Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is the most common fatal genetic disease diagnosed in childhood. The disease almost always affect boys, and they tend to be diagnosed before the age of 5. Duchenne muscular dystrophy is classified as a rare disease. There are around 2,500 patients in the UK and an estimated 300,000 sufferers worldwide.

Children born with Duchenne muscular dystrophy have a fault, known as a mutation, on their dystrophin gene, the longest gene in the body. The fault means that they cannot produce dystrophin, a protein that is vital for muscle strength and function. This lack of dystrophin results in a progressive deterioration of muscle strength and function.

What Is Duchenne Muscular Dystrophy?

Duchenne muscular dystrophy or DMD is a genetic (inherited) disorder that causes muscle weakness and wasting. The muscle weakness starts in early childhood and symptoms are usually first noticed between the ages of 2 and 5 years.

The weakness mainly affects the ‘proximal’ muscles which are those near the trunk of the body, around the hips and shoulders, and so the first signs are often when the child has difficulty getting up from the floor, walking or running. The weakness progresses through childhood and adolesence eventually affecting all the muscles used for moving and also those used for breathing and the heart muscle as well.

Duchenne affects approximately 1 in every 3500 new born boys and is found in children in all countries and cultures. Very rarely it can also affect girls. In the UK there are around 2500 boys and young men with Duchenne. The name Duchenne comes from the doctor who first described the condition.

In general, a steady decline in muscle strength between the ages of 6 and 11 is expected and by 12 years many children are confined to a wheelchair. By their late teens most young people with Duchenne lose the ability to move their arms and experience more problems with breathing and with the heart.

Those with Duchenne do have shortened lives, it is unusual for someone with Duchenne to live beyond their 30s. However, advances in management of the condition are increasing life expectancy and enabling more young adults with Duchenne to lead independent lives.

There are other types of muscular dystrophy and the different types vary as to how severe the muscle weakness is and how quickly it progresses. Becker muscular dystrophy or BMD is similar to Duchenne but less severe with symptoms starting in the teenage years or early twenties.

What Causes Duchenne?

Our body is made of cells and each cell has a control centre which contains genes. Genes are made of DNA and genes are the instruction manual for building the proteins that make our bodies work.

Duchenne is caused by a defect (mutation) in one of the genes in the body.

Humans have around 20,000 genes and one of the largest is called the dystrophin or DMD gene. The role of the DMD gene is to make a protein called dystrophin. Duchenne is caused when very little or no dystrophin is made by the DMD gene because the DMD gene has a defect.

Dystrophin is a protein that is found in all muscles used for movement (skeletal) and in heart (cardiac) muscle. A small amount of dystrophin is also found in nerve cells in the brain. In muscles, dystrophin is one of a group of proteins (dystrophin complex) that work together to strengthen muscle fibres. It is thought that these proteins act as a ‘shock absorber’ to protect muscle fibres from injury as muscles contract and relax.

Without enough dystrophin, skeletal and cardiac muscles become damaged as they repeatedly contract and relax with use. The damaged cells weaken and die over time, causing the characteristic muscle weakness and wasting and heart problems seen in Duchenne.

The dystrophin complex may also play a role in cell signaling by interacting with cells that send and receive chemical signals. Little is known about the role of dystrophin in the brain, research has shown that it may be important for cell to cell communication. Intellectual impairment may occur in some boys but it is not inevitable and if present, does not worsen as the condition progresses.

The genetic defect that causes Duchenne can either be:

  • Inherited (passed down through the family)

          or

  • Caused by a new change in the DMD gene that occurs in the child

This new genetic change is known as a ‘spontaneous mutation’ and is the cause in more than one third of cases of Duchenne. The genetic change occurs very early in development of the egg that has been fertilised which means that the change is found in all of the cells of the body.

How Is Duchenne Inherited?

In around two thirds of the cases of Duchenne the genetic change is passed down through the family from the mother.

Each person inherits a set of genes from their father and another set from their mother. The genes have been copied from the parents' cells into the child's cells.

Genes are found on 'chromosomes'. The DMD gene is located on a chromosome called the X chromosome. Boys have one X chromosome and one Y chromosome; girls have two X chromosomes.

DMD is inherited in a pattern called 'X-linked inheritance'. The DMD gene is 'carried' by women, but does not usually cause problems in girls or women (with rare exceptions, below). This is because of there being two X chromosomes in women: one X chromosome has the 'faulty' DMD gene, and the other X chromosome has a normal gene, which compensates for the faulty one.

In contrast, boys with the DMD gene do not have a second X chromosome and so they cannot compensate for the faulty gene. Therefore, boys with the DMD gene always have symptoms of the disease.

Overall with each pregnancy, the likelihood of each of the 4 outcomes is equal. There is a 1 in 4 chance that a boy with DMD will be born. There is also a 1 in 4 chance that a daughter who carries the DMD gene will be born.

On the other hand, if a man with Duchenne was to have children with a non-carrier woman, none of their sons would have Duchenne although all of their daughters would be carriers.

Girls & Duchenne

Duchenne affects approximately 1 in every 3,500 boys that are born but only around 1 in 50 million girls.

This difference is because Duchenne is caused by a fault in the DMD gene which is only found on the X chromosome (see section on how Duchenne is inherited for more information). Boys have one X chromosome and one Y chromosome while girls have two X chromosomes.

A girl can have Duchenne if both of her X chromosomes have faults in the DMD gene.

This is extremely unlikely although it could happen in a number of different ways. A girl could inherit a faulty DMD gene on one of her X chromosomes from her mother and also develop a spontaneous mutation in her other X chromosome. She could also develop spontaneous mutations in the DMD gene on both of her X chromosomes.

It is also thought that the healthy DMD gene on one X chromosome can become ‘switched off’ by a process called X-linked inactivation in some girls that have inherited a faulty DMD gene on their other X chromosome.

Alternatively, if a man with DMD and a woman who carried a defective DMD gene ‘a carrier’ had a child, it is possible that a daughter would have Duchenne.

Female carriers of a faulty DMD gene can also have very mild symptoms of Duchenne that progress slowly. These women are called ‘manifesting carriers’ because they produce reduced amounts of dystrophin and may have symptoms of fatigue and mild muscle weakness and cramping.

Germline Mosaicism

A small number of women who do not test positive as carriers for Duchenne may still be able to pass a faulty DMD gene to their children. This situation is called germline mosaicism and is caused by a mutation in the DMD gene in the cells of some of the mother’s eggs. The mutation is not seen in the DMD gene in the rest of the mother’s cells. If one of the affected eggs is fertilized, the resulting child will have DMD if a boy or be a female carrier if a girl. It is estimated that around 15% of mothers of boys with Duchenne, who do not appear to be carriers, could pass a faulty DMD gene to their children in this way.

Mutations In The DMD Gene That Cause Duchenne

Duchenne is caused by a fault or mutation in the DMD gene. Genes are made from DNA (deoxyribonucleic acid). The DNA in the DMD gene holds the information necessary for our bodies to make the protein called dystrophin.

The DMD gene is made up from 79 pieces called ‘exons’. Each exon contains hundreds of letters of genetic code. To make protein, another molecule called ribonucleic acid (RNA) goes to work and carries a copy of the DNA code from the gene to another part of the cell.

The RNA, interacting with particles in the cell called ribosomes, ‘reads’ the code and makes the protein called dystrophin. Dystrophin is essential for muscle function.

There are three different types of changes or mutations in the DMD gene that can cause Duchenne:

  • Deletions of one or more whole exons – this is the most common type of mutation and is the cause of around 70% of cases of Duchenne.
  • Duplications (additions) of whole exons – this type of mutation is the cause of around 10% of cases of Duchenne.
  • Other small changes in parts of the genetic code, for example point mutations – this type of mutation is the cause of around 20% of cases of Duchenne.

Dystrophin will not be made at all or, if some dystrophin is made, it will not work well if the genetic code for making it is changed in any of these three ways. Without dystrophin, muscle cells weaken and get damaged over time as they contract and relax.