Charcot-Marie-Tooth disease (CMT) is caused by mutations in genes that affect the peripheral nerves.
To understand the causes of CMT, it is useful to first understand how peripheral nerves work.
The peripheral nerves
The peripheral nerves are a network of nerves that run from the brain and spinal cord (the central nervous system) and carry impulses to and from the rest of the body, such as the limbs and organs. Peripheral nerves are responsible for the body’s senses and movements.
A peripheral nerve is similar to an electrical cable, which is made up of two parts: the axon and the myelin sheath.
- The axon is like the wiring in an electrical cable. It is the part of the nerve that transmits the electrical information between your brain and limbs.
- The myelin sheath acts like the insulation of an electrical cable. It is wrapped around the axon to protect it and ensure the electrical signal is not broken.
Damage to the nerves
In some types of CMT, faulty genes (units of genetic material) cause the myelin sheath to disintegrate. Without the protection of the myelin sheath, the axons become damaged, and the muscles and senses no longer receive proper messages from the brain. This leads to the muscle weakness and numbness.
In other types of CMT, the axons are directly affected. Due to faulty genes, the axons do not transmit electrical signals at the proper strength, which means muscles and senses are under-stimulated. Again, this leads to symptoms of muscle weakness and numbness.
The genetics of CMT
CMT is an inherited (genetic) disorder, which is caused by mutated (changed) genes you inherit from your parents. The genes involved produce proteins that affect either the axon of the peripheral nerve, or the myelin sheath.
There is no single mutated gene that causes CMT. The many varieties of CMT are caused by different genetic mutations.
CMT is an unusual genetic disorder because the mutated genes can be inherited in several different ways. These ways are described below.
Autosomal dominant
Autosomal dominant inheritance of CMT occurs when one copy of a mutated gene is enough to cause the condition. If either parent carries a defective gene, there is a 1-in-2 chance that the condition will be passed on to any children they have.
Autosomal recessive
Autosomal recessive inheritance of CMT occurs when two copies of the defective gene are needed to cause the condition. You inherit one copy from each parent. As your parents have only one copy of the gene, they do not develop CMT themselves.
If both you and your partner are carriers of the autosomal recessive CMT gene:
- there is a 1-in-4 chance that your child will develop CMT
- there is a 1-in-2 chance they will inherit one of the defective genes and become a carrier (although they will not have any of the symptoms of CMT)
- there is a 1-in-4 chance they will receive a pair of healthy genes
If only you have the autosomal recessive gene, and your partner does not, your child will not develop CMT. However, there is a 1-in-2 chance your child will carry the defective gene.
X-linked inheritance
In X-linked inheritance, the mutated gene is located on the X chromosome and passed from mother to son. Chromosomes are the sections of your body’s cells that carry your genes.
Men have XY sex chromosomes. They receive the X chromosome from their mother and the Y chromosome from their father. Women have XX sex chromosomes. They receive one X chromosome from their mother and the other X chromosome from their father.
A woman with the defective X chromosome will usually have none or very mild symptoms because the other healthy X chromosome counters the effect of the defective one. However, there is a 50% chance that she will pass on the defective gene to her son and that he will develop CMT.
If a woman with the defective X chromosome only has daughters, CMT can skip a generation until one of her grandsons inherits it.
Other causes
As well as identifying the different genes that are involved in CMT, future research may also consider other factors that could affect the development of the condition.
Even among family members with the same type of CMT, symptoms can vary widely. It is therefore possible that other genetic or environmental factors affect the development of CMT.
Types of CMT
There are different types of CMT are all caused by different mutations (changes) in your genes. The most common types of CMT are outlined below.
- CMT 1 – caused by defective genes that are involved in the production of the myelin sheath. The defects cause the myelin sheath to slowly break down. CMT 1 is the most common type of CMT, accounting for around a third of cases.
- CMT 2 – caused by defects in the axon. It is less common than CMT 1, accounting for around one in six cases.
- CMT 3 – also known as Dejerine-Sottas disease, it is a rare and severe type of CMT that affects the myelin sheath. It is characterised by extreme muscle weakness and sensory problems. Unlike other types of CMT, symptoms usually begin in early childhood.
- CMT 4 – another rare type of CMT that also affects the myelin sheath. The exact genes that cause CMT 4 have not yet been identified, but it is thought several different genetic processes may be involved. As with CMT 3, symptoms of CMT 4 usually begin in childhood, and many people with the condition are unable to walk.
- CMT X – caused by a mutation in the ‘x’ chromosome, (one of the chromosomes that determine what sex you are.) CMT X is more common in men than in women, and is estimated to account for around 1 in 10 CMT cases.
