Charcot-Marie-Tooth disease - Causes of Charcot-Marie-Tooth disease

Charcot-Marie-Tooth disease (CMT) is caused by mutations (faults) in genes that cause the peripheral nerves to become damaged.

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, and is made up of two parts:

• 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.

In some types of CMT, faulty genes cause the myelin sheath to disintegrate. The axons become damaged without this protection, which affects the transmission of messages between the brain and the muscles and senses. This leads to muscle weakness and numbness.

In other types of CMT, the axons are directly affected and do not transmit electrical signals at the normal strength, which means muscles and senses are understimulated. Again, this leads to symptoms of muscle weakness and numbness.

How CMT is inherited

A child with CMT may have inherited the genetic fault responsible for the disease from just one or both of their parents.

There is no single faulty gene that causes CMT. The many varieties of CMT (see below) are caused by different genetic mutations.

CMT is an unusual genetic disorder because the faulty 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 faulty gene, there is a 50% chance the condition will be passed on to each child 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 only have 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 25% chance each child you have will develop CMT
• there is a 50% chance each child you have will inherit one of the defective genes and be able to pass the condition to any children they have (known as being a 'carrier'), although they will not have any of the symptoms of CMT themselves
• there is a 25% chance each child you have will receive a pair of healthy genes and won't develop CMT

If only one parent has the autosomal recessive gene, your children will not develop CMT. However, there is a 50% chance each child will be a carrier.

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 parts of 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 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 no or very mild symptoms because the other healthy X chromosome counters the effect of the defective one. However, there is a 50% chance 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.

Types of CMT

There are many different types of CMT that are all caused by different mutations (changes) in your genes.

The main types of CMT are:

• CMT 1 – caused by defective genes that cause the myelin sheath to slowly break down. The most common type.
• CMT 2 – caused by defects in the axon. Less common and usually less severe than CMT 1.
• CMT 3 – also known as Dejerine-Sottas disease, a rare and severe type of CMT that affects the myelin sheath. Characterised by severe muscle weakness and sensory problems. Unlike other types of CMT, symptoms usually begin in early childhood.
• CMT 4 – another rare type of CMT that affects the myelin sheath. The exact genes that cause it have not yet been identified. As with CMT 3, symptoms usually begin in childhood and many people with the condition are eventually unable to walk.
• CMT X – caused by a mutation in the 'X' chromosome. More common in men than women.