What is the cause and effects of Duchenne muscular dystrophy (DMD) in a patient?

Duchenne Muscular Dystrophy: Cause and Effects

Genetic Cause

DMD is caused by mutations in the dystrophin gene located on the X chromosome, which codes for the protein dystrophin—a critical sarcolemma-cytoskeleton linker protein. 1

• The dystrophin gene mutations disrupt the reading frame, resulting in nearly complete absence of functional dystrophin protein 2
• This is an X-linked recessive inheritance pattern, affecting approximately 1 in 3,000 to 1 in 5,000 live male births 1, 3
• Males are predominantly affected because they have only one X chromosome, so a single mutated gene results in disease manifestation 3
• Female carriers typically remain asymptomatic due to their second, normal X chromosome, though some may develop mild to moderate dilated cardiomyopathy in their fifth decade 3

Molecular Mechanism

• Dystrophin normally localizes to the cytoplasmic face of the sarcolemma and provides critical connection between the subsarcolemmal cytoskeleton and the extracellular matrix 2
• The protein's amino-terminus binds to sarcomeric actin, while the carboxy-terminus interacts with α-dystroglycan and the dystrophin-associated protein complex 2
• In DMD, the absence of dystrophin leads to drastic reduction in all dystrophin-associated proteins in the sarcolemma, increasing susceptibility of muscle fibers to necrosis and damage 2

Clinical Diagnosis

• Clinical diagnosis is made after consideration of history, physical findings, and elevated serum creatine kinase levels 1
• Diagnosis is confirmed by finding an abnormality in the dystrophin gene through mutation analysis of blood leukocyte DNA 1
• If DNA analysis is normal (occurs in 1/3 of patients), diagnosis should be confirmed by finding absent or abnormal dystrophin using immunohistology or protein analysis of muscle tissue 1

Progressive Effects on Morbidity and Mortality

Skeletal Muscle Manifestations

DMD is characterized by progressive loss of muscle strength, eventually resulting in loss of ambulation, loss of respiratory muscle strength, and death from respiratory insufficiency. 1

• Average age of diagnosis in the UK is around 4 years 1
• Patients experience progressive muscle weakness and wasting leading to gradual decline in motor function 1
• Patients typically stop walking in their early teens after loss of ambulation 1
• Skeletal muscles progressively undergo damage, resulting in fibrosis and fat replacement over time 1

Respiratory Complications

Respiratory complications are a major cause of morbidity, unplanned hospital admission, and remain the second most frequent cause of death in DMD, after cardiac failure. 1

• The impact on respiratory function, largely from intercostal and diaphragm muscle weakness, normally becomes noticeable after loss of ambulation in adolescence and into adulthood 1
• Inspiratory muscle weakness initially causes nocturnal hypoventilation and contributes to sleep-disordered breathing 1
• Expiratory muscle weakness causes poor cough and inability to effectively manage respiratory secretions 1
• Consequences of untreated respiratory muscle weakness include respiratory failure and pneumonia 1
• Ventilatory support is frequently required at this stage—initially overnight but later may be needed 24 hours/day 1

Cardiac Manifestations

• The majority of patients develop cardiomyopathy 1
• DMD affects the heart muscle and leads to progressive dilated cardiomyopathy 1
• Early introduction of cardiac medication can delay the onset and/or slow progression of cardiomyopathy 1
• Cardiac involvement can impact respiratory function, and in turn, respiratory failure can trigger cardiac arrhythmias or exacerbate cardiac failure 1

Prognosis and Life Expectancy

• With current standard of care in the UK, the median life expectancy for males with DMD is between 29 and 30 years of age 1
• Death typically occurs from respiratory insufficiency or cardiac failure 1

Current Treatment Approach

Corticosteroids are routinely recommended from a young age because they slow the rate of decline in muscle function and prolong ambulation. 1

• Deflazacort is FDA-approved for treatment of DMD in patients 5 years of age and older at a recommended once-daily dosage of approximately 0.9 mg/kg/day 4
• Corticosteroids have been shown to delay respiratory decline and help preserve ventilatory function for longer 1
• The precise mechanism by which deflazacort exerts its therapeutic effects in DMD patients is unknown, though it acts through the glucocorticoid receptor to exert anti-inflammatory and immunosuppressive effects 4
• There is currently no effective cure for DMD 1

Important Caveats

• Maintaining respiratory health is vital to prolonging survival and quality of life in DMD 1
• Family screening is essential as approximately 30-50% of dilated cardiomyopathy cases in DMD families show inherited patterns 3
• Female carriers require cardiac surveillance given their risk of late-onset cardiomyopathy 3