Duchenne is a degenerative muscle disease
Duchenne muscular dystrophy or DMD is a degenerative hereditary muscle disease. When you are born with Duchenne (hereditary), your muscles slowly break down and weaken over time (degenerative). The signs and symptoms can start to manifest from two years of age. Over time, the affected muscles become so weak that they cannot function any more.
Duchenne almost exclusively affects boys, although there are exceptions. One in 3,500 boys is born with Duchenne. Toddlers with Duchenne fall frequently and have trouble running. For longer distances, they need to be transported in a buggy and at older ages, their first wheelchair. By about 10 years of age many Duchenne children are completely dependent on a wheelchair. It also becomes more difficult for them to use their arm muscles. If the muscles used for breathing become too weak, a respirator is needed. DMD is ultimately fatal because the heart muscle fails. There is currently no known cure.
What is the cause of Duchenne?
An error in the dystrophin gene on the X chromosome results in a lack of protein, dystrophin, in the muscle cell wall. The dystrophin gives the muscles resilience and firmness. Without dystrophin the muscle cells become damaged and die over time. The cells are replaced with connective tissue.
Muscle is composed of muscle fibres surrounded by a membrane. The membrane is made of a protein complex that help the muscles function properly.
When one of the interdependent underlying proteins, like dystrophin, in the complex is absent this results in Duchenne Muscular Dystrophy.
If dystrophin is present but dysfunctional, this results in Becker Muscular Dystrophy.
Duchenne muscular dystrophy is a hereditary disease passed on by the mother (via the X-chromosome). Sons of a carrier have a 50% chance of developing the disease, daughters have a 50% chance of becoming carriers. In 30% of cases the gene mutation is spontaneous (a new mutation) not inherited from the mother, but can be transmitted onward. In cases of new mutations it is also possible that the mother, who was not a carrier, passed on several ova with the damaged gene. This is known as germ cell mosaicism. This form is caused by a previous mutation during the physical development of the mother. The risk of Duchenne mothers who are not carriers of having a second child with DMD is increased to approximately 7%.
Errors or mutations in the Dystrophin gene
Duchenne Muscular Dystrophy is one of the most common hereditary diseases in humans. About one in 3500 boys is born with the disease worldwide, which is caused by a mutation (error) in the dystrophin gene. The structure of the gene was mapped in 1986 and is the largest gene ever described. The average gene has about 22 exons (packets of genetic information to build protein). The dystrophin gene has 79 exons and is therefore up to four times longer. Errors or mutations can occur in various places in the gene. The severity of DMD depends on the position, type and number of mutations in the gene. This is important is some of the current research attempts to find the cure (eg exonskipping)
In about 60% of Duchenne patients there are defects (deletions) in the dystrophin gene
In 5% of cases parts of the gene are doubled.
In the remaining 35% of patients there are point mutations ie. one nucleotide has been altered to generate an incorrect amino acid or a stop codon occurs (the protein production stops).
A gene is a piece of DNA that contains information for making a particular protein. DNA consists of a sequence of nucleotides. A triplet of three consecutive nucleotides can be translated by the cell into an amino acid. The correct sequence of amino acids generates a functional protein.
The reading frame is the correct order in which these triplets of nucleotides should be grouped and translated to the intended amino acids. If the reading frame is shifted by an error in the DNA then the correct order of nucleotides is lost. This results in the wrong amino acid order in the protein product or if the mutation results in triplet ‘stop codon’ then the protein production will stop completely. These faulty collections of amino acids form small pieces of proteins that cannot function in the muscle fibre anymore.
To understand how this works, you can imagine the genetic code of a protein as a sentence. Cells should read the genetic phrase in three-letter groups. For example:
The dog let the cat eat the bug
Mutations (errors) that retain the reading frame can occur when a part of the sentence disappears (deletion) that consists of 3 letter words without disturbing the words left and right of the missing part. You will then get a shorter but readable sentence.
The dog let the cat eat the bug
The dog let the bug
Reading frame-retaining mutations in the dystrophin gene lead to the creation of a shorter but still (partly) functional dystrophin protein. This is known as Becker Muscular Dystrophy (BMD). Boys with Becker's disease have fewer complaints and the disease rate among them is also less serious.
Mutations (errors) that disrupt the reading frame arise when a deletion occurs that interferes with the 3-letter pattern, resulting in nonsense words. This makes the sentence unreadable. Such an illegible sentence is similar to a non-functional dystrophin mutation in Duchenne.
The dog let the cat eat the bug
The dog let hec ate att heb ug
Does Duchenne only occur in boys?
Because boys have an XY chromosome pair they will always become ill when they have an X chromosome with a mutated dystrophin gene. Girls with a mutated X chromosome, on the other hand, have a “spare” X chromosome which usually allows them to create enough dystrophin protein to protect them from the disease.
Early on in embryological development in girls one X chromosome from the mother or father will be switched off. The X chromosome that gets shut off is a random in each cell. There is a 50% chance that the healthy X chromosome is activated while the other is switched off. Normally it does not matter how many of the mother’s X chromosomes and how many of the father’s X chromosome are inactivated. But if a gene like dystrophin is mutated it becomes very important.
If a girl has too many cells in which the mutated X chromosome is activated, she may have insufficient dystrophin and will start to manifest Duchenne or Becker dystrophy symptoms. In most cases however, girls will not display the serious symptoms that boys manifest. They may show muscle weakness in the back, legs and arms. In addition, they can have heart problems that can lead to serious life-threatening complications is not treated.
In very rare cases, the second X chromosome may be completely absent or severely damaged. In those cases, she may produce little to no dystrophin and can also develop Duchenne or Becker muscle dystrophy symptoms like a boy.
Female family members of a Duchenne patient can be tested to determine if they are a carrier. This is important for future family planning but it can also determine whether they should be monitored in particular for possible cardiac problems and other symptoms.
Muscle fibres are composed of a fusion of different individual muscle cells. One fibre will therefore contain multiple nuclei that may or may not produce dystrophin in carriers.
Two mechanisms partially capture the deficiency or absence of dystrophin nuclei.
In the heart muscle however, individual cells are involved.
Symptoms and diagnosis
Children with Duchenne Muscular Dystrophy are often diagnosed between four and six years, but sometimes it can occur a lot later. Some studies show that the DMD diagnosis is being made far earlier nowadays than in the past. There is still however an average delay of two years from the moment the parents see the first signs and present to the medical services and a definitive CK test is done. Neonatal screening for DMD could reduce this delay but this is only available in very few countries.
In a CK test, the blood is examined for the presence of creatine kinase (CK). In Duchenne, the CK content is greatly increased. With DNA test, a dystrophin gene mutation can be demonstrated in many cases.
In some cases a muscle biopsy can be performed. A small piece of muscle is removed and examined under a microscope. This can reveal degradation and repair of the muscle fibers. It can also show whether the protein dystrophin is present in the muscle tissue. That protein is lacking (almost) completely in someone with Duchenne.
Prenatal testing for Duchenne is usually possible. In a carrier, a test between the tenth and thirteenth week of pregnancy can show whether the baby is male and whether there is a mutation in the dystrophin gene.
Early recognition of the symptoms and signs of DMD is the best tool we currently have at the moment
Recognising the symptoms
In nearly 40% of the children with Duchenne the ability to sit up unsupported is delayed and in 70% of cases, supported walking is delayed and may not occur for up to 18 months. Because the leg muscles don’t function well, children with Duchenne have difficulties lifting themselves off of the ground. They often use their upper body muscles to lift themselves to standing (known as Gower’s manoeuvre). Their motor skills develop more slowly and they find running and climbing stairs more difficult. Hopping and jumping are often not possible. They tend to fall easily and adopt an abnormal posture with a protruding belly and an arched back. The gait is typically wobbling and they walk on the tips of their toes. As a result, their calves feel thicker and harder than normal. The muscles in the legs weaken first, followed by the arms and their stamina becomes depleted. After mild effort they will often complain of pains in the legs.
Some children with Duchenne muscle dystrophy also have a lag in mental development (learning disorders occur more often) and there is sometimes delayed speech development
Need for earlier diagnosis
The above-mentioned symptoms should sound the alarm bell and be followed as soon as possible by a CK test. Early detection is very important to start with custom therapy as soon as possible. This has an important impact on the course of illness. With the correct diagnosis, you can also manage the child's limitations, for example, by not forcing them to continue when they become tired. One can also prevent several boys with Duchenne being born to the same family and tracing other carriers in the family circle on time.
Here you can watch a video about the first signs of Duchenne's.
Up until the 1990s, the life expectancy of boys with Duchenne was only 19 years. Advances in cardiac and respiratory care have increased life expectancy. Young adults with DMD stay in school longer, have a job, marry and have children. The average life expectancy is currently 25-30 years and there have been cases of men live as long as 40 years.
In addition, it is an exciting, hopeful time. A lot of research is being done into new treatments for Duchenne. Different approaches are being investigated globally at the same time. Still, it will take years before an effective treatment for Duchenne is developed.
Research has to pass through many stages before it can become available to patients. Approval for new treatments have to be obtained to market medications, governments have to commit to supporting research financially and fund new treatments.
Research costs a lot of time and money but the more money that is made available for research, the more resources and investigators that can be brought on board, the faster the goals can be achieved. As anyone affected by Duchenne will tell you, time is not on our side. Therefore, one of our primary goals is to raise money to invest in carefully vetted, promising research.