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Description of Duchenne Muscular Dystrophy (DMD):
DMD is a fatal hereditary disease for which there is currently no treatment. Progressive muscle weakness starts at age 5, leads to wheelchair confinement by age 10-12, and death from respiratory complications or secondary heart disease between 17 and 30 years. DMD is caused by an X-linked genetic defect leading to the absence of dystrophin.1 Dystrophin is normally located under the muscle membrane, and it links the cytoskeleton via a group of proteins called (the dystrophin complex) located in the membrane with the extracellular matrix.2 The absence increases the vulnerability of muscle fibers to damage during normal activity.
Muscle fibers are cellular syncitia. Fibers damaged during normal activity are repaired by proliferation and fusion of stem cells, called satellite cells, located close to the muscle fibers under the basal lamina. When proliferating, these satellite cells are called myoblasts. Unfortunately, in the case of DMD, the repaired muscle fibers still lack dystrophin and are thus still vulnerable to subsequent activity. This leads to frequent repair of the muscle fibers, progressive myoblast senescence and loss of regenerative potential by 4 to 5 years.3 Damaged muscle fibers are no longer adequately repaired and are gradually replaced by fat and connective tissue leading to progressive muscle weakness.
Dystrophin is a very large gene (2.6 million base pairs) containing 79 exons. This produces a final messager RNA containing 14,000 bases coding for a large protein (427 kDa). Mutations in this gene can result in Duchenne or in Becker Muscular Dystrophy (BMD), a less severe disease, the patient being confined to a wheel chair later or sometimes not at all.1 The mutations leading to these dystrophies can be either deletions, duplications or in about 30% of the cases point mutations. In the case of DMD the deletion of one or several exons causes a shift in the reading frame of the messager RNA. The end of the dystrophin protein is thus missing and the protein can not form a complex with the glycoproteins forming the dystrophin complex. This complex is thus totally absent from the membrane. In BMD, a multiple of 3 nucleotides is deleted so that there is no change of the reading frame of the messager RNA and thus the beginning and...