WHAT IS DUCHENNE MUSCULAR DYSTROPHY?    1   1  mm

Duchenne muscular dystrophy (DMD) is the most common muscle disease of childhood. Approximately, one in every 5,000 newborn boys have Duchenne. Very rarely it also affects girls (approximately 1 in 50 million girls). It occurs across all races and cultures.

Symptoms of Duchenne usually appear between ages two and five years and may include difficulty: running, jumping, climbing, and rising from the floor, frequent falls, enlarged calf muscles, toe walking and delays in language development.

The first muscles affected are those around the hips and upper thigh. Weakness gradually progresses to include all the muscles used for movement (skeletal muscles), the muscles used for breathing and the heart.

Becker muscular dystrophy (BMD) is a genetic condition that infants are born with but may not cause symptoms until five years of age. BMD is caused by an insufficient amount of the protein called dystrophin in the muscle cell which causes the muscle to breakdown over time. BMD occurs 1 in 18,000 to 1 in 30,000 newborn boys have Becker and the average age of diagnosis is between 5 – 15 years of age.

(Reference: https://mdnsw.org.au/wp-content/uploads/2019/05/Becker-Muscular-Dystrophy-FACT-SHEET.pdf)

WHAT CAUSES DUCHENNE ? 

Duchenne is caused by a change to a gene that provides the instructions to produce the protein called ‘dystrophin’.

As a result, very little or no dystrophin protein is produced. Dystrophin normally protects muscle cells from damage and without it, the muscle cells deteriorate, and the symptoms of Duchenne muscular dystrophy develop. The genetic change is often referred to as a ‘mutation’

The genetic mutation that causes Duchenne is either:

passed down through the family (inherited), or

caused by a new genetic change that occurs in the child.

The new genetic change is known as a ‘spontaneous mutation’ and this happens in more than one third of Duchenne cases. The dystrophin gene is particularly susceptible to new mutations because of its large size. This explains why Duchenne can appear in a family with no prior history of the condition in previous generations. The spontaneous genetic change happens very early in development – in the egg that is fertilised at the beginning of a pregnancy. New mutations may also occur in the mother, causing her to be the first carrier in the family.

NOTE: the likelihood of the possible four outcomes in the diagram is equal, so in each pregnancy there is a one in four chance of having a boy with Duchenne.

 HOW IS DUCHENNE INHERITED?    

In around two thirds of cases of Duchenne the faulty dystrophin gene is passed down through the family. The gene that is affected in Duchenne – the dystrophin gene – is located on the X chromosome. This is one of the chromosomes that determines our gender.

Males have one X chromosome inherited from their mother and one Y chromosome inherited from their father. If their X chromosome contains a faulty dystrophin gene, they will have Duchenne muscular dystrophy. Females on the other hand, have two X chromosomes, one inherited from each parent. If one X chromosome contains a faulty dystrophin gene the healthy dystrophin gene on the other X chromosome can compensate for it and therefore females usually don’t show any symptoms or symptoms are very mild. These girls are known as carriers and could potentially pass the condition on to their sons.

If a male with Duchenne were to have children with a non-carrier female, their sons would not inherit the condition and their daughters would all be carriers. It is important to remember that Duchenne is nobody’s fault, and nobody did anything wrong to cause it. An appointment with a genetic counsellor can help with understanding the inheritance of Duchenne.

What is Germline Mosaicism?    

Mosaicism in genetics is when a proportion of cells are genetically different to the rest. For example, in a black and white cat, some of the hair cells have the genetic code to make black fur and some have the instructions to make white fur. Germline refers to egg and sperm cells. In Duchenne, germline mosaicism refers to a proportion of a woman’s eggs containing the mutation that causes Duchenne. 

It is thought that around 15 percent of women who have a son with Duchenne, but her blood tests negative for being a carrier, have germline mosaicism. Germline mosaicism is of concern because even though a woman is not a carrier, there is an increased risk of having another son with Duchenne, or daughters who are carriers. However, it is practically impossible to test for germline mosaicism (unless a couple goes through IVF and has genetic testing done), so it is difficult to give an accurate estimate of the risk.

What are the types of mutations that cause Duchenne?    

The dystrophin gene has 79 pieces called ‘exons. Each exon contains on average a few hundred ‘letters’ of genetic code.

There are three different types of genetic changes (mutations) that cause Duchenne:

- Large deletions (missing whole exons)

- Large duplications (additional whole exons)

- Small point mutations (changed, inserted or deleted letters of code)

Large deletions are the most common type of mutation, accounting for around 80 percent of mutations.

The other types are rarer – point mutations (10 to 15 percent) and large duplications (5 to 11 percent).

How do mutations affect the dystrophin gene?  

The dystrophin gene has 79 pieces called ‘exons. Each exon contains on average a few hundred ‘letters’ of genetic code.

The letters of genetic code contained within a gene are “read” by the body in “sentences” of three-letter words.

Can girls be born with Duchenne?

A girl could have Duchenne if both of her copies of the dystrophin gene are faulty either through two spontaneous mutations or she inherits a faulty dystrophin gene AND her second ‘back-up’ copy of the dystrophin gene acquires a spontaneous mutation. 

This is extremely unlikely, and it is thought to be more probable that the whole X chromosome that carries the healthy copy of the dystrophin gene is ‘switched off’. 

This prevents it being used to make dystrophin.

CAN GIRLS WITH DUCHENNE PARTICIPATE IN CLINICAL TRIALS? 

Switching off of the X-chromosome is a process called ‘X-linked inactivation’. This process happens naturally in all females but usually it happens randomly so that half of a woman’s cells use one X-chromosome and half use the other X-chromosome. If this is the case, enough dystrophin is made to keep the muscles healthy. But in some females, X-linked inactivation is skewed so that for some reason one X-chromosome is favoured, and if this happens to be the X-chromosome that carries the faulty dystrophin gene, not enough dystrophin is made and symptoms of Duchenne develop. Depending on the degree of skewing of X-linked inactivation, the severity could be the same as a boy with Duchenne, but usually their condition is milder. This is just one theory as to how girls develop Duchenne and research is ongoing to better understand this.

Alternatively, if a young man with Duchenne had a child with a woman who was a carrier of Duchenne, it is possible that they could have a daughter with Duchenne. This is very rare since men with Duchenne usually have poor health by the time they are old enough to have a child and it would be unlikely that their partner would also be a carrier.

Female carriers of Duchenne can have mild symptoms of Duchenne that progress very slowly – these women are called ‘manifesting carriers’. This is because they produce a reduced amount of dystrophin protein. Symptoms include mild muscle weakness, fatigue (a tired feeling), or cramping in their muscles. It is also estimated that 10 to 50 percent of carriers have changes to their heart. Therefore it is advised that all female Duchenne carriers have regular check-ups so that any problems can be picked up early and treated.

WHAT IS DUCHENNE MUSCULAR DYSTROPHY?    1   1  mm

Duchenne muscular dystrophy (DMD) is the most common muscle disease of childhood. One in every 3,500 newborn boys have Duchenne. Very rarely it also affects girls (approximately 1 in 50 million girls). It occurs across all races and cultures.

Symptoms of Duchenne usually appear between ages two and five years and may include difficulty: running, jumping, climbing, and rising from the floor, frequent falls, enlarged calf muscles, toe walking and delays in language development.

The first muscles affected are those around the hips and upper thigh. Weakness gradually progresses to include all the muscles used for movement (skeletal muscles), the muscles used for breathing and the heart.

Becker muscular dystrophy (BMD) is a genetic condition that infants are born with but may not cause symptoms until five years of age. BMD is caused by an insufficient amount of the protein called dystrophin in the muscle cell which causes the muscle to breakdown over time. BMD occurs 1 in 18,000 to 1 in 30,000 newborn boys have Becker and the average age of diagnosis is between 5 – 15 years of age.

(Reference: https://mdnsw.org.au/wp-content/uploads/2019/05/Becker-Muscular-Dystrophy-FACT-SHEET.pdf)

WHAT CAUSES DUCHENNE ? 

Duchenne is caused by a change to a gene that provides the instructions to produce the protein called ‘dystrophin’.

As a result, very little or no dystrophin protein is produced. Dystrophin normally protects muscle cells from damage and without it, the muscle cells deteriorate, and the symptoms of Duchenne muscular dystrophy develop. The genetic change is often referred to as a ‘mutation’

The genetic mutation that causes Duchenne is either:

passed down through the family (inherited), or

caused by a new genetic change that occurs in the child.

The new genetic change is known as a ‘spontaneous mutation’ and this happens in more than one third of Duchenne cases. The dystrophin gene is particularly susceptible to new mutations because of its large size. This explains why Duchenne can appear in a family with no prior history of the condition in previous generations. The spontaneous genetic change happens very early in development – in the egg that is fertilised at the beginning of a pregnancy. New mutations may also occur in the mother, causing her to be the first carrier in the family.

NOTE: the likelihood of the possible four outcomes in the diagram is equal, so in each pregnancy there is a one in four chance of having a boy with Duchenne.

 HOW IS DUCHENNE INHERITED?    

In around two thirds of cases of Duchenne the faulty dystrophin gene is passed down through the family. The gene that is affected in Duchenne – the dystrophin gene – is located on the X chromosome. This is one of the chromosomes that determines our gender.

Males have one X chromosome inherited from their mother and one Y chromosome inherited from their father. If their X chromosome contains a faulty dystrophin gene, they will have Duchenne muscular dystrophy. Females on the other hand, have two X chromosomes, one inherited from each parent. If one X chromosome contains a faulty dystrophin gene the healthy dystrophin gene on the other X chromosome can compensate for it and therefore females usually don’t show any symptoms or symptoms are very mild. These girls are known as carriers and could potentially pass the condition on to their sons.

If a male with Duchenne were to have children with a non-carrier female, their sons would not inherit the condition and their daughters would all be carriers. It is important to remember that Duchenne is nobody’s fault, and nobody did anything wrong to cause it. An appointment with a genetic counsellor can help with understanding the inheritance of Duchenne.

What is Germline Mosaicism?    

Mosaicism in genetics is when a proportion of cells are genetically different to the rest. For example, in a black and white cat, some of the hair cells have the genetic code to make black fur and some have the instructions to make white fur. Germline refers to egg and sperm cells. In Duchenne, germline mosaicism refers to a proportion of a woman’s eggs containing the mutation that causes Duchenne. 

It is thought that around 15 percent of women who have a son with Duchenne, but her blood tests negative for being a carrier, have germline mosaicism. Germline mosaicism is of concern because even though a woman is not a carrier, there is an increased risk of having another son with Duchenne, or daughters who are carriers. However, it is practically impossible to test for germline mosaicism (unless a couple goes through IVF and has genetic testing done), so it is difficult to give an accurate estimate of the risk.

What are the types of mutations that cause Duchenne?    

The dystrophin gene has 79 pieces called ‘exons. Each exon contains on average a few hundred ‘letters’ of genetic code.

There are three different types of genetic changes (mutations) that cause Duchenne:

- Large deletions (missing whole exons)

- Large duplications (additional whole exons)

- Small point mutations (changed, inserted or deleted letters of code)

Large deletions are the most common type of mutation, accounting for around 80 percent of mutations.

The other types are rarer – point mutations (10 to 15 percent) and large duplications (5 to 11 percent).

How do mutations affect the dystrophin gene?  

The dystrophin gene has 79 pieces called ‘exons. Each exon contains on average a few hundred ‘letters’ of genetic code.

The letters of genetic code contained within a gene are “read” by the body in “sentences” of three-letter words.

Can girls be born with Duchenne?

A girl could have Duchenne if both of her copies of the dystrophin gene are faulty either through two spontaneous mutations or she inherits a faulty dystrophin gene AND her second ‘back-up’ copy of the dystrophin gene acquires a spontaneous mutation. 

This is extremely unlikely, and it is thought to be more probable that the whole X chromosome that carries the healthy copy of the dystrophin gene is ‘switched off’. 

This prevents it being used to make dystrophin.

CAN GIRLS WITH DUCHENNE PARTICIPATE IN CLINICAL TRIALS? 

Switching off of the X-chromosome is a process called ‘X-linked inactivation’. This process happens naturally in all females but usually it happens randomly so that half of a woman’s cells use one X-chromosome and half use the other X-chromosome. If this is the case, enough dystrophin is made to keep the muscles healthy. But in some females, X-linked inactivation is skewed so that for some reason one X-chromosome is favoured, and if this happens to be the X-chromosome that carries the faulty dystrophin gene, not enough dystrophin is made and symptoms of Duchenne develop. Depending on the degree of skewing of X-linked inactivation, the severity could be the same as a boy with Duchenne, but usually their condition is milder. This is just one theory as to how girls develop Duchenne and research is ongoing to better understand this.

Alternatively, if a young man with Duchenne had a child with a woman who was a carrier of Duchenne, it is possible that they could have a daughter with Duchenne. This is very rare since men with Duchenne usually have poor health by the time they are old enough to have a child and it would be unlikely that their partner would also be a carrier.

Female carriers of Duchenne can have mild symptoms of Duchenne that progress very slowly – these women are called ‘manifesting carriers’. This is because they produce a reduced amount of dystrophin protein. Symptoms include mild muscle weakness, fatigue (a tired feeling), or cramping in their muscles. It is also estimated that 10 to 50 percent of carriers have changes to their heart. Therefore it is advised that all female Duchenne carriers have regular check-ups so that any problems can be picked up early and treated.