What is Chacot-Marie-Tooth disease?

Charcot-Marie-Tooth disease is a hereditary disorder marked by slowly progressive muscle weakness in the feet, lower legs, hands and forearms, and a mild loss of sensation in limbs, fingers, and toes. The weakness results from the degeneration of nerves that stimulate muscle rather than from a degenerative process in the muscle tissue itself.

The disorder, named for three physicians who first identified it in 1886, is also known as peroneal muscular atrophy because if primarily affects the peroneal muscles. which are located in the lower leg. There are now thought to be at least two types of the disease – hypertrophic and neuronal – that differ to some degree in severity.

It may also be referred to as:

  • hereditary motor and sensory neuropathy (HMSN)
  • peroneal muscular atrophy (PMA)
  • Roussy-Levy Syndrome (CMT with the presence of tremours

What is the nervous system?

The nervous system consists of motor neurons and sensory neurons. One set of nerves carries messages from the brain outward to the rest of the body and one brings messages from the extremities back to the brain. Messages that travel from the brain down the spinal cord, through the lower motor neurons (such as the sciatic nerve of the leg) to the muscles of the body are part of the motor neuron circuitry. Messages that travel upward from the sensory input to the spinal cord and finally the brain are sent by sensory neurons.

The nervous system consists of motor neurons and sensory neurons. One set of nerves carries messages from the brain outward to the rest of the body and one brings messages from the extremities back to the brain. Messages that travel from the brain down the spinal cord, through the lower motor neurons (such as the sciatic nerve of the leg) to the muscles of the body are part of the motor neuron circuitry. Messages that travel upward from the sensory input to the spinal cord and finally the brain are sent by sensory neurons.

The peripheral nervous system is also comprised of motor and sensory nerve fibers, and since CMT affects the peripheral nerves, it results in both motor symptoms (weakness and muscle wasting) and sensory symptoms (numbness). The peripheral nerves are often described as being like electrical wires with an inner core (the axon), which is wrapped in insulation (a sheath called myelin).

What are the early symptoms?

People with CMT slowly lose normal use of their feet/legs and hands/arms, as nerves to the extremities degenerate and the muscles become weakened because of the loss of stimulation by the affected nerves. CMT is a slowly progressive condition, but does not generally affect life expectancy.

A typical feature includes weakness of the foot and lower leg muscles, which may result in foot drop and a high-stepped gait with frequent tripping or falls. Foot abnormalities, such as high arches and hammertoes (a condition in which the middle joint of a toe bends upwards), are also characteristic due to weakness of the small muscles in the feet. In addition, the lower legs may take on an “inverted champagne bottle” appearance due to the loss of muscle bulk.

Later in the condition, weakness and muscle atrophy may occur in the hands, resulting in difficulty with fine motor skills. Although sensory nerves are also involved, patients rarely notice significant numbness or pain. Many patients also have some loss of sensory nerve function and is associate with the loss of sensation or touch is often accompanied by tingling and burning sensations in the hands and feet.

The severity of the condition can vary widely, even in the same family.

In what other ways do the hypertrophic and neuronal types differ?

The small muscles of the hand are more affected in the hypertrophic type than they are in the neuronal, and sensory changes are more pronounced. This form of Charcot-Marie-Tooth disease is also characterised by enlarged (hypertrophic) nerves and by degeneration of the sheath of fatty material (myelin) that insulates many of the body's nerve fibres. The neuronal form of Charcot-Marie-Tooth disease affects lower limb functions more than the hypertrophic form, and there is comparatively greater loss of muscle bulk below the knee. Weakness in the ankles and feet is also likely to be more severe in the neuronal type.

How does a person get Charcot-Marie-Tooth disease?

The disease is usually inherited as a dominant trait in both the hypertrophic and neuronal types. This means that it is only necessary for one parent to carry the defective gene for the disease to be transmitted. It also means that this parent will have the disease, although he or she might be unaware of it if the disorder is very mild with no apparent symptoms. There is a fifty percent chance that a child will inherit the disorder if either parent carries the gene. Male and female children are equally affected.

How is Charcot-Marie-Tooth disease diagnosed?

Diagnosis is usually made through a physical examination that includes tests of muscle function and sensory responses, supplemented with a laboratory test (electromyogram) that measures the electrical activity of muscle cells. In addition, a complete family medical history is taken to determine if the patient's disorder is an inherited one. In some cases, nerve and muscle biopsies may be done to enable the physician to confirm the diagnosis, especially when symptoms are very mild and family history of the disease is not apparent. Both electromyography and muscle biopsy tests help to distinguish between the hypertrophic and neuronal types of the disorder.

Is there any cure?

There is no known cure for Charcot-Marie-Tooth disease. However, foot deformities can be treated with carefully fitted shoes and proper foot care. A regular program of moderate excerise can build up muscles and increase the mobility of joints.

What research is being done?

Scientists are exploring the basic areas of nerve function, development, degeneration, and of nerve muscle interaction to uncover the underlying pathological process in Charcot-Marie -Tooth disease. Fundamental defects of lipid (fat) metabolism have been found in several inherited neuromuscular diseases that are clinically similar to Charcot-Marie-Tooth disease, and the possibility that this abnormality may also be of significance in Charcot-Marie-Tooth disease under investigation.

What are all the types of CMT?

When the myelin is damaged (like that in Type 1 CMT), the nerve impulses are conducted more slowly than normal. If the axon itself is damaged (like that in Type 2 CMT), the speed of nerve conductionis almost normal, but the strength of the signal is reduced.

All forms of CMT are either demyelinating or axonal in nature. Since CMT is a multi-gene disorder, there are many different defective genes which cause the disorder. Since 1991, more than 30 different genes causing CMT have been identified and the loci are known for at least another ten causes. The ones that have been identified to date are:

CMT Type 1

With the exception of Type 1X, which is inherited through the XChromosome, CMT Type 1 is inherited in an autosomal dominant pattern. CMT Type 1 accounts for more than two-thirds of all cases of CMT.

Type 1A

This is the most common form of CMT, comprising at least 60 percent of all patients with CMT Type 1. The disorder is caused by a duplication of the PMP22 gene on Chromosome 17. Instead of having two copies of the gene (one of each paired chromosome), there are three copies, two on one chromosome and one on the other. PMP22 is a peripheral myelin protein, but its exact function in causing CMT is still not known. It is inherited in an autosomal dominant fashion.

CMT1A usually presents with a typical CMT phenotype (clinical presentation). Patients are slow runners in childhood, develop high arches, hammer toes and often require orthotics (braces) for ankle support. Varying degrees of hand weakness occur, often appearing as much as ten years after foot and leg problems. Problems with balance because of ankle weakness and loss of proprioception are common. Most patients remain ambulatory throughout life and life expectancy is normal.

Type IB

This type is caused by a defect of the MPZ gene on chromosome 1. Again, MPZ is peripheral myelin protein, but its role is not known. Type 1B is an autosomal dominant disorder. Patients with 1B have a somewhat typical phenotype, but often with more pronounced calf wasting. There is a wide range of severity within Type 1B, from very severe forms such as Dejerine-Sottas (infantile onset) to milder cases with onset much later in life. (More than one type of CMT may be referred to as Dejerine-Sottas since the term refers to an age of onset of less than three years rather than to a unique genetic defect.)

Type 1C

Researchers at the University of Washington have recently identified the locus of Type 1C as Chromosome 16, the LITAF/SIMPLE gene. Type 1C is also autosomal dominant in inheritance. There is limited clinical information on patients with 1C, but they develop distal weakness, atrophy, and sensory loss and have slow nerve conduction velocity scores.

Type 1D

This type is caused by an early growth response protein 2, known as ERG2, found on Chromosome 10. Inheritance is autosomal dominant. Most cases of 1D are severe, such as Dejerine-Sottas, while a few have milder phenotypes presenting later in life.

Type 1F

Type 1F accounts for a very small percentage of cases. It is an autosomal dominant form of CMT in which the defect is on Chromosome 8 and the neurofilament light chain protein.

Type 1X

This second most common of form of CMT, accounting for 10-16 percent of all cases is found on the X Chromosome, one of sex chromosomes. The flaw is caused by a gap junction beta 1 protein connected to connexin 32. Typically, this form has onset in adolescence or childhood and often affects males more severely than females. An affected male with CMT1X cannot pass the defect to his son, but will pass it to all his daughters. An affected female has a 50% chance of passing the mutation to either her sons or her daughters.

Hereditary Neuropathy with Liability to Pressure Palsies (HNPP)

HNPP is also inherited in an autosomal dominant pattern and is also located on Chromosome 17 at the PMP 22 gene, as is Type 1A. The difference is that there is a deletion rather than a duplication at the gene site. Clinically, HNPP defers from CMT in that patients with HNPP typically have transient episodes of weakness or sensory loss, which can last from hours to days. Thickening of myelin is the hallmark of HNPP.

CMT Type 2

CMT Type 2 represents axonal forms that are dominantly inherited and make up about one-third of all dominant CMT cases. The clinical presentation is similar to Type 1: distal weakness, muscle atrophy, sensory loss and foot deformities. Patients with Type 2 have a wider age range for onset of the disorder and more variation in degree of disability. They are slightly more likely to maintain their deep tendon reflexes.

Type 2A

The defect causing CMT 2A is found on chromosome 1p36 at the MFN2 gene. This gene is mutated and is involved in the fusion of mitochondria, the metabolic engines of the cells.

Type 2B

Type 2B is characterized by severe ulceration problems and the defect is located on chromosome 3, the RAB 7 protein. CMT 2B is predominantly a sensory disorder and there is some thought that it is not really CMT, but a pure sensory neuropathy.

Type 2C

This type is a very rare form in which patients may have diaphragm or vocal cord paresis in addition to the other problems of CMT. Linkage to chromosome 12 has been found.

Type 2D

The CMT 2D locus is on chromosome 7p14 and the genetic cause has been identified as mutations in the glycyl RNA synthetase gene. CMT 2D is a confusing disorder because some patients have sensorimotor neuropathies, while others have only motor symptoms.

Type 2E

CMT type 2E has been established with linkage to chromosome 8p21 and studies have identified mutations in the neurofilament light gene.

CMT Type 3

Dejerine-Sottas syndrome

Type 3 is a particularly severe variant. The term Dejerine-Sottas syndrome (DSS) is used to describe patients who are severely disabled and develop CMT in infancy. This term was coined before the genetic causes of CMT were identified. As a result, the usage of this term is somewhat confusing. Dejerine-Sottas was originally thought to be a severe and disabling neuropathy beginning in infancy with an autosomal recessive inheritance pattern. Recently, it has been shown that DSS patients also have autosomal dominant mutations of PMP22, MPZ, EGR2 and even PRX and GDAP. Most patients with DSS have extremely slow nerve conduction velocities. Most children with DSN have severe demyelination while others show predominantly axonal loss when sural nerve biopsies are done. Currently, the term Dejerine-Sottas is used to define patients who have onset by 3 years of age, delayed motor milestones, and severe motor, sensory and skeletal defects.

Congenital hypomyelination

Congenital hypomyelination (CH) is a term originally used to describe peripheral nerves that were so abnormal that they suggested a developmental failure of the peripheral nervous system myelination. Patients with CH were hypotonic within the first year of life, had developmental delays in walking and had swallowing or respiratory difficulties. Some patients with CH were considered “floppy” infants. It is difficult to distinguish between DSS and CH since both have severe pathological changes on sural nerve biopsies and both have very slow nerve conduction velocities.

CMT Type 4

All Type 4 instances of CMT are inherited in an autosomal recessive pattern and are considered rare. They have various phenotypical presentations but are more severe than autosomal dominantly inherited disorders. These disorders often have systemic symptoms, such as cataracts and deafness. CMT 4A and B are demyelinating and 4C is axonal.

Type 4A

CMT Type 4 is linked to Chromosome 8 and is caused by mutations in the GDAP 1 protein, of unknown function. This form was first described in four families in Tunisia who were highly inbred. Clincial onset began at age 2 with delayed developmental milestones of sitting or walking. Many patients are wheelchair dependent by the end of the first decade of life. Hoarse voice and vocal cord paresis have been reported.

Type 4B

The genetic location for the defect causing Type 4B is on chromosome 11 and presents with focally folded myelin sheaths in nerve biopsies. Affected patients become symptomatic early in life, with an average age of onset at 34 months. Unlike most types of CMT, both proximal and distal weakness is common.

Type 4C

Type 4C is a childhood onset form of hereditary motor and sensory neuropathy (HSMN) with early onset scoliosis. The protein defect defines a new family of unknown function.

Type 4D

This form was first described as a separate disorder with linkage to Chromosome 8 in a Gypsy population with autosomal recessive inheritance. The clinical features included distal weakness, muscle wasting and sensory loss, foot and hand deformities and loss of deep tendon reflexes. Deafness is always found in these patients and occurs by the third decade. Nerve conduction is severely reduced in younger patients and completely unattainable after age 15.

Type 4F

CMT type 4F is a severe form of recessive CMT that has been defined in a large Lebanese family with mutations in the PRX gene on Chromosome 19. Nerve conduction studies are markedly slow and onion bulb formations are observed in nerve biopsies.

Treatment and Management of CMT

Although there is no cure for CMT at the present time, there are many therapies that can greatly improve life and function for CMT patients. The general advice for patients seeking assistance is to look first for the least invasive way to correct their problems.

Medical professionals:

Treatment of CMT is done in conjunction with medical professionals of various specialties. After diagnosis by a neurologist, CMT patients are usually directed to either a podiatrist for care of their foot problems, an orthosis for the manufacture and fitting of braces, an orthopedic surgeon for surgeries to straighten toes, lengthen heel cords or lower arches, or a physical therapist or occupational therapist to design exercise programs to strengthen muscles or learn energy conservation.

Physical therapy:

In general, it is important for people with CMT to maintain what movement, muscle strength and flexibility they have. Hence, physical therapy 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 physical therapist can design an exercise program that fits a patient’s personal strengths and flexibility. It is impossible to build up muscles already atrophied by CMT, so the best program works on strengthening unaffected muscles that can help do the work of those that have atrophied because of CMT.

Braces, orthosis and footware:

Bracing is another non-invasive form of correcting problems caused by CMT. Often gait abnormalities can be corrected by the use of either articulated (hinged) or unarticulated, molded braces called AFOs (ankle-foot orthosis). These braces help control foot drop and ankle instability and often provide a better sense of balance for patients. There are many new forms of bracing available for CMT patients, depending, of course, on the severity of their foot deformities and muscle weaknesses.

Appropriate footwear is important for people with CMT, but they often have difficulty finding well-fitting shoes because of their high arched feet and hammered toes. For this reason, custom-made shoes are often necessary. Large shoe stores often have podiatrists on staff who are certified in fitting shoes for the special foot. They can cast the foot for custom-made shoes or design inserts to make ready-made shoes fit more correctly.

Surgery:

The final decision a patient might make in caring for his/her foot or leg deformities is to have surgery. Many patients 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. Recovery from these surgeries can be long and sometimes difficult. Before considering surgery, a patient should always ask what the benefits may reasonably be considered to be and that must be weighed against the problems that might be incurred.

Pain:

An additional problem related to CMT that needs to be addressed by a medical professional is the pain that some patients experience. Pain might be sharp and sudden or the gnawing, continuous ache of chronic pain. Some pain is associated with dysfunctional nerves that fire off sporadically and some can be attributed to weakened and poorly functioning muscles. Joints and ligaments in the feet and ankles are often painful because of the extra strain put on them by other muscles that have been rendered useless by CMT. Because the causes of pain vary, so will the treatments. No one, however, should be told that there is no pain associated with CMT, since pain is experienced in a very personal and individual way.

Maintaining general health and wellbeing:

Although medical professionals are involved in many stages and forms of treatment, the patients themselves are responsible for much of the management of their CMT. Basically, people with CMT are healthy individuals and they must work to maintain that health. Because circulation is a problem in individuals with CMT, people must take care to keep their hands and feet as warm as possible. They also should take extra care to avoid falling because fractures take longer to heal in someone with an underlying disease process. Additionally, the resulting inactivity may cause the CMT to worsen. Falls can generally be avoided by watching where one walks and by wearing appropriate footwear.

Nutrition:

There is no magic nutritional diet to treat CMT, but it is important for CMT patients to control their weight. Not only does extra weight make physical activity more difficult, but it also increases the stress on already compromised joints and muscles.

Stress management:

Finally, stress management is important in maintaining a healthy body. Any disabling condition can affect the way people think and feel about themselves, but having a chronic illness like CMT, which is often unseen, places stress on individuals and often causes depression. People with CMT can suffer from low self-esteem and relationships with others can be affected. Even when a person has learned to live with CMT, the progressive nature of the disorder may bring about more loss and the grieving process can begin again.

Some patients cope successfully on their own or with the support of family and friends; others find it therapeutic to talk to a professional counselor or to participate in a support group.

MDA's Purpose and Programme.

The Muscular Dystrophy Association (MDA) is committed to providing HOPE for people who suffer from the devastating nerve and muscle disorders. The only way this can be done id an all out offensive to find a control or cure for such diseases. MDA supports medical and scientific research to the extent that funds will allow, it runs a comprehensive public education program and provides physical aids, welfare, moral support and counselling to persons in need. The Muscular Dystrophy Association's programs are funded, almost entirely, by voluntary contributions from concerned individuals and community organisations.

Last Reviewed: 26/09/2013

Reproduced with kind permission from the Muscular Dystrophy Association.


References

1. Muscular Dystrophy Australia. Peripheral Nerve: Chacot-Marie-Tooth. http://www.mda.org.au/Disorders/Peripheral/CMT.asp (accessed Sept 2013).