Neuromuscular Diseases: Muscular Dystrophies (Dystrophinopathies and Limb-Girdle Muscular Dystrophy)
Muscular dystrophies are a heterogeneous group of inherited progressive myopathies characterized by degeneration and weakness of skeletal muscles due to defects in muscle structural proteins. The most common and severe types are dystrophinopathies (Duchenne and Becker muscular dystrophy), while limb-girdle muscular dystrophies (LGMDs) primarily affect shoulder and pelvic girdle muscles.
I. DYSTROPHINOPATHIES (Duchenne and Becker Muscular Dystrophy)
Genetic and Molecular Basis
- Gene: DMD gene on X chromosome (Xp21) — one of the largest human genes (~2.5 Mb).
- Protein: Dystrophin – a cytoskeletal protein that links the muscle fiber cytoskeleton (actin) to the sarcolemma and extracellular matrix via the dystrophin-associated glycoprotein complex (DGC).
- Inheritance: X-linked recessive.
- Molecular defect:
- Duchenne Muscular Dystrophy (DMD): Frameshift or nonsense mutations → complete absence of dystrophin.
- Becker Muscular Dystrophy (BMD): In-frame deletions or missense mutations → abnormal but partially functional dystrophin.
Function of Dystrophin
- Acts as a mechanical stabilizer during muscle contraction.
- Anchors actin filaments to the sarcolemma → prevents damage from mechanical stress.
- Loss of dystrophin makes the sarcolemma fragile → repeated contraction leads to myofiber necrosis and degeneration.
Pathophysiology
- 1. Absence or deficiency of dystrophin destabilizes the sarcolemma.
- 2. Repeated mechanical stress causes sarcolemmal tears → calcium influx into myocytes.
- 3. Calcium accumulation activates proteases → necrosis of muscle fibers.
- 4. Dead fibers are replaced by fatty and fibrous tissue → pseudohypertrophy of muscles (especially calves).
- 5. Progressive muscle loss leads to weakness, contractures, and respiratory failure.
Clinical Features
Other Findings
- Cognitive impairment (mild, in some DMD patients due to dystrophin in CNS).
- Respiratory weakness → chronic hypoventilation.
- Scoliosis due to paraspinal muscle weakness.
Diagnosis
1. Laboratory Tests
- Serum creatine kinase (CK): markedly elevated (>10–20× normal).
- Aldolase, AST, ALT – also elevated.
2. Molecular / Genetic
- Multiplex PCR or MLPA detects deletions/duplications in DMD gene.
- Sequencing for point mutations.
- Carrier detection and prenatal diagnosis possible.
3. Muscle Biopsy
- Dystrophin immunostaining:
- Absent in DMD, reduced in BMD.
- Histology:
- Variation in fiber size, necrosis, regeneration, fibrosis, fat infiltration.
4. Electromyography (EMG)
- Myopathic pattern: low amplitude, short-duration potentials.
Management
- Glucocorticoids (Prednisone, Deflazacort): slow progression and preserve strength.
- Cardiac care: ACE inhibitors, β-blockers for cardiomyopathy.
- Respiratory support: Noninvasive ventilation, cough-assist devices.
- Physical therapy: Prevent contractures and maintain mobility.
- New gene-based therapies:
- Eteplirsen (exon skipping therapy for exon 51 deletion).
- Ataluren for nonsense mutations (promotes read-through).
- Gene replacement (micro-dystrophin) under research.