Duchenne Muscular Dystrophy
Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder with a worldwide occurrence of one in four thousand newborn males, with approximately one-third of the cases arising from new mutations. DMD was named after the French neurologist Duchenne de Boulogne, who described the disorder in 1861. Becker muscular dystrophy (BMD), named after Peter Becker, a German geneticist who first described it in the mid-1950s, is a disorder that is very similar to DMD but has a much milder course. In 1983 these disorders were first shown to be located on the short arm of the X chromosome. The disorders are now known to be allelic, meaning an alternate form of the DMD gene causes BMD.
Because DMD is X-linked, almost all cases occur in males. Boys with DMD are normal at birth, and their early motor milestones occur at normal times. The manifestations of DMD are frequently apparent from the time they begin to walk, due to the developing weakness of the hip-girdle and upper-leg muscles. Their gait is unsteady and clumsy, resulting in frequent falls. If running is attempted, it is slow and waddling. The calf muscles often are enlarged enough to be termed "hypertrophic," implying that these children are muscular and strong. In reality calf pseudo hypertrophy is present: When the calves are examined microscopically, the amount of muscle tissue is markedly reduced, having been replaced by fat and fibrous tissue.
As the disorder progresses, the Achilles tendons tighten, causing toe-walking, which further compromises patients' gait and balance. Stair-climbing, rising from a fall, and even walking on level ground becomes more arduous. Even if they undergo Achilles tendon lengthening surgery or use leg braces, virtually all DMD boys require a wheelchair for mobility before the age of thirteen. Weakening of the muscles of the upper extremities and neck and of the respiratory muscles occurs in parallel to that of the lower extremities, although at a slower rate. By some time in their twenties, if not before, nearly all DMD patients will die, often due to an overwhelming respiratory infection resulting in respiratory failure, cardiac arrest, or both.
The causative gene for DMD (named dystrophin) and the protein product (also named dystrophin) were identified in 1986. Dystrophin is found on the inner side of the membrane that surrounds skeletal muscle fibers (the sarcolemma). It is usually absent or severely deficient in DMD boys, and this causes the sarcolemma to weaken and develop tears, allowing excess calcium to enter the muscle fiber. This eventually leads to the death of muscle fibers, and, when a sufficient number of fibers are involved, muscle weakness results.
The dystrophin gene is the largest known human gene, encompassing two thousand kilobases (two million bases) of genomic DNA. In 55 percent to 65 percent of DMD or BMD cases, large deletions of the dystrophin gene can be found. Duplications within the gene account for about 5 percent of cases. DNA testing, available through a number of commercial laboratories in the United States, is based on the identification of these large deletions and duplications. DNA tests can confirm a diagnosis of DMD or BMD, and they can be used for accurate carrier or prenatal testing.