann cells causes abnormal axon structure and function. They may cause axon degeneration. Or they may simply cause axons to malfunction.

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).

There are many different genetic variants. Most cases are inherited as an autosomal dominant condition, but some are inherited in an autosomal recessive or x-linked pattern.

Treatment:
Although there is no current standard treatment, the use of ascorbic acid has been proposed, and has shown some benefit in animal models. 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. 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. 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.

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 physical therapist 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.

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.”

There are also several corrective surgical procedures that can be done to improve physical condition.

Genetic testing is available for many of the different types of Charcot-Marie-Tooth and may help guide treatment.

Lifestyle & Homeremedies:
Certain tactics may prevent complications caused by Charcot-Marie-Tooth disease and improve your ability to manage the effects of the disorder.

Started early and followed regularly, at-home activities can provide protection and relief:

*Stretch regularly. The goal of stretching is to improve or maintain the range of motion of your joints. Stretching improves your flexibility, balance and coordination. Stretching may also reduce your risk of injury. If you have Charcot-Marie-Tooth disease, regular stretching can prevent or reduce joint deformities that may result from uneven pulling of muscle on your bones.

*Exercise daily. Exercising every day keeps your bones and muscles strong. Low-impact exercises, such as biking and swimming, are less stressful on fragile muscles and joints. By strengthening your muscles and bones, you can improve your balance and coordination, reducing your risk of falls.

*Improve your stability. Muscle weakness associated with Charcot-Marie-Tooth disease may cause you to be unsteady on your feet, which can lead to falling and serious injury. Walking with a cane or a walker can increase your stability. Good lighting at night can help you avoid stumbling and falling.
Foot care is important
Because of foot deformities and loss of sensation, regular foot care is important to help relieve symptoms and to prevent complications:

*Inspect your feet. Daily inspection of your feet is important to prevent calluses, ulcers, wounds and infections.

*Take care of your nails. Cut your nails regularly. To avoid ingrown toenails and infections, cut straight across and avoid cutting into the nailbed edges. Consider regular professional pedicures.

*Wear the right shoes. Use shoes that fit properly and are roomy and protective. Consider wearing boots or high-top shoes for ankle support.

*Soak and moisturize the skin of your feet. Brief, daily cold and warm foot soaks followed by the application of moisturizing lotions keep the skin of the feet moist and pliable. This can be very effective in reducing neuropathic pain and foot discomfort.

Coping & Support:
Support groups, in conjunction with your doctor’s advice, can be valuable in dealing with Charcot-Marie-Tooth disease. Support groups bring together people who are coping with the same kinds of challenges, along with their families and friends, and offer a setting in which people can share their common problems.

Ask your doctor about support groups in your community. Your local health department, public library and telephone book and the Internet also may be good sources to find a support group in your area.

Disclaimer: This information is not meant to be a substitute for professional medical advise or help. It is always best to consult with a Physician about serious health concerns. This information is in no way intended to diagnose or prescribe remedies.This is purely for educational purpose.

Resources:
http://www.bbc.co.uk/health/physical_health/conditions/charcotmarietooth1.shtml
http://www.mayoclinic.com/health/charcot-marie-tooth-disease/DS00557
http://www.genome.gov/11009201
http://emedicine.medscape.com/article/1232386-overview

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