DMD is X-linked, affects mostly males, and, according to the National Center for Biotechnology Information, strikes one in 3,500 boys worldwide. The gene for DMD is located on the X chromosome and encodes a large protein called dystrophin. (See Figure 5.15.) Dystrophin provides structural support for muscle cells and without it, the cell membrane becomes penetrable, allowing extracellular components into the cell. (See Figure 5.16.) These additional components increase the intracellular pressure, causing the muscle cell to die.
With myotonic dystrophy the muscles contract but have diminishing ability to relax, and there is muscle weakening and wasting. Typically, the initial complaints are the loss of hand strength or tripping while walking or climbing stairs. Along with decreased muscle strength, myotonic dystrophy may cause mental deficiency, hair loss, and cataracts. It is an autosomal dominant disorder that occurs in one in 20,000 people; it usually begins in young adulthood but can start at any age and varies in terms of severity.
The myotonic dystrophy gene is a protein kinase gene found on the long arm of chromosome 19. (See Figure 5.17.) The defect is a repeated set of three nucleotides—cytosine (C), thymine (T), and guanine (G)—in the gene. The symptoms of myotonic dystrophy frequently become more severe with each generation because mistakes in copying the gene from one generation to the next result in amplification of a genomic AGC/CTG triplet repeat, similar to the process observed in Huntington's disease. Unaffected individuals have CTG repeats with between three and thirty-seven iterations (repetitions) of the triplet. In contrast, people with the mild phenotype of myotonic dystrophy have between forty and 170, and those with more serious forms of the disease have between 100 and 1,000 iterations.
The symptoms of this disorder generally become more severe with each successive generation. This is because mistakes in the reliable copying of the gene from one generation to the next result in the amplification of a
FIGURE 5.15
Chromosome X and the gene related to Duchenne muscular
dystrophy
Dystrophin and utrophin: similar proteins
Myotonic dystrophy and chromosome 19
All of the various disorders labeled MD cause progressive weakening and wasting of muscle tissues. They vary, however, in terms of the usual age at the onset of symptoms, rate of progression, and initial group of muscles affected. The most common type, DMD, affects young boys, who show symptoms in early childhood and usually die from respiratory weakness or damage to the heart before adulthood. The gene is passed from the mother to her children. Females who inherit the defective gene generally do not manifest symptoms—they become carriers of the defective genes, and their children have a 50% chance of inheriting the disease. Other forms of MD appear later in life and are usually not fatal.
In 1992 scientists discovered the defect in the gene that causes myotonic dystrophy. In people with this disorder, a segment of the gene is enlarged and unstable. This finding helps physicians more accurately diagnose myotonic dystrophy, which affects at least one in 8,000 people. Researchers have since identified genes linked to other types of MD, including DMD, Becker MD, limb-girdle MD, and Emery-Dreifuss MD.
In January 2005 researchers from the Mayo Clinic in Rochester, Minnesota, identified a new form of muscular dystrophy that involves mutations in a protein called ZASP, which binds to cardiac (heart) and skeletal muscles. The researchers detected ZASP mutations in eleven patients; in seven of these, they observed a dominant pattern of inheritance (Duygu Selcen and Andrew G. Engel, "Mutations in ZASP Define a Novel Form of Muscular Dystrophy in Humans," Annals of Neurology, February 2005).
In addition to its commitment to MD research, the Muscular Dystrophy Association supports research into the causes and treatment of related neuromuscular illnesses, such as amyotrophic lateral sclerosis (also known as Lou Gehrig's disease), Charcot-Marie-Tooth disease, and myasthenia gravis. All of these are progressive, wasting, and weakening conditions that rob individuals of their ability to live, work, and function normally. Genes linked to these diseases were identified during the 1990s.
Treatment and Hope
There is no known cure for MD, but patients can be made more comfortable and functional by a combination of physical therapy, exercise programs, and orthopedic devices (special shoes, braces, or powered wheelchairs) that help them to maintain mobility and independence as long as possible.
Genetic research offers hope of finding effective treatments, and even cures, for these diseases. Gene therapy experiments designed to find a cure or a treatment for one or more of these types of MD are ongoing. Research teams have identified the crucial proteins produced by these genes, such as dystrophin, beta sarcoglyan, gamma sarcoglyan, and adhalin. One experimental treatment approach involves substituting a protein of comparable size, such as utrophin for dystrophin, to compensate for the loss of dystrophin. (See Figure 5.16.)
Since defective or absent proteins cause MD, researchers hope that experimental treatments to transplant normal muscle cells into wasting muscles will replace the diseased cells. Muscle cells, unlike other cells in the body, fuse together to become giant cells. Scientists hope that if cells with healthy genes can be introduced into the muscles and accepted by the body's immune system, the muscle cells will then begin to produce the missing proteins.
New delivery methods called vectors are also being tested, such as implanting a healthy gene into a virus that has been stripped of all of its harmful properties, and then injecting the modified virus into a patient. Researchers hope this will reduce the amount of rejection by the patient's immune system, allowing the healthy gene to restore the missing muscle protein.
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