Charcot-Marie-Tooth disease (CMT) is the most common inherited neuromuscular condition, affecting approximately 1 in in every 2,500 people. It is named after the three neurologists who first described the condition in 1886. CMT is also sometimes called “hereditary motor and sensory neuropathy” (HMSN).

CMT affects the motor and sensory peripheral nerves. These are the nerves that connect the spinal cord to the muscles, joints and skin and carry messages in both directions. When these nerves do not function properly weakness and wasting of the muscles below the knees and hands occurs. Many people with CMT also have loss of feeling in the hands and feet.

CMT is not in fact a single disorder but a group of conditions that have some similarities. They are genetic conditions and more than 30 different genes have been shown to cause the different types of CMT. Disease onset usually occurs during the first decades of life and gets worse slowly. Severity is highly variable, even within families, but the condition only rarely leads to severe disability.

In this factsheet:
• What are the types and causes of CMT?
• How is CMT inherited?
• What are the symptoms and what is the prognosis?
• How is CMT diagnosed?
• How can the symptoms be managed?
• What research is being done?
• Further information
• References

What are the types and causes of Charcot-Marie-Tooth disease?
CMT is a group of genetic conditions caused by mistakes in the DNA (which are often referred to as ‘mutations’). These DNA errors are within genes that contain the instructions for the production of proteins that are important for the functioning of the peripheral nerves. There are more than 30 different types of CMT, each caused by a mutation in a different gene.

The classification of CMT into its subtypes is very complicated and to add to the confusion there isn’t a classification system universally used by all doctors around the world. However, the main distinction is based on the results of nerve conduction studies which measure the speed that signals travel down the nerves.

As mentioned above, CMT is caused by problems with the peripheral nerves. The peripheral nerves are often described as being like electrical wires with an inner core (the axon), which is wrapped in insulation (the myelin sheath). When the myelin sheath is damaged, the nerve impulses are conducted more slowly than normal and this is classified as Type 1 CMT. If the axon itself is damaged, the speed of nerve conduction is almost normal, but the strength of the signal is reduced – this is Type 2 CMT.

CMT Type 1 accounts for more than two-thirds of all cases of CMT. The symptoms of type 1 and 2 are similar but those with type 2 tend to have a wider age range of onset of the disorder and more variation in the degree of disability. The pattern of inheritance – the way that it is passed down through families – is another way in which types of CMT are categorised. This is explained below in the section “How is CMT inherited?”

Letters are used to further divide the subtypes (CMT1A, CMT1B, CMT2A, etc.) according to the genetic error that causes that subtype. CMT1A is the most common form of CMT – accounting for at least 60 percent of all patients with CMT Type 1. It is caused by the presence of an extra copy of a gene that carries the information for making a protein called “peripheral myelin protein 22” (PMP22). In these patients excessive amounts of PMP22 are produced which impairs the formation of the myelin sheath.

Children with severe symptoms of CMT are sometimes classified as having CMT type 3, congenital hypomyelinating neuropathy (CHN) or Dejerine-Sottas disease (DSD). There is a move towards classifying these children as having severe CMT type 1, but the other terms are still used.

People with CMT type 1 that is “autosomal recessively inherited” (see explanation below) are sometimes given the diagnosis of CMT type 4. In general, the symptoms of CMT4 appear at a younger age and are more severe than typical CMT type 1.

Other closely related conditions include the Hereditary Sensory and Autonomic Neuropathies (HSAN), Hereditary Motor Neuropathies (HMNs) and Hereditary Neuropathy with Liability to Pressure Palsies (HNPP).

How is CMT inherited?
Autosomal dominant
CMT is most commonly inherited in a pattern known as “autosomal dominant”. We all generally have two copies of each gene – one inherited from each parent. The inheritance of one altered copy of the gene from either parent is sufficient for a person to be affected by an autosomal dominant disorder. This altered gene over-rides the healthy copy inherited from the other parent. Each affected person usually has one affected parent. The chance of a child inheriting the condition from a parent with the condition is 50 percent, or 1 in 2.

X-linked
The second most common type of CMT – CMT 1X is inherited in an “X-linked recessive” pattern. This is because the causative gene (GJB1) is located on the X-chromosome. Females have two X chromosomes — one inherited from each parent — so in most cases females who inherit a faulty GJB1 gene will show no symptoms or only mild symptoms of the disorder because the normal gene on her other X chromosome will compensate. Females with one faulty GJB1 gene are known as carriers and they can pass the condition on to their sons.

Males have one X chromosome which they inherit from their mother and one Y chromosome which they inherit from their father. If a boy’s mother is a carrier of a faulty GJB1 gene there is a 50:50 chance that he will inherit this gene and will have CMT because, unlike females, he doesn’t have another X chromosome to make up for the faulty one. The daughters of carriers each have a 50:50 chance of being carriers.

If a male with CMT 1X has children with a non-carrier female, their sons would not inherit the condition and their daughters would all be carriers.

Autosomal recessive
More rarely, CMT is inherited in an “autosomal recessive” pattern which means that for an individual to develop the condition they need to inherit two altered genes – one from each parent. The parents of an individual with this type of CMT each carry one copy of the altered gene, and are known as ‘carriers’, but they typically do not have symptoms of the condition. Their other ‘good’ copy of the gene is enough to prevent the condition developing. If both parents are carriers the likelihood of a child inheriting the condition is 25 percent, or 1 in 4. Autosomal recessive inheritance is more common in cultures where marriage within families occurs.

What are the symptoms and what is the prognosis?
CMT is a highly variable condition, even between members of the same family so the symptoms described here may not apply to all people with CMT.

In the most common types of CMT, symptoms usually begin before the age of 20 years and the typical symptoms are:

• Weakness and wasting of muscle in the lower legs and feet
• High arches in the feet (known medically as pes cavus) and curled toes
• Foot drop (inability to hold foot horizontal)
• Numbness in the feet
• Difficulty with balance
• Hand weakness and numbness, often appearing as much as ten years after foot and leg problems
• Fatigue as a result of the extra effort required to perform daily activities.

The muscles that support the foot while walking are among the first to be affected by CMT so the first noticeable signs are often difficulty in walking because of problems picking up the feet. The toes drop as the foot is lifted, causing a tendency to trip and an awkward walking style. Children with CMT may be described as clumsy or not good at sport before any other symptoms are noticed.

High arched feet can lead to instability of the foot and ankle, with twisting of the ankles becoming very common. Curled or hammer toes are a very common symptom and can result in pain from ill-fitting shoes.

Symptoms can progress noticeably at the time of the growth spurt associated with puberty.

Some sensory loss and numbness usually occurs in both the arms and legs, but is rarely troublesome. However, occasionally this numbness can be severe, leading to a risk of injury without knowing it. Extremely cold hands and feet are also common.

Later, as the condition progresses the hands and forearms tend to become affected, but this is often as many as ten years after foot and leg problems appear. This can lead to loss of fine motor control, dexterity and overall hand strength, making doing up buttons difficult and undoing jam-jars and bottles almost impossible.

Pain is often a feature of CMT, and is usually a result of poor walking putting additional stress on the knees, hips, back and even shoulders and neck. More rarely, the damaged nerves themselves cause pain, known as neuropathic pain.

Some people with CMT experience tremor in both the arms and legs. Severe tremor and CMT is given the name ‘Roussy-Levy Syndrome’.

Most people with CMT remain able to walk throughout life and life expectancy is normal. However, later in life walking aids may be needed, such as orthoses (splints) and walking sticks. Many people use wheelchairs for occasional use, to relieve the pain and effort of walking but it is rare for someone with CMT to become a full-time wheelchair user.

Some very rare symptoms of CMT include; curvature of the spine (scoliosis) and speech, swallowing and breathing difficulties, particularly when lying flat in bed at night.

How is CMT diagnosed?
The first step towards a diagnosis involves a neurologist taking a detailed patient history, including family history. A neurological examination will then look for evidence of muscle weakness and wasting and reduced reflexes and sensory loss. Any foot problems will also be examined.

Tests which measure the speed and strength of nerve signals are then done which can help to narrow down the diagnosis into CMT types 1 and 2. If the nerve impulses travel slowly, this is classified as Type 1 CMT and if the speed is almost normal, but the strength of the signal is reduced – this is Type 2 CMT. Nerve conduction tests involve placing electrodes on the skin which give a mild electrical shock. The shock stimulates the sensory and motor nerves and the speed and size of the transmitted signal is measured. Electromyography (EMG) is sometimes also done which involves a needle electrode being inserted through the skin to measure the electrical activity of the muscles.

The next stage of diagnosis is to do a genetic test to try and determine the type of CMT. Certain symptoms, the results of nerve testing and the family history will give the doctor clues as to what genes to test first. Arriving at this very specific diagnosis is not always straightforward because two patients with very different symptoms could have errors in the same gene. Conversely two patients with very similar symptoms could have changes to different genes. Also, not all the genes causing CMT have been identified yet, or are commonly available to test, so a genetic diagnosis may not be possible.

How can the symptoms be managed?
The symptoms of CMT can be well managed with access to the right help. After diagnosis by a neurologist, referrals can be made to other health professionals as required such as: a podiatrist, orthotist, orthopaedic surgeon, physiotherapist and/or occupational therapist (OT).

Feet
The feet are often one of the first parts of the body to be affected by CMT, with problems including very high arches, hammer toes, loss of feeling, foot drop and weak ankles. Some of the health care professionals that may be enlisted to help manage these problems include podiatrists, orthotists and surgeons.

Orthotics or splints can help improve walking, control foot drop and ankle instability and often provide a better sense of balance. It is also important for people with CMT to find appropriate footwear that is comfortable and provides good arch support.

Surgery on the feet may be pursued as a last resort after weighing up the potential risks and benefits. Procedures include straightening and pinning the toes, lowering the arch, and sometimes, fusing the ankle joint to provide stability.

Lack of feeling in the feet can make it dangerous for people with CMT to trim nails or remove calluses and corns on the feet so it is important to consult a podiatrist. If there is lack of feeling it is also important to avoid bruises, blisters, splinters, burns, cuts, cracks and sores on the feet and if they do occur seek medical advice. Check your feet every day for problems such as these and if they are not healing properly talk to your doctor promptly. It is also advised to keep the hands and feet warm since CMT can cause poor circulation.

Falls
CMT can increase the chance of falls. This is particularly hazardous for people with CMT as fractured bones take longer to heal and inactivity while recovering from a fall may exacerbate existing muscle weakness.

Making sure you are wearing good shoes (with orthoses, if necessary), clearing any trip hazards from your home and taking particular care on uneven ground can all help you avoid falls.

Fatigue
People with CMT experience fatigue as a result of the extra effort required to perform daily activities. An occupational therapist can give advice on energy conservation strategies. Other strategies to manage fatigue include:

• eat small amounts of healthy food more often
• exercise regularly
• get enough sleep
• keep well hydrated
• maintain a healthy weight
• reduce stress
• cut out caffeine
• reduce alcohol consumption

There is also some evidence that talking therapies such as counselling or cognitive behavioural therapy (CBT) might help to fight fatigue.

Physiotherapy and exercise
It is important for people with CMT to maintain what movement, muscle strength and flexibility they have. Hence, physiotherapy and moderate activity are recommended. Overexertion, however, should be avoided. Swimming or water therapy is an excellent form of exercise since it does not put undue stress on the joints. A physiotherapist can design an exercise program that fits a patient’s personal strengths and flexibility. Strengthening unaffected muscles that can help do the work of those that are weak is of particular value. More information about exercise and physiotherapy is available here.

Maintaining a healthy weight is important for people with CMT. Not only does extra weight make physical activity more difficult, but it also increases the stress on already compromised joints and muscles.

Pain and stress
Help to manage pain should be obtained from medical professionals. Pain can range from sharp, sudden pain to continuous dull aches and pains. Pain can originate from dysfunctional nerves and/or weakened muscles. Joints and ligaments in the feet and ankles are often painful because of the extra strain put on them by weakened muscles. Because the causes of pain vary, so will the treatments.

Any disabling, chronic condition can affect the way people think and feel about themselves, and often causes stress and depression. Some patients cope successfully on their own or with the support of family and friends; others find it therapeutic to talk to a professional counsellor or to participate in a support group.

Breathing problems
A very small percentage of people with severe CMT have problems with their breathing. However, it is still worth being aware of the early signs of breathing difficulty which usually occur at night. These signs include frequent chest infections, daytime sleepiness and morning headaches. If you think you are having breathing problems you should be referred to a specialist for sleep studies. If a breathing problem is diagnosed a non-invasive ventilator device can be used, which is usually only needed at night. People with respiratory weakness can be prone to chest infections so it is recommended that the flu and pneumococcal vaccines are given and that any respiratory infections are promptly treated.

What research is being done?
Much of the research ongoing around the world is focussed on understanding how the changes to the many CMT genes cause the symptoms of the condition. Each gene has a different role in the functioning of the peripheral nerves and unravelling this is an essential step to developing therapies. Scientists are also developing the tools to study the conditions, such as animal models.

Understandably, the greatest is known about the most common type of CMT — CMT1A — which is caused by the presence of an extra copy of a gene that carries the information for making a protein called “peripheral myelin protein 22” (PMP22). This results in excessive amounts of PMP22 being produced which impairs the formation of the myelin sheath. Treatment strategies currently being developed for CMT1A involve reducing the production of PMP22 protein. One way of doing this would be to use ‘gene silencing’ which uses small pieces of genetic material called ‘siRNA’ or ‘antisense oligonucleotides’ to specifically interfere with the reading of the PMP22 gene. However, gene silencing is a relatively new technique so applying it to CMT may be some way off yet. In the meantime more conventional drugs are being investigated for their ability to ‘switch off’ PMP22.

Vitamin C is one substance that has been shown in mouse models to reduce levels of PMP22 and improve mobility. As such, clinical trials of high dose Vitamin C have been conducted in various centres around the world. Four of them have been completed, but unfortunately none of them resulted in significant improvements in symptoms. So, now researchers are looking at other substances that might be more effective in humans.

Researchers are screening collections of thousands of chemicals, including drugs that are already available for treating other conditions, for those that are effective at switching off the PMP22 gene. This is known as “high throughput screening”. Some promising candidates have been identified and the next step will be to test them in animal models. Care will need to be taken in the dosing though, because it is known that reducing levels of PMP22 too much can cause another related neuromuscular condition called Hereditary Neuropathy with Liability to Pressure Palsy (HNPP). High throughput screening has also been proposed for other types of CMT – projects focusing on CMT1B, CMT2A and CMT2E have received funding.

Swiss company Addex Therapeutics has been doing preclinical testing of a drug called ADX71441 in a rat model of CMT1A with promising results. ADX71441 is similar to a known drug called baclofen but has been modified to hopefully be longer acting and have fewer side effects. The company has said that it is planning a clinical trial of ADX71441 for CMT1A but no further details are available at this time.

French biopharmaceutical company Pharnext has conducted a phase 2 clinical trial of a potential treatment called PXT3003 which combines low doses of two already approved drugs and one nutrient. The company claims that that the outcome of the trial was positive although no results have been released. Pharnext has joined forces with Ipsen Pharmaceuticals to move the treatment into larger clinical trials.

Other possible treatments that are being researched include:

• Curcumin, a component of the spice turmeric, has been shown to benefit mice with CMT1A and 1B. This laboratory based research may lead to a clinical trial and if successful may also be applicable to some other types of CMT.
• The supplement L-serine has shown promise in mice and a small pilot clinical trial in humans for treating ‘hereditary sensory and autonomic neuropathy type 1’ (HSAN1) ¬— a condition closely related to CMT. A larger clinical trial has now started.
• Gene therapy which involved injecting a virus carrying the neurotrophin 3 gene has been shown to benefit mice with a disease resembling CMT1A. In these mice neurotrophin 3 protein was produced which promotes nerve growth and survival.
• Drugs that block a molecule in the body called ‘HDAC6’ have been shown to benefit a mouse model of CMT2F. HDAC6 inhibitors are currently in clinical trial for other conditions such as cancer.

The Charcot-Marie-Tooth Association Australia (CMTAA) has a list of clinical studies currently recruiting in Australia. One study is investigating footwear, fatigue and falls and two others are researching different strength training regimes. There are also several observational clinical studies, which document the natural progression of various different types of CMT, being conducted at Westmead Hospital in Sydney. This research is essential to further understand CMT, improve care and prepare for future clinical trials.

NOTE: Research is moving forward at a fast pace, so this research summary may not be up-to-date at the time of reading.

Further information
• Other useful websites for people affected by CMT are:
o Charcot-Marie-Tooth Association (USA)
o CMT United Kingdom
o Hereditary Neuropathy Foundation (USA)
Clinical trials – your questions answered
• For definitions of any terms that you are not familiar with please take a look at our glossary
• You can get regular updates by becoming a friend of the MDA Facebook page

For further information on any of the areas discussed above, please contact MDA:
Phone: (03) 9320 9555
Email: info@mda.org.au

Revised 2 June 2014.

References
Saporta MA, Shy ME. Inherited peripheral neuropathies. Neurol Clin. 2013 May;31(2):597-619.

Reilly MM, Shy ME. Diagnosis and new treatments in genetic neuropathies. J Neurol Neurosurg Psychiatry. 2009 Dec;80(12):1304-14