Muscular Dystrophies and Myopathies

MDs vs Myopathies: Basics - Muscle Mayhem Kickoff

Dystrophinopathies (DMD/BMD) - Dystrophin's Drama

• X-linked recessive; DMD gene (Xp21) defect → dystrophin protein deficiency.
• Dystrophin: anchors muscle fiber cytoskeleton (actin) to extracellular matrix.
• Duchenne Muscular Dystrophy (DMD):
  • Frameshift/nonsense mutations → near absent/truncated dystrophin.
  • Severe: onset <5 years, wheelchair by ~12 years, death by 20s-30s (respiratory/cardiac failure).
  • Key signs: Gower's sign, calf pseudohypertrophy (fibrofatty replacement), markedly ↑CK.
• Becker Muscular Dystrophy (BMD):
  • In-frame mutations → partially functional/reduced amount of dystrophin.
  • Milder: later onset, slower progression, variable severity, longer lifespan.
• Diagnosis: ↑↑ Serum CK (DMD > BMD), genetic testing (confirmatory), muscle biopsy (dystrophin staining).

⭐ Serum Creatine Kinase (CK) levels are often >10x normal in DMD, typically highest in early childhood.

📌 DMD = Deleted/non-functional dystrophin (severe); BMD = Better/partially functional dystrophin (milder).

Other Major Dystrophies - Diverse Muscle Breakdown

• Myotonic Dystrophy (DM):
  • DM1 (Steinert disease): Autosomal Dominant (AD). CTG repeat expansion (DMPK gene).
    • Features: Myotonia (grip, percussion), progressive weakness (distal, facial, SCM), cataracts, frontal balding, cardiac conduction defects, testicular atrophy.
    • 📌 Mnemonic: "My Tonia Can't Open Her Grip" (Myotonia, Cataracts, Open mouth/Hatchet facies, Heart block, Gonadal atrophy).
  • DM2 (PROMM - Proximal Myotonic Myopathy): AD. CCTG repeat (CNBP gene). Milder; often proximal weakness, myalgia, cataracts.
• Facioscapulohumeral Dystrophy (FSHD):
  • AD. D4Z4 repeat contraction (chromosome 4q35) → aberrant DUX4 gene expression.
  • Features: Weakness of facial muscles (orbicularis oris/oculi), scapular winging (often asymmetric), humeral weakness (Popeye sign). Sensorineural hearing loss possible.
• Limb-Girdle Muscular Dystrophies (LGMDs):
  • Genetically heterogeneous group. Progressive proximal muscle weakness (shoulder & pelvic girdles).
  • Inheritance: Autosomal Dominant (LGMDD, e.g., LGMDD1 from DNAJB6) or Recessive (LGMDR, e.g., LGMDR1 from CAPN3).
  • Key types: Calpainopathy (LGMDR1/LGMD2A), Sarcoglycanopathies (e.g., LGMDR3-6/LGMD2C-F), Dysferlinopathy (LGMDR2/LGMD2B).

⭐ In Myotonic Dystrophy Type 1 (DM1), "anticipation" (earlier onset and increased severity in subsequent generations) is a key genetic feature due to the unstable CTG repeat expansion. EMG classically shows myotonic discharges ("dive-bomber" sound).

Congenital & Metabolic Myopathies - Inborn Muscle Flaws

• Congenital Myopathies: Infantile hypotonia, weakness; often static. Biopsy diagnostic.
  • Central Core Disease: RYR1 gene.

    ⭐ Associated with malignant hyperthermia susceptibility.

  • Nemaline Myopathy: Nemaline (rod) bodies (Z-band).
  • Myotubular Myopathy: Central nuclei; X-linked (MTM1) common.
• Metabolic Myopathies: Exercise intolerance, cramps, rhabdomyolysis.
  • Glycogenoses:
    • McArdle (GSD V): Myophosphorylase def. 📌 "M" for Muscle, McArdle.
    • Pompe (GSD II): Acid maltase def; cardiomegaly (infantile).
  • Lipid Myopathy: CPT II def. (rhabdomyolysis trigger).
  • Mitochondrial: "Ragged red fibers" (Gomori).

Mito & Inflammatory Myopathies - Energy & Immune Woes

Mitochondrial Myopathies:

• Defect: Impaired mitochondrial ATP production (energy failure).
• Histo: Ragged Red Fibers (RRF) on Gomori trichrome; "parking lot" inclusions (EM).
• Clinical: Proximal weakness, exercise intolerance, ophthalmoplegia, ptosis.
• E.g., MELAS, MERRF, Kearns-Sayre.

Inflammatory Myopathies:

• Patho: Immune-mediated muscle damage.
• Polymyositis (PM):
  • CD8+ T-cell mediated; endomysial inflammation.
  • Symmetrical proximal weakness.
• Dermatomyositis (DM):
  • CD4+ T-cell, humoral; perifascicular atrophy, perimysial inflammation.
  • Heliotrope rash, Gottron's papules.

  ⭐ Associated with ↑ risk of malignancy (e.g., ovarian, lung, GI).

• Inclusion Body Myositis (IBM):
  • Affects individuals >50 years.
  • Asymmetric weakness (distal > proximal); rimmed vacuoles.

High‑Yield Points - ⚡ Biggest Takeaways

• Duchenne Muscular Dystrophy (DMD): X-linked recessive, absent dystrophin (frameshift mutation), Gower's sign, markedly ↑ CK, calf pseudohypertrophy.
• Becker Muscular Dystrophy (BMD): Milder, X-linked, reduced/altered dystrophin (in-frame mutation), later onset.
• Myotonic Dystrophy (DM1): Autosomal dominant, CTG repeat expansion (DMPK gene), myotonia, cataracts, cardiac issues, frontal balding.
• Limb-Girdle Muscular Dystrophies (LGMDs): Genetically heterogeneous group, proximal muscle weakness of shoulder and pelvic girdles.
• Mitochondrial Myopathies: Exhibit ragged red fibers on Gomori trichrome stain, often with ophthalmoplegia and exercise intolerance.
• Dermatomyositis: Heliotrope rash, Gottron's papules/sign, perifascicular atrophy; associated with malignancy in adults.
• Polymyositis: Endomysial inflammation with CD8+ T cells, proximal muscle weakness, no significant skin involvement.