Charcot-Marie-Tooth Disease

 Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth disease is an inherited, genetic condition. It occurs when there are mutations in the genes that affect the nerves in your feet, legs, hands and arms. Sometimes, these mutations damage the nerves. Other mutations damage the protective coating that surrounds the nerve (myelin sheath).

Overview

Charcot (shahr-KOH)-Marie-Tooth disease is a group of inherited disorders that cause nerve damage. This damage is mostly in the arms and legs (peripheral nerves). Charcot-Marie-Tooth disease is also called hereditary motor and sensory neuropathy.

Charcot-Marie-Tooth disease results in smaller, weaker muscles. You may also experience loss of sensation and muscle contractions, and difficulty walking. Foot deformities such as hammertoes and high arches also are common. Symptoms usually begin in the feet and legs, but they may eventually affect your hands and arms.

Symptoms of Charcot-Marie-Tooth disease typically appear in adolescence or early adulthood, but may also develop in midlife.

Symptoms

Signs and symptoms of Charcot-Marie-Tooth disease may include:

Weakness in your legs, ankles and feet

Loss of muscle bulk in your 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 or a loss of feeling in your legs and feet

As Charcot-Marie-Tooth disease progresses, symptoms may spread from the feet and legs to the hands and arms. The severity of symptoms can vary greatly from person to person, even among family members.

Causes

Charcot-Marie-Tooth disease can be caused by mutations in many different genes. These genes provide instructions for making proteins that are involved in the function of peripheral nerves in the feet, legs, and hands. The gene mutations that cause Charcot-Marie-Tooth disease affect the function of the proteins in ways that are not fully understood; however, they likely impair axons, which transmit nerve impulses, or affect the specialized cells that produce myelin. In most cases, longer nerves that transmit impulses to the appendages of the body are more likely to be affected. As a result, peripheral nerve cells slowly lose the ability to stimulate the muscles in the feet, legs, and eventually the hands, and to transmit sensory signals from these appendages to the brain. Different mutations within a single gene may cause signs and symptoms of differing severities or lead to different types of Charcot-Marie-Tooth disease.

Between 70 and 80 percent of individuals with CMT1 have mutations affecting the PMP22 gene. Most of these cases occur when there is an extra copy of the gene resulting from a small duplication of genetic material on chromosome 17. Another 10 to 12 percent of individuals with CMT1 have mutations in the MPZ gene. MPZ gene mutations are also occasionally identified in people with other forms of the disorder. The most common cause of CMT2 is mutations in the MFN2 gene, which accounts for about 20 percent of cases. Approximately 90 percent of people with CMTX have GJB1 gene mutations. Mutations in dozens of other genes have been identified in smaller numbers of people with these and the other types. The list of genes associated with Charcot-Marie-Tooth disease continues to grow as researchers study this disorder.

Types of Charcot-Marie-Tooth disease

There are many different types of CMT, which may share some symptoms but vary by pattern of inheritance, age of onset, and whether the axon or myelin sheath is involved.

CMT1 is caused by abnormalities in the myelin sheath. Other less common causes of CMT1 result from mutations within the SIMPLE (also called LITAF), EGR2, PMP22, and NEFL genes, respectively.

CMT1A results from a duplication of the gene on chromosome 17 that carries the instructions for producing the peripheral myelin protein-22 (PMP22). The PMP22 protein is a critical component of the myelin sheath. Overexpression of this gene causes the abnormal structure and function of the myelin sheath. CMT1A is usually slowly progressive. Individuals experience weakness and atrophy of the muscles of the lower legs beginning in childhood; later they experience hand weakness, sensory loss, and foot and leg problems. A different neuropathy distinct from CMT1A called hereditary neuropathy with predisposition to pressure palsy (HNPP) is caused by a deletion of one of the PMP22 genes. In this case, abnormally low levels of the PMP22 gene result in episodic, recurrent demyelinating neuropathy.

CMT1B is caused by mutations in the gene that carries the instructions for manufacturing the myelin protein zero (MPZ, also called P0), which is another critical component of the myelin sheath. Most of these mutations are point mutations, meaning a mistake occurs in only one letter of the DNA genetic code. To date, scientists have identified more than 120 different point mutations in the P0 gene. CMT1B produces symptoms similar to those found in CMT1A.

CMT2 results from abnormalities in the axon of the peripheral nerve cell, rather than the myelin sheath, and is less common than CMT1. This autosomal dominant disorder has more than a dozen subtypes (some of which have their own variants), with each subtype being associated with mutations in a specific gene. Symptoms are similar to those seen in CMT1, but people with CMT2 often have less disability and sensory loss than individuals with CMT1. The onset of CMT2 is usually in childhood or adolescence. Some types of CMT2 may have vocal cord or phrenic nerve involvement, causing speech or breathing problems.

CMT3, or Dejerine-Sottas disease, is a particularly severe demyelinating neuropathy that begins in infancy. Symptoms may progress to severe disability, loss of sensation, and curvature of the spine.  This rare disorder can be caused by mutations in multiple genes, including PMP22, MPZ, and EGR2, and can be inherited either dominantly or recessively. Infants have:

Severe muscle atrophy

Weakness

Delayed motor skills development

Sensory problems

CMT4 comprises several different subtypes of demyelinating and axonal and motor neuropathies that are inherited autosomal recessively.   Each neuropathy subtype is caused by a mutation in a different gene (several genes have been identified in CMT4). The mutations may affect a particular ethnic population and produce distinct physiologic or clinical characteristics. People with CMT4 generally develop symptoms of leg weakness in childhood and by adolescence they may not be able to walk. CMT4 is rare in the U.S.

CMTX1 (also called CMT X, Type 1) is the second most common form of CMT. This X-linked disease is caused by mutations in a gene that provides instructions for making the protein connexin-32. The connexin-32 protein is found in myelinating Schwann cells—cells that wrap around nerve axons and make up the myelin sheath. Males who inherit the mutated gene show moderate to severe symptoms of the disease beginning in late childhood or adolescence. Females who inherit a mutated gene often develop milder symptoms than males or do not show symptoms.

Diagnosis

If you have early symptoms of Charcot-Marie-Tooth disease (CMT), your GP will ask about your symptoms and may carry out a physical examination.

They may want to know:

when your symptoms started

how severe your symptoms are

if anyone in your family has CMT

During a physical examination, your GP will look for evidence of the condition, such as muscle weakness, poor or absent reflexes, and foot deformities, such as high arches or flat feet.

Further tests

If CMT is suspected, you may be referred to a doctor who specialises in treating conditions of the nervous system (a neurologist) for further testing.

Here are some tests you may have.

Nerve conduction test

A nerve conduction test measures the strength and speed of signals transmitted through your peripheral nerves, the network of nerves that run from the brain and spinal cord to and from the rest of the body, such as the limbs and organs.

Small metal discs called electrodes are placed on your skin, which release a small electric shock that stimulates the nerves.

The speed and strength of the nerve signal is measured. An unusually slow or weak signal could indicate CMT.

Electromyography (EMG)

Electromyography (EMG) uses a small needle-shaped electrode placed in your skin to measure the electrical activity of your muscles.

Some types of CMT cause a distinctive change in the pattern of electrical activity that can be detected by an EMG.

Genetic testing

Genetic testing involves taking a blood sample and testing it for defective genes known to cause CMT.

So far, many of these genes have been found, but there may be more not yet identified.

Most people with CMT should be able to have their diagnosis confirmed by genetic testing and find out exactly which type of CMT they have.

For others, genetic testing may prove inconclusive because an unidentified gene may be involved.

Nerve biopsy

In a small number of cases where other tests have been inconclusive, a test called a nerve biopsy may be carried out.

This is a minor surgical procedure where a sample of a peripheral nerve is removed from your leg for testing.

CMT can cause physical changes to the shape of the nerve, which can be seen under a microscope.

The biopsy is carried out under a local anaesthetic, so you'll be awake but will not feel any pain.

Being diagnosed with CMT

Everyone reacts differently when told they have CMT.

You may experience feelings of shock, denial, confusion or fear. Some people are relieved that there's finally an explanation for their symptoms.

If you have recently been diagnosed with CMT, you may find it useful to:

take all the time you need – do not rush into making important decisions about your health

find the support you need – talk to your family and friends when you feel ready; you may also find it helpful to contact other people with CMT through the charity Charcot-Marie-Tooth UK

find out what you can about CMT – both from your healthcare team and reliable online resources, such as Charcot-Marie-Tooth UK

get involved in your care – work closely with your healthcare team to come up with a treatment plan that best suits you

Tests before and during pregnancy

Couples with a family history of CMT who are thinking of having a baby can be referred to a genetics specialist for advice.

A genetic counsellor can help you work through the decision-making process and explain possible tests that can be carried out and any alternatives you may want to consider, such as adoption.

Find out more about genetic testing and counselling

The main tests that can be carried out during pregnancy to check if a baby will develop certain types of CMT are:

chorionic villus sampling (CVS) – where a small sample of placenta is removed from the womb and tested for known CMT genes, usually during weeks 11 to 14 of pregnancy

amniocentesis – where a sample of amniotic fluid is taken for testing, usually during weeks 15 to 20 of pregnancy

If these tests show that your child is likely to have CMT, you can discuss with your genetic counsellor whether you want to continue the pregnancy or have a termination (abortion).

It's important to be aware that the results of these tests will not indicate how serious your child's CMT will be.

This is because the symptoms and progression of the condition can vary widely, even among family members with the same type of CMT.

It's also important to bear in mind that both tests can slightly increase your chances of having a miscarriage.

Pre-implantation genetic diagnosis

For some couples at risk of having a child with CMT, pre-implantation genetic diagnosis (PGD) may be an option.

PGD involves using in vitro fertilisation (IVF), where eggs are removed from a woman's ovaries before being fertilised with sperm in a laboratory.

After a few days, the resulting embryos can be tested for certain types of CMT and a maximum of 2 unaffected embryos transferred into the womb.

Funding for PGD is decided on an individual basis.

For example, you may be considered ineligible for PGD on the NHS if you already have unaffected children or if the chances of having a successful pregnancy are thought to be low.

In these cases, you can choose to fund PGD yourself, although each attempt is likely to cost at least £8,000 (including medication costs).

Treatment

There's no cure for Charcot-Marie-Tooth disease (CMT), but therapies are available to help reduce your symptoms and enable you to live as independently as possible.

As CMT gets worse over time, you'll need to be assessed regularly to check for any changes in your condition.

How often you're assessed depends on the type of CMT you have and the severity of your symptoms.

Your treatment programme may involve a number of healthcare professionals working together in a multidisciplinary team (MDT).

A doctor will usually co-ordinate your treatment programme, and makes sure every aspect of your condition is closely monitored and treated if necessary.

Physiotherapy

Physiotherapy is one of the most important therapies for improving the symptoms of CMT and reducing the risk of muscle contractures, where muscles shorten and lose their normal range of movement.

Physiotherapy uses physical methods, such as massage and manipulation, to promote healing and wellbeing.

It usually involves low-impact exercises such as stretching, swimming and moderate weight training.

There's a lack of good-quality medical research into the benefits of exercise for people with CMT, but it's possible that some types of exercise are beneficial.

For example:

strengthening exercises that focus on improving muscle strength, such as lifting weights, may help improve overall strength and reduce foot drop

aerobic exercise, such as walking or swimming, which raises your heart rate and makes you breathe harder, may improve your fitness and your ability to function on a day-to-day basis

posture and balance exercises, such as yoga, may also be beneficial

Any exercise needs to be carefully planned as part of a personalised exercise programme.

A certain level of exercise may be safe, but you risk making your symptoms worse if you do not follow proper instructions or overexert yourself.

Speak to your GP or physiotherapist about arranging a suitable exercise programme that will allow you to pace yourself.

Occupational therapy

Occupational therapy involves identifying problem areas in your everyday life, such as dressing yourself, then working out practical solutions.

Occupational therapy will be useful if muscle weakness in your arms and hands makes it difficult for you to do day-to-day tasks, such as dressing or writing.

An occupational therapist will teach you how to use adaptive aids to compensate for your difficulties, such as clothing with clasps instead of buttons and magnetic tubes that allow you to pick up objects.

Orthoses and walking aids

Orthoses are devices worn inside your shoes or on your legs to improve the strength and functionality of your limbs, or to correct your gait (the way you walk).

There are several different types of orthoses, including:

insoles in your shoes

custom-made shoes that support your ankles

ankle or leg braces

thumb splints that can improve your hand strength

It's unusual for a person with CMT to completely lose the ability to walk.

But moving around can be difficult, so using a wheelchair every now and again can help by giving you a chance to rest.

Taking care of yourself

In addition to the treatment you receive, there are some general precautions you can take to avoid further problems.

These may include:

trying to maintain a healthy weight – being overweight can make moving around more difficult and put more strain on your body

taking good care of your feet – make sure you check and clean your feet regularly, as there's a risk of injury and infection if you have reduced sensation in your feet

avoiding drinking too much alcohol – this has many health risks, which may be worse if you have CMT

avoiding caffeine (found in tea, coffee, cola and energy drinks) and nicotine (found in tobacco) if you have tremors (shaking) – they can make this worse

avoid medicines that can cause nerve damage – Charcot-Marie-Tooth UK has a list of medications to avoid or use with caution if you have CMT

Ask your MDT if they have specific lifestyle advice for you, as risks may vary from person to person.

Controlling pain

There are 2 types of pain associated with CMT:

joint and muscle pain – caused by the stresses that CMT places on your body

neuropathic pain – caused by damage to your nerves (this is less common)

Joint and muscle pain can usually be controlled by taking non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen.

Neuropathic pain may be treated with tricyclic antidepressants (TCAs) or an anticonvulsant medication (a medicine often used to prevent seizures).

These medications were not originally designed to be painkillers, but there's evidence to suggest they're effective in treating long-term nerve pain in some people.

Surgery

If CMT causes significant deformities, surgery may be needed to correct them.

Osteotomy

An osteotomy is a surgical procedure used to correct severe flatness of the feet.

A cut (incision) is made in your foot and the surgeon removes or repositions the bones in your foot to correct its shape.

After surgery, your foot (or feet) will need to be kept in plaster for several weeks until the bones have healed.

Arthrodesis

Arthrodesis involves fusing the 3 main joints in the back of your feet to strengthen your feet, correct their shape and relieve pain.

It can be used to correct flat feet and heel deformities, and relieve joint pain.

After surgery, your foot (or feet) will be put in plaster, and you will not be able to place any weight on them for 6 weeks.

During this time, you'll need to use crutches or a wheelchair.

Once you can put weight on your feet, you'll need to wear the cast for another 6 weeks (12 weeks in total).

But it may take up to 10 months for you to fully recover from the operation.

Plantar fascia release

Plantar fascia release is a surgical procedure used to relieve persistent heel pain caused by inflamed tendons. Tendons are the fibrous cords that join bones to muscle.

During the procedure, part of the tendon is removed and the remaining tendon repositioned and allowed to heal.

Afterwards, you'll need to wear a cast for 3 weeks and will not be able to put any weight on your feet during this time.

Spinal surgery

Although abnormal curvature of the spine (scoliosis) can often be treated using a back brace, corrective surgery may be needed.

Find out more about treating scoliosis

Research into treatments

There's some promising research that may provide new ways of treating people with CMT.

This research includes:

using stem cells (cells at an early stage of development) to repair nerve damage

using hormones (powerful chemicals) and gene therapy to slow the progression of the condition

TYPE OF DOCTOR DEPARTMENT:- Neurology, Orthopedic Surgery, Physical Medicine and Rehabilitation