Duchenne muscular dystrophy (DMD) is the most common and most severe muscular dystrophy.
- Affects boys
- Incidence: 1 in 3,500 boys worldwide
- Prevalence: 63 cases per million
Duchenne muscular dystrophy results from a mutation in the dystrophin (DMD) gene on the short arm of the X chromosome.
- DMD is the largest known protein-coding human gene associated with an increased risk for mutations.
- Most commonly inherited X-linked recessive pattern
- ⅓ of mutations occur from a de novo frameshift mutation.
- DMD gene encodes for normal dystrophin protein, which is essential for the structural stability of myofibers.
- Dystrophin forms a large glycoprotein complex (dystrophin-associated glycoprotein complex):
- Acts as a mechanical link between the cytoskeleton and extracellular matrix of muscle
- Allows for normal muscle function
Pathophysiology of DMD:
- Mutation in the DMD gene that encodes dystrophin, leading to abnormal dystrophin protein
- Abnormal dystrophin is unable to form a functional glycoprotein complex → defective mechanical link between the cytoskeleton and extracellular matrix of muscle
- Abnormal glycoprotein complex is degraded by proteases → loss of dystrophin
- Muscles are more susceptible to damage → inadequate attempts at muscle regeneration → replacement of muscle with fibrous and fatty tissue
Duchenne muscular dystrophy presents with progressive muscle weakness.
- Initially, the proximal muscles are affected.
- DMD 1st affects the lower extremities, and then progresses to the neck, shoulders, and arms.
- Myopathy is present at birth.
- Clinical symptoms present at 2–3 years of age.
- Most patients are non-ambulatory by 12 years of age.
- Death due to cardiac or respiratory failure at about 20 years of age
- Early ambulatory stage:
- Delay in attaining motor skills (e.g., head lag, late walker)
- Difficulty in running and jumping
- Toe walking
- Late ambulatory stage:
- Increased difficulty in walking
- Cannot arise from the floor
- Difficulty climbing stairs
- Easily fatigued
- Early nonambulatory stage:
- Unable to ambulate, but can self-propel for short periods
- Can maintain posture
- Scoliosis starts to develop.
- Late nonambulatory stage:
- Unable to maintain posture
- Contractures start to develop.
- Waddling gait
- Gower’s sign:
- The use of arms and hands to maneuver the body to a standing position
- Results from proximal muscle weakness
- Calf pseudohypertrophy:
- Large but weak gastrocnemius muscle
- Due to replacement of muscle with fibrous and fatty tissue
- Hypotonia and muscle wasting
- Scoliosis and lumbar lordosis
- Hyporeflexia or areflexia
- Contractures occur often:
- ↑ CK:
- Found before clinical signs appear
- Often > 10–20 times the upper normal limit
- Levels peak at 2 years of age and gradually decline as muscle is replaced by fibrous and fatty tissue.
- ↑ Aldose
- ↑ AST and ALT
- Multiplex ligation-dependent probe amplification (MLPA):
- To identify abnormalities in the DMD gene
- Primary confirmatory test
- Complete gene sequencing:
- Can detect small genetic changes
- Used if MLPA is negative, but clinical suspicion is high
- Other techniques:
- Indicated if genetic testing is not confirmatory, but clinical suspicion remains high
- Necrotic muscle fibers of varying sizes
- Replacement of muscle with fat and fibrous tissue
- Immunostaining reveals the absence of dystrophin.
- Almost never used, but may help differentiate DMD from other forms of muscle weakness
- Shows small polyphasic potentials
There is no cure for DMD. Management is mainly supportive and palliative, and often guided by individual preferences.
- Multidisciplinary care is required.
- Physical therapy and exercise to regain muscle strength and prevent contractures
- Fall prevention and use of mobility aids
- Nutritional support
- Appropriate mental-health screening and support
- Corticosteroids (e.g., prednisone, deflazacort):
- Slows the progression of muscle weakness
- Delays the loss of ambulation
- Reduces the risk of scoliosis
- Improves pulmonary function
- Chronic use is often limited by side effects.
- Avoid abrupt cessation to prevent adrenal crisis.
- Data are limited.
- May provide a modest benefit to help slow progression
- Exon-skipping therapy:
- Novel therapeutic approach in genetics with unproven clinical benefits
- Works like “molecular patches” on the abnormal DMD gene
- Allows for the production of a more functional (but not entirely normal) dystrophin protein
- Options: eteplirsen, golodirsen, and viltolarsen
- Surgery indicated for tendon release in contractures
- Treatment of scoliosis
- A feeding tube may be considered for patients with significant dysphagia.
- Tracheostomy for ventilator support may be considered in patients with respiratory failure.
- Evaluation and monitoring of cardiomyopathy:
- Echocardiogram or cardiac MRI
- Respiratory management includes:
- Monitoring of vital capacity using pulmonary function test
- Sleep study with capnography
Palliative care and advanced planning
- Patients and families should be informed of the long-term prognosis.
- Address end-of-life issues.
- Palliative measures can be used at any point in the disease.
- Cardiac muscle fibrosis leads to:
- Dilated cardiomyopathy
- Conduction abnormalities and arrhythmias
- Cardiac complications are the most common cause of death.
- Cardiac muscle fibrosis leads to:
- Progressive impaired pulmonary function results from:
- Weak chest-wall muscles
- Poor trunk posture from scoliosis and lordosis
- Assisted ventilation is eventually required.
- Increased risk for pneumonia
- Progressive impaired pulmonary function results from:
- Fractures secondary to falls
- Intellectual disability is common.
- Increased association with:
- Becker muscular dystrophy (BMD): 2nd most common form of muscular dystrophy. Becker muscular dystrophy can result from an X-linked recessive mutation in the DMD gene. Becker muscular dystrophy is less severe than DMD, resulting in a later onset of symptoms, slower clinical progression, and longer life expectancy. Creatine kinase levels are less elevated and intellectual disability is uncommon in BMD. Confirmation is with genetic testing. Muscle biopsy shows sparing of muscle fibers. Dystrophin can be visualized using immunostaining. Management is supportive.
- Facioscapulohumeral muscular dystrophy: an autosomal dominant disorder resulting from mutations in DUX4 or SMCHD1 genes. Both boys and girls are affected. Patients present with progressive weakness of facial, scapular, and muscles of the upper arm by 20 years of age. Cardiac involvement is rare. There is a modest elevation in CK and the diagnosis is confirmed by genetic testing. Management is supportive.
- Limb-girdle muscular dystrophy: a group of myopathic disorders resulting from varying genetic defects. Both boys and girls are affected. The time of onset for the disease varies and is characterized by slowly progressive atrophy and weakness of the proximal muscles of the hip and shoulder. Cardiac disease is not typical. Diagnosis of limb-girdle muscular dystrophy is confirmed by genetic testing. Management is supportive.
- Myotonic dystrophy: a group of autosomal dominant disorders that can affect multiple systems. Myotonic dystrophy can be congenital or adult onset. Findings include myotonia, distal and facial muscle wasting, cataract, intellectual disability, and endocrine disorders. The diagnosis is based on genetic testing, and management is mainly supportive.
- Emery-Dreifuss dystrophy: a genetic disease with various modes of inheritance. Emery-Dreifuss dystrophy is characterized by slowly progressive weakness of the upper arms and lower legs, contractures, and cardiac abnormalities in the 1st or 2nd decade of life. Modestly elevated CK may be seen. Genetic testing is used to confirm the diagnosis. Management is supportive, and most individuals do not lose the ability to ambulate.
- Spinal muscular atrophy: a group of autosomal recessive disorders leading to degeneration of the anterior horn cells of the spinal cord and brainstem. The clinical presentation of spinal muscular atrophy varies. More severe forms of spinal muscular atrophy present in infancy to early childhood with progressive weakness, muscle atrophy, gross motor delay, tongue atrophy and fasciculations, dysphagia, and respiratory insufficiency. Diagnosis is confirmed based on genetic testing. Management is supportive, and life expectancy varies by the disease type.
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