What Is Charcot-Marie-Tooth Disease (CMT)? What Causes Charcot-Marie-Tooth Disease?

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Main Category: Neurology / Neuroscience
Also Included In: Rehabilitation / Physical Therapy;  Pain / Anesthetics;  Bones / Orthopedics
Article Date: 24 Nov 2009 - 9:00 PDT


Charcot-Marie-Tooth Disease (CMT) , also known as Chacot-Marie-Tooth hereditary neuropathy, peroneal muscular atrophy, and hereditary motor and sensory neuropathy, is a genetic disease of nerves, typically with progressive muscle weakness, particularly the arms and legs. The hallmark feature of CMT is a clear wasting of the distal extremities, especially the peroneal muscle groups in the calves - the patient develops stork legs. In most cases, patients experience weakening of the legs before the arms.

Two French neurologists, Jean Charcot (1825-1893), Pierre Marie (1853-1940), and the English physician Howard Henry Tooth (1856-1925) were the first to fully clinically describe the disease; hence the name. Jean Charcot was Sigmund Freud's mentor.

According to Medilexicon's medical dictionary, peroneal muscular atrophy is:

"a generic title for at least three distinct hereditary neuromuscular disorders, all of which share the common features of pes cavis and marked wasting of the more distal portion of the limbs, particularly the peroneal muscle groups (resulting in the characteristic "stork legs"). Included in this designation are hereditary motor and sensory neuropathy, type I (formerly known as Charcot-Marie-Tooth, type I, or the hypertrophic type of peroneal muscular atrophy); hereditary and motor sensory neuropathy, type II (formerly known as Charcot-Marie-Tooth, type II, or the neuronal type of peroneal muscular atrophy); and distal hereditary motor neuronopathy (formerly known as Charcot-Marie-Tooth, type III, the spinal type of peroneal muscular atrophy, or distal spinal muscular atrophy)."

The periphery nerves - the ones affected - are located outside the main central nervous system. Periphery nerves control muscles, as well as relaying data from our arms and legs to our brain, which allow us to sense touch.

In countries where public health data is well recorded, such as those in Europe, North America, Japan and Australasia, CMT is one of the most common inherited conditions affecting the periphery nerves. According to the NHS (National Health Service), UK, approximately 23,000 British people are affected with CMT.

CMT affects both sexes equally, as well as all ethnic groups.

What are the signs and symptoms of Charcot-Marie-Tooth Disease?

A symptom is something the patient feels and reports, while a sign is something other people, including a doctor or a nurse may detect. For example, pain may be a symptom while a rash may be a sign.

CMT symptoms and their intensities may vary considerably from patient-to-patient, even among close relatives who have inherited the condition. In the most severe cases the patient may require a wheelchair, while others may need a leg brace, special shoes, or other orthopedic devices.

In the vast majority of cases, patients with CMT should live a lifespan equal in length to other healthy individuals.

Early symptoms of Charcot-Marie-Tooth disease (CMT)

Symptoms of CMT gradually worsen over time - it is a progressive condition. Early signs and symptoms, especially among children, may not be detectable because they are so mild.

The following signs and symptoms may point towards childhood CMT:

• The child is clumsier (more prone to accidents) than other children of the same age.


• Walking may be slightly different, because of difficulties in lifting their feet off the ground with each step.


• As the child lifts his/her feet, the toes may drop forward.

Common signs and symptoms of Charcot-Marie-Tooth disease

Signs and symptoms tend to become noticeable when the child has finished puberty and enters adulthood - when the body is fully developed - but they can occur at any age, from very young to late 70s. The most common signs and symptoms include:

• Weakness in the muscles of the lower feet, legs and ankles


• Ankle becomes unstable because the feet are very highly arched, or less commonly, very flat.


• Hammertoes (curled toes)


• Lifting up of the foot is difficult because of weak ankle muscles (footdrop)


• A step (stride) which is higher than normal (an awkward step/gait)


• Numbness in the arms and feet


• Changing leg shape - the section of the leg below the knee becomes very thin, while the thighs retain their normal muscle volume and shape (stork legs)

As CMT progresses muscle weakness will affect the patient's arms and hands more and more.

Progressive signs and symptoms may include:

• The patient's hands and arms become more affected.


• Problems with manual dexterity, such as doing up buttons, or opening jars and bottle tops.


• Muscle and joint pain resulting from problems with walking and posture which place a strain on the body.


• Neuropathic pain cause by damaged nerves (less common).


• General walking and mobility problems, especially with older patients.

What are the risk factors of Charcot-Marie-Tooth disease?

As CMT is a hereditary disease, people who have close family members with CMT have a higher risk of developing the condition themselves.

What are the causes of Charcot-Marie-Tooth disease?

Understanding how the periphery nerves function is important if you want to have a better appreciation of what causes CMT.

How the periphery nerves work - the periphery nerve consists of two main parts:

• The axon - the inside of the nerve. Like the metal part of an electric cable. The electrical information between the brain and the limbs passes through the axon, in the same way electricity passes through the metal part of a cable (wire).


• The myelin sheath - the insulation around the axon, in the same way a wire/cable may have some kind of plastic insulation around it. The myelin sheath wraps around the axon, protecting it, as well as helping restore the quality of the electrical signal.

Either the axon or myelin sheath, or both, may be affected when a patient has CMT - it depends on the type. Mutated (faulty) genes cause the disintegration of the myelin sheath. If the myelin sheath wastes away it becomes thinner and thinner, eventually the axon becomes damaged and the patient's muscles no longer receive clear messages from the brain, resulting in muscle weakness and loss of sensation (numbness).

In some types of CMT the axons are directly targeted; also as a result of faulty genes. For some reason the electrical signals are not transmitted at the required strength to activate muscles and senses, resulting in weaker muscles and poorer tactile sensitivity (numbness).

There are various types of CMT:

• CMT 1 - the genes involved in myelin sheath production are faulty. The myelin sheath gradually wastes away. Approximately one third of all CMT cases are of this type.


• CMT 2 - approximately 17% of all CMT cases. The defect is in the axon itself.


• CMT 3 - also known as Dejerine-Sottas disease. This is a rare type of CMT. The myelin sheath is affected. The patient experiences severe muscle weakness and his/sense of touch is also affected severely. Children with CMT 3 may have noticeable symptoms.


• CMT 4 - also affects the myelin sheath. CMT 4 is rare. Experts believe several different genetic processes are involved in the development of CMT 4, but they are not sure which genes. Symptoms generally appear during childhood. Wheelchairs are commonly required by patients with CMT 4.


• CMT X - this type of CMT is caused by an X-chromosome mutation. This type of CMT is more commonly diagnosed in male patients. If female patients have CMT X, symptoms will be very mild. Approximately one tenth of all CMT cases in the UK are of this type.

Genes, inheritance and CMT

CMT is a genetic disease - it is an inherited disease. It is caused by inherited mutated genes that are involved in producing substances (proteins) which affect either the axon or myelin sheath of the peripheral nerve. In all cases of CMT, several mutated genes are involved in causing the condition (not just one).

The mutated genes may be inherited in several different ways:

• Autosomal dominant - only one parent with the defective genes is needed for offspring to inherit the disease. If one of the parents has the defective genes, each offspring has a 50% risk of developing the disease.


• Autosomal recessive - two copies of the defective gene are required for offspring to inherit the disease (and genetic defect). If each parent only has one copy, they do not have the disease themselves, but can pass it on to their children (if they have one copy each).
  
  If both parents have the autosomal recessive CMT gene, each of their offspring has a 25% risk of developing CMT. Each offspring carries a 50% risk of being a carrier - not having the disease but passing it on to their own offspring if their future partner also carries the autosomal recessive CMT gene.


• X-linked inheritance - this is where the mutated gene is located on the X-chromosome and is inherited from a mother by her son.
  
  Males have an X and a Y chromosome, while females have an X and an X chromosome. Males receive their X chromosome from their mothers and their Y chromosomes from their fathers. Females receive one X chromosome from their mothers and one X chromosome from their fathers.
  
  A woman with a defective X-chromosome will either have no CMT symptoms, or very mild symptoms. This is because their other X-chromosome is healthy and makes up for the defects in the other one.
  
  A male offspring, on the other hand, who inherits the faulty X-chromosome from his mother, has no other X chromosome to compensate for the faulty gene (his other one is a Y-chromosome), and will develop CMT.
  
  Male offspring have a 50% risk of inheriting the defective X-chromosome and developing CMT.
  
  If the mother has only daughters, CMT will not appear in her children, but may appear in the next generation if some of the grandchildren are males.

How is Charcot-Marie-Tooth disease diagnosed?

If the patient is seen by a GP (general practitioner, primary care physician), they may ask questions about symptoms and whether the patient has any relatives with the disease (family history). The GP will carry out a physical examination, looking out for evidence of muscle weakness, reduced muscle tone, flat feet, or high feet arches. If the GP suspects the patient may have CMT, he/she will be referred to a neurologist for further tests.

• Nerve conduction studies - the aim here is to measure the strength and speed of the electrical signals that pass through the nerves. Electrodes, which are placed on the skin, deliver tiny electric shocks that stimulate the nerve. If there is either a delayed or weak response (or both), the patient most likely has a nerve disorder, and possibly CMT.


• EMG (electromyography) - a thin needle is inserted through the patient's skin and into the targeted muscle. As the patient relaxes or tightens, muscle electrical activity is measured. As different muscles are tested the doctor will be able to determine which muscles are affected (disease distribution).


• Biopsy - the doctor makes an incision through the skin of the calf and takes a small piece of peripheral nerve - the sample is tested in a lab. This test can tell whether the patient has CMT or some other nerve disorder.


• Genetic testing - this is done by extracting a sample of the patient's blood. The doctor and patient will then know whether the patient carries the faulty gene(s). There is a chance that this test remains inconclusive because not all the faulty genes are identifiable.

What are the treatment options for Charcot-Marie-Tooth disease?

CMT is an incurable disease - there is nothing modern medicine can to get rid of the disease. However, some therapies may help relieve some of the signs and symptoms, as well as delaying the start of eventual physical disabilities.

• Pain - People with CMT may experience either/both types of pain described below:
  
  
  • Joint and muscle pain - resulting from stresses that are placed on parts of the body because of CMT.
    
    NSAIDs (non-steroidal anti-inflammatory drugs), such as ibuprofen, can help reduce joint and muscle pain.
  
  
  • Neuropathic pain - caused by damaged nerves (less common).
    
    NSAIDs can sometimes help alleviate the symptoms of neuropathic pain.
    
    TCAs (tricyclic antidepressants) - if NSAIDs are not effective, the patient may be prescribed a TCA. TCAs, although originally designed to treat patients with depression, are also effective in alleviating neuropathic pain symptoms. TCAs may have the following side effects:
    
    Constipation
    Sweating
    Problems urinating
    Vision problems (blurring)
    Drowsiness
    Dry mouth
    
    As the body gets used to the medication the side-effects usually go away - after 7 to 10 days. Patients taking a TCA should not take cannabis is it may accelerate the heart beat.


• Physical therapy (UK: physiotherapy) - with a good physical therapist the patient can strengthen and stretch muscles, which help maintain muscle strength for longer and prevent muscle tightening. Sessions usually involve low-impact exercises and stretching techniques. If physical therapy starts early on, it can make a significant difference in slowing down nerve deterioration and muscle weakness, resulting in a delay of disabilities.


• Occupational therapy - this may help patients who have problems with finger movements and gripping, which may severely affect the individual's ability to do up button's, write, or carry out otherwise straightforward activities, such as turning a door-knob, opening a bottle or jar, or tying up shoelaces.


• Devices - these are usually orthopedic devices which help the individual maintain mobility and prevent injury. Leg and ankle braces or splints can help the patient walk and go up stairs. High top shoes or special boots may provide extra ankle support. Specially made shoe inserts, or even shoes, may help the individual maintain a better gait. Thumb splints may help with dexterity.
  
  If the patient has scoliosis - curvature of the spine - he/she may have to wear a back brace. In very severe cases surgery may be required.


• Surgery - in severe cases, the patient's foot may require surgical intervention to alleviate pain and make walking easier. Possible surgical procedures include:
  
  
  • Osteotomy - used to correct severe flat feet. The surgeon either repositions or removes bones in the foot. After the operation the foot will be in plaster for a number of weeks.
  
  
  • Arthrodesis - used to correct flat feet, relieve joint pain, and correct heel deformities. The three main joints in the back of the feet are fused, resulting in a stronger foot, better shape, and often less pain. After surgery the foot will be placed in a cast for a number of weeks. It can take up to 10 months before the foot recovers completely.
  
  
  • Planter fascia release - inflamed tendons can cause continuous heel pain. Part of the tendon is surgically removed, while the remaining tendon is repositioned. The patient's foot will be in a cast for about 3 weeks.

Possible complications

• Breathing - if the nerves that control the diaphragm are affected the patient may feel out of breath. The doctor may prescribe bronchodilator medications. If symptoms are severe the patient may need a ventilator. Obese/overweight people with CMT and breathing difficulties will find that their breathing is easier if they lose weight.


• Depression - the mental stresses, anxieties and frustrations of living with a progressive disease, such as CMT, can eventually raise the risk of developing depression. It is important to see your doctor if you have any of the signs and symptoms of depression. Joining a support group, where you can meet other people who have something in common with you can also help. CBT (cognitive behavioral therapy) may also help lower the risk of developing depression (see below).


• CBT (cognitive behavioral therapy) - CBT has been shown to help patients with CMT cope better. CBT trains the patient to react differently to his/her condition. CBT includes relaxation techniques as well as maintaining a positive outlook, resulting in less pain and mental stress.

Written by Christian Nordqvist
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today

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