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Duchenne muscular dystrophy - Muscle wasting at its worst |
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Written by Lev Prasov
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May 06, 2006 at 10:25 PM |
Duchenne muscular dystrophy is an X-linked recessive disorder that results from mutations in the dystrophin gene. The loss of this protein leads to significant weakness and eventually muscle wasting and scarring.
Taking a long run can do some damage to muscles cells. The sheer force from all of these muscle contractions can ultimately lead cells to burst and release their contents. The result is the soreness that we have all experienced after a long workout. Muscles become weak from the damage. Inflammatory cells (neutrophils and macrophages) come in to eat up the debris and they cause some pain and swelling. This is a perfectly normal response, and generally the muscle fibers regenerate and we're back to killing them all over again in the next marathon run. What happens if these muscle fiber are much more susceptible to damage? Rather than the clean muscle cell regeneration that occurs from occasional wear and tear damage, muscle tissue begins to scar, because there is just too much damage to clean up. Duchenne muscular dystrophy is an example of this type of disease and it is the topic for this week's DOTW.
 Figure I: Structure of a muscle. In the Duchenne muscular dystrophy, the attachment of muscle fibers to their surrounding endomysium (extracellular matrix) becomes weakened due to mutations in the dystrophin gene. ( Image courtesy of the National Cancer Institute)
Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder (it is carried on the X-chromosome) that results from a mutation in the dystrophin gene. Men are much more likely to get this disease, as they only need to inherit the diseased gene from one of their mother's X-chromosomes, whereas women must inherit two copies of the diseased gene (one from their mother and one from their father). Mutations in the coding sequence for the dystrophin gene lead to the production of poorly folded dystrophin protein. This misfolded protein does not function as well as the normal protein and it is degraded more rapidly. Dystrophin is part of a large group of proteins that are involved in making contacts between muscle cells and their surrounding extracellular matrix. These protein complexes help muscle cells to withstand the shearing forces of contraction. Thus, the absence of dystrophin leads to increased death and destruction. In turn, scar tissue (a mix of collagen and blood vessels) replaces the muscle fibers, and it can gradually contract leading to increased muscle rigidity.
The breakdown of muscle fibers and the infiltration of fibrous scar tissue lead to most of the symptoms observed in DMD. The symptoms of the disease first appear between the ages of 3 and 5. Kids usually develop muscle weakness, which then progresses to muscle wasting. Lower extremities are often the first to be affected. As a result, many patient will be completely unable to walk by the age of 11. The contraction of fibrous scar tissue around muscle cells can lead to muscle deformity and severely impair muscle function. Additionally, as muscles are the frameworks that hold bones in place, skeletal abnormalities can result when bones start to grow. DMD may also affect the muscle of respiration, leaving patients unable to breathe or speak. Some muscles may actually enlarge to compensate for poor muscle function, but eventually all of this muscle tissue is replaced with fat and scar tissue. About 30% of patients with DMD also suffer from significant cognitive impairment, suggesting that the dystrophin protein is also important in the brain.
Unfortunately, there are no treatments for Duchenne muscular dystrophy. Physical therapy and orthopedic appliances (wheelchairs, braces, etc.) can improve patient mobility. Patients often use ventilators to assist with breathing. These palliative measures can improve quality of life, but the grim reality is that most people with DMD die by the age of 25 (mostly due to respiratory problems). While nothing can currently be done for these patients, researchers are actively working to find a cure. Most of the efforts are directed towards gene therapy, replacing the bad dystrophin gene with a normal version. Although there are numerous potential complications for this approach, it has been promising in the lab. In fact, the first gene therapy trial for DMD was recently started at Columbus Children's Hospital. Hopefully, it will be successful, but we'll have to wait and see.
For more information on Duchenne muscular dystrophy, check out the following resources:
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