9.3 Muscular Dystrophies & Neuromuscular Disease in Children
Key Takeaways
- Duchenne Muscular Dystrophy (DMD) is an X-linked recessive disorder caused by frame-shift mutations in the DMD gene on Xp21, leading to complete deficiency of the protein dystrophin.
- Clinical hallmarks of DMD include early motor delays, calf pseudohypertrophy, Gower sign, serum CK >10,000 U/L, and historical loss of independent ambulation at age 10-12 years.
- Corticosteroid therapy (prednisone 0.75 mg/kg/day or deflazacort 0.9 mg/kg/day) is the mainstay medical treatment, delaying loss of ambulation by 2-5 years and reducing scoliosis incidence.
- Targeted therapies for DMD include exon-skipping antisense oligonucleotides (e.g., Eteplirsen for exon 51) and AAV gene replacement therapy delivering micro-dystrophin.
- Becker Muscular Dystrophy (BMD) stems from in-frame Xp21 mutations producing partially functional dystrophin, resulting in a milder phenotype with ambulation preserved past age 16.
Pathophysiology and Genetics of Duchenne Muscular Dystrophy
Duchenne Muscular Dystrophy (DMD) is an X-linked recessive disorder affecting 1 in 3,500-5,000 live male births. It is caused by mutations in the DMD gene on the short arm of the X chromosome (Xp21)—the largest human gene, making it susceptible to spontaneous mutations (~33% of cases).
Genetic Diagnostics & Carrier Manifestations
Genetic confirmation utilizes Multiplex Ligation-dependent Probe Amplification (MLPA) to detect exon deletions or duplications (accounting for ~70% of mutations), followed by gene sequencing for point mutations. Female carriers (heterozygous) are typically asymptomatic but carry a 2-5% risk of carrier cardiomyopathy or mild muscle weakness, warranting baseline cardiac screening with echocardiography or cardiac MRI starting in early adulthood (every 5 years).
The Role of Dystrophin
Dystrophin anchors the actin cytoskeleton to the extracellular matrix via the dystrophin-glycoprotein complex (DGC). In DMD, frame-shift mutations (deletions/duplications disrupting the reading frame) cause complete absence of dystrophin (<1% of normal). Sarcolemmal instability results in micro-tearing during contraction, calcium influx, chronic muscle necrosis, and replacement of muscle with fibroadipose tissue.
Clinical Presentation and Early Functional Signs
Symptoms manifest between ages 2 and 5 years:
- Motor Delays: Walking delayed past 18 months, frequent falls, stair difficulty.
- Gower Sign: Proximal hip extensor (gluteus maximus) weakness. To stand from prone, the child turns, pushes onto hands/knees, and "walks" hands up thighs.
- Calf Pseudohypertrophy: Gastrocnemius enlargement due to fibroadipose infiltration replacing lost muscle fibers.
- Serum Creatine Kinase (CK): Markedly elevated (>10,000 to 30,000 U/L), reflecting continuous sarcolemmal leakage.
| Clinical Feature | Pathophysiology / Mechanism | Diagnostic Significance |
|---|---|---|
| Gower Sign | Proximal hip extensor & quadriceps weakness | Classic physical hallmark of DMD |
| Calf Pseudohypertrophy | Fibroadipose tissue replacement of muscle | Differentiates dystrophy from neurogenic atrophy |
| Toe Walking | Achilles tendon tightness & contracture | Compensatory posture for quadriceps weakness |
| Serum CK >10,000 U/L | Massive sarcolemmal leakage of enzyme | Essential screening test for early diagnosis |
Natural History and Multisystem Complications
- Loss of Ambulation: Occurs historically at age 10 to 12 years without steroids.
- Spinal Deformity: Rapidly progressive scoliosis develops after loss of ambulation in >90% of untreated boys.
- Pulmonary Complications: Progressive diaphragm and intercostal weakness causes restrictive lung disease and nocturnal hypoventilation. BiPAP is typically required by late adolescence.
- Cardiac Complications: Dilated cardiomyopathy and arrhythmias occur in virtually all patients by age 18. Baseline cardiac imaging (ECHO/MRI) is recommended at diagnosis or age 6, repeating every 2 years until age 10, then annually.
Pharmacological and Disease-Modifying Therapies
Corticosteroids (Standard of Care)
Daily corticosteroids are recommended for ambulatory boys aged ≥4 years:
- Regimens: Prednisone (0.75 mg/kg/day) or Deflazacort (0.9 mg/kg/day).
- Benefits: Delays loss of ambulation by 2-5 years, preserves upper limb and respiratory function, reduces scoliosis progression by >70%, and delays cardiomyopathy onset.
- Side Effects: Weight gain, cushingoid appearance, growth suppression, osteopenia, vertebral fractures, cataracts.
Targeted Genetic Therapies
- Exon-Skipping Antisense Oligonucleotides (ASOs): Bind pre-mRNA to skip target exons and restore the open reading frame, generating a shortened, partially functional dystrophin:
- Eteplirsen: Skips exon 51 (~13% of patients).
- Golodirsen & Viltolarsen: Skip exon 53 (~8% of patients).
- Casimersen: Skips exon 45 (~8% of patients).
- Gene Therapy: AAV vector delivery (Delandistrogene moxeparvovec) of micro-dystrophin.
Multidisciplinary Care & Transition of Care
As life expectancy expands into the 30s with advanced cardiopulmonary management, structured transition of care from pediatric to adult multidisciplinary clinics is vital. Key components include continuous cardiac monitoring (ACE inhibitors/beta-blockers for early left ventricular dysfunction), bone health management (bisphosphonates for osteoporotic compression fractures), and adaptive equipment (power tilt-in-space wheelchairs, environmental control units, and customized seating).
Becker Muscular Dystrophy (BMD)
Becker Muscular Dystrophy (BMD) results from in-frame mutations in the DMD gene (Xp21).
Distinction between DMD and BMD:
- Dystrophin Expression: Dystrophin is truncated but retains partial activity (10-40% of normal).
- Ambulation: Preserved past age 16 years (often into adulthood).
- Onset: Later onset (mean age 11-12 years).
- Cardiac Risk: Dilated cardiomyopathy can occur early and be disproportionately severe relative to skeletal weakness.
| Diagnostic Category | Gene Mutation Type | Dystrophin Protein | Age at Ambulation Loss | Cardiac Involvement |
|---|---|---|---|---|
| Duchenne (DMD) | Out-of-frame (frame-shift) | Absent (<1% of normal) | 10 - 12 years (untreated) | Universal by age 18; dilated cardiomyopathy |
| Becker (BMD) | In-frame mutation | Truncated/Reduced (10-40%) | Preserved past age 16 | Can be severe; out of proportion to muscle weakness |
Differential Diagnosis: Spinal Muscular Atrophy (SMA)
Autosomal recessive degeneration of anterior horn cells caused by SMN1 gene (5q13) mutations. Disease-modifying therapies have revolutionized outcomes:
- Nusirensern (Spinraza): Intrathecal antisense oligonucleotide that modifies SMN2 pre-mRNA splicing to increase full-length SMN protein production.
- Risdiplam (Evrysdi): Daily oral small-molecule SMN2 splicing modifier.
- Onasemnogene abeparvovec (Zolgensma): One-time intravenous AAV9 gene replacement therapy delivering a functional copy of the SMN1 gene to motor neurons.
Clinical Subtypes of SMA:
- SMA Type 1 (Werdnig-Hoffmann): Onset <6 months; severe hypotonia ("floppy infant"), paradoxical breathing, tongue fasciculations; non-sitters.
- SMA Type 2: Onset 6-18 months; achieve sitting, non-ambulators.
- SMA Type 3 (Kugelberg-Welander): Onset >18 months; achieve independent ambulation.
A 5-year-old boy presents with difficulty running and frequent falls. Physical examination demonstrates calf pseudohypertrophy and a positive Gower sign. Serum creatine kinase is 16,200 U/L. Genetic testing confirms an out-of-frame deletion in the DMD gene on Xp21. Which medical therapy is recommended as standard of care to prolong ambulation and preserve pulmonary function?
A 14-year-old boy with Duchenne muscular dystrophy who became wheelchair-dependent at age 11 is evaluated in the rehabilitation clinic. Which routine organ-system surveillance evaluation must be performed at least annually throughout adolescence?
A 17-year-old young man presents with progressive proximal lower extremity weakness. He continues to ambulate independently without devices and climbs stairs holding a handrail. Genetic testing reveals an in-frame mutation in the Xp21 gene resulting in a truncated, partially functional dystrophin protein. What is the most likely diagnosis?