Charcot-Marie-Tooth Disease
Charcot-Marie-Tooth disease
Definition
Charcot-Marie-Tooth disease (CMT) is the name of a group of inherited disorders of the nerves in the peripheral nervous system. These are the nerves throughout the body that communicate motor and sensory information to and from the spinal cord. CMT causes weakness and loss of sensation in the limbs.
Description
CMT is named for the three neurologists who first described the condition in the late 1800s. It is also known as hereditary motor and sensory neuropathy and is sometimes called peroneal muscular atrophy, referring to the muscles in the leg that are often affected. The age of onset of CMT can vary anywhere from young childhood to the 50s or 60s. Symptoms typically begin by the age of 20. For reasons unknown as of 2004, the severity in symptoms can also vary greatly, even among members of the same family .
Although CMT has been described for many years, it is only since the early 1990s that the genetic cause of many of the types of CMT have become known. Therefore, knowledge about CMT increased dramatically shortly thereafter.
The peripheral nerves
CMT affects the peripheral nerves, those groups of nerve cells carrying information to and from the spinal cord. CMT decreases the ability of these nerves to carry motor commands to muscles, especially those furthest from the spinal cord located in the feet and hands. As a result, the muscles connected to these nerves eventually weaken. CMT also affects the sensory nerves that carry information from the limbs to the brain. Therefore, people with CMT also have sensory loss. This loss causes symptoms such as not being able to tell if something is hot or cold or having difficulties with balance.
There are two parts of the nerve that can be affected in CMT. A nerve can be likened to an electrical wire, in which the wire part is the axon of the nerve and the insulation surrounding it is the myelin sheath. The job of the myelin is to help messages travel very fast through the nerves.
CMT is usually classified depending by which part of the nerve is affected. Children who have problems with the myelin have CMT type 1 and children who have abnormalities of the axon have CMT type 2. Specialized testing of the nerves, called nerve conduction testing (NCV), can be performed to determine if CMT1 or CMT2 is present. These tests measure the speed at which messages travel through the nerves. In CMT1, the messages move too slowly, but in CMT2 the messages travel at the normal speed.
Demographics
Charcot-Marie-Tooth is the most common inherited neurological disorder, affecting approximately 150,000 Americans. It is the most common type of inherited neurological condition, occurring in approximately one in 2,500 people worldwide, in all races and ethnic groups.
Causes and symptoms
Genetic causes
CMT is caused by changes (mutations) in any one of a number of genes that carry the instructions on how to make the peripheral nerves. Genes contain the instructions for how the body grows and develops before and after a person is born. There are probably at least 15 different genes that can cause CMT. However, as of 2004, not all had been identified.
CMT types 1 and 2 can be broken down into subtypes based upon the gene that causes CMT. The subtypes are labeled by letters, so there is CMT1A, CMT1B, etc. Therefore, the gene with a mutation that causes CMT1A is different from the one that causes CMT1B.
Types of CMT
CMT1A The most common type of CMT, called CMT1A, is caused by a mutation in a gene called peripheral myelin protein 22 (PMP22) located on chromosome 17. The job of this gene is to make a protein (PMP22) that makes up part of the myelin. In most people who have CMT, the mutation that causes the condition is a duplication (doubling) of the PMP22 gene. Instead of having two copies of the PMP22 gene (one on each chromosome) there are three copies. It is not known how this extra copy of the PMP22 gene causes the observed symptoms. A small percentage of people with CMT1A do not have a duplication of the PMP22 gene, but rather they have a point mutation in the gene. A point mutation is like a typo in the gene that causes it to work incorrectly.
HEREDITY NEUROPATHY WITH LIABILITY TO PRESSURE PALSIES (HNPP) HNPP is a condition that is also caused by a mutation in the PMP22 gene. The mutation is a deletion. Therefore, there is only one copy of the PMP22 gene instead of two. People who have HNPP may have some of the signs of CMT. However, they also have episodes when they develop weakness and problems with sensation after compression of certain pressure points such as at the elbows or knee. Often these symptoms resolve after a few days or weeks, but sometimes they are permanent.
CMT1B Another type of CMT, called CMT1B, is caused by a mutation in a gene called myelin protein zero (MPZ), located on chromosome 1. The job of this gene is to make the layers of myelin stick together as they are wrapped around the axon. The mutations in this gene are point mutations because they involve a change (either deletion, substitution, or insertion) at one specific component of a gene.
CMTX Another type of CMT, called CMTX, is usually considered a subtype of CMT1 because it affects the myelin, but it has a different type of inheritance than type 1 or type 2. In CMTX, the CMT-causing gene is located on the X chromosome and is called connexin 32 (Cx32). The job of this gene is to code for a class of protein called connexins that form tunnels between the layers of myelin.
CMT2 There are at least five different genes that can cause CMT type 2. Therefore, CMT2 has subtypes A, B, C, D and E. As of early 2001, scientists have narrowed in on the location of most of the CMT2-causing genes. However, the specific genes and the mutations have not yet been found as of 2004 for most types. In the early 2000s, the gene for CMT2E was found. The gene is called neurofilament-light (NF-L). Because it has just been discovered, not much is known about how mutations in this gene cause CMT.
CMT3 In the past a condition called Dejerine-Sottas disease was referred to as CMT3. This is a severe type of CMT in which symptoms begin in infancy or early childhood. It is known as of 2004 that this is not a separate type of CMT; in fact, people who have onset in infancy or early childhood often have mutations in the PMP22 or MPZ genes. Children with type 3 CMT may not develop early motor skills such as walking until they are three or four years old.
CMT4 CMT4 is a rare type of CMT in which the nerve conduction tests have slow response results. However, it is classified differently from CMT1 because it is passed through families by a different pattern of inheritance. There are five different subtypes, and each has as of 2004 only been described in a few families. The symptoms in CMT4 are often severe and other symptoms such as deafness may be present. There are three different genes that have been associated with CMT4 as of early 2001. They are called MTMR2, EGR2, and NDRG1. More research is required to understand how mutations in these genes cause CMT.
Inheritance
Children with CMT have an increased risk for passing on the genes that cause the condition when they start a family of their own.
CMT1A and 1B, HNPP, and all of the subtypes of CMT2 have autosomal dominant inheritance. Autosomal refers to the first 22 pairs of chromosomes that are the same in males and females. Therefore, males and females are affected equally in these types. In a dominant condition, only one gene of a pair needs to have a mutation in order for a person to have symptoms of the condition. Therefore, individuals who have these types have a 50 percent, or one in two, chance of passing CMT on to each of their children. This chance is the same for each pregnancy and does not change based on previous children.
CMTX has X-linked inheritance. Since males only have one X chromosome, they only have one copy of the Cx32 gene. Thus, when a male has a mutation in his Cx32 gene, he will have CMT. However, females have two X chromosomes and, therefore, have two copies of the Cx32 gene. If they have a mutation in one copy of their Cx32 genes, they will only have mild to moderate symptoms of CMT that may go unnoticed. This is because their normal copy of the Cx32 gene does make normal myelin.
Females pass on one or the other of their X chromosomes to their children—sons or daughters. If a woman with a Cx32 mutation passes her normal X chromosome, she will have an unaffected son or daughter who will not pass CMT on to his or her children. If the woman passes the chromosome with Cx32 mutation on she will have an affected son or daughter, although the daughter will be mildly affected or have no symptoms. Therefore, a woman with a Cx32 mutation has a 50 percent, or a one in two, chance of passing the mutation to her children: a son will be affected, and a daughter may only have mild symptoms.
When males pass on an X chromosome, they have a daughter. When they pass on a Y chromosome, they have a son. Since the Cx32 mutation is on the X chromosome, a man with CMTX will always pass the Cx32 mutation on to his daughters. However, when he has a son, he passes on the Y chromosome, and the son will not be affected. Therefore, an affected male passes the Cx32 gene mutation on to all of his daughters, but to none of his sons.
CMT4 has autosomal recessive inheritance. Males and females are equally affected. In order for individuals to have CMT4, they must have a mutation in both of their CMT-causing genes, one inherited from each parent. The parents of an affected person are called carriers. They have one normal copy of the gene and one copy with a mutation. Carriers do not have symptoms of CMT. Two carrier parents have a 25 percent, or one in four, chance of passing CMT on to each of their children.
Symptoms
The onset of symptoms is highly variable, even among members of the same family. Symptoms usually progress very slowly over a person's lifetime. The main problems caused by CMT are weakness and loss of sensation mainly in the feet and hands. The first symptoms are usually problems with the feet such as high arches and problems with walking and running. Tripping while walking and sprained ankles are common. Muscle loss in the feet and calves leads to foot drop in which the foot does not lift high enough off the ground when walking. Complaints of cold legs are common, as are cramps in the legs, especially after exercise . Most children with CMT remain able to walk throughout their lives.
In many people, the fingers and hands eventually become affected. Muscle loss in the hands can make fine movements such as working buttons and zippers difficult. Some patients develop tremor in the upper limbs. Loss of sensation can cause problems such as numbness and the inability to feel if something is hot or cold.
Diagnosis
When CMT is suspected in a child, the diagnosis begins with a careful neurological exam to determine the extent and distribution of weakness. A thorough family history should be taken at this time to determine if other people in the family are affected. Testing may also be performed to rule out other causes of neuropathy.
A nerve conduction velocity test should be performed to measure how fast impulses travel through the nerves. This test may show characteristic features of CMT, but it is not diagnostic of CMT. Nerve conduction testing may be combined with electromyography (EMG), an electrical test of the muscles.
A nerve biopsy (removal of a small piece of the nerve) may be performed to look for changes characteristic of CMT. However, this testing is not diagnostic of CMT and is usually not necessary for making a diagnosis.
Definitive diagnosis of CMT is made only by genetic testing, usually performed by drawing a small amount of blood. As of early 2001, testing is available to detect mutations in PMP22, MPZ, Cx32 and EGR2. However, research is progressing rapidly and new testing is often made available every few months. All affected members of a family have the same type of CMT. Therefore, once a mutation is found in one affected member, it is possible to test other members who may have symptoms or are at risk of developing CMT.
Prenatal diagnosis
Testing during pregnancy to determine whether an unborn child is affected is possible if genetic testing in a family has identified a specific CMT-causing mutation. This can be done after ten to 12 weeks of pregnancy using a procedure called chorionic villus sampling (CVS). CVS involves removing a tiny piece of the placenta and examining the cells. Testing can also be done by amniocentesis after 16 weeks gestation by removing a small amount of the amniotic fluid surrounding the baby and analyzing the cells in the fluid. Each of these procedures has a small risk of miscarriage associated with it, and those who are interested in learning more should check with their doctor or genetic counselor. Couples interested in these options should obtain genetic counseling to carefully explore all of the benefits and limitations of these procedures.
Treatment
As of 2004, there was no cure for CMT. However, physical and occupational therapy are an important part of CMT treatment. Physical therapy is used to preserve range of motion and minimize deformity caused by muscle shortening, or contracture. Braces are sometimes used to improve control of the lower extremities and can help with balance. After wearing braces, children often find that they have more energy because they are using less energy to focus on their walking. Occupational therapy is used to provide devices and techniques that can assist tasks such as dressing, feeding, writing, and other routine activities of daily life. Substances such as caffeine and alcohol should be avoided if tremor is present. Voice-activated software can also help children who have problems with fine motor control.
It is very important that individuals with CMT avoid injury that causes them to be immobile for long periods of time. It is often difficult for people with CMT to return to their original strength after injury.
There is a long list of medications that should be avoided if possible by people diagnosed with CMT, such as the high blood pressure-reducing medication hydralazine (Apresoline), megadoses of vitamin A, B6, and D, and large intravenous doses of penicillin. Complete lists are available from the CMT support groups. Parents considering providing any of these medications to their children with CMT should weigh the risks and benefits with their physician.
Prognosis
The symptoms of CMT usually progress slowly over many years but do not usually shorten life expectancy. The majority of children with CMT do not need to use a wheelchair at any time during their lives. Most people with CMT are able to lead full and productive lives despite their physical challenges.
Prevention
As of 2004 there was no known way to prevent CMT. Genetic counseling for parents with CMT can help them understand the risk they face of having children with the disorder.
Parental concerns
The goal for children with CMT is to live as normal a life as possible. Along with seeing that children obtain proper healthcare from a specialist knowledgeable about the condition, parents can take the following precautions to help minimize problems:
- Children should be properly dressed in cold weather to avoid chilled hands and feet.
- The home should be designed to avoid the risk of falls, including installing handrails on steps, removing throw rugs, using nonskid bathmats, and arranging furniture so it does not block passage through rooms.
- Learning about CMT and discussing it with teachers, classmates, friends, and family members may help normalize the disorder and create support for the child.
KEY TERMS
Axon —A long, threadlike projection that is part of a neuron (nerve cell).
Myelin —A fatty sheath surrounding nerves throughout the body that helps them conduct impulses more quickly.
Nerve condition velocity (NCV) —Technique for studying nerve or muscle disorders, measuring the speed at which nerves transmit signals.
Neuropathy —A disease or abnormality of the peripheral nerves (the nerves outside the brain and spinal cord). Major symptoms include weakness, numbness, paralysis, or pain in the affected area.
Peripheral nerves —Nerves outside the brain and spinal cord that provide the link between the body and the central nervous system.
Resources
ORGANIZATIONS
Charcot Marie Tooth Association (CMTA). 2700 Chestnut Parkway, Chester, PA 19013. Web site: < >.
CMT International. 1 Springbank Dr., St. Catherine's, ONT L2S2K1, Canada. Web site: <www.cmtint.org>.
Muscular Dystrophy Association. 3300 East Sunrise Dr., Tucson, AZ 85718. Web site: <www.mdausa.org>.
Neuropathy Association. 60 E. 42nd St., Suite 942, New York, NY 10165. Web site: <www.neuropathy.org>.
WEB SITES
"Charcot-Marie-Tooth Disease." Health and Disease Information A to Z, February 27, 2004. Available online at <www.hmc.psu.edu/healthinfo/c/cmt.htm> (accessed December 7, 2004).
"Charcot-Marie-Tooth Disorder Information Page." NINDS Charcot-Marie-Tooth Disorder Information Page, February 27, 2004. Available online at <www.ninds.nih.gov/health_and_medical/disorders/charcot_doc.htm> (accessed December 7, 2004).
Christine Kuehn Kelly
Charcot-Marie-Tooth Disease
Charcot-Marie-Tooth disease
Definition
Charcot-Marie-Tooth disease (CMT) is the name of a group of inherited disorders of the nerves in the peripheral nervous system (nerves throughout the body that communicate motor and sensory information to and from the spinal cord) causing weakness and loss of sensation in the limbs.
Description
CMT is named for the three neurologists who first described the condition in the late 1800s. It is also known as hereditary motor and sensory neuropathy and is sometimes called peroneal muscular atrophy, referring to the muscles in the leg that are often affected. The age of onset of CMT can vary anywhere from young childhood to the 50s or 60s. Symptoms typically begin by the age of 20. For reasons yet unknown, the severity in symptoms can also vary greatly, even among members of the same family.
Although CMT has been described for many years, it has only been since the early 1990s that the genetic cause of many types of CMT have become known. Therefore, knowledge about CMT has increased dramatically within a short time.
The peripheral nerves
CMT affects the peripheral nerves, those groups of nerve cells carrying information to and from the spinal cord and decreases their ability to carry motor commands to muscles, especially those furthest from the spinal cord located in the feet and hands. As a result, the muscles connected to these nerves eventually weaken. CMT also affects the sensory nerves that carry information from the limbs to the brain. Therefore, people with CMT also have sensory loss. This causes symptoms such as not being able to tell if something is hot or cold or difficulties with balance.
There are two parts of the nerve that can be affected in CMT. A nerve can be likened to an electrical wire, in which the wire part is the axon of the nerve and the insulation surrounding it is the myelin sheath. The job of the myelin is to help messages travel very fast through the nerves. CMT is usually classified depending on which part of the nerve is affected. People who have problems with the myelin have CMT type 1 and people who have abnormalities of the axon have CMT type 2.
Specialized testing of the nerves, called nerve conduction testing (NCV), can be performed to determine if a person has CMT1 or CMT2. These tests measure the speed at which messages travel through the nerves. In CMT1, the messages move too slow, but in CMT2 the messages travel at the normal speed.
Genetic profile
CMT is caused by changes (mutations) in any one of a number of genes that carry the instructions to make the peripheral nerves. Genes contain the instructions for how the body grows and develops before and after a person is born. There are probably at least 15 different genes that can cause CMT. However, as of early 2001, many have not yet been identified.
CMT types 1 and 2 can be broken down into subtypes based upon the gene that is causing CMT. The subtypes are labeled by letters. So there is CMT1A, CMT1B, etc. Therefore, the gene with a mutation that causes CMT1A is different from that which causes CMT1B.
Types of CMT
CMT1A
The most common type of CMT is called CMT1A. It is caused by a mutation in a gene called peripheral myelin protein 22 (PMP22) located on chromosome 17. The job of this gene is to make a protein (PMP22) that makes up part of the myelin. In most people who have CMT, the mutation that causes the condition is a duplication (doubling) of the PMP22 gene. Instead of having two copies of the PMP22 gene (one on each chromosome), there are three copies. It is not known how this extra copy of the PMP22 gene causes the observed symptoms. A small percentage of people with CMT1A do not have a duplication of the PMP22 gene, but rather have a point mutation in the gene. A point mutation is like a typo in the gene that causes it to work incorrectly.
Hereditary neuropathy with liability to pressure palsies (HNPP)
HNPP is a condition that is also caused by a mutation in the PMP22 gene. The mutation is a deletion resulting in only one copy of the PMP22 gene instead of two. People who have HNPP may have some of the signs of CMT. However, they also have episodes where they develop weakness and problems with sensation after compression of certain pressure point, such as the elbows or knee. These symptoms will often resolve after a few days or weeks, but sometimes they are permanent.
CMT1B
Another type of CMT, called CMT1B, is caused by a mutation in a gene called myelin protein zero (MPZ) located on chromosome 1. The job of this gene is to make the layers of myelin stick together as they are wrapped around the axon. The mutations in this gene are point mutations because they involve a change (either deletion, substitution, or insertion) at one specific component of a gene.
CMTX
Another type of CMT, called CMTX, is usually considered a subtype of CMT1 because it affects the myelin, but it has a different type of inheritance than type 1 or type 2. In CMTX, the CMT causing gene is located on the X chromosome and is called connexin 32 (Cx32). The job of this gene is to code for a class of protein called connexins that form tunnels between the layers of myelin.
CMT2
There are at least five different genes that can cause CMT type 2. Therefore, CMT2 has subtypes A, B, C, D and E. Scientists have narrowed in on the location of most of the CMT2 causing genes. However, the specific genes and the mutations have not yet been found for most types. Very recently, the gene for CMT2E has been found. The gene is called neurofilament-light (NF-L). Because it has just been discovered, not much is known about how mutations in this gene cause CMT.
CMT3
In the past a condition called Dejerine-Sottas disease was referred to as CMT3. This is a severe type of CMT in which symptoms begin in infancy or early childhood. It is now known that this is not a separate type of CMT and in fact people who have onset in infancy or early childhood often have mutations in the PMP22 or MPZ genes.
CMT4
CMT4 is a rare type of CMT in which the nerve conduction tests have slow response results. However, it is classified differently from CMT1 because it is passed through families by a different pattern of inheritance. There are five different subtypes and each has only been described in a few families. The symptoms in CMT4 are often severe and other symptoms such as deafness may be present. There are three different genes that have been associated with CMT4. They are called MTMR2, EGR2, and NDRG1. More research is required to understand how mutations in these genes cause CMT.
Inheritance
Autosomal dominant inheritance
CMT1A and 1B, HNPP, and all of the subtypes of CMT2 have autosomal dominant inheritance. Autosomal refers to the first 22 pairs of chromosomes that are the same in males and females. Therefore, males and females are affected equally in these types. In a dominant condition, only one gene of a pair needs to have a mutation in order for a person to have symptoms of the condition. Therefore, anyone who has these types has a 50%, or one in two, chance of passing CMT on to each of their children. This chance is the same for each pregnancy and does not change based on previous children.
X-linked inheritance
CMTX has X-linked inheritance. Since males only have one X chromosome, they only have one copy of the Cx32 gene. Thus, when a male has a mutation in his Cx32 gene, he will have CMT. However, females have two X chromosomes and therefore have two copies of the Cx32 gene. If they have a mutation in one copy of their Cx32 genes, they will only have mild to moderate symptoms of CMT that may go unnoticed. This is because their normal copy of the Cx32 gene produces sufficient amounts of myelin.
Females pass on one or the other of their X chromosomes to their children—sons or daughters. If a woman with a Cx32 mutation passes her normal X chromosome, she will have an unaffected son or daughter who will not pass CMT on to their children. If the woman passes the chromosome with Cx32 mutation on she will have an affected son or daughter, although the daughter will be mildly affected or have no symptoms. Therefore, a woman with a Cx32 mutation has a 50%, or a one in two chance of passing the mutation to her children: a son will be affected, and a daughter may only have mild symptoms.
When males pass on an X chromosome, they have a daughter. When they pass on a Y chromosome, they have a son. Since the Cx32 mutation is on the X chromosome, a man with CMTX will always pass the Cx32 mutation on to his daughters. However, when he has a son, he passes on the Y chromosome, and therefore the son will not be affected. Therefore, an affected male passes the Cx32 gene mutation on to all of his daughters, but to none of his sons.
Autosomal recessive inheritance
CMT4 has autosomal recessive inheritance. Males and females are equally affected. In order for a person to have CMT4, they must have a mutation in both of their CMT causing genes—one inherited from each parent. The parents of an affected person are called carriers. They have one normal copy of the gene and one copy with a mutation. Carriers do not have symptoms of CMT. Two carrier parents have a 25%, or one in four chance of passing CMT on to each of their children.
Demographics
CMT has been diagnosed in people from all over the world. It occurs in approximately one in 2,500 people, which is about the same incidence as multiple sclerosis . It is the most common type of inherited neurologic condition.
Signs and symptoms
The onset of symptoms is highly variable, even among members of the same family. Symptoms usually progress very slowly over a person's lifetime. The main problems caused by CMT are weakness and loss of sensation mainly in the feet and hands. The first symptoms are usually problems with the feet such as high arches and problems with walking and running. Tripping while walking and sprained ankles are common. Muscle loss in the feet and calves leads to "foot drop" where the foot does not lift high enough off the ground when walking. Complaints of cold legs are common, as are cramps in the legs, especially after exercise.
In many people, the fingers and hands eventually become affected. Muscle loss in the hands can make fine movements such as working buttons and zippers difficult. Some patients develop tremor in the upper limbs. Loss of sensation can cause problems such as numbness and the inability to feel if something is hot or cold. Most people with CMT remain able to walk throughout their lives.
Diagnosis
Diagnosis of CMT begins with a careful neurological exam to determine the extent and distribution of weakness. A thorough family history should be taken at this time to determine if other people in the family are affected. Testing may be also performed to rule out other causes of neuropathy.
A nerve conduction velocity test should be performed to measure how fast impulses travel through the nerves. This test may show characteristic features of CMT, but it is not diagnostic of CMT. Nerve conduction testing may be combined with electromyography (EMG), an electrical test of the muscles.
A nerve biopsy (removal of a small piece of the nerve) may be performed to look for changes characteristic of CMT. However, this testing is not diagnostic of CMT and is usually not necessary for making a diagnosis.
Definitive diagnosis of CMT is made only by genetic testing , usually performed by drawing a small amount of blood. Testing is available to detect mutations in PMP22, MPZ, Cx32, and EGR2. However, research is progressing rapidly and new testing is often made available every few months. All affected members of a family have the same type of CMT. Therefore once a mutation is found in one affected member, it is possible to test other members who may have symptoms or are at risk of developing CMT.
Prenatal diagnosis
Testing during pregnancy to determine whether an unborn child is affected is possible if genetic testing in a family has identified a specific CMT-causing mutation. This can be done after 10-12 weeks of pregnancy using a procedure called chorionic villus sampling (CVS). CVS involves removing a tiny piece of the placenta and examining the cells. Testing can also be done by amniocentesis after 16 weeks gestation by removing a small amount of the amniotic fluid surrounding the baby and analyzing the cells in the fluid. Each of these procedures has a small risk of miscarriage associated with it, and those who are interested in learning more should check with their doctor or genetic counselor. Couples interested in these options should obtain genetic counseling to carefully explore all of the benefits and limitations of these procedures.
Treatment and management
There is no cure for CMT. However, physical and occupational therapy are an important part of CMT treatment. Physical therapy is used to preserve range of motion and minimize deformity caused by muscle shortening, or contracture. Braces are sometimes used to improve control of the lower extremities that can help tremendously with balance. After wearing braces, people often find that they have more energy because they are using less energy to focus on their walking. Occupational therapy is used to provide devices and techniques that can assist tasks such as dressing, feeding, writing, and other routine activities of daily life. Voice-activated software can also help people who have problems with fine motor control.
It is very important that people with CMT avoid injury that causes them to be immobile for long periods of time. It is often difficult for people with CMT to return to their original strength after injury.
There is a long list of medications that should be avoided if possible by people diagnosed with CMT such as hydralazine (Apresoline), megadoses of vitamin A, B6, and D, Taxol, and large intravenous doses of penicillin. Complete lists are available from the CMT support groups. People considering taking any of these medications should weigh the risks and benefits with their physician.
Prognosis
The symptoms of CMT usually progress slowly over many years, but do not usually shorten life expectancy. The majority of people with CMT do not need to use a wheelchair during their lifetime. Most people with CMT are able to lead full and productive lives despite their physical challenges.
Resources
BOOKS
Parry, G. J., ed. Charcot-Marie-Tooth Disorders: A Handbook for Primary Care Physicians. Available from the CMT Association, 1995.
PERIODICALS
Keller. M. P., and P. F. Chance. "Inherited peripheral neuropathies." Seminars in Neurology 19, no. 4 (1999): 353–62.
Quest. A magazine for patients available from the Muscular Dystrophy Association.
Shy, M. E., J. Kamholz, and R. E. Lovelace, eds. "Charcot-Marie-Tooth Disorders." Annals of the New York Academy of Sciences 883 (1999).
ORGANIZATIONS
Charcot-Marie-Tooth Association (CMTA). 2700 Chestnut Parkway, Chester, PA 19013. (610) 499-9264 or (800) 606-CMTA. Fax: (610) 499-9267. [email protected]. <http://www.charcot-marie-tooth.org>.
CMT International. Attn: Linda Crabtree, 1 Springbank Dr. St. Catherine's, ONT L2S2K1. Canada (905) 687-3630. <http://www.cmtint.org>.
Muscular Dystrophy Association. 3300 East Sunrise Dr., Tucson, AZ 85718. (520) 529-2000 or (800) 572-1717. <http://www.mdausa.org>.
Neuropathy Association. 60 E. 42nd St. Suite 942, New York, NY 10165. (212) 692-0662. <http://www.neuropathy.org>.
WEBSITES
GeneClinics. University of Washington, Seattle. <http://www.geneclinics.org>.
HNPP—Hereditary Neuropathy with liability to Pressure Palsies. Online Support Group, <http://www.hnpp.org>.
OMIM—Online Mendelian Inheritance in Man. <http://www.ncbi.nlm.nih.gov/Omim>.
Karen M. Krajewski, MS, CGC
Charcot-Marie-Tooth disease
Charcot-Marie-Tooth disease
Definition
Charcot-Marie-Tooth disease (CMT) is the name of a group of inherited disorders of the nerves in the peripheral nervous system (nerves throughout the body that communicate motor and sensory information to and from the spinal cord) causing weakness and loss of sensation in the limbs.
Description
CMT is named for the three neurologists who first described the condition in the late 1800s. It is also known as hereditary motor and sensory neuropathy and is sometimes called peroneal muscular atrophy, referring to the muscles in the leg that are often affected. The age of onset of CMT can vary anywhere from young childhood to the 50s or 60s. Symptoms typically begin by the age of 20. For reasons yet unknown, the severity in symptoms can also vary greatly, even among members of the same family.
Although CMT has been described for many years, it is only since the early 1990s that the genetic cause of many types of CMT have become known. Therefore, knowledge about CMT has increased dramatically within a short time.
The peripheral nerves
CMT affects the peripheral nerves, those groups of nerve cells carrying information to and from the spinal cord and decreases their ability to carry motor commands to muscles, especially those furthest from the spinal cord located in the feet and hands. As a result, the muscles connected to these nerves eventually weaken. CMT also affects the sensory nerves that carry information from the limbs to the brain. Therefore, people with CMT also have sensory loss. This causes symptoms such as not being able to tell if something is hot or cold or difficulties with balance.
There are two parts of the nerve that can be affected in CMT. A nerve can be likened to an electrical wire, in which the wire part is the axon of the nerve and the insulation surrounding it is the myelin sheath. The job of the myelin is to help messages travel very fast through the nerves. CMT is usually classified depending on which part of the nerve is affected. People who have problems with the myelin have CMT type 1 and people who have abnormalities of the axon have CMT type 2.
Specialized testing of the nerves, called nerve conduction testing (NCV), can be performed to determine if a person has CMT1 or CMT2. These tests measure the speed at which messages travel through the nerves. In CMT1, the messages move too slow, but in CMT2 the messages travel at the normal speed.
Genetic profile
CMT is caused by changes (mutations) in any one of a number of genes that carry the instructions to make the peripheral nerves. Genes contain the instructions for how the body grows and develops before and after a person is born. There are probably at least 15 different genes that can cause CMT. However, as of early 2001, many have not yet been identified.
CMT types 1 and 2 can be broken down into subtypes based upon the gene that is causing CMT. The subtypes are labeled by letters. So there is CMT1A, CMT1B, etc. Therefore, the gene with a mutation that causes CMT1A is different from that which causes CMT1B.
Types of CMT
CMT1A
The most common type of CMT is called CMT1A. It is caused by a mutation in a gene called peripheral myelin protein 22 (PMP22) located on chromosome 17. The job of this gene is to make a protein (PMP22) that makes up part of the myelin. In most people who have CMT, the mutation that causes the condition is a duplication (doubling) of the PMP22 gene. Instead of having two copies of the PMP22 gene (one on each chromosome), there are three copies. It is not known how this extra copy of the PMP22 gene causes the observed symptoms. A small percentage of people with CMT1A do not have a duplication of the PMP22 gene, but rather have a point mutation in the gene. A point mutation is like a typo in the gene that causes it to work incorrectly.
Hereditary neuropathy with liability to pressure palsies (HNPP)
HNPP is a condition that is also caused by a mutation in the PMP22 gene. The mutation is a deletion, resulting in only one copy of the PMP22 gene instead of two. People who have HNPP may have some of the signs of CMT. However, they also have episodes where they develop weakness and problems with sensation after compression of certain pressure points such as the elbows or knee. Often, these symptoms will resolve after a few days or weeks, but sometimes they are permanent.
CMT1B
Another type of CMT, called CMT1B, is caused by a mutation in a gene called myelin protein zero (MPZ) located on chromosome 1. The job of this gene is to make the layers of myelin stick together as they are wrapped around the axon. The mutations in this gene are point mutations because they involve a change (either deletion, substitution, or insertion) at one specific component of a gene.
CMTX
Another type of CMT, called CMTX, is usually considered a subtype of CMT1 because it affects the myelin, but it has a different type of inheritance than type 1 or type 2. In CMTX, the CMT causing gene is located on the X chromosome and is called connexin 32 (Cx32). The job of this gene is to code for a class of protein called connexins that form tunnels between the layers of myelin.
CMT2
There are at least five different genes that can cause CMT type 2. Therefore, CMT2 has subtypes A, B, C, D and E. As of early 2001, scientists have narrowed in on the location of most of the CMT2 causing genes. However, the specific genes and the mutations have not yet been found for most types. Very recently, the gene for CMT2E has been found. The gene is called neurofilament-light (NF-L). Because it has just been discovered, not much is known about how mutations in this gene cause CMT.
CMT3
In the past a condition called Dejerine-Sottas disease was referred to as CMT3. This is a severe type of CMT in which symptoms begin in infancy or early childhood. It is now known that this is not a separate type of CMT and in fact people who have onset in infancy or early childhood often have mutations in the PMP22 or MPZ genes.
CMT4
CMT4 is a rare type of CMT in which the nerve conduction tests have slow response results. However, it is classified differently from CMT1 because it is passed through families by a different pattern of inheritance. There are five different subtypes and each has only been described in a few families. The symptoms in CMT4 are often severe and other symptoms such as deafness may be present. There are three different genes that have been associated with CMT4 as of early 2001. They are called MTMR2, EGR2, and NDRG1. More research is required to understand how mutations in these genes cause CMT.
Inheritance
Autosomal dominant inheritance
CMT1A and 1B, HNPP, and all of the subtypes of CMT2 have autosomal dominant inheritance. Autosomal refers to the first 22 pairs of chromosomes that are the same in males and females. Therefore, males and females are affected equally in these types. In a dominant condition, only one gene of a pair needs to have a mutation in order for a person to have symptoms of the condition. Therefore, anyone who has these types has a 50%, or one in two, chance of passing CMT on to each of their children. This chance is the same for each pregnancy and does not change based on previous children.
X-linked inheritance
CMTX has X-linked inheritance. Since males only have one X chromosome, they only have one copy of the Cx32 gene. Thus, when a male has a mutation in his Cx32 gene, he will have CMT. However, females have two X chromosomes and therefore have two copies of the Cx32 gene. If they have a mutation in one copy of their Cx32 genes, they will only have mild to moderate symptoms of CMT that may go unnoticed. This is because their normal copy of the Cx32 gene produces sufficient amounts of myelin.
Females pass on one or the other of their X chromosomes to their children—sons or daughters. If a woman with a Cx32 mutation passes her normal X chromosome, she will have an unaffected son or daughter who will not pass CMT on to their children. If the woman passes the chromosome with Cx32 mutation on she will have an affected son or daughter, although the daughter will be mildly affected or have no symptoms. Therefore, a woman with a Cx32 mutation has a 50%, or a one in two chance of passing the mutation to her children: a son will be affected, and a daughter may only have mild symptoms.
When males pass on an X chromosome, they have a daughter. When they pass on a Y chromosome, they have a son. Since the Cx32 mutation is on the X chromosome, a man with CMTX will always pass the Cx32 mutation on to his daughters. However, when he has a son, he passes on the Y chromosome, and therefore the son will not be affected. Therefore, an affected male passes the Cx32 gene mutation on to all of his daughters, but to none of his sons.
Autosomal recessive inheritance
CMT4 has autosomal recessive inheritance. Males and females are equally affected. In order for a person to have CMT4, they must have a mutation in both of their CMT causing genes—one inherited from each parent. The parents of an affected person are called carriers. They have one normal copy of the gene and one copy with a mutation. Carriers do not have symptoms of CMT. Two carrier parents have a 25%, or one in four chance of passing CMT on to each of their children.
Demographics
CMT has been diagnosed in people from all over the world. It occurs in approximately one in 2,500 people, which is about the same incidence as multiple sclerosis. It is the most common type of inherited neurologic condition.
Signs and symptoms
The onset of symptoms is highly variable, even among members of the same family. Symptoms usually progress very slowly over a person's lifetime. The main problems caused by CMT are weakness and loss of sensation mainly in the feet and hands. The first symptoms are usually problems with the feet such as high arches and problems with walking and running. Tripping while walking and sprained ankles are common. Muscle loss in the feet and calves leads to "foot drop" where the foot does not lift high enough off the ground when walking. Complaints of cold legs are common, as are cramps in the legs, especially after exercise.
In many people, the fingers and hands eventually become affected. Muscle loss in the hands can make fine movements such as working buttons and zippers difficult. Some patients develop tremor in the upper limbs. Loss of sensation can cause problems such as numbness and the inability to feel if something is hot or cold. Most people with CMT remain able to walk throughout their lives.
Diagnosis
Diagnosis of CMT begins with a careful neurological exam to determine the extent and distribution of weakness. A thorough family history should be taken at this time to determine if other people in the family are affected. Testing may be also performed to rule out other causes of neuropathy.
A nerve conduction velocity test should be performed to measure how fast impulses travel through the nerves. This test may show characteristic features of CMT, but it is not diagnostic of CMT. Nerve conduction testing may be combined with electromyography (EMG), an electrical test of the muscles.
A nerve biopsy (removal of a small piece of the nerve) may be performed to look for changes characteristic of CMT. However, this testing is not diagnostic of CMT and is usually not necessary for making a diagnosis.
Definitive diagnosis of CMT is made only by genetic testing , usually performed by drawing a small amount of blood. As of early 2001, testing is available to detect mutations in PMP22, MPZ, Cx32, and EGR2. However, research is progressing rapidly and new testing is often made available every few months. All affected members of a family have the same type of CMT. Therefore once a mutation is found in one affected member, it is possible to test other members who may have symptoms or are at risk of developing CMT.
Prenatal diagnosis
Testing during pregnancy to determine whether an unborn child is affected is possible if genetic testing in a family has identified a specific CMT-causing mutation. This can be done after 10-12 weeks of pregnancy using a procedure called chorionic villus sampling (CVS). CVS involves removing a tiny piece of the placenta and examining the cells. Testing can also be done by amniocentesis after 16 weeks gestation by removing a small amount of the amniotic fluid surrounding the baby and analyzing the cells in the fluid. Each of these procedures has a small risk of miscarriage associated with it, and those who are interested in learning more should check with their doctor or genetic counselor. Couples interested in these options should obtain genetic counseling to carefully explore all of the benefits and limitations of these procedures.
Treatment and management
There is no cure for CMT. However, physical and occupational therapy are an important part of CMT treatment. Physical therapy is used to preserve range of motion and minimize deformity caused by muscle shortening, or contracture. Braces are sometimes used to improve control of the lower extremities that can help tremendously with balance. After wearing braces, people often find that they have more energy because they are using less energy to focus on their walking. Occupational therapy is used to provide devices and techniques that can assist tasks such as dressing, feeding, writing, and other routine activities of daily life. Voice-activated software can also help people who have problems with fine motor control.
It is very important that people with CMT avoid injury that causes them to be immobile for long periods of time. It is often difficult for people with CMT to return to their original strength after injury.
There is a long list of medications that should be avoided if possible by people diagnosed with CMT such as hydralazine (Apresoline), megadoses of vitamin A, B6, and D, Taxol, and large intravenous doses of penicillin. Complete lists are available from the CMT support groups. People considering taking any of these medications should weigh the risks and benefits with their physician.
Prognosis
The symptoms of CMT usually progress slowly over many years, but do not usually shorten life expectancy. The majority of people with CMT do not need to use a wheelchair during their lifetime. Most people with CMT are able to lead full and productive lives despite their physical challenges.
Resources
BOOKS
Parry, G. J., ed. Charcot-Marie-Tooth Disorders: A Handbook for Primary Care Physicians. Available from the CMT Association, 1995.
PERIODICALS
Keller. M. P., and P. F. Chance. "Inherited peripheral neuropathies." Seminars in Neurology 19, no. 4 (1999): 353–62.
Quest. A magazine for patients available from the Muscular Dystrophy Association.
Shy, M. E., J. Kamholz, and R. E. Lovelace, eds. "Charcot-Marie-Tooth Disorders." Annals of the New York Academy of Sciences 883 (1999).
ORGANIZATIONS
Charcot Marie Tooth Association (CMTA). 2700 Chestnut Parkway, Chester, PA 19013. (610) 499-9264 or (800) 606-CMTA. Fax: (610) 499-9267. [email protected]. <www.charcot-marie-tooth.org>.
CMT International. Attn: Linda Crabtree, 1 Springbank Dr. St. Catherine's, ONT L2S2K1. Canada (905) 687-3630. <www.cmtint.org>.
Muscular Dystrophy Association. 3300 East Sunrise Dr., Tucson, AZ 85718. (520) 529-2000 or (800) 572-1717. <http://www.mdausa.org>.
Neuropathy Association. 60 E. 42nd St. Suite 942, New York, NY 10165. (212) 692-0662. <www.neuropathy.org>.
WEBSITES
HNPP—Hereditary Neuropathy with liability to Pressure Palsies. Online Support Group, <http://www.hnpp.org>.
GeneClinics. University of Washington, Seattle. <www.geneclinics.org>.
OMIM—Online Mendelian Inheritance in Man. <www.ncbi.nlm.nih.gov/Omim>.
Karen M. Krajewski, MS, CGC