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Duchenne Muscular Dystrophy and Becker Muscular Dystrophy
Duchenne's Muscular Dystrophy; Becker's Muscular Dystrophy)
Duchenne muscular dystrophy and Becker muscular dystrophy are X-linked recessive disorders characterized by progressive proximal muscle weakness caused by muscle fiber degeneration. Becker dystrophy has later onset and causes milder symptoms. Diagnosis is suggested clinically and is confirmed by analysis of the protein product (dystrophin) of the mutated gene. Treatment focuses on maintaining function through physical therapy and the use of braces and orthotics; prednisone or deflazacort is given to some patients with severe functional decline.
Duchenne dystrophy and Becker dystrophy are caused by mutations of the dystrophin gene, the largest known human gene, at the Xp21.2 locus. In Duchenne dystrophy, this mutation results in the severe absence (< 5%) of dystrophin, a protein in the muscle cell membrane. In Becker dystrophy, the mutation results in production of abnormal dystrophin or insufficient dystrophin.
Duchenne dystrophy affects 1/4700 live male births. Becker dystrophy affects 1/30,000 live male births. Female carriers may have asymptomatic elevated CK levels and possibly calf hypertrophy.
This disorder manifests typically between ages 2 yr and 3 yr. Weakness affects proximal muscles, typically in the lower limbs initially. Children frequently toe walk and have a waddling gait and lordosis. They have difficulty running, jumping, climbing stairs, and rising from the floor. Children fall frequently, often causing arm or leg fractures (in about 20% of patients). Progression of weakness is steady, and limb flexion contractures and scoliosis develop in nearly all children. Firm pseudohypertrophy (fatty and fibrous replacement of certain enlarged muscle groups, notably the calves) develops. Most children are confined to a wheelchair by age 12 and die of respiratory complications by age 20.
Consequences of cardiac muscle involvement include dilated cardiomyopathy, conduction abnormalities, and arrhythmias. Such complications occur in about one third of patients by age 14 and in all patients over age 18; however, because these patients are not able to exercise, cardiac involvement is usually asymptomatic until late in the disease. About one third have mild, nonprogressive intellectual impairment that affects verbal ability more than performance.
Diagnosis is suspected by characteristic clinical findings, age at onset, and family history suggestive of X-linked recessive inheritance. Myopathic changes are noted on electromyography (rapidly recruited, short duration, low-amplitude motor unit potentials) and muscle biopsy (necrosis and marked variation in muscle fiber size not segregated by motor unit). CK levels are elevated to up to 100 times normal.
Diagnosis is confirmed by analysis of dystrophin with immunostaining of biopsy samples. Dystrophin is undetectable in patients with Duchenne dystrophy. In patients with Becker dystrophy, dystrophin is typically abnormal (lower molecular weight) or present in low concentration. Mutation analysis of DNA from peripheral blood leukocytes can also confirm the diagnosis by identifying abnormalities in the dystrophin gene (deletions in about 70% of patients with Duchenne dystrophy and 85% of patients with Becker dystrophy and duplications in about 10% of both groups).
Patients with Duchenne dystrophy should have a baseline assessment of cardiac function with ECG and echocardiography at the time of diagnosis or by age 6 yr.
Carrier detection and prenatal diagnosis are possible by using conventional studies (eg, pedigree analysis, CK determinations, fetal sex determination) combined with recombinant DNA analysis and dystrophin immunostaining of muscle tissue.
No specific treatment exists. Gentle (ie, submaximal) active exercise is encouraged for as long as possible to avoid disuse atrophy or complications of inactivity. Passive exercises may extend the period of ambulation. Orthopedic interventions should be aimed at maintaining function and preventing contractures. Ankle-foot orthoses worn during sleep may help prevent flexion contractures. Leg braces may temporarily help preserve ambulation or standing. Corrective surgery is sometimes needed, particularly for scoliosis. Obesity should be avoided; caloric requirements are likely to be less than normal because of decreased physical activity.
Respiratory insufficiency may be treated with noninvasive ventilatory support (eg, nasal mask—see Status asthmaticus (SA)). Elective tracheotomy is gaining acceptance, allowing children with Duchenne dystrophy to live into their 20s. For children with dilated cardiomyopathy, an ACE inhibitor and/or a β-blocker may help prevent or slow progression.
In Duchenne dystrophy, daily prednisone or deflazacort is considered for patients > age 5 yr who are no longer gaining, or those with declining, motor skills. These drugs start working as early as 10 days after initiation of therapy; efficacy peaks at 3 mo and persists for 6 mo. Long-term use prolongs ambulation by 3 to 4 yr, improves timed function testing (a measurement of how fast a child completes a functional task, such as walking or getting up from the floor), maintains pulmonary function, reduces orthopedic complications, and stabilizes cardiac function. Alternate-day prednisone is not effective. Weight gain and cushingoid facies are common adverse effects after 6 to 18 mo. Risk of vertebral compression and long bone fractures also is increased. Use of prednisone or deflazacort in Becker dystrophy has not been adequately studied.
Gene therapy is not yet available. Genetic counseling is indicated (see Prenatal Genetic Counseling and Evaluation).
Duchenne dystrophy and Becker dystrophy are X-linked recessive disorders that cause a decrease in dystrophin, a protein in muscle cell membranes.
Patients have significant, progressive weakness that causes severe disability, including difficulty walking, frequent falls, dilated cardiomyopathy, and early death due to respiratory insufficiency.
Active and passive exercise is helpful, along with leg braces and ankle-foot orthoses.
Daily prednisone or deflazacort can improve muscle strength and mass in Duchenne dystrophy, although adverse effects are common.
An ACE inhibitor and/or a β-blocker may help prevent or slow progression of cardiomyopathy.
Ventilatory support (noninvasive and, later on, invasive) can help prolong life.
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