Classification

The most common of the dystrophies and the first to be described was that delineated by Guillaume B. A. Duchenne, a French neurologist, in 1868. Duchenne muscular dystrophy (DMD) is a sex-linked recessive disorder. Consequently, it clinically affects only males and is inherited through female carriers of the gene. Although affected boys have abnormally elevated concentrations of muscle cell enzymes such as creatine phosphokinase in their blood, this abnormality is also found in about three-fourths of the asymptomatic female carriers. DMD appears to have a rather uniform incidence worldwide, with a mean incidence estimated to be about 1 case per 4,000 live male births, or 15 to 33 cases per 100,000. Most surveys have been of predominantly Caucasian populations, but the results of a study in Japan were consistent with the others. A family history of DMD can be obtained in only about one-third of cases. The others are attributed to either a previously unexpressed carrier state or to a new mutation.

Cases can be identified during the first week of life by an excessive concentration of creatine phosphokinase in the blood, although the infant appears to be normal. The boy learns to walk somewhat late, falls easily, and has difficulty in getting up again. The gait gradually becomes broad based and waddling. Nevertheless, the diagnosis usually is not made before the age of 5 years. Unless the boy has been identified by biochemical screening during infancy and the parents receive genetic counseling, their risk of producing additional dystrophic children remains high.

The appearance of the child may be perplexing because, although he is weak, his muscles may appear to be unusually well developed. This pseudohypertrophy is due to the infiltration of muscle and replacement of muscle fibers by fat and connective tissue. As the disease progresses, muscle fibers increasingly appear abnormal microscopically, and others disappear. The upper extremities are affected later but in the same fashion as the pelvic girdle and lower limbs. Smooth muscle (e.g., intestinal tract, bladder) is not affected. As a result of subnormal stress on the developing skeleton from the weak musculature, ossification of long bones is delayed, and the mineral content of bones is deficient. Once weakness has resulted in confinement to wheelchair or bed, contractures of extremity joints and kyphoscoliosis (deformity of the vertebral column) supervene. A moderate degree of mental retardation frequently is an associated problem. Death is generally due to respiratory failure before the age of 20.

The defective gene of DMD was identified in 1986. Soon thereafter it was discovered that this genetic abnormality causes a deficiency of a protein, now called dystrophin, in the membrane of muscle fibers. Although this substance normally constitutes only 0.002 percent of the total muscle protein, its deficiency can now be detected and can serve as a specific diagnostic test.

At the other extreme from DMD in the spectrum of severity, there is facio-scapulo-humeral dystrophy (FSHD), which was described by the French neurologists Louis T. Landouzy and Joseph J. Dejerine in 1884. Onset usually occurs during adolescence, but can be much later. Its incidence has been estimated to be from 5 percent to 50 percent of the incidence of DMD. Inheritance is autosomal dominant, and FSHD occurs equally in both sexes. As the name indicates, the muscles of the face and shoulder girdle are affected first. Sometimes only facial muscles are involved. An affected person may be unable to close the eyelids completely or to purse the lips. Muscular involvement progresses downward to the pelvic girdle and legs, but it may become arrested at any time. Reproduction is not impaired. Death from sudden heart failure occurs in some cases. So far there is no effective treatment for the underlying abnormality of any of the muscular dystrophies.

Thomas G. Benedek

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