Pathology of Skeletal Muscle

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Pathology of Skeletal Muscle

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

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