Muscular Dystrophy
Muscular DystrophyMuscular dystrophy refers to, not one, but a group of muscle diseases. These diseases have three features in common: they are hereditary; they are progressive; and each causes a characteristic and selective pattern of weakness. Duchenne muscular dystrophy (DMD) is the most prevalent and severe childhood form of this group of diseases.
Each form of muscular dystrophy is caused by a defect in a specific gene. In 1986, scientists discovered exactly which piece of genetic material is missing in Duchenne muscular dystrophy patients. They named it for Guillaume Benjamin Amand Duchenne(1806-1875), a French neurologist who was one of the first doctors to discover and study the disease. When functioning properly, the Duchenne gene carries instructions for assembling a muscle protein known as dystrophin. At about 2,500,000 nucleotides, dystrophin is one of the largest genes known. Dystrophin is largely responsible for reinforcing and stabilizing the sarcolemma. Dystrophin associates with the muscle fiber sarcolemma by interacting with the actin microfilaments and with a transmembrane protein complex linked to the extracellular matrix. This latter dystrophin-associated glycoprotein complex (DAGC) includes the extracellular proteoglycan, [Alpha]-dystroglycan, which binds to merosin in muscle fiber basal laminae, as well as a number of other integral and cytoplasmic membrane proteins: [Alpha]-dystroglycan; [Alpha]-, [Beta]- and [Gamma]- sarcoglycans (see Figure 1). The DAGC provides a physical link and, potentially, a signaling pathway between the extracellular matrix and the internal scaffolding of the muscle cells. Mutations in the Duchenne gene result in dystrophin deficiency, which constitutes the pathogenic basis of DMD. Dystrophin is either absent or severely deficient in a person with DMD. When dystrophin is lost through gene mutation, the muscle falls apart under the tension generated when it contracts. Without dystrophin, the muscle fibers also lose their ability to regenerate and are eventually replaced with adipose tissue and fibrous connective tissue (see Fig. 2 and Fig. 3).
The Duchenne gene has been located on the short arm of the X chromosome. This means that Duchenne muscular dystrophy is inherited as an X-linked recessive disease. Females have two X chromosomes, while males have one X chromosome and one Y chromosome. Therefore, in females, a normal X chromosome can mask a disease carrying X chromosome. In males, who only have one X chromosome, an X chromosome disease has to be expressed. This is why DMD usually only affects males, with rare exceptions. Men with DMD will pass on the defective gene to their daughters, making them carriers, but never to their sons. A carrier has a 50% chance of passing the gene for DMD to her daughter, who will also become a carrier. The son of a carrier also has a 50% chance of being affected (see Fig. 4). Mothers of boys who have DMD are not necessarily carriers. The child could have been affected by a new mutation.
Duchenne muscular dystrophy,...
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