1. MUSCLE DISEASES Patrick C.J. Ward, MB.BCh. Summer 2008

2. MUSCLE DISEASES Duchenne Muscular Dystrophy Becker Muscular Dystrophy Myotonic Dystrophy Dermatomyositis Polymyositis Myasthenia Gravis

3. MUSCLE DISEASES Duchenne Muscular Dystrophy

4. Duchenne Dystrophy Autographed copy of: De la Paralysie Musculaire Pseudo-hypertrophique... 1868 From NLM Guillaume-Benjamin Duchenne de BoulogneNLM

5. DUCHENNE MUSCULAR DYSTROPHY: CLINICAL 1/3500 live male births Walking often delayed in infancy Weakness: pelvic extending to shoulder girdle Wheelchair dependence by 10-12 yrs. Untreated, death by early 20’s Treated, death by 25-35 yrs

6. DMD: HISTOPATHOLOGY Variation in fiber size Increased internalization of nuclei Evidence of fiber regeneration (blue fibers) Proliferation of endomysial connective tissue ± necrosis / phagocytosis ± subendocardial interstitial fibrosis

14. DMD: PSEUDOHYPERTROPHY OF CALF Definition: enlargement of calf ‘muscles’ u classic feature of DMD u are muscles really hypertrophied? CPK initially elevated, then normal. Why?

16. Ewing EP, Jr., CDC

17. From: A Kornberg Duchenne muscular dystrophy Standing from supine position Pestronk, A., Neuromuscular Disease Center, Washington University, St. Louis, MO

18. Gowers’ Sign in Patient with Duchenne Muscle Dystrophy

19. DMD: BIOCHEMISTRY Dystrophin: juxtasarcolemmal cytoplasmic protein u conc. at plasma membrane over Z–bands strong mechanical link to cytoplasmic actin Superficially attached to sarcolemmal proteins u thence by laminin–2 to outside connective tissue When dystrophin is absent or defective: u connecting forces (actin–CT) are missing Muscle degenerates (into what?)

22. DMD: GENETICS Abnormalities of dystrophin gene on Xp21 u deletions (majority of cases) u frameshift mutations u point mutations Familial (2/3) versus spontaneous (1/3) In familial disease, females are carriers but u their CPK levels are elevated and they are u at risk for dilated cardiomyopathy later in life

23. van Deutekom J et al. N Engl J Med 2007;357:2677-2686 Schematic Representation of Exon Skipping

24. MUSCULOSKELETAL SYSTEM Duchenne Muscular Dystrophy Becker Muscular Dystrophy

25. BECKER MUSCULAR DYSTROPHY (BMD) Lesion at same genetic locus as DMD Later age of onset, even adolescence Some dystrophin present, but mol. size is altered Nearly normal life span

26. Becker, adult

32. Becker

33. From: A Kornberg Pestronk, A., Neuromuscular Disease Center, Washington University, St. Louis, MO

35. MUSCULOSKELETAL SYSTEM Duchenne Muscular Dystrophy Becker Muscular Dystrophy Myotonic Dystrophy

36. MYOTONIC DYSTROPHY: CLINICAL Onset in late childhood Sustained invol. contraction of muscle groups u complaints of ‘stiffness’ u cannot say goodbye easily (why?) Thenar tap sign Gait problems: dorsi-flexor weakness of foot Hand muscle and wrist extensor atrophy Facial atrophy, ptosis

37. MYOTONIC DYSTROPHY: ASSOC. FEATURES Cataracts Frontal balding Gonadal atrophy Cardiomyopathy Decreased IgG Abnormal glucose tolerance ± dementia Can you remember these?

38. MYOTONIC DYSTROPHY: PATHOLOGY Massive internalization of nuclei Ring fibers Sarcoplasmic masses

44. MYOTONIC DYSTROPHY: MOLECULAR BIOLOGY Trinucleotide repeat of CTG on 19q13.2 - 13.3 Normal: 30 repeats Increased numbers lead to disease In severe disease, may be several 1000 repeats u these adversely affect mRNA for DMPK More and more protein product is formed Anticipation (as in what other disease you studied?)

46. Neil Miller, Johns Hopkins

47. MUSCULOSKELETAL SYSTEM Duchenne Muscular Dystrophy Becker Muscular Dystrophy Myotonic Dystrophy Dermatomyositis

48. DERMATOMYOSITIS: MAJOR FINDINGS Proximal muscle weakness, myalgias Dysphagia Heart / lung inflammation Scaling, erythematous rash Heliotrope upper eyelids with periorbital edema Göttron lesions

56. DERMATOMYOSITIS: MUSCLE PATHOLOGY Hypoperfusion resulting from endothelial injury Associated with perimysial atrophy / inflammation ± necrosis ± regeneration throughout fascicle

66. MUSCULOSKELETAL SYSTEM Duchenne Muscular Dystrophy Becker Muscular Dystrophy Myotonic Dystrophy Dermatomyositis Polymyositis

67. POLYMYOSITIS: CLINICAL Predominantly in adults presenting with u subacute or chronic proximal weakness u elevated CPK Is a cell-mediated autoimmune disorder

68. POLYMYOSITIS:GENERAL Non-infectious, inflammatory myopathy Two manifestations: u myopathy is isolated u component of more systemic disease (10% of SS) Pathology: u endomysial CD8+ cells, MФs u necrotic / regenerating fibers throughout fascicle Rx: immunosuppressive therapy is beneficial

74. MUSCULOSKELETAL SYSTEM Duchenne Muscular Dystrophy Becker Muscular Dystrophy Myotonic Dystrophy Dermatomyositis Polymyositis Myasthenia Gravis

75. MYASTHENIA GRAVIS: GENERAL STATS 3 / 100,000 population < 40 years ♀ > ♂ Thymus u hyperplasia u thymoma (in 15%) Electrophysiologic tests diagnostic

76. MYASTHENIA GRAVIS: CLINICAL Ptosis Diplopia (ΔΔ?) Generalized weakness, curiously fluctuating Anticholinesterase as diagnostic test (tensilon) R x : prostigmine, prednisone, plasmapheresis Surgery : thymectomy With therapy, 95% five year survival

77. Myasthenia Gravis Foundation Coalition of Canada, 2008

79. Esterase stain

80. Neuromuscular Junctions

81. Posey & Spiller Fatigue (Ptosis) in a patient with MG Repetitive nerve stimulation: Decrement Pestronk, A., Neuromuscular Diseases Center, Washington, University, St. Louis, MO

83. Myasthenia Gravis Foundation of California, Los Angeles, CA