What are the symptoms, prognosis, and inheritance pattern of Duchenne muscular dystrophy in young males?

Duchenne Muscular Dystrophy: Inheritance, Symptoms, and Prognosis

Inheritance Pattern

Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder caused by mutations in the dystrophin gene, affecting approximately 1 in 5,000 live male births. 1

• Males are affected because they have only one X chromosome; a single mutated dystrophin gene results in disease 1
• Females are typically carriers and asymptomatic, though when symptomatic, they present with mild to moderate dilated cardiomyopathy in the fifth decade of life 2
• Genetic counseling should be offered to all female family members at risk, including mothers and sisters, as carrier testing is essential for family planning 3
• The diagnosis should be suspected irrespective of family history, as approximately one-third of cases result from de novo mutations 1

Clinical Symptoms

Early Presentation (Infancy to Early Childhood)

DMD should be suspected in male children presenting with delayed walking (not walking by 16-18 months), frequent falls, or difficulty with running and climbing stairs. 1, 4

• Delayed attainment of developmental milestones, including independent walking or language delays 1
• Gowers' sign (using hands to "climb up" the legs when rising from the floor) is a hallmark finding, especially in children under 5 years 1, 4
• Waddling gait and toe walking may be present 1
• Markedly elevated creatine kinase (CK) levels, often exceeding 10,000 U/L, with highest levels typically seen between 3-5 years of age 3
• Elevated transaminases (AST/ALT) are a classic presentation, as these enzymes are produced by both muscle and liver cells; DMD should be considered before liver biopsy in any male child with unexplained elevated transaminases 1, 4, 3

Progressive Skeletal Muscle Involvement

• Progressive proximal muscle weakness leading to wheelchair dependence, typically by age 12 years without treatment 5
• Loss of dystrophin results in progressive muscle fiber necrosis, chronic inflammation, and fibrotic replacement of muscle tissue 4

Cardiac Involvement

Cardiomyopathy has become the most common cause of death in DMD patients, surpassing respiratory failure due to improved respiratory therapies. 2

• Risk of left ventricular dysfunction increases dramatically with age: 5% in boys under 10 years to over 75% in men over 20 years, with average age for abnormal ejection fraction being 14.3 years 2
• Some patients develop reduced ejection fraction as early as 8 years of age, though myocardial damage on a cellular level starts much earlier 2
• Only 30% of boys with DMD have cardiac symptoms at diagnosis, making surveillance essential 1
• Early signs of cardiac failure may not appear clinically due to limitations of movement from skeletal muscle disease 2
• DMD cardiomyopathy has less ventricular dilation early in disease course compared to other dilated cardiomyopathies, beginning with dysfunction without dilation 2

Respiratory Complications

• Progressive respiratory muscle weakness requiring assisted ventilation 6
• Historically, respiratory failure was the most common cause of death 1

Prognosis

Without supportive care, young men with DMD typically die in their late teens to early twenties. 1, 4

Factors Improving Prognosis

• Corticosteroid use is associated with delayed loss of ambulation (hazard ratio 0.42), better pulmonary function tests, prolonged time with FVC%p > 50%, reduced need for assisted ventilation, and delayed cardiomyopathy 6
• Longer corticosteroid treatment duration (>1 year compared to <1 year) is associated with later loss of ambulation (hazard ratio 0.50) 6
• Use of ACE inhibitors reduces the risk of heart failure and death in patients with cardiac involvement 6
• Non-invasive respiratory support and active surveillance of complications have improved ambulation, function, quality of life, and life expectancy 5

Mortality Determinants

With improved respiratory support, cardiomyopathy leading to heart failure and arrhythmias has become an increasingly important source of morbidity and mortality. 1, 4

• Left ventricular dysfunction and forced vital capacity (FVC) <1 L increase the risk of heart failure and death 6
• DMD cardiomyopathy has higher mortality compared to other dilated cardiomyopathies 1

Important Caveats

• Early corticosteroid treatment start (aged <5 years) may be associated with early cardiomyopathy and higher fracture risk, requiring careful monitoring 6
• Genotype appears to be an independent driver of loss of ambulation in some studies 6
• Higher baseline physical function tests (e.g., 6-minute walk test) are associated with delayed loss of ambulation 6