What is muscular dystrophy?

• The term muscular dystrophy encompasses a number of diseases characterised by progressive muscle wasting. These include:
• Duchenne muscular dystrophy
  • This is the most common form of muscular dystrophy but also the most severe.
  • The symptoms present in infancy.
  • Most affected individuals are wheelchair-bound by 11 years old.
  • It usually affects boys rather than girls. Women and girls can carry the ‘faulty’ gene but don’t normally have the muscle weakness or any symptoms.
• Becker muscular dystrophy
  • This is a less aggressive form of muscular dystrophy.
  • It has a later age of onset and milder symptoms.
  • It usually affects boys rather than girls.
• For Duchenne muscular dystrophy the incidence is one in 3,500 males. With Becker muscular dystrophy, the incidence is one in 20,000 males.

Genetics

• Both Duchenne and Becker muscular dystrophy are single gene disorders caused by different mutations in the DMD gene, which is located on the X chromosome.
• They are both recessive diseases, which means two copies of the mutated gene are needed for the disorders to occur.
• However, because the gene is on the X chromosome, the disease is much more common in males. Males only have one X chromosome and therefore only need to inherit one copy of the mutated gene to develop the disease.
• The DMD gene is the largest known gene in the human genome (2.2 million base pairs!).

Biology

• The DMD gene codes for the protein dystrophin, which is located in muscle cells.
• Dystrophin’s function is to join the muscle cell’s internal framework to proteins in the connective tissue outside of cells. It acts like glue that binds cells together.
• When the DMD gene is mutated either very little dystrophin is produced or the dystrophin that is produced doesn’t work properly.
• In Duchenne muscular dystrophy very little dystrophin is produced. This causes muscle cells to become leaky and eventually swell and burst. As the cells burst they are replaced with fat cells and connective tissue reducing the amount of muscle in the body.
• In Becker muscular dystrophy near normal amounts of dystrophin are produced but the protein doesn’t function properly.

Cross-section through a nerve in mouse skeletal muscle showing the location of dystrophin (in red) in the muscle cells.
Image credit: Prof. Peter Brophy, Wellcome Images

Symptoms

Duchenne muscular dystrophy

• This affects boys from about three years old.
• It causes gradually worsening muscle weakness.
• Initial symptoms usually include difficulty walking and getting off the floor.
• It may lead to reliance on a wheelchair by the age of 11 years.
• The disease is generally fatal by age 18 years because of its impact on heart muscle and the muscles that enable breathing.
• Despite the loss of muscle mass, the size of certain muscles appears increased because of the presence of high levels of fat and connective tissue.

Becker muscular dystrophy

• Symptoms are similar to Duchenne muscular dystrophy, but they generally don’t appear until the patient is in their teens.
• Progression of the disease is much slower than Duchenne muscular dystrophy.
• People with Becker muscular dystrophy usually have a normal lifespan.

Diagnosis

• The increased permeability of the muscles cells leads to the release of muscle-specific proteins that can be detected in the blood.
• One of these proteins, the enzyme creatine kinase, is used as an indicator of the disease in patients showing initial symptoms. However the results of this test alone are insufficient to identify the disease.
• A series of tests are usually carried out to find out more about the spread of any muscle damage. These can include:
  • electrical tests on the nerves and muscles
  • chest and heart scans
  • muscle biopsies, where a sample of muscle tissue is removed for testing.
• Genetic testing can also be carried out to look for the characteristic mutation in the DMD gene as a cause for muscle complaints.

Treatment

• Regular physiotherapy can help prolong mobility.
• There is currently no curative treatment for either condition.
• Both conditions are prime candidates for gene therapy because only one gene is affected.
• Key studies and clinical trials are currently being carried out to assess the effectiveness of new treatments for muscular dystrophy. The physical abilities and progress of children with muscular dystrophy are assessed to determine if the new treatments are effective in treating the disease.
• One of these treatments, a drug called drisapersen, is given as a weekly injection. It acts by forming a ‘bridge’ over the mutation in the DMD gene enabling the cellular machinery to produce a slightly shorter, but still functional, form of dystrophin.
• The effectiveness of these drugs is assessed with a six-minute endurance walking test to measure muscle strength. If the drug is effective and dystrophin is being produced, the patient should be able to walk further in six minutes.

Screening

• Genetic screening/testing can be used to find out whether a person is carrying a particular genetic mutation that may cause a medical condition, either in the future or in their future children.
• Screening can be used to identify women who are carriers of muscular dystrophy (individuals carrying one copy of the mutated DMD gene).
• If a woman is found to be a carrier of the mutated DMD gene, couples trying for a baby can be referred to a genetic counsellor to discuss their options.
• Genetic testing can also be done for prenatal diagnosis in male babies. This is done after 11 weeks of the pregnancy by either removing tissue from the placenta or taking a sample of amniotic fluid through a needle into the belly. The cells from these samples are then tested for the mutation in the DMD gene.