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MUSCLE DISEASES
Patrick C.J. Ward, MB.BCh.
Summer 2008
MUSCLE DISEASES
• Duchenne Muscular Dystrophy
• Becker Muscular Dystrophy
• Myotonic Dystrophy
• Dermatomyositis
• Polymyositis
• Myasthenia Gravis
MUSCLE DISEASES
• Duchenne Muscular Dystrophy
Duchenne Dystrophy
Autographed copy of: De la Paralysie Musculaire Pseudo-hypertrophique...1868 From NLM
Guillaume-Benjamin
Duchenne de Boulogne
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
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
DMD: PSEUDOHYPERTROPHY OF CALF
• Definition: enlargement of calf ‘muscles’
classic feature of DMD are muscles really hypertrophied?
• CPK initially elevated, then normal. Why?
Ewing EP, Jr., CDC
From: A Kornberg
Duchenne muscular dystrophyStanding from supine position
Pestronk, A., Neuromuscular Disease Center, Washington University, St. Louis, MO
Gowers’ Sign in Patient with Duchenne Muscle Dystrophy
DMD: BIOCHEMISTRY
• Dystrophin: juxtasarcolemmal cytoplasmic protein
conc. at plasma membrane over Z–bands
• strong mechanical link to cytoplasmic actin
• Superficially attached to sarcolemmal proteins
thence by laminin–2 to outside connective tissue
• When dystrophin is absent or defective:
connecting forces (actin–CT) are missing
• Muscle degenerates (into what?)
DMD: GENETICS
• Abnormalities of dystrophin gene on Xp21
deletions (majority of cases)
frameshift mutations
point mutations
• Familial (2/3) versus spontaneous (1/3)
• In familial disease, females are carriers but
their CPK levels are elevated and they are
at risk for dilated cardiomyopathy later in life
van Deutekom J et al. N Engl J Med 2007;357:2677-2686
Schematic Representation of Exon Skipping
MUSCULOSKELETAL SYSTEM
• Duchenne Muscular Dystrophy
• Becker Muscular Dystrophy
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
Becker, adult
Becker
From: A Kornberg
Pestronk, A., Neuromuscular Disease Center, Washington University, St. Louis, MO
Pestronk, A., Neuromuscular Disease Center, Washington University, St. Louis, MO
MUSCULOSKELETAL SYSTEM
• Duchenne Muscular Dystrophy
• Becker Muscular Dystrophy
• Myotonic Dystrophy
MYOTONIC DYSTROPHY: CLINICAL
• Onset in late childhood
• Sustained invol. contraction of muscle groups
complaints of ‘stiffness’
cannot say goodbye easily (why?)
• Thenar tap sign
• Gait problems: dorsi-flexor weakness of foot
• Hand muscle and wrist extensor atrophy
• Facial atrophy, ptosis
MYOTONIC DYSTROPHY: ASSOC. FEATURES
• Cataracts
• Frontal balding
• Gonadal atrophy
• Cardiomyopathy
• Decreased IgG
• Abnormal glucose tolerance
• ± dementia
Can you remember these?
MYOTONIC DYSTROPHY: PATHOLOGY
• Massive internalization of nuclei
• Ring fibers
• Sarcoplasmic masses
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
these adversely affect mRNA for DMPK
• More and more protein product is formed
• Anticipation (as in what other disease you studied?)
Neil Miller, Johns Hopkins
MUSCULOSKELETAL SYSTEM
• Duchenne Muscular Dystrophy
• Becker Muscular Dystrophy
• Myotonic Dystrophy
• Dermatomyositis
DERMATOMYOSITIS: MAJOR FINDINGS
• Proximal muscle weakness, myalgias
• Dysphagia
• Heart / lung inflammation
• Scaling, erythematous rash
• Heliotrope upper eyelids with periorbital edema
• Göttron lesions
DERMATOMYOSITIS: MUSCLE PATHOLOGY
• Hypoperfusion resulting from endothelial injury
• Associated with perimysial atrophy / inflammation
• ± necrosis
• ± regeneration throughout fascicle
MUSCULOSKELETAL SYSTEM
• Duchenne Muscular Dystrophy
• Becker Muscular Dystrophy
• Myotonic Dystrophy
• Dermatomyositis
• Polymyositis
POLYMYOSITIS: CLINICAL
• Predominantly in adults presenting with subacute or chronic proximal weakness elevated CPK
• Is a cell-mediated autoimmune disorder
POLYMYOSITIS:GENERAL
• Non-infectious, inflammatory myopathy
• Two manifestations:
myopathy is isolated
component of more systemic disease (10% of SS)
• Pathology:
endomysial CD8+ cells, MФs
necrotic / regenerating fibers throughout fascicle
Rx: immunosuppressive therapy is beneficial
MUSCULOSKELETAL SYSTEM
• Duchenne Muscular Dystrophy
• Becker Muscular Dystrophy
• Myotonic Dystrophy
• Dermatomyositis
• Polymyositis
• Myasthenia Gravis
MYASTHENIA GRAVIS: GENERAL STATS
• 3 / 100,000 population
• < 40 years
• ♀ > ♂
• Thymus hyperplasia thymoma (in 15%)
• Electrophysiologic tests diagnostic
MYASTHENIA GRAVIS: CLINICAL
• Ptosis
• Diplopia (ΔΔ?)
• Generalized weakness, curiously fluctuating
• Anticholinesterase as diagnostic test (tensilon)
Rx: prostigmine, prednisone, plasmapheresis
• Surgery : thymectomy
• With therapy, 95% five year survival
Myasthenia Gravis Foundation Coalition of Canada, 2008
Esterase stain
Esterase stain
Neuromuscular Junctions
Posey & Spiller
Fatigue (Ptosis) in a patient with MG
Repetitive nerve stimulation: Decrement
Pestronk, A., Neuromuscular Diseases Center, Washington, University, St. Louis, MO
Myasthenia Gravis Foundation of California, Los Angeles, CA