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 1 in 4, 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.