NeurometPlus

Incidence

DMD follow an X-linked pattern of inheritance. A true incidence of 26 to 29 per 100,000 (approximately 1 in 3500) seems likely in most population for DMD. The combined incidence of DMD and BMD is approximately 33/100,000, or about 1 in 3000 male births.

Clinical Characteristics

The muscular dystrophies form a group of genetically determined, progressive, primary disorders of muscle. The various forms can be distinguished by a combination of clinical, genetic, and pathologic criteria. DMD is a severe muscle-wasting disorder, resulting in early confinement to a wheelchair and often death by the age of 20. The gene responsible for Duchenne and Becker muscular dystrophies (the DMD gene) maps to the short arm of the X chromosome at band Xp21. Positional cloning has resulted in the identification of the gene and its protein product, dystrophin. Dystrophin, the primary product of the DMD gene, is a high-molecular-weight (427 kDa) cytoskeletal protein that belongs to the spectrin family of proteins. In muscle it is localized at the inner surface of the sarcolemmal membrane. The biological function of dystrophin remains unknown. Dystrophin is not confined to muscle. Boys with DMD have little or no functional dystrophin. Boys with DMD are phenotypically unremarkable at birth and remain so for the first year or two of life. Only rarely, in families who are attuned to the illness, are symptoms noted before this stage. The first subtle indication of muscle weakness is usually noted when the child starts to walk. He is less agile than his peers and may fall frequently. At 4 to 5 years of age he will have difficulty climbing stairs and rising from a sitting position on the floor. Walking is made abnormal by a tendency to walk and balance on the ball of the foot (\"toe walking\"), and the ability to jump is severely compromised. School introduces new problems, including hyperactivity and distractibility. This is complicated by an overall reduction in IQ equivalent to about 20 points, about one-fifth of patients having a significant mental handicap. In the untreated patient the ability to walk independently is lost at around 9 or 10 years, but aggressive use of bracing and surgery can delay this stage to about 12 years of age. Once the patient is in a wheelchair, contractures of hips and knees worsen, and severe scoliosis may develop. In the absence of treatment, scoliosis, respiratory compromise, and inanition take their toll, and death from respiratory failure may occur in the middle of the second decade. Maintenance of life to age 25 or more is now possible with the aid of a respirator. Serum CK is markedly elevated, to 50 to 100 times the upper limit of normal, the result of leakage of the muscle isoform from the sarcoplasm into the bloodstream. While several other sarcoplasmic enzymes are elevated in the early stages of the disease, none are better than CK for diagnosis or carrier detection. Although rhabdomyolysis and hypothyroidism may also be associated with very high CK levels, these conditions can be readily differentiated on clinical grounds. In polymyositis, CK is less markedly elevated. CK is elevated at birth in DMD and BMD, but the frequency of high CK levels in normal neonates makes it unwise to use cord blood for diagnostic evaluation. By the end of the first week the normal range is less variable, so that a high value (several thousand international units per liter) at this time is diagnostic for muscle disease. Conversely, a value in the normal range in the first few months of life provides assurance that the disease will not develop. The CK level remains high in the early stages, before the disease has become apparent clinically, and declines progressively throughout life, presumably owing to the decrease in muscle bulk. Measurement of CK is also of value for carrier detection, although in carrier females the range of values overlaps the normal range, making the test less than definitive. Although a clinical diagnosis of DMD backed by a high serum CK is often beyond doubt, the gravity of the prognosis usually dictates confirmation by study of a muscle biopsy specimen. Therapeutic approaches to DMD are in their infancy.

Precipitants

no

Provocation Tests

no

Diagnostic Procedures

In many medical centers, the last 5 years have seen major changes in the diagnostic workup of DMD and BMD patients. Frequently it involves DNA analysis to determine the nature of the mutation and/or protein analysis to determine the quality and quantity of dystrophin in a muscle biopsy specimen. Prior to the development of molecular diagnostic tests, the diagnosis was confirmed primarily by measuring serum creatine kinase (CK) levels, by muscle histology, and by electromyography (EMG). Diagnostic evaluation of DMD and BMD patients now routinely includes analysis of dystrophin in muscle biopsies-western blot analysis to estimate quantity and molecular weight; immunolabeling of sections to determine the distribution at the muscle membrane. Diagnostic evaluation also includes Southern blot or PCR analysis of DNA to determine the nature of the mutation, since this information is of prognostic value for the patient and is a necessary prerequisite for carrier identification and prenatal diagnosis in the family.