Charcot-Marie-Tooth disorder

Definition

The name Charcot-Marie-Tooth disorder (CMT) refers to a group of hereditary diseases, all involving chronic motor and sensory neuropathies. Drs. Charcot and Marie of France, and Dr. Tooth of England first described the disorder in 1886 when they found patients with progressive muscle weakness and muscle loss in their feet and lower legs. Over time, this weakness progressed to their hands and forearms. More is now known about the numerous disease subtypes, including their complex genetics and inheritance patterns.

Description

Charcot-Marie-Tooth disorder is also known by the names hereditary motor and sensory neuropathy, and peroneal muscular atrophy. A person with CMT often has distal muscle weakness and atrophy that involves the feet, legs, and hands. Many people with CMT are diagnosed later in life as adults. However, diagnosis can happen as early as the first to third decade of life when there is a family history of CMT. The muscle weakness may begin painlessly, symmetrically, and slowly. Many CMT subtypes seem similar and may only be identified through further neurological or genetic testing.

Learning problems are not commonly associated with CMT, but psychological issues from living with progressive muscle weakness can occur. Only some rare X-linked forms of CMT involve mental retardation or deafness as occasional symptoms, but these are not typical of classical CMT.

Demographics

CMT is the most common genetic cause of neuropathy. It is estimated to affect between one in 2,500 to one in 5,000 people, with most of them having CMT type 1 (CMT1). About 20% of people who come to neuromuscular clinics with a chronic peripheral neuropathy have some form of CMT. The condition affects people of all ethnic groups worldwide. Most forms affect males and females equally, with the exception of the X-linked form, which usually affects males more severely than females.

As of 2004, numerous genes have been found responsible for various subtypes of CMT. Genetic testing is available for some types. For other types, genetic testing is not yet available.

Causes and symptoms

Mutations in several genes cause the various types of CMT to occur. The most common form of the disorder, CMT1A, is caused by duplication in the peripheral myelin protein 22 (PMP22) gene. In these cases, the PMP22 gene is too active from the extra genetic material, so it makes too much myelin protein. The correct amount of myelin protein is important for normal muscle strength and movement, so the extra amount can cause these problems.

CMT is inherited in many ways, as seen by varying family histories of the condition. CMT1 and CMT2 are typically inherited in an autosomal dominant manner. This means that an affected individual has a 50/50 chance of passing a disease-causing mutation to his or her children, regardless of gender. In these cases, a strong family history of the condition may be seen.

CMT4 and some forms of CMT2 are inherited in an autosomal recessive manner. This means that an affected individual has parents who each carry the CMT gene. These parents run the risk of having a child with CMT with every pregnancy.

CMT is also inherited in an X-linked manner, and the most common type is called CMTX. Women may be carriers of this type. They are usually more at risk to have affected sons. Daughters may be carriers and they may or may not show milder symptoms.

The neurological symptoms in CMT can progress slowly, but may become problematic over time. Muscle weakness is usually found first in the foot and lower leg muscles. It can eventually include the upper leg and hips in severely affected people. Since the middle of the legs are usually stronger, most people with CMT can still usually walk with the aid of ankle splints.

Some early signs of CMT may be gait abnormalities, or clumsiness in running. Many people with CMT develop pes cavus with very high arches in their feet, and this can be associated with curled-up toes. Loss of nerve functioning can lead to the inability to notice very hot and cold sensations, or the sensation of touch.

Upper limb muscles may become weaker, and this includes the hands and forearms. Due to this, people may have difficulty with fine motor tasks like writing. People with more advanced CMT may develop bone changes, like scoliosis. This may cause back pain if it is very severe.

A specific sign of CMT1A is the "onion bulb" formation in muscular nerves. Nerves with repeated myelination and demyelination (due to abnormalities in the PMP22 gene) may eventually take on the shape of an onion bulb, which is how the finding was named.

Diagnosis

Until the discovery of the CMT genes, the diagnosis of the condition was made on a clinical basis. The difficulties lie in the similarities with other neuropathies like hereditary neuropathy with liability to pressure palsies (HNPP) and those associated with disorders like alcoholism, drug dependence, and diabetes.

An important first step to diagnosing CMT is taking a careful family history. A positive family history is an indicator that the neuropathy may be hereditary. Additionally, the pattern of affected individuals can give clues about the inheritance type in the family.

Carefully documenting the timing of symptoms is also important. Only a minority of people with CMT seek a medical opinion in childhood, since most are diagnosed later in life. An exception might be the highly informed family in which there is a strong history of the condition.

Skeletal signs like pes cavus and scoliosis occur in hereditary neuropathies, but tend to show up when the symptoms begin early. They may be absent when the onset is later in life, even in CMT. This may be an important clue when attempting to diagnose CMT. CMT may also include symptoms like mental retardation and hearing loss, as seen in some rarer X-linked forms.

A slow progression of symptoms is typical of CMT. Some hereditary neuropathies, like HNPP, may have periods of severe symptoms that get better and then worsen later. Again, careful documentation of symptoms is important to diagnose CMT.

Some signs of CMT are found through electrophysiological studies, like electromyography (EMG) and nerve conduction velocity (NCV) testing. EMG results are usually abnormal, and NCV studies may show slowed nerve conduction, a sign of muscle weakness. Those with CMT type 1 usually show severe slowing in NCV studies, and type 2 is associated with mild or no slowing.

EMG and NCV studies are very important tools for physicians to use when thinking of a hereditary neuropathy. These are often abnormal, with reduced NCV values. A nerve biopsy is rarely necessary to pinpoint a specific type of CMT, because onion-bulb abnormalities are a sign of CMT1A.

It may still be difficult to diagnose CMT with electrophysiological test results and clinical information. The results from testing may help to determine which genetic testing to pursue. Genetic testing is useful for confirming a clinical diagnosis or for family testing when there is an identified CMT gene mutation in the family. As of 2004, genetic testing for CMT type 1 is more available than testing for CMT type 2.

Genetic testing is not perfect and results can be tricky to interpret. An informative test result is one that identifies a known mutation in a CMT gene, and this confirms that the person has CMT. A negative test result means a mutation was not found in the gene. This either means that the tested individual does not have CMT, or has a mutation that cannot be found through testing. It may also mean the individual has a different type of CMT or another disorder altogether. Medical geneticists and genetic counselors can be very helpful in interpreting complex genetic test results.

Treatment team

Treatment for people with CMT is often dependent upon symptoms. A multi-disciplinary team and approach can be helpful. A treatment team may include a neurologist , medical geneticist, genetic counselor, orthopedic surgeon, otolaryngologist, physical therapist, occupational therapist, social worker, physiatrist, neuropsychologist , and a primary care provider. Oftentimes there are pediatric specialists in these fields who aid in the care for children. The key is good communication between the various specialists to coordinate medical care.

Treatment

There is no cure for Charcot-Marie-Tooth disorder. No specific treatment is known to reverse, slow, or stop the progressive nature of the disease.

In order to keep flexibility and muscle length in the ankles and feet, daily stretching of the heel cords can be helpful. Special shoes with ankle and orthopedic inserts may help to improve walking and movement. Corrective surgery by an orthopedic surgeon is required in some cases. Others need forearm crutches or canes to keep stable while walking, but fewer than 5% of people with CMT need wheelchair assistance. Splints, specific exercises, orthopedic devices, and sometimes surgery are needed to keep hands functioning well.

Certain medications can be helpful for people with CMT, while others should be avoided because they can cause nerve damage. Examples of drugs to be avoided include alcohol, high doses of vitamins A and D, penicillin, taxol, and certain chemotherapy medications (vincristine, cisplatin).

For overall health, a good diet and regular exercise are recommended. Exercise is particularly important because it keeps muscles functioning and maintains endurance levels.

Recovery and rehabilitation

Rehabilitation can be ongoing in CMT, particularly if the muscle weakness has progressed considerably. Since the disorder does not typically get better with time, physical therapy and strength maintenance is very important. The disease's early stages may not cause problems for walking or daily activities, but over time it can greatly impact a person's life. Physical therapy may be relatively infrequent early on, but may increase as time goes on.

Children may have difficulty with tasks in school, such as writing and other fine motor skills. Occupational therapists, often available at school, are helpful in these situations. Overall, a person's time spent in recovery and rehabilitation is variable. Specialists in physical medicine and rehabilitation can be helpful in coordinating a plan to help someone retain his or her strength for as long as possible.

Prognosis

Prognosis for someone with Charcot-Marie-Tooth disorder is unique to the person. The severity of the symptoms can vary greatly, even within the same family. Those who develop the disease as children may have more severe muscle weakness by the time others first see signs of the disease. However, only about 5% of people with CMT need wheelchairs at any point in their lives. CMT is not considered a fatal disease. Symptoms are chronic and progressive, and can negatively impact a person's life.

Genetic testing now helps identify people before they even develop symptoms, so personalized medical care can begin as early as possible. This has helped to reduce the risk of complications and increase the quality of life for many. Medical screening may be further tailored to the individual as scientific studies identify medical complications associated with specific CMT mutations in families.

Special concerns

Due to specific muscular weakness and difficulty with fine motor tasks, careful career and job consideration is helpful for people with CMT.

Resources

BOOKS

Parker, James N., and Philip M. Parker. The Official Patient's Sourcebook on Charcot-Marie-Tooth Disorder: A Revised and Updated Directory for the Internet Age. San Diego: Icon Health Publishers, 2002.

Parry, Gareth J. Charcot-Marie-Tooth Disorders: A Handbook for Primary Care Physicians. DIANE Publishing Co., 1995.

PERIODICALS

Bell, Christine, and Neva Haites. "Genetic Aspects of Charcot-Marie-Tooth Disease." Archives of Disease in Childhood (April 1998) 78: 296–300.

Benstead, Timothy J., and Ian A. Grant. "Charcot-Marie-Tooth Disease and Related Inherited Peripheral Neuropathies." Canadian Journal of Neurological Sciences (2001) 28: 199–214.

Berciano, Jose, and Onofre Combarros. "Hereditary Neuropathies." Current Opinion in Neurology (2003) 16: 613–622.

Pareyson, Davide. "Diagnosis of Hereditary Neuropathies in Adult Patients." Journal of Neurology (2003) 250: 148–160.

Vallat, Jean-Michel. "Dominantly Inherited Peripheral Neuropathies." Journal of Neuropathology and Experimental Neurology (July 2003) 62(7): 699–714.

WEBSITES

National Institute of Neurological Disorders and Stroke. (March 30, 2004). <http://www.ninds.nih.gov/index.htm>.

Online Mendelian Inheritance in Man. (March 30, 2004). <http://www.ncbi.nlm.nih.gov/omim/>.

ORGANIZATIONS

Charcot-Marie-Tooth Association. 2700 Chestnut Street, Chester, PA 19013-4867. (800) 606-CMTA; Fax: (610) 499-9267. [email protected]. <www.charcot-marietooth.org>.

CMT World. P.O. Box 601, Hillsburgh, Ontario N0B 1Z0, Canada. (519) 855-6376; Fax: (519) 855-6746. [email protected]. <www.cmtworld.org/index.php>.

Muscular Dystrophy Campaign U.K. 7-11 Prescott Place, London SW4 6BS, U.K. +44 (0)171-720-8055; Fax: +44 (0)171-498-0670. [email protected]. <www.muscular-dystrophy.org>.

Deepti Babu, MS, CGC