Muscular Dystrophy Study Notes

Introduction to Muscular Dystrophy

  • Overview of muscular dystrophies
    • Muscular dystrophies are heterogeneous neuromuscular disorders characterized by progressive muscle degeneration.
    • Commonly accompanied by cardiomyopathy.
    • More than 20 known types of muscular dystrophies exist, each associated with a different genetic mutation.
    • Distinct phenotypes exist depending on which muscles are affected:
    • Proximal vs. distal muscle weakness.

Types of Muscular Dystrophy

  • Focus on specific muscular dystrophies:
    • Duchenne Muscular Dystrophy (DMD):
    • Affects proximal muscles before distal muscles; e.g., quadriceps before calf muscles.
    • Becker Muscular Dystrophy (BMD): Similar to DMD but less severe; effects on muscle function manifest later.
    • Facioscapulohumeral Muscular Dystrophy (FSHD):
    • Affects shoulder and face muscles, including muscle groups like calf muscles.
    • Oculopharyngeal Muscular Dystrophy:
    • Specifically affects muscles around the eyes and swallowing.
    • Limb Girdle Muscular Dystrophy:
    • Primarily affects shoulder, upper arms, and upper legs.

Mechanism of Muscle Degeneration

  • Importance of dystrophin in muscle integrity:
    • Dystrophin is a vital protein that links the inside and outside of the muscle cell membrane (sarcolemma) and maintains membrane stability.
    • Location: Located on the X chromosome; largest human gene characterized by positional cloning.
    • Consists of over 79 exons and spans over 2.5 megabases.
  • Consequences of dystrophin mutations:
    • Mutations can lead to absence or partial function of dystrophin.
    • Absence in DMD: Results in severe muscle degeneration and membrane fragility, leading to cell damage and eventual cell death.
    • In BMD: A shortened form of dystrophin still maintains some function.

Structure of Dystrophin Protein

  • Size: 427 kDa which poses challenges in protein analysis.
  • Dystrophin domains:
    • N-terminal domain.
    • Two actin binding domains (Actin Binding Domain 1 and 2).
    • Rod domain consisting of 24 spectrin-like repeats and 4 hinges, enabling flexibility.
    • C-terminal domain includes dystroglycan binding.
    • Dystrophin is integral to the dystrophin-associated glycoprotein complex (DAGC) including proteins like alpha-dystroglycan, beta-dystroglycan, and various sarcoglycans.

Dystrophin-Associated Glycoprotein Complex

  • Provides mechanical and signaling links between the scaffolding (collagen/laminin) and muscle cell contractile elements.
  • Ensures sarcolemma stability during muscle contractions that generate high mechanical strain.

Pathophysiology of Duchenne Muscular Dystrophy

  • Mutations in the dystrophin gene:
    • No functional dystrophin leads to membrane instability, calcium influx, myofibril death, and eventual replacement by fibrous and fatty tissue.
  • Clinical manifestations of DMD include:
    • Prevalence: Approximately 1 in 3,500 boys, with an X-linked inheritance pattern.
    • Onset: Between ages 2 to 4.
    • Symptoms include proximal to distal muscle weakness, Gowers' maneuver, calf hypertrophy, elevated serum muscle enzymes (e.g., creatine kinase can increase 40 to 100-fold).
    • Wheelchair dependency by age 13 and life expectancy typically into early 30s.
    • Proximal muscles affected more than distal muscles; bilateral and symmetrical muscle weakness.
    • The Gowers maneuver showcases how children use their arms to rise from the floor due to weakness in leg muscles.

Genetic Basis of Dystrophinopathies

  • Gene identified in 1984; larger alterations lead to different forms of muscular dystrophy.
  • Types of mutations can result in varying severity:
    • Duchenne: Out-of-frame mutations resulting in no functional protein.
    • Becker: In-frame mutations lead to a partially functional dystrophin.
  • Mutation specifics:
    • Deletions of greater than 36 exons often result in DMD; deletions less than 36 may result in BMD.
    • Large deletions/duplication account for 72% of mutations; point mutations account for 20%.

Current Therapeutic Approaches

  • There is no cure for DMD; treatment is mainly palliative:
    • Corticosteroids (e.g., prednisone, deflazacort) may slow progression and improve mobility.
  • Physical therapy is critical to maintain muscle flexibility and prevent fibrosis.
  • Promising pharmacological interventions:
    • Gene therapies targeting restoration of dystrophin expression.
    • Exon-skipping drugs designed to preserve reading frames in deletions.
    • Stop codon suppression to allow translation of dystrophin protein despite mutations.

Muscle Contraction Dynamics

  • Muscle contraction types:
    • Isometric contraction: No change in muscle length, only tension generated.
    • Isotonic contraction: Muscle shortens and moves, generating tension around joints.
    • Eccentric contraction: Lengthening muscles while under tension, causing more damage in dystrophic muscles due to increased strain.
  • Dystrophic muscles are more susceptible to damage from lengthening contractions due to membrane instability.

Muscle Regeneration and Repair

  • Muscle cells can regenerate after damage through activation of satellite cells.
  • In healthy muscles, some damage promotes growth and adaptation (e.g. through weightlifting).
  • In DMD, regenerative capacity is eventually overwhelmed by chronic damage, leading to cell atrophy and replacement by non-contractile tissues and fibrosis.