Duchenne Muscular Dystrophy and Becker Muscular Dystrophy

This disorder affects about 10/100,000 live male births and 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 Idiopathic Scoliosis Idiopathic scoliosis is lateral curvature of the spine. Diagnosis is clinical and includes spinal x-rays. Treatment depends on the severity of the curvature. Idiopathic scoliosis is the most... read more 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 Dilated Cardiomyopathy Dilated cardiomyopathy is myocardial dysfunction causing heart failure in which ventricular dilation and systolic dysfunction predominate. Symptoms include dyspnea, fatigue, and peripheral edema... read more , conduction abnormalities Overview of Arrhythmias The normal heart beats in a regular, coordinated way because electrical impulses generated and spread by myocytes with unique electrical properties trigger a sequence of organized myocardial... read more , and arrhythmias Overview of Arrhythmias The normal heart beats in a regular, coordinated way because electrical impulses generated and spread by myocytes with unique electrical properties trigger a sequence of organized myocardial... read more . 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 Intellectual Disability Intellectual disability is characterized by significantly subaverage intellectual functioning (often expressed as an intelligence quotient < 70 to 75) combined with limitations of adaptive... read more that affects verbal ability more than performance.

Compared to Duchenne dystrophy, Becker dystrophy affects < 8/100,000 live male births, typically becomes symptomatic much later, and is milder. Ambulation is usually preserved until at least age 15, and many children remain ambulatory into adulthood. Most affected children survive into their 30s and 40s.

In Duchenne dystrophy, the most recent guidelines strongly recommend daily prednisone or deflazacort for patients > age 5 years who are no longer gaining or have declining motor skills (1 Treatment references 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... read more ). 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 Treatment references 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... read more ). 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. Three such therapies are eteplirsen, golodirsen, and viltolarsen. 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 and viltolarsen skip exon 53. They 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, and the dosage of viltolarsen is 80 mg/kg IV infusion 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 for use in the US (2 Treatment references 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... read more ).