Duchenne Muscular Dystrophy

What is Duchenne Muscular Dystrophy?

Duchenne Muscular Dystrophy (sometimes referred to as Duchenne or DMD) is a rare and severe genetic disease that has serious effects on different muscles throughout the body, from the skeletal muscles that support movement, to muscles vital for the essential functions of the heart and lungs. [1, 2] Duchenne can also have effects on the brain. [2]

Duchenne is caused by a mistake (mutation) in the gene for dystrophin, [1] an important protein that is vital for muscle strength and function. This genetic mistake blocks the production of dystrophin, [1] meaning that muscles gradually weaken and become increasingly damaged over time. As a result, several different systems in the body can be seriously affected by Duchenne.

Duchenne progresses differently for every person, [3] but symptoms are usually first identified in early childhood and worsen with age. [1] In children, skeletal muscle loss can first lead to weakness in the hips, thighs, shoulders and pelvis, which can affect their movement and flexibility. [2] Some children may also have a curved spine (scoliosis), caused by Duchenne’s effects on the skeleton. [1] Muscle loss can then progress to the arms, lower legs and core in adolescence: [2] most people with Duchenne will need to use a wheelchair by the time they are 10–12 years old. [1] The lungs and heart will also be affected, leading to breathing difficulties and usually a reliance on assisted ventilation (use of a device that blows air in and out of the airways at pressure) by the time a person with Duchenne turns 20 years old. [1, 2] Assisted ventilation may initially only be required during the night but eventually patients may also need it during the day. [4] A lack of dystrophin in the brain has also been linked to learning and behavioural difficulties, although its role is not fully understood. [2, 5]

Symptoms of Duchenne have an impact on all aspects of daily life and need to be carefully managed. Until recently, people with Duchenne often only lived until their teenage years before succumbing to heart and/or lung failure. [1] However, extensive improvements to care mean that people with Duchenne may now enjoy productive and fulfilling lives into adulthood. [6]

How does someone get Duchenne?

The gene for dystrophin (the DMD gene) is carried on the X chromosome. [1] Boys have only one copy of the X chromosome (alongside a Y chromosome), while girls have two copies. [7] Without the back-up copy that girls carry, a mutation in the DMD gene will stop dystrophin from being made effectively in boys, leading to Duchenne. [8] As a result, Duchenne mostly affects boys: 1 in 3,500–5,000 male births have Duchenne. [9]

In 2 out of 3 cases, Duchenne is passed down to a child from a mother carrying a mutated DMD gene on one X chromosome (see diagram). [7] However, in 1 out of 3 cases, the dystrophin mutation occurs spontaneously (with no known cause) as a new event during early pregnancy. [10] Spontaneous mutations can therefore also lead to girls having Duchenne, but this happens in only 1 in 50 million female births. [11]

How is Duchenne diagnosed?

Duchenne is usually diagnosed in early childhood. Boys will typically be diagnosed when they are roughly 4 years old. [2] This may be after family members or teachers notice that the child is developing differently compared with children around them: they may be struggling to stand, balance, walk and talk. However, sometimes a diagnosis can be made after a blood test for an unrelated reason.

In 95 out of every 100 cases, a combination of two blood tests is used to make a Duchenne diagnosis. [8] The first test looks to see if a child has high levels of a protein called creatine kinase in the blood. [1] Creatine kinase may be found at levels 10–100 times higher than normal in people with Duchenne, [12] sometimes even higher. Creatine kinase is released from damaged muscle cells and high levels can indicate that there may be long-term muscle damage because of a lifelong condition such as Duchenne or that there has simply been a short-term muscular injury. [1]

It can be difficult to make a Duchenne diagnosis from this test alone, so the second test looks at the DNA in a child’s blood to confirm whether there is a mutation in the dystrophin gene (genetic test). Doctors can also see what kind of mutation has affected the gene, as this can impact the treatments available. [1]

Sometimes a third test is needed to confirm a Duchenne diagnosis. In this test, a doctor needs to take a small sample (biopsy) of muscle from a numbed area, so that they can look at the muscle fibres under a microscope. [1] This test allows doctors to see exactly how much dystrophin is being made by the muscle, so they can decide if the levels are normal or lower than would be expected.

What does it mean to be a carrier for Duchenne?

As the DMD gene for Duchenne is carried on the X chromosome, only females can be carriers for the disease without showing all of the symptoms. [13]

Most females who are carriers will not experience any Duchenne symptoms, but there are cases where medical care is needed. Although 80–90% of female carriers won’t have any muscular problems, some may experience some muscle weakness, tiredness (fatigue) or cramping and may benefit from advice and treatment from a specialist. Similarly, up to 1 in 2 female carriers may experience changes to the health of their heart and so regular check-ups with a cardiologist (heart specialist) are recommended. [10]

Genetic testing can identify women who are carriers. This can be very important for women who have a history of Duchenne in their family, particularly if they are planning to have children, either for the first time or as a sibling for children they already have. [9]

Women who are carriers are advised to discuss family planning with a genetic counsellor before conceiving. If a woman is a carrier of Duchenne, she may pass on the mutated gene to her child. If she were to have a son, there would be 1 in 2 chance that he would have Duchenne and if she were to have a daughter, there would be a 1 in 2 chance that her daughter would be a carrier of Duchenne. [9]

No one can control the genes that are passed onto their children, but a genetic counsellor can explain the different options available so that women who are carriers can make informed choices about a potential pregnancy. [9, 13, 14]

What treatments are available for Duchenne?

Although care for people with Duchenne has improved over the past 30 years, there is still no cure for Duchenne. [1] Instead, Duchenne is currently managed using a multidisciplinary approach. This means that many healthcare professionals with different specialties, such as cardiologists (heart specialists), respiratory doctors (lung specialists), speech therapists, physiotherapists and dieticians, work together to help manage symptoms in the best way possible. This helps people with Duchenne to have a good quality of life. [1]

Lots of clinical trials are ongoing for researchers to look for different ways of treating Duchenne. Many treatments are ‘mutation-specific’, which means that they are designed to treat Duchenne caused by a particular kind of mistake in the dystrophin gene. [15] Genetic testing confirms whether people with Duchenne can use these treatments. Examples include ‘exon-skipping’ treatments, designed to make the protein-building machinery in muscle cells ‘skip over’ mutations so that smaller, but functional, dystrophin can be made, and ‘nonsense mutation readthrough’ treatments, designed to make the protein-building machinery ignore the faulty instructions that block dystrophin production. [15, 16]

Other research tactics aim to directly tackle the mistakes in the genetic instructions for dystrophin, in order to improve its production by muscle cells. [1]

One such approach is gene therapy, which is explained in this helpful video. Gene therapy aims to provide muscle cells with the missing genetic instructions for dystrophin using an adeno-associated virus (AAV). The virus cannot cause disease but it can act as a messenger to deliver new genetic instructions to muscle cells. As the genetic instructions for dystrophin are so long, there isn’t enough space for all of them inside the virus. To overcome this, researchers have condensed the vital parts, removing sections that aren’t essential, to create a shorter set of genetic instructions for a smaller version of dystrophin (micro-dystrophin) that should work in the same way. [16]

Gene editing is a different approach that uses ‘molecular scissors’ (technology known as CRISPR/Cas9) to remove or replace faulty instructions within the mutated dystrophin gene. [15]

Neither genetic approach has been approved for use in people with Duchenne yet: researchers need to confirm they are safe and effective in clinical trials first.

Another treatment approach aims to preserve muscle tissue and support muscle growth by using steroids to minimise inflammation and scarring (fibrosis). [1] As steroids are linked to lots of side effects if used for a long time, [1] researchers are continuing to look for alternative, new steroids that might be safer for long-term use in people with Duchenne.

Not all clinical trials lead to positive results but negative trials still help researchers to learn more about Duchenne and how it can be treated. Roche’s experimental treatment called taldefgrobep alfa (also known as RO7239361/RG6206 and anti-myostatin) was designed to block the activity of a protein called myostatin. [17] In healthy people, myostatin stops muscles from growing too big. [1] Researchers hoped that blocking myostatin would improve muscle growth in people with Duchenne. The clinical trial programme for RO7239361/RG6206 included two studies: THUNDERJET and SPITFIRE. Both trials were cut short because of the treatment’s lack of efficacy (it didn’t work as well as expected). [17, 18]

What is the outlook for Duchenne?

Developing a new treatment is a complicated process. There can be many years between initial laboratory experiments and a drug being approved for use in patients. This can be incredibly frustrating and upsetting for families, particularly considering progressive diseases such as Duchenne. The treatment landscape for Duchenne has expanded beyond recognition in recent years and it is hoped that these advances will continue with the wealth of clinical trials that are currently exploring novel approaches. [19, 20]