Duchenne Muscular Dystrophy
Duchenne Muscular Dystrophy, short DMD, is a genetic disease affecting almost exclusively boys. DMD occurs in 1 in about 3500 males born worldwide and is one of the most serious genetic diseases in children.
DMD is an X-linked recessive disease which means that it can only be inherited from the mother or by spontaneous mutations. To explain this a little bit further, recessive means that both copies of a gene need to be mutated for a disease to develop. In X-linked diseases, however, boys only have one copy of the X chromosome. The other sex chromosome is a Y chromosome inherited from the father. Therefore, a mutation in the X chromosome is all that’s needed to develop the disease. Girls are only rarely affected. About 1 in 50,000,000 girls is born with DMD. This is because girls inherit a wild-type gene from their father. So, even if the mother is a carrier of the disease and passes the mutated gene on to her daughter, the daughter will also only be a carrier.
DMD is also a monogenic disease, which means that only one gene is affected and responsible for all the symptoms. It is a severe form of muscular dystrophy that leads to muscle weakness and breakdown.
Symptoms of DMD usually start between the ages of 2-3 years, sometimes later, and include delays in motor activity, difficulties standing up, frequent falls and toe-walking. Diagnosed is the disease usually via blood tests to detect serum creatine kinase levels, genetic screens, or muscle biopsies, which are the most invasive diagnostic test but gold standard for a very long time. Once started, the disease progresses pretty quickly with most children being wheelchair bound by the age of 12. In the beginning, muscle weakness is most prevalent in the lower body but eventually extends to the upper body.
Other symptoms include cardiac, respiratory, intellectual, and orthopedic symptoms. Cardiac symptoms include cardiomyopathy and arrhythmia. As a result, patients may feel fatigued, short of breath or dizzy which can also lead to fainting.
Whereas not all patients suffer from cardiac symptoms, chronic respiratory insufficiency is inevitable in patients with DMD. This is due to restrictive lung disease which is the inability to expand the chest enough to inhale sufficiently.
About 30% of boys with DMD show impaired intelligence and attention deficit hyperactivity disorder (ADHD) is common among patients as well.
Orthopedic symptoms include 1) scoliosis, which is a sideways curvature of the spine leading to impairment of respiratory capacity and 2) osteoporosis, which is the loss of bone density often resulting in frequent breaks of bones.
So what exactly happens in boys with DMD? Let’s check out some biology background first to better understand the disease:
Genes carry the information required for the synthesis of proteins. The steps from DNA to protein include first a process called transcription in which proteins scan the DNA, read the code and produce a messenger molecule called mRNA. Afterwards mRNAs get translated into proteins.
The structure of genes consists of a regulatory region, followed by an open reading frame and another regulatory region at the end. The regulatory regions include sequences that promote or inhibit the transcription of the gene. The open reading frame is the part of the gene that gets transcribed into mRNA molecules. Open reading frames consist of two different kinds of regions, called introns and exons. Exons are the parts of the open reading frame that make up the information for the protein. Between exons are the introns, which do not carry protein coding information and have long been thought to be genomic waste. It is now known, however, that they are extremely important in many regulatory processes.
To make this a little more complicated, the original transcript from DNA to mRNA contains both, introns and exons. This is called the pre-mRNA. For proper protein synthesis however, we need a mature mRNA molecule that only contains exons. The process that converts pre-mRNA into mature mRNA is called splicing, which basically means cutting out the introns and connecting the exons. A really cool thing about splicing is that the same pre-mRNA molecule can result in multiple different mature mRNAs and proteins depending on how the molecule is cut up and put together. This means that one gene can ultimately lead to multiple proteins. Such a great example for nature’s efficiency.
Back to Duchenne Muscular Dystrophy. The gene mutated in DMD is called DMD gene and it is located on the short arm of the X chromosome. The DMD gene is one of the largest genes known making up 0.1% of the entire human genome. The protein encoded by the DMD gene is called dystrophin. It is produced, or expressed in muscle tissue, such as skeleton muscle and heart muscle, as well as in the brain. This expression pattern explains the symptoms discussed earlier.
The DMD gene consists of 79 exons, which is a huge number. As a reference, the average number of exons per gene is 8-9. The most common mutation found in DMD is the deletion of one or multiple exons. Less common is the duplication of exons and other kinds of mutations are rare.
Duchenne muscular dystrophy is a result of “out-of-frame” mutations whereas “in-frame” mutations of the DMD gene result in a less severe form of muscular dystrophy called Becker’s muscular dystrophy or BMD.
The dystrophin protein has a very important function in muscle cells, also called myocytes. It is part of a large protein complex located at the myocyte membrane and connects the cytoskeleton of the cell to the extracellular matrix which is connective tissue between cells. This connection is important for myocyte stability. When dystrophin is missing or it’s function is drastically reduced, myocyte stability is impaired which makes the cell more prone to rupture during muscle contractions. Ruptured myocytes secrete proteins such as creatine kinase which can be found at highly elevated levels in the blood of DMD patients. Unfortunately, ruptured myocytes don’t get replaced with new myocytes but with adipose tissue which is rich in fat and can’t perform the function of muscle cells. This is why patients with DMD lose muscle mass over time.
What does all of this mean in terms of prognosis for boys with DMD?
As mentioned earlier, most patients are wheelchair bound by the time they are 12 years old. A few decades ago, affected boys would only live into their late teens or maybe twenties. With improved medical treatment, life expectancy is now 30 - 40 years. In some cases, patients even live into their 50s.
Treatment options include preventative measures, such as physiotherapy to prolong ambulation and cardiac monitoring to keep a close eye on the heart. But more invasive treatments are also available. For example, some DMD patients undergo surgery to correct orthopedic symptoms. A very common treatment is ventilation support. Depending on the progression of the disease this may mean getting additional oxygen through a mask or needing a more invasive ventilation such as a tracheotomy.
Different drugs are available as well, however all with unsatisfactory success which means that there is still a great need for better, more effective drugs. In recent years, a relatively new technology has brought several drugs for DMD to the market. This method is called exon skipping. The goal of this technique is to skip certain exons to restore the open reading frame. This is a pretty exciting technology, however, it is not a cure for muscular dystrophy and at best leads to the less severe form of Becker’s muscular dystrophy.
Literature used
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4594321/
