Muscular Dystrophy

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Muscular Dystrophy

Muscular dystrophies (MDs) are a group of disorders that share three characteristics: They are inherited, they cause progressive weakness and muscle wasting, and the primary defect is localized to skeletal muscle, sparing the nerves. Although selected limb muscles develop some degree of weakness in all dystrophies, to distinguish among the different types, it is critical to know the mode of inheritance, the age of onset, and whether muscles other than limb muscles are also affected. For example, some dystrophies additionally affect eye and lip closure; another type affects eye movement ability, as well as swallowing and speech.

More than thirty types of MDs are now recognized. Three of the more prevalent forms—Duchenne, myotonic, and limb-girdle dystrophies—will be discussed from the standpoint of the presenting symptoms, age of onset, inheritance pattern, causative genes, and the availability of prenatal and presymptomatic molecular testing.

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is present: When the calves are examined microscopically, the amount of muscle tissue is markedly reduced, having been replaced by fat and fibrous tissue.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.

Myotonic Muscular Dystrophy

Myotonic muscular dystrophy (DM, or dystrophia myotonica) is the most common adult-onset muscular dystrophy, having a frequency of one per twenty thousand persons in the general population. Myotonia, the delayed relaxation of a voluntary muscle after it is contracted, and muscle weakness are the hallmarks of the disorder. For example, a person with DM using a hammer will not immediately be able to release his grip on the handle when finished. It is an autosomal dominant disorder, but there is great variability in the disorder's severity and in the number of manifestations it leads to.

A unique feature of this dystrophy is a genetic phenomenon called pleiotropy, or multisystem involvement, despite the single genetic defect. The potential involvement includes multiple organs and organ systems other than skeletal muscle, including the cardiac, respiratory, gastrointestinal, central nervous, endocrine, and dermatologic systems, as well as bone or eyes. A congenital variety occurs in which infants are born floppy, often require respiratory assistance, have extremity deformities, and are both physically and mentally retarded.

Patients often initially complain of a loss of hand strength (they have difficulty twisting off caps from bottles, for example) or of tripping while walking or climbing stairs, due to the weakness of muscles that extend the feet and toes. Weakness may progress to involve the shoulder and hip girdles and, in some cases, is severe enough to necessitate the use of a wheel-chair. Droopy eyelids, wasting of facial and neck muscles, and frontal balding frequently occur, producing atypical facial appearance.

The gene for DM is a protein kinase gene (known as DMPK ) and is located on the long arm of chromosome 19. The disorder arises from a repeated sequence of three nucleotides—cytosine (C), thymine (T), and gua-nine (G)—in the gene. Individuals without DM have C-T-G repeats that contain between 5 and 37 iterations of the triplets. By contrast, repeats that are between 40 and 170 iterations long are found in the mild phenotype, repeats between 100 and 1,000 iterations are found in the "classic pheno-type," and repeats of between 500 and 3,000 are found in the congenital phenotype. A number of laboratories in the United States perform this triplet repeat assay for diagnostic, prenatal, and presymptomatic testing.

Limb-Girdle Muscular Dystrophy

Limb-girdle muscular dystrophy (LGMD) has been described both as a heterogeneous group of disorders and as a diagnosis of exclusion. Any patient who has weakness of the shoulder and hip-girdle muscles and who otherwise has been excluded from the other MDs will be diagnosed with LGMD. Using the patterns of inheritance that exist within LGMD, a classification system has been created to simplify the heterogeneity: Both autosomal dominant (LGMD1) and recessive families (LGMD2) are well recognized. The number of LGMD genes that have already been identified has further improved the classification.

The frequency of LGMD in the general population is reported to be one in twenty-five thousand. The age at onset may vary widely. In some individuals, onset is in early childhood and in others it occurs in the forties and fifties, but most commonly it occurs in the teens to early adulthood. The characteristic pattern of muscle involvement is symmetric weakness, beginning initially in the hip and shoulder girdle, but usually noticed in the hips before the shoulders. Thus slowness in running, difficulty rising from a low seat, and difficulty ascending stairs are all common complaints from affected individuals. As LGMD progresses, it will involve upper-leg and arm muscles and may eventually affect the muscles that extend the feet and wrists. Lower-extremity weakness may become severe enough to require a wheelchair.

Among the LGMD1 types, five have chromosomal linkages, but only in one is the protein product of the gene known. LGMD2 is better characterized, with nine chromosomal localizations, five with known proteins. Almost all these proteins are membrane-associated proteins (just as dystrophin is). When they are abnormal in structure or deficient in quantity, they affect the stability of the muscle membrane, resulting in the same pathological process that was described for DMD. Commercial testing in the United States is only available for some of the LGMD2 types and is performed using muscle tissue.

Treatment of the Muscular Dystrophies

As of mid-2002, gene therapy treatment of LGMD was tried in a very small number of patients. These early experiments delivered a functional gene to a very small muscle in the foot and were designed to test the long-term safety and effectiveness of the treatment. Gene therapy for DMD is much more problematic, because of the immense size of the gene and the distribution throughout the body that would be required for effective treatment. Drug treatment with prednisone or other corticosteroids is being used, although at best this provides another six to twelve months of mobility before a wheelchair becomes necessary. There are no effective treatments for myotonic dystrophy as of 2002, although research continues in many laboratories worldwide.

see also Gene Therapy; Genetic Testing; Inheritance Patterns; Prenatal Diagnosis; Triplet Repeat Disease.

Jeffrey M. Stajich

Bibliography

Emery, Alan E. H., ed. Neuromuscular Disorders: Clinical and Molecular Genetics. Chichester, U.K.: John Wiley & Sons, 1998.

———. Muscular Dystrophy, The Facts. Oxford, U.K.: Oxford University Press, 2000.

Hoffman, Eric P. "Muscular Dystrophy: Identification and Use of Genes for Diagnostics and Therapeutics." Archives of Pathology and Laboratory Medicine 123 (1999): 1050-1052.