Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Pathology of Skeletal Muscle

10,559 views

Published on

Published in: Health & Medicine

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>

×