Pathology of Skeletal Muscle

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  • 1. Diseases of Skeletal Muscle December 9 th , 2008
    • Describe the morphologic effects of denervation (and reinnervation) on skeletal muscle.
    • Apply the “reading frame hypothesis” to the pathogenesis of dystrophinopathies.
    • Discuss the limitations of routine muscle biopsy in the diagnosis of:
      • Muscular dystrophies
      • Mitochondrial diseases
    • Describe the pathologic features that distinguish dermatomyositis and inclusion body myositis from “polymyositis”.
  • 2. Skeletal muscle: Histology
    • Multinucleated syncitia
    • Peripheral nuclei
    • Minimal endomysial fibrous tissue
    • Admixture of fiber types
  • 3. Neurogenic or Myopathic?
    • Neurogenic
    • bimodal size distribution
    • angulated fibers
    • apparent increase in nuclei
    • no necrosis, regeneration, or fibrosis*
    • Myopathic
    • random size variation
    • round fibers
    • centralization of nuclei
    • necrosis, regeneration, +/- fibrosis, inflammation
    *except in longstanding denervation and in elderly patients
  • 4. In elderly patients with weakness, mildly elevated CPK does not equal (primary) myopathy!
  • 5. Neurogenic V. Myopathic
  • 6.
    • Grouped atrophy involving both type 1 and type 2 fibers
    • Fiber type grouping (secondary to reinnervation) ‏
    • Formation of target fibers
  • 7. Endomysial fibrosis = Muscular dystrophy
  • 8. Dystrophin Dystrophin Actin -Largest known gene, by far (the average gene consists of 3000 bases; the dystrophin gene comprises 2.4 million) -Short arm of X chromosome
  • 9.  
  • 10. Duchenne muscular dystrophy
    • Early childhood weakness
    • Gower sign
    • Calf hypertrophy
    • Wheelchair dependence by age 12
    • Death from cardiomyopathy with conduction defects, respiratory weakness, & pneumonia
  • 11. Duchenne muscular dystrophy Dystrophin Actin
  • 12. Duchenne muscular dystrophy Actin
  • 13. Duchenne muscular dystrophy Actin
  • 14. Duchenne muscular dystrophy Actin
  • 15. Dystrophin: Duchenne muscular dystrophy “ Revertant fibers” result from reading frame restoring mutations
  • 16. Becker muscular dystrophy Dystrophin Actin -Dystrophin present, but abnormally short due to in-frame deletions -Variety of clinical presentations and progressions, most involving at least some degree of proximal weakness
  • 17. Dystrophin: Becker muscular dystrophy Immunohistochemical staining is non-specific!
  • 18. Dystrophinopathy: Diagnosis
    • Deletions or duplications in DNA isolated from peripheral blood
      • ~70% of Duchenne
      • ~85% of Becker
    • Muscle biopsy
      • Immunostaining for dystrophin
      • Immunblot analysis
      • Evaluation of related proteins
  • 19. Limb-Girdle Muscular Dystrophies
    • Autosomally determined face-sparing, proximally predominant, progressive muscular dystrophies
      • 10% autosomal dominant (6 subtypes, LGMD1A-F) ‏
      • 90% autosomal recessive (11 subtypes, LGMD2A-K) ‏
    • Age at onset varies greatly (usually 1 st – 3 rd decade) ‏
    • Defective proteins coded by mutant genes may be detected by immunohistochemistry or immunoblotting
  • 20. Dysferlinopathy (LGMD-2B) ‏
    • Relatively sudden onset in late teens
    • Early inability to tiptoe
    • Calf pain and swelling
    • Good prior muscular prowess
    • Very high serum CK
    • Inflammation may be prominent
  • 21. How dysferlin works Dystrophin Actin
  • 22. Dystrophin Actin
  • 23. Dystrophin Actin
  • 24. Dystrophin Actin
  • 25. Polymyositis “ Invasion of non-necrotic fibers”
  • 26. Dermatomyositis
  • 27. DM = Complement mediated, small vessel vasculitic myopathy
  • 28. Primary myopathies with inflammation
    • Limb-girdle muscular dystrophy, types 2A (calpainopathy) & 2B (dysferlinopathy)
    • Duchenne muscular dystrophy
    • Fascioscapulohumeral dystrophy
    • Inclusion body myositis
  • 29. Inclusion body myositis
    • Time of onset generally after age 40
    • Preference for quadriceps, especially in men, finger flexors, and pharyngeal muscles
    • Highly variable rate of progression (older age of onset associated with faster progression) ‏
    • Serum CK usually less than 12x upper limit of normal, but higher values do not exclude IBM
  • 30. IBM: Pathologic diagnosis
    • H&E and /or Gomori trichrome staining to visualize vacuolated muscle fibers and mononuclear cell inflammation
    • Immunohistochemical staining for paired helical filaments (SMI-31) ‏
    • Electron microscopy is not required
  • 31. IBM: Pathologic diagnosis
  • 32.  
  • 33.  
  • 34. IBM-accumulated proteins
    • Myostatin
    • Beta-amyloid & its precursor protein
    • Phosphorylated tau protein
    • Cellular prion protein
    • Alpha-synuclein
    • Parkin
    • DJ-1
  • 35. SMI-31 Immunostaining
  • 36. Inclusion body myositis as a degenerative disease
    • Strongly age-dependent/realted
    • Biochemical evidence of oxidative stress
    • Accumulation of mitochondrial mutations
  • 37. Mitochondrial disorders
    • Syndromes associated with defects in oxidative phosphorylation
    • Genetics may be mitochondrial OR nuclear (mendelian) ‏
    • Adults usually demonstrate myopathy with variable CNS involvement
    • Children usually manifest psychomotor delay, hypotonia, acidosis, and cardiorespiratory failure
  • 38. Stochastic segregation during cell division results in tissue and cellular heteroplasmy
  • 39. Heteroplasmy results in a threshold effect , both clinically and pathologically
  • 40. Cellular heteroplasmy/threshold effect
  • 41. Developmental heteroplasmy Skeletal muscle Heart Eye Liver Kidney Pancreas Blood Inner Ear GI Tract Brain A single mitochondrial mutation may demonstrate heterogenous phenotypes!
  • 42. Diseases of Skeletal Muscle December 9 th , 2008
    • Describe the morphologic effects of denervation (and reinnervation) on skeletal muscle.
    • Apply the “reading frame hypothesis” to the pathogenesis of dystrophinopathies.
    • Discuss the limitations of routine muscle biopsy in the diagnosis of:
      • Muscular dystrophies
      • Mitochondrial diseases
    • Describe the pathologic features that distinguish dermatomyositis and inclusion body myositis from “polymyositis”.