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Duchenne muscular dystrophy pathophysiology clinical features 2025
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"Duchenne muscular dystrophy"[MeSH Terms] AND treatment
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Here is a thorough explanation of Duchenne Muscular Dystrophy (DMD):
Duchenne Muscular Dystrophy (DMD)
What Is It?
DMD is the most common severe neuromuscular disease in humans - an X-linked recessive disorder caused by mutations in the dystrophin gene (located at Xp21.2). It has an incidence of approximately 1 in 5,000 male births. About one-third of cases arise from de novo mutations with no family history.
Genetics & Pathophysiology
- The dystrophin gene is one of the largest in the human genome (~2.4 megabases, 79 exons)
- Over 7,000 variants are associated with DMD; exon deletions (80%) and duplications are most common
- A frameshift mutation causes complete absence of the dystrophin protein
- Dystrophin normally forms a mechanical link between the sarcomere and sarcolemma (muscle cell membrane)
- Without it, a calcium leak occurs across the membrane, triggering muscle fiber necrosis
- Repeated cycles of degeneration and regeneration lead to replacement of muscle by fat and fibrous connective tissue
Clinical Features
Early childhood (ages 2-5):
- Delayed motor milestones
- Difficulty running, frequent falls
- Calf pseudohypertrophy (calves look enlarged due to fat infiltration)
- Gowers' sign - child uses hands to "walk up" legs to stand from the floor
Progression:
- Progressive proximal muscle weakness (lower limbs first)
- Most patients lose the ability to walk by ages 10-15
- Scoliosis and joint contractures develop as weakness progresses
- By age 20: kyphoscoliosis worsens respiratory compromise
Cardiac involvement:
- Dilated cardiomyopathy (DCM) due to cardiac fibrosis (most common)
- Rhythm and conduction abnormalities
- Can lead to heart failure and fatal arrhythmias
Respiratory:
- Chronic respiratory insufficiency develops in all patients
- Cardiorespiratory failure is the primary cause of death
Cognitive/neurological:
- Lower IQ and nonprogressive cognitive impairment in some patients
- Associated with autism, ADHD, and learning disorders (correlated with mutation location in the gene)
Diagnosis
| Test | Finding |
|---|---|
| Serum CK | 20-100x elevated (markedly raised due to leaking muscle) |
| Genetic testing | Positive in 90-95% of patients - confirms frameshift mutation |
| Muscle biopsy | Used if genetic testing is negative; shows fiber necrosis, inflammation, fibrosis, variation in fiber size |
| Immunohistochemistry | Absent dystrophin staining (except "revertant fibers") |
Treatment
Multidisciplinary approach is essential.
Pharmacological:
- Glucocorticoids (prednisone 0.75 mg/kg/day or deflazacort 0.9 mg/kg/day) - prolong ambulation, improve muscle strength; deflazacort causes less weight gain
- ACE inhibitors + beta-blockers - slow cardiac fibrosis progression and manage DCM
Exon-skipping therapies (FDA conditionally approved):
- Eteplirsen - skips exon 51 (30 mg/kg IV weekly)
- Golodirsen - skips exon 53 (30 mg/kg IV weekly)
- Viltolarsen - skips exon 53 (80 mg/kg IV weekly)
- Casimersen - skips exon 45 (30 mg/kg IV weekly)
These work by restoring a partial reading frame so a truncated but partially functional dystrophin is produced.
Supportive:
- Physical therapy to prevent contractures
- Noninvasive ventilation for respiratory failure
- Spinal fusion for scoliosis when indicated
- Wheelchairs and assistive devices
Carrier Females
- Most are asymptomatic (one normal X chromosome compensates)
- Up to 20% of carrier females can show some symptoms (muscle weakness, elevated CK, or DCM) depending on X-inactivation patterns
DMD vs. Becker MD (BMD)
| Feature | DMD | BMD |
|---|---|---|
| Mutation | Frameshift - no dystrophin | In-frame - reduced/abnormal dystrophin |
| Onset | 2-5 years | Teens/adulthood |
| Ambulation loss | ~12-15 years | After 16 years (often later) |
| Severity | Severe | Milder |
Sources: Goldman-Cecil Medicine International Edition; Tietz Textbook of Laboratory Medicine, 7th Edition
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