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What is CMT?
CMT is an inherited peripheral neuropathy. Inherited means that something can be passed on from generation to generation. Neuropathy means that there is a problem with the nerves. Peripheral refers to the peripheral nervous system, which is all of the nerves that branch from the central nervous system (brain and spinal cord) and travel to the feet and hands - the periphery of the body. People with CMT usually have problems with their feet and hands, including feet deformity (high arches and hammertoes), foot drop, abnormal sensations (and loss of fine motor skills. Not everyone with CMT is affected in the same way. Some patients have mild neuropathy, while others may have more severe problems with walking, hands, and/or sensation.
Who gets CMT?
CMT occurs in both men and women and can affect children and adults. There is no known predisposition to having CMT based on race or ethnicity.
What causes CMT?
CMT is a genetic condition. For a person to be affected with CMT, that person must have one (or two, depending on the type of CMT) disease causing mutation in one of the genes that causes CMT. There are at least forty different genes that cause CMT when mutated. A mutation in any one of them can cause the disease.
How is CMT diagnosed?
The diagnosis of CMT is made by combining clinical features with a nerve conduction study, which is a test where an electrical signal is sent down the nerve. CMT is an inherited peripheral neuropathy - a person must have a peripheral neuropathy based on a nerve conduction test in order to be affected with the condition. Genetic testing can also be done in order to identify a specific sub-type of CMT. Once a sub-type is identified in the family, other family members may just need the nerve conduction or the genetic testing in order to determine if that person is also affected.
What is the treatment for CMT?
Treatment of CMT is supportive. Ambulation aids, such as foot orthotics and braces (ankle-foot-orthotics, AFOs) are commonly needed to help with foot deformity and foot drop. Surgery to correct foot alignment or to lengthen or transfer tendons is often performed. Physical and occupational therapies are instrumental in providing long lasting quality of life. There is no cure for CMT nor any drug or vitamin known at this time to make CMT better.
Is there a treatment or a cure for CMT?
At the moment, treatment for CMT is symptomatic. People with foot drop benefit from ankle foot orthotics (AFOs) which can lift the foot and help the gait, joints, and posture of a person with CMT. People with CMT often need shoe inserts (orthotics) that are molded to the person’s feet. The foot of a person with CMT is often different from that of the general population, and people with CMT should be careful to find an orthotist who has seen CMT and helped people successfully.
Physical therapy (PT) and occupational therapy (OT) can be helpful for people with CMT. PT can be used to help improve the range of motion of joints, such as the ankles. Some people are able to gain or maintain strength with the help of PT, though this is not always the case. A good PT program will be able to provide the person with a home exercise program. OT is useful for people who are having difficulty with their hands or activities of daily living. The most useful OT programs are not those that work on strengthening the hand muscles, but those that show the person with CMT devices that will be helpful on a daily basis to make little things easier (such as using a button hook to close buttons).
People with CMT should try to remain active. It has been our experience that those who exercise do better over time than those who do not. Low impact exercises, such as biking and swimming, are especially good for people with CMT. Other things, such as yoga and tai chi, are also great activities for someone with CMT.
There is currently no cure for CMT and no medication that is known to make the symptoms of CMT better. As CMT is caused by mutations in one of at least forty genes, it may be that there is not one medication that will work for all types of CMT, but rather there will be medications specific for the specific subtypes.
I have heard that CMT is hereditary. How is CMT inherited?
There are three types of inheritance that apply to CMT, called autosomal dominant, autosomal recessive, and X-linked. In order to go into more details about what each of these mean, a short course in genetics is necessary.
Humans typically have 46 chromosomes in nearly every cell in the body. These chromosomes contain all of the information the body needs to grow, develop, and function properly. The chromosomes come in pairs, so that there are 23 pairs of chromosomes. The two members of the pair contain the same information, so that there are two copies of each piece of information that the body uses. One member of each chromosome pair is inherited from the mother, and the other member of the pair is inherited from the father. Of the 23 chromosome pairs, the first 22 are the same between males and females – they contain all of the same information. These are called the autosomes. The only place where males and females differ is in the last pair of chromosomes, which are called the sex chromosomes: the X and the Y. Females have two X chromosomes, and males have an X and a Y chromosome. When having children, one of each member of the chromosome pair is passed on from each parent, so that 23 chromosomes are inherited from each parent, totaling the expected 46 chromosomes. For the sex chromosomes, females will always pass on the X chromosome, since they only have X chromosomes, and males will either pass on an X or a Y chromosome. If the X is passed down, the child will be a female, since she will have two X chromosomes. If the Y is passed down, the child will be a male, as he will have one X and one Y chromosome.
Arranged on the chromosomes are the genes, which are smaller packages of information that have a specific function in the body. There are 25,000 genes along the 46 chromosomes, and as there are two of every chromosome, there is also two of every gene – one from the mother and one from the father. Genes are made up of DNA, which is essentially a genetic code that can be thought of as a series of four letters – A, C, T, and G – that create a sequence. When this sequence is in the expected order, it is not expected to cause any condition. Problems happen when there is a typo in this code, which is called a mutation. A mutation would be any alteration of the code – an extra letter, a missing letter, a letter that is replaced by a different letter – anything that alters that code has the potential to cause a condition such as CMT.
For people who have autosomal dominant conditions, they have one copy of the gene in question that has a mutation. For some types of CMT, such as CMT1A and HNPP, the mutation is actually the wrong number of the entire gene (an extra copy in CMT1A, and a missing copy in HNPP). For most other types of CMT, there is a change in the code that causes the condition. The key to autosomal dominant inheritance is that only one copy of the gene needs to have the change – the other copy of the gene is unchanged. Autosomal dominant conditions affect men and women equally, and both men and women have a 50% chance in each pregnancy of passing on the condition. If a child inherits the mutation, that child will have CMT and will have a 50% chance of passing it on again. If the child does not inherit the change, that child will not have CMT, will not have symptoms, and will not be able to pass on the change that is in the family in the future.
For people with autosomal recessive conditions, there has to be a change in both copies of the gene in question. Therefore neither copy of the gene is working properly. In almost all cases, the changes in the gene were inherited from the parents. Each parent has one copy of the gene with a change, but because that person has one copy of the gene without a change, that person does not have symptoms of CMT and is called a “carrier.” Only people with autosomal recessive forms of CMT in the family can be considered carriers. Both males and females are affected equally with autosomal recessive conditions, and there is an equal chance of passing it on to a child, no matter the sex. If two people are carriers of an autosomal recessive form of CMT, there is a one in four, or 25%, chance of both passing down the copies of the genes that do not work to a child in each pregnancy. It is only the child that inherits two copies of the gene that have mutations that will have CMT. For a person who has a recessive type of CMT, that person will pass on one of the copies of the gene with the mutation to all of that person’s children. However, only if that person’s partner is also a carrier of a mutation in this gene will it be possible to have a child that is affected with the condition. If the partner is not a carrier, it is not possible to have children affected with a recessive form of CMT, but all children will be carriers.
For a person with an X-linked form of CMT, the inheritance is different depending on the sex of the person affected. X-linked forms of CMT (such as CMT1X) are caused by a mutation in a gene carried on the X chromosome. Recall that females have two X chromosome and males have an X and a Y chromosome. If a female has a mutation in an X chromosome gene, she will have a 50% chance of passing on that mutation to each of her children, no matter the sex of the child. However, if a male has a mutation in an X chromosome gene, the sex of the child does make a difference. As males pass on their X chromosome to their daughters and their Y chromosome to their sons, all of the daughters of a male with an X-linked mutation will inherit the condition, and none of the sons will.
The inheritance of a type of CMT does not change. If a specific genetic cause is identified in the family, a genetic counselor can help you figure out who else is at risk in the family for the same condition. You may find a genetic counselor in your area by going to the website of the National Society of Genetic Counselors www.nsgc.org, and clicking on Find a Counselor.
What type of CMT do I have or how can I find out?
Figuring out what type of CMT someone has can be difficult. Your doctor or health care provider should assist in this process. Each person can get a general idea of which group of CMT based on the nerve conduction studies. In this procedure, electrical shocks are sent down the arm and/or leg to stimulate the nerves. Based on the speed and strength of the signal it is usually possible to determine if a person has a demyelinating or axonal form of CMT. Then depending on the way that the condition is inherited in the family, the major subtypes of the condition are determined.
- CMT type 1 (CMT1): demyelinating and autosomal dominant inheritance
- CMT type 2 (CMT2): axonal and autosomal dominant inheritance
- CMT type X (CMTX): typically intermediate conduction speeds with X-linked inheritance
- CMT type 4 (CMT4): autosomal recessive inheritance (demyelinating or axonal)
For some people, it is possible to find the genetic cause of the CMT which gives a more specific type than those listed above. Only by doing genetic testing is a person able to get a letter after the number for each of the types (i.e. CMT1A, CMT1B, CMT2A, CMT4C, etc). Genetic testing can be expensive and is not always covered by insurance. In almost all cases the genetic testing options can be narrowed down from the list of commercially available genes. One study found that 98% of patients with genetic diagnoses had one of five types of CMT: CMT1A, HNPP, CMT1X, CMT1B, and CMT2A. Genetic testing should be guided by pattern of nerve conduction, family history, clinical examination, and medical/developmental history. Panel testing is available to look at multiple genes at once from a commercial laboratory in the United States, but this can be expensive and is not more likely to find a genetic cause than doing single gene testing in a logical order and is not recommended.
Is there a way of determining how my CMT will progress over time?
CMT is a progressive disorder, meaning that it is expected to get worse over time. In general, it is difficult to predict the exact course that the progression is expected to take. For some types of CMT there is natural history information that can guide an average course of the disorder. Part of this research project is to gather more information about four kinds of CMT – CMT1B, CMT2A, CMT4A, and CMT4C – to be able to give information about progression.
Can CMT skip a generation? If my kids don't have it, can my grandkids get it?
CMT does not skip generations genetically. For people with autosomal dominant and X-linked conditions, a person will either have the condition or not. If a parent has CMT that has been genetically confirmed, a child can be tested when that child is at least 18 years of age and with appropriate genetic counseling. It is not recommended to test children who do not have any symptoms for CMT, as that child could be stigmatized or could be treated differently due to a label. If a person does not inherit the condition from a parent, that person will not have CMT and cannot pass it on in the future. If your kids have been confirmed to not have CMT, your grandkids will not be able to inherit the mutation in the family.
There is one situation where CMT can seem to skip a generation. Recall that a person needs to have two copies of the gene with a mutation in order to have CMT and that all children of a person who has an autosomal recessive form of CMT will be carriers of the condition (one gene has the mutation, and one does not). If that child’s partner is then a person who is also a carrier for the same condition, there is a one in four or 25% chance of having a child that is affected with the condition. In this situation, the grandparent and grandchild are affected, but the parent is not. Thus, the CMT symptoms have skipped a generation, but the genetics behind the condition have not skipped. This is more likely to occur in relationships where family members marry each other, as it is more likely in these groups that the mutation in the gene has been passed on through carriers than in the general population.
- NCBI Gene Tests Web Site
- Office for Human Research Protections (OHRP) - Public Outreach
- The Genetics Home Reference Web Site
- Charcot Marie Tooth Association - cmtausa.org
- PubMed Health Charcot-Marie-Tooth Disease (CMT) Information Page
- Wikipedia Entry for Charcot-Marie-Tooth Disease (CMT)
- MDA Charcot-Marie-Tooth Disease (CMT) Information Page
- NINDS Charcot-Marie-Tooth Disease Fact Sheet