What are the onset, symptoms, treatments, and progression of muscular dystrophy?

Muscular Dystrophy: Onset, Symptoms, Treatments, and Progression

Muscular dystrophies are a heterogeneous group of genetic disorders characterized by progressive muscle weakness and degeneration with varying onset, symptoms, and progression depending on the specific type, requiring multidisciplinary management focused on respiratory and cardiac complications which are the leading causes of mortality. 1, 2

Types and Onset

Duchenne Muscular Dystrophy (DMD)

• Most common and severe form affecting 1 in 3,600-9,300 male births
• Diagnosis typically around age 4 years
• X-linked inheritance pattern
• Caused by mutations in the dystrophin gene 1, 2

Myotonic Dystrophy (DM)

• Two main types:
  • Type 1 (DM1/Steinert disease): Onset between 5-15 years (can be congenital)
  • Type 2 (DM2/PROMM): Later onset (20-70 years)
• Autosomal dominant inheritance
• DM1 caused by CTG trinucleotide repeat expansion in DMPK gene
• DM2 caused by CCTG repeat expansion in CNBP gene 1

Limb-Girdle Muscular Dystrophy (LGMD)

• Onset typically during childhood or adolescence
• Autosomal dominant (LGMD1) or recessive (LGMD2) inheritance
• Multiple genetic subtypes with prevalence of 1 in 14,500 to 1 in 123,000 1

Symptoms and Clinical Manifestations

Skeletal Muscle Symptoms

• DMD: Progressive proximal muscle weakness, pseudohypertrophy of calves, loss of ambulation by early teens 1, 2
• DM1: Progressive facial, neck, and distal limb weakness, myotonia (delayed muscle relaxation) 1
• DM2: Primarily myotonia and muscle wasting, milder course than DM1 1
• LGMD: Primarily affects pelvic or shoulder girdle musculature 1

Respiratory Complications

• Progressive weakness of respiratory muscles (intercostal and diaphragm)
• Initially causes nocturnal hypoventilation and sleep-disordered breathing
• Poor cough and inability to manage secretions
• Eventually leads to respiratory failure
• Major cause of morbidity and second most common cause of death 1, 2

Cardiac Complications

• DMD/BMD: Dilated cardiomyopathy; average age for abnormal left ventricular ejection fraction is 14.3 years 1, 2
• DM1: Cardiac manifestations in ~80% of patients; conduction defects, tachyarrhythmias, dilated cardiomyopathy 1
• DM2: Cardiac problems less severe (10-20% of patients) 1
• LGMD: Variable cardiac involvement depending on subtype 1

Other System Involvement

• DM1: Cataracts, neurological/neuropsychiatric deficits, endocrine/metabolic abnormalities 1
• Congenital DM1: Developmental delay, respiratory distress, hypotonia, intellectual disability 1

Progression

DMD

• Progressive decline in motor function
• Loss of ambulation typically in early teens
• Respiratory complications become noticeable after loss of ambulation
• Cardiac dysfunction correlates with increasing age and disease severity
• Current median life expectancy in the UK is 29-30 years with multidisciplinary care 1, 2

DM1

• Variable progression based on repeat expansion size
• Anticipation phenomenon: successive generations show earlier onset/more severe symptoms
• Respiratory complications and cardiac arrhythmias are primary causes of death 1

DM2

• More variable clinical manifestations and age of onset
• Generally more favorable clinical course and life expectancy than DM1
• No genetic anticipation or congenital form 1

LGMD

• Broad clinical heterogeneity among subtypes
• Variable progression from mild to severe
• Loss of ambulation varies from age 10 to young adulthood 1

Diagnostic Approach

Genetic Testing

• Gold standard for definitive diagnosis
• Essential for determining inheritance patterns, genetic counseling, and guiding treatment
• For DM1: Testing for CTG trinucleotide repeat expansion in DMPK gene
• For DMD: Testing for dystrophin gene mutations 1, 3

Muscle Biopsy

• Traditionally used but now often secondary to genetic testing
• Still valuable when genetic testing is negative or inconclusive 3

Cardiac Evaluation

• Echocardiography (with limitations in DMD)
• Cardiac MRI with late gadolinium enhancement (more sensitive for early myocardial damage)
• Regular screening essential even in asymptomatic patients 2

Respiratory Assessment

• Pulmonary function tests (FVC, PCF, PEM)
• Sleep studies to detect nocturnal hypoventilation 1, 2

Treatment Strategies

Respiratory Management

• Non-invasive ventilation (initially at night, progressing to 24-hour as needed)
• Airway clearance techniques and assisted cough
• Management of respiratory infections
• Regular monitoring of respiratory function 1, 2

Cardiac Management

• Early intervention with ACE inhibitors or ARBs (by age 10 in DMD or earlier)
• Beta-blockers typically added after ACE inhibitors/ARBs
• Mineralocorticoid receptor antagonists to slow decline in left ventricular function
• Device therapy (ICDs) for advanced cardiomyopathy (EF <35%)
• Regular cardiac monitoring 2

Corticosteroid Therapy

• Standard of care for DMD
• Slows rate of decline in muscle function
• Prolongs ambulation
• Delays respiratory decline and preserves ventilatory function 1

Emerging Therapies

• Antisense oligonucleotides for exon skipping in DMD
• Gene replacement strategies
• CRISPR gene editing
• Cell-based therapies
• Small molecule compounds 4, 5, 6

Common Pitfalls in Management

• Underdiagnosis of cardiac involvement: Cardiac symptoms often masked by limited mobility
• Variable progression: Poor correlation between genotype and phenotype
• Delayed treatment: Early intervention before symptom onset has greater impact
• Incomplete evaluation: Standard echocardiography may miss early cardiac involvement 2

Special Considerations

• Anesthesia and sedation risks: Increased risk of respiratory complications
• Nutritional management: Malnutrition affects respiratory muscle strength
• Female carriers of DMD/BMD: Should undergo cardiac evaluation 2