pathology of skeletal muscle
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TRANSCRIPT
- 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:
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- Muscular dystrophies
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- 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
- 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
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- ~70% of Duchenne
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- ~85% of Becker
- Muscle biopsy
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- Immunostaining for dystrophin
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- Immunblot analysis
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- Evaluation of related proteins
- 19. Limb-Girdle Muscular Dystrophies
- Autosomally determined face-sparing, proximally predominant, progressive muscular dystrophies
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- 10% autosomal dominant (6 subtypes, LGMD1A-F)
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- 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.