Muscular dystrophies are inherited, progressive muscle disorders resulting from defects in one or more genes needed for normal muscle structure and function; dystrophic changes (eg, muscle fiber necrosis and regeneration) are seen on biopsy specimens.
Duchenne dystrophy and Becker dystrophy are the second most prevalent muscular dystrophy (after facioscapulohumeral muscular dystrophy). They are caused by mutations of the dystrophin gene, the largest known human gene, at the Xp21.2 locus. About 70% of Duchenne dystrophy is caused by a single- or multiexon deletion or duplication. In Becker dystrophy, 85% of patients have a deletion, and 10% have a duplication.
In Duchenne dystrophy, these mutations result in the severe absence (< 5%) of dystrophin, a protein in the muscle cell membrane. In Becker dystrophy, the mutations result in production of abnormal dystrophin or insufficient dystrophin.
Duchenne dystrophy and Becker dystrophy together affect 5/1000 people; the majority have Duchenne. Female carriers may have asymptomatic elevated creatine kinase levels and possibly calf hypertrophy.
This disorder manifests typically between 2 and 3 years of age. 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 need to use 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, when done, muscle biopsy shows necrosis and marked variation in muscle fiber size not segregated by motor unit. Creatinine kinase levels are elevated up to 100 times normal.
Mutation analysis of DNA from peripheral blood leukocytes using multiplex ligation-dependent probe amplification (MLPA) is the primary confirmatory test; it can identify abnormalities in the dystrophin gene. If an abnormality is not detected by MLPA but Duchenne or Becker dystrophy is still suspected, full sequencing of the dystrophin gene can be done to detect small genetic changes, such as point mutations.
If genetic testing does not confirm the diagnosis, then analysis of dystrophin with immunostaining of muscle biopsy samples should be done. 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.
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 years.
Carrier detection and prenatal diagnosis are possible by using conventional studies (eg, pedigree analysis, creatinine kinase 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). Elective tracheotomy is gaining acceptance, allowing children with Duchenne dystrophy to live into their 20s.
For children with dilated cardiomyopathy, an angiotensin-converting enzyme inhibitor and/or a beta-blocker may help prevent or slow progression.
In Duchenne dystrophy, daily prednisone or deflazacort is considered for patients > age 5 years who are no longer gaining or have declining motor skills. These drugs start working as early as 10 days after initiation of therapy; efficacy peaks at 3 months and persists for 6 months. Long-term use improves strength, delays the age at which ambulation is lost by 1.4 to 2.5 years, improves timed function testing (a measurement of how fast a child completes a functional task, such as walking or getting up from the floor), improves pulmonary function, reduces orthopedic complications (eg, the need for scoliosis surgery), stabilizes cardiac function (eg, delays onset of cardiomyopathy until 18 years of age), and increases survival by 5 to 15 years (1). Alternate-day prednisone is not effective. Weight gain and cushingoid facies are common adverse effects after 6 to 18 months. Risk of vertebral compression and long bone fractures also is increased. Deflazacort may be associated with a greater risk of cataracts than prednisone. Use of prednisone or deflazacort in Becker dystrophy has not been adequately studied.
Exon-skipping therapies have been approved for the treatment of Duchenne dystrophy. Two such therapies are eteplirsen and golodirsen. These drugs are called antisense oligonucleotides and work like molecular patches to the abnormal dystrophin gene in which one or more exons are missing (the missing exons prevent the full protein from being assembled thus causing severe symptoms). The drugs mask an exon so that it will be skipped and ignored during protein production, allowing the production of a dystrophin protein that, while not normal, is functional and may lessen symptoms so that they are more like those in boys with the less severe Becker muscular dystrophy.
Eteplirsen skips exon 51. Limited data suggest that eteplirsen leads to increased dystrophin in muscle and increased walking performance on timed tests in the 13% of patients with Duchenne dystrophy who have a dystrophin gene mutation that is amenable to exon 51 skipping. The drug's approval has been criticized because it was based on a small trial that relied on a surrogate outcome (dystrophin in muscle biopsy), and clinical benefit remains unproved. The recommended dosage of eteplirsen is 30 mg/kg IV infusion over 35 to 60 minutes once a week.
Golodirsen skips exon 53. It can be used in the 8% of patients with Duchenne dystrophy who have a mutation in the dystrophin gene amenable to exon 53 skipping. Clinical benefit remains unproved. The recommended dosage of golodirsen is 30 mg/kg IV infusion over 35 to 60 minutes once a week.
Ataluren (PTC124) is an orally administered drug available in the European Union and United Kingdom for the treatment of genetic defects caused by nonsense (premature stop) mutations. It is an option for Duchenne dystrophy patients who are 2 years of age and older, who are ambulatory, and whose disease is caused by nonsense mutations, which cause the production of the dystrophin protein in the cell to stop too early, resulting in a protein that cannot function normally. Clinical benefit is also unproved and it is not yet approved in the US (2).
Investigational therapies for Duchenne dystrophy and Becker dystrophy include gene therapy, creatine, myostatin inactivation, skeletal muscle progenitors, and the antioxidant idebenone.
Genetic counseling is indicated.
1. Gloss D, Moxley RT 3rd, Ashwal S, Oskoui M: Practice guideline update summary: Corticosteroid treatment of Duchenne muscular dystrophy: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology 86:465–472, 2016. doi: 10.1212/WNL.0000000000002337
2. McDonald CM, Campbell C, Torricelli RE, et al: Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): A multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 390:(10101):1489–1498, 2017. doi: 10.1016/S0140-6736(17)31611-2
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.
In Duchenne dystrophy, daily prednisone or deflazacort can improve muscle strength and mass, improve pulmonary function, and help delay onset of cardiomyopathy, although adverse effects are common.
For patients with certain mutations, eteplirsen or golodirsen, despite limited evidence of clinical benefit, may be used as well.
An angiotensin-converting enzyme inhibitor and/or a beta-blocker may help prevent or slow progression of cardiomyopathy.
Ventilatory support (noninvasive and, later on, invasive) can help prolong life.
The following are some English-language resources that may be useful. Please note that THE MANUAL is not responsible for the content of these resources.
Muscular Dystrophy News Today: A news and information web site about muscular dystrophy
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