Inherited Diseases of Muscle: Histologic Features

1. InheritedDiseases of Muscle:Histologic Features David Lacomis, MD

2. Classification of Myopathies

3. Opaque or hyaline fibers Increase in endomysial connective tissue Frozen Section from a Patient withDuchenne Muscular Dystrophy Group of basophilic regenerating fibers

4. Normal Immunohistochemical Stain for DystrophinSubsarcolemmal staining

5. Duchenne Muscular Dystrophy Absent staining for dystrophin

6. Becker Muscular Dystrophy Reduced but present staining split fiber (non-specific chronic change)

7. Female Carrier of Duchenne Muscular DystrophyA mosaic staining pattern

8. Female Carrier of Duchenne Muscular DystrophyA mosaic staining pattern

9. Mutations in “Limb-Girdle” & Other Dystrophies

10. Locations of Affected Proteinsin Muscular Dystrophies Extracellular Matrix Laminin-2 Dystroglycan complex a g a b  b sarcoglycans Sarcolemma Lamin A/C (emerin) Caveolin 3 Dysferlin Dystrophin nucleus Actin

11. Emery-Dreifuss Muscular DystrophyGomori trichrome-stained frozen section Necrotic fiber • Variation in fiber size with many hypertrophic fibers • Increase in endomysial connective tissue • Nonspecific so-called dystrophic changes seen in many of the muscular dystrophies. • Can also be seen in any chronic myopathic disorder. • This disorder is due to loss of the protein emerin.

12. Myotonic Dystrophy • Chronic changes • Marked excess in internalized nuclei • Variation in fiber sizes • Nuclear clumps (not shown)

13. H & E, paraffin The excess of internalized nuclei can lead to nuclear chains.

14. Myotonic DystrophyNADH-reacted section Ring fibers in which myofilaments are organized in different directions

15. The majority of dystrophies do not have a specific histopathologic appearance. Clinical features are also very important. For example, winging of the scapula is characteristic of FSHD. Fascioscapulohumeral Dystrophy (FSHD)

16. Variable non-specific changes Range from scattered atrophy to “dystrophic” features. Inflammation can be present. FSH Dystrophy

17. Basophilic subsarcolemmal structures are sarcoplasmic masses. • Sometimes occur in chronic myopathies such as FSH and myotonic dystrophy.

18. Sarcoplasmic MassesStained darkly with NADH reaction

19. Variation in muscle fiber size with atrophic angulated fibers Sometimes contain rimmed vacuoles Oculopharyngeal Muscular Dystrophy (OPD)

20. Higher power view of Gomori trichrome-stained section • Angulated fibers • Fiber containing a large rimmed vacuole

21. Oculopharyngeal DystrophyGomori trichrome • Ragged red fibers are sometimes seen. • Characteristic of proliferation of abnormal mitochondria.

22. May be identified by electron microscopy in OPD Intranuclear Filamentous Inclusions

23. Central areas of absent staining in the dark type I fibers Mitochondria absent Congenital Myopathies: Central Core MyopathyNADH

24. Congenital Myopathies: Central Core MyopathyNADH • The core consists of disorganized myofibrils and the area is devoid of mitochondria.

25. Congenital Fiber Type DisproportionH&E • Bimodal size population

26. Congenital Fiber Type DisproportionATPase pH 4.3 • Smaller fibers are type I • More numerous • Stain lightly • Larger or normal fibers are type II

27. Nemaline Myopathy • Eosinophilic inclusions present

28. Nemaline MyopathyGomori trichrome • Eosinophilic inclusions stain darkly

29. Named for thread-like appearance Inclusions extend from Z-band to Z-band Nemaline MyopathyElectron microscopy

30. Muscle Biopsy from an Infant • Internalized nuclei predominant • Consistent with centronuclear myopathy • Can be seen in other disorders such as myotonic dystrophy with congenital onset

32. Muscle Biopsy from an Infant:Centronuclear Myopathy • Central position of the nucleus resembling an embryonic myotube

33. Metabolic: Inherited – MitochondrialMELAS Syndrome • Ragged red fiber present

34. MELAS SyndromeSuccinic dehydrogenase reaction • SDH-rich fibers are seen with mitochondrial proliferation

36. “Ragged-red” Fibers H&E

37. SDH-rich Fibers

38. Cox Normal Fibers

39. Many COX-negative Fibers • COX-negative fibers are usually seen with mtDNA mutations.

40. Mitochondrial DisordersElectron Microscopy • Aggregates of mitochondria containing paracrystalline inclusions are frequent. • Non-specific

41. Mitochondrial DisordersElectron Microscopy Higher power view of paracrystalline inclusion

42. Oil-red-O stain • Increased lipid storage • Seen in carnitine deficiency states (primary or secondary) • Sometimes as a consequence of certain toxins • Focal increases can be non-specific

43. Lipid Storage MyopathyElectron microscopy

44. Glycogen Storage Myopathies • Some glycogen storage myopathies, such as myophosphorylase deficiency (McArdle’s Disease), cause subsarcolemmal blebs. • PAS-positive due to the presence of glycogen.

45. McArdles Disease:Phosphorylase Reaction Disease (Absent) Normal Control

46. McArdle’s DiseaseElectron Microscopy Subsarcolemmal collection of glycogen is shown.

47. Acid Maltase DeficiencyAcid phosphatase • Due to the intralysosomal activity of this enzyme • Prominent staining with acid phosphatase in vacuoles Vacuolar myopathy noted.

48. Normal GlycogenPAS stain (control)

49. Increased Glycogen • Acid maltase deficiency • Increased glycogen (diffusely and in vacuoles)

50. Glycogen is digested by diastase in most glycogen storage diseases.