Charcot-Marie-Tooth Disease

Jean Martin Charcot. Source: National Library of Medicine.

Charcot-Marie-Tooth disease (CMT) is an inherited disease that affects both motor and sensory functions of peripheral nerves. It typically affects the lower legs and usually manifests as leg weakness and loss of sensation. Over time, this commonly leads to structural foot deformities (pes cavus, callouses, hammer toes) as well. The disease comprises a group of disorders caused by mutations in genes that affect the normal function of the peripheral nerves. The peripheral nerves lie outside the brain and spinal cord, and connect to the muscles and sensory receptors in the limbs. Supportive care and slowing progression is the most common treatment for CMT because there is no definitive treatment for this debilitating disease at this time. Continued genetic and bio-research is needed for this group of hereditary disorders.

Other Names

• Hereditary motor and sensory neuropathy (HMSN)
• Peroneal muscular atrophy

Types

Diagram of a neuron. 1-Dendrite; 2-Axon; 3-Nodes of Ranvier; 4-Axon Terminals; 5-Schwann cell (Myelin Sheath); 6-Cell body; 7-Nucleus. Source: Nick Gorton, Wikimedia Commons.

There are a number of subtypes of Charcot-Marie-Tooth disease.

Type 1

This type, caused by abnormalities in the myelin sheath of the nerve, has three subtypes:

• CMT1A is an autosomal dominant disease resulting from a duplication of the gene on chromosome 17 that carries the instructions for producing the peripheral myelin protein-22 (PMP-22). The PMP-22 protein is a critical component of the myelin sheath. An overabundance of this gene causes the structure and function of the myelin sheath to be abnormal. Patients experience weakness and atrophy of the muscles of the lower legs beginning in adolescence; later they experience hand weakness and sensory loss. Hereditary neuropathy with predisposition to pressure palsy (HNPP), a separate but distinct type of CMT1 is caused by a deletion of one of the PMP-22 genes. In this case, abnormally low levels of the PMP-22 gene result in episodic, recurrent symptoms.
• CMT1B is an autosomal dominant disease caused by mutations in the gene that carries the instructions for manufacturing the myelin protein zero (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 30 different point mutations in the P0 gene. As a result of abnormalities in P0, CMT1B produces symptoms similar to those found in CMT1A.
• CMT1C, which also produces symptoms similar to that of CMT1A. The gene defect has not yet been identified.

Type 2

CMT2 results from abnormalities in the axon of the peripheral nerve cell rather than the myelin sheath. There are many subtypes of CMT2, designated by the letters from A-L. Each subtype is characterized by the mode of inheritance and associated clinical features. The genetic loci have been identified for some subtypes. Recently, a mutation was identified in the gene that codes for the kinesin family member 1B-beta protein in families with CMT2A. [Kinesins (KIF gene family)|Kinesins]] are proteins that act as motors to help power the transport of materials along the train tracks (microtubules) of the cell. Another recent finding is a mutation in the neurofilament-light gene, identified in a Russian family with CMT2E. Neurofilaments are structural proteins that help maintain the normal shape of a cell.

Type 3

CMT3 or Dejerine-Sottas Disease is a severe demyelinating neuropathy that begins in infancy. Infants have severe muscle atrophy, weakness, and sensory problems. This rare disorder can be caused by a specific point mutation in the P0 gene or a point mutation in the PMP-22 gene.

Type 4

CMT4 comprises several different subtypes of autosomal recessive demyelinating motor and sensory neuropathies. Each neuropathy subtype is caused by a different genetic mutation, may affect a particular ethnic population, and produces distinct physiologic or clinical characteristics. The subtypes include: ^[1]

• CMT 4A 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.
• CMT 4B involves a chromosomal defect on chromosome 11. The defect involves a folded myelin sheath which can be seen on a nerve biopsy. 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.
• CMT 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.
• CMT 4D appears to be a separate disorder with linkage to Chromosome 8 and autosomal recessive inheritance. Symptoms include 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.
• CMT 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.

Type X

CMTX is an X-linked dominant disease and is caused by a point mutation in the connexin-32 gene on the X chromosome. The connexin-32 protein is expressed in Schwann cells-cells that wrap around nerve axons, making up a single segment of the myelin sheath. This protein may be involved in Schwann cell communication with the axon. Males who inherit one mutated gene from their mothers show moderate to severe symptoms of the disease beginning in late childhood or adolescence (the Y chromosome that males inherit from their fathers does not have the connexin-32 gene). Females who inherit one mutated gene from one parent and one normal gene from the other parent may develop mild symptoms in adolescence or later or may not develop symptoms of the disease at all.

Signs and Symptoms

Hammer toe. Source: Wikimedia Commons.

Typical features of this disease include:

• Weakness of the foot and lower leg muscles which may lead to foot drop and a high-stepped gait with frequent tripping or falls.
• Foot deformities, 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.
• The lower legs may take on an "inverted champagne bottle" appearance due to the loss of muscle bulk.
• Later in the disease, weakness and muscle atrophy may occur in the hands, resulting in difficulty with fine motor skills.

Onset of symptoms is most often in adolescence or early adulthood, however presentation may be delayed until mid-adulthood. The severity of symptoms is quite variable in different patients and even among family members with the disease. Progression of symptoms is gradual. Pain can range from mild to severe, and some patients may need to rely on foot or leg braces or other orthopedic devices to maintain mobility. Although in rare cases patients may have respiratory muscle weakness, CMT is not considered a fatal disease and people with most forms of CMT have a normal life expectancy.

Causes

The peripheral nervous system involves motor neurons (carry messages from the brain to the body through the spinal cord) and sensory neurons (carry messages from the body to the spinal cord and the brain).

Upper motor neurons run from the brain to the spinal cord. They remain within the central nervous system. They synapse (connect) with the lower motor neurons, which carry signals from the spinal cord to the muscles of the body.

Because CMT affects the peripheral nervous system, which contains both motor and sensory neurons, both motor (weakness and muscle wasting) and sensory (numbness) symptoms may occur.

The peripheral nerves consist of an inner core, called the axon, which is wrapped in insulation known as the myelin sheath. When the myelin is damaged as in Type 1 CMT, the nerve impulses are conducted more slowly than normal. If the axon itself is damaged (Type 2 CMT), the speed of nerve conduction is almost normal, but the strength of the signal is reduced.

The various forms of CMT all involve abnormalities in either the axon or myelin. Since CMT is a multi-gene disorder, there are many different defective genes which cause the disorder. There are also many different manifestations of the disease. For a description by type, see the Types section above.

Diagnosis

The diagnosis of CMT begins with a thorough patient history, family history, and physical examination. The history involves thorough questioning of the patient about the character and duration of symptoms and whether other family members have similar symptoms.

The physical examination focuses on the neurological examination, particularly any muscle weakness in the arms, legs, hands, and feet, decreased muscle bulk, reduced tendon reflexes, and sensory loss. The examining physicial will also look for evidence of foot deformities, such as high arches, hammertoes, inverted heel, or flat feet as well as for any other associated orthopedic problems (like scoliosis). Physical examination may also reveal hypertrophic nerves, caused by abnormally thickened myelin sheaths.

Exams and tests

When the physical examination and history suggest CMT, further testing is usually done. This testing may include:

• Nerve conduction studies. In this test, electrodes are placed on the skin over a peripheral motor or sensory nerve. The electrodes produce a small electric shock that stimulates the sensory and motor nerves. The resulting electrical activity is recorded by electrodes further down the nerve's pathway. The distance between electrodes and the time it takes for electrical impulses to travel between electrodes are used to determine the speed of the nerve signals.
• Electromyography (EMG) involves inserting a needle electrode through the skin to measure the electrical activity of muscles. The electrical activity detected by this electrode is displayed on an oscilloscope, and may be heard through a speaker. Abnormalities in this test suggest degeneration of the nerve axon.
• A nerve biopsy involves removing a small piece of peripheral nerve through an incision in the skin. This is most often done by removing a piece of the nerve that runs down the calf of the leg. The nerve is then examined under a microscope. Patients with CMT1 typically show signs of abnormal myelination. Specifically, "onion bulb" formations may be seen which represent axons surrounded by layers of demyelinating and remyelinating Schwann cells. Patients with CMT2 usually show signs of axon degeneration. ^[1]

Genetic testing is available for some types of CMT and may soon be available for other types; such testing can be used to confirm a diagnosis and may give information about the risk of transmitting the disease to one's offspring.

Treatment

There is no cure for CMT, but physical therapy, occupational therapy, braces and other orthopedic devices, and orthopedic surgery can help people cope with the disabling symptoms of the disease. In addition, pain medicine can be prescribed for patients who have severe pain.

Medications

Common types of medication used for the pain associated with CMT include:

• Tricyclic antidepressants (TCAs) like amitryptyline, nortriptyline, and desipramine. This older class of antidepressant medicine is often used for chronic pain. The mechanism of action is thought to be blockage of norepinephrine receptors. These medicines are sedating and usually taken at night.
• Gabapentin, a medicine used for the treatment of epilepsy, is also commonly employed for the treatment of chronic pain. It appears to work by mimicing the neurotransmitter GABA.
• Narcotics, especially long-acting narcotics such as the fentanyl patch, MS Contin (morphine, and oxycodone (oxycontin).
• Carbamazepine, another anti-seizure medication, appears to work by blocking sodium channels.
• Anti-inflammatory medicines like ibuprofen, naproxyn sodium, and celecoxib as well as corticosteroids, are often used to treat this condition.

Therapies

Physical therapy and occupational therapy, the preferred treatment for CMT, involve muscle strength training, muscle and ligament stretching, stamina training, and moderate aerobic exercise. Most therapists recommend a specialized treatment program designed with the approval of the patient's physician to fit individual abilities and needs. Therapists also suggest entering into a treatment program early; muscle strengthening may delay or reduce muscle atrophy, so strength training is most useful if it begins before nerve degeneration and muscle weakness progress to the point of disability.

Stretching may prevent or reduce joint deformities that result from uneven muscle pull on bones. Exercises to help build stamina or increase endurance will help prevent the fatigue that results from performing everyday activities that require strength and mobility. Moderate aerobic activity can help to maintain cardiovascular fitness and overall health. Most therapists recommend low-impact or no-impact exercises, such as biking or swimming, rather than activities such as walking or jogging, which may put stress on fragile muscles and joints.

Many CMT patients require ankle braces and other orthopedic devices to maintain everyday mobility and prevent injury. Ankle braces can help prevent ankle sprains by providing support and stability during activities such as walking or climbing stairs. High-top shoes or boots can also give the patient support for weak ankles. Thumb splints can help with hand weakness and loss of fine motor skills. Assistive devices should be used before disability sets in because the devices may prevent muscle strain and reduce muscle weakening. Some CMT patients may decide to have orthopedic surgery to reverse foot and joint deformities.

Clinical Trials

A list of ongoing U.S. government-sponsored clinical trials is available: Charcot-Marie-Tooth trials

Research

• A combination of vitamins has been evaluated as a possible treatment for CMT Type 1. This study contends that vitamin A and vitamin E should not be given together with ascorbic acid as they appear to counteract the positive effects of ascorbic acid. ^[2]
• Health-related quality of life was assessed in Australian patients with CMT. Quality of life in CMT was predicted strongly by lower limb weakness and to a lessor extent by leg cramps, suggesting clinical trials targeting weakness and cramps may improve health-related quality of life in patients with CMT. ^[3]
• The importance of pain as a symptom of CMT, especially as it relates to quality of life, was studied in a recent clinical trial. The study recommends further studies on this subject. ^[4]
• The incidence of sleep apnea appears to be increased in patients with CMT1. This may be a result neuropathy in the upper airway leading to more frequent collapse of the airway during sleep. ^[5]
• A subset of CMT1 appears to have worsening symptoms over successive generations. The cause of this process is unknown. ^[6]

Expected Outcome

Onset of symptoms of CMT is most often in adolescence or early adulthood. However presentation may be delayed until mid-adulthood. Progression of symptoms is very gradual. CMT is not fatal and people with most forms of CMT have a normal life expectancy.

History

The disease is named for the three physicians who first identified it in 1886 - Jean-Martin Charcot and Pierre Marie in Paris, France, and Howard Henry Tooth in Cambridge, England.

Epidemiology

Incidence

Charcot-Marie-Tooth disease (CMT) is one of the most common inherited neurological disorders, affecting approximately 1 in 2,500 people in the United States. ^[7]

An study is ongoing to determine the prevalence of CMT in Southwestern Pennsylvania. ^[8]

References

1. ↑ ^{1.0 1.1} Charcot-Marie-Tooth Association web site. Types and Causes of CMT
2. ↑ Kaya F, Belin S, Micallef J, Blin O, Fontés M. Analysis of the benefits of vitamin cocktails in treating Charcot-Marie-Tooth disease type 1A. Muscle Nerve. 2008 Aug;38(2):1052-4. Abstract
3. ↑ Redmond AC, Burns J, Ovrier RA. Factors that influence health-related quality of life in Australian adults with Charcot-Marie-Tooth disease. Neuromuscul Disord. 2008 Aug;18(8):619-25. Epub 2008 Jul 24. Abstract
4. ↑ Padua L, Cavallaro T, Pareyson D, Quattrone A, Vita G, Schenone A; the Italian CMT QoL Study Group. Padua Charcot-Marie-Tooth and pain: correlations with neurophysiological, clinical, and disability findings. Neurol Sci. 2008 Jun;29(3):193-194. Epub 2008 Jul 9. Abstract
5. ↑ Dziewas R, Waldmann N, Böntert M. Increased prevalence of obstructive sleep apnoea in patients with Charcot-Marie-Tooth disease: a case control study. J Neurol Neurosurg Psychiatry. 2008 Jul;79(7):829-31. Abstract
6. ↑ Steiner I, Gotkine M, Steiner-Birmanns B, et al. Increased severity over generations of Charcot-Marie-Tooth disease type 1A. J Neurol. 2008 Apr 30. [Epub ahead of print] Abstract
7. ↑ National Institute of Neurological Disorders and Stroke. Charcot-Marie-Tooth Disease Fact Sheet
8. ↑ Charcot-Marie-Tooth Association web site. Expanded CMT Prevalence Study in Southwestern Pennsylvania

External Links

Charcot-Marie-Tooth Association (US)

Charcot-Marie Tooth Association (Australia)

Genetics Home Reference: Charcot-Marie-Tooth disease

Muscular Dystrophy Association

National Human Genome Research Institute