4/14 Inherited Disease of Sk M - Corbett Flashcards
development of skeletal muscle
organization (-mysiums)
- endomysium: layer of reticular fibers surrounding individ muscle fibers
-
perimysium: thicker conn tissue around a group of fibers → bundle/fascicle
* larger blood vessels, nerves -
epimysium: sheath of dense conn tissue surrounding entire muscle
* major vascular and nerve supply of muscle
segments of muscle fiber
Z disk
I, H, A, M
relationship between actin and myosin
thin filaments
F actin: composed of G actin subunits
- myosin-binding sites typically covered by tropomyosin
- movement of tropomyosin dictated by troponin & Ca-binding sites on it
thick filaments
- myosin heads, ATPase activity, power stroke, etc
types of myopathies
6 types
1. idiopathic infl myopathy
- polymyositis
- dermatomyositis
- inclusion body
2. congenital muscular dystrophy
3. muscular dystrophy
- X linked
- Duchenne
- Becker
- Emergy-Dreifuss
- fascioscapulohumeral
4. myotonic syndromes
- myotonic dystrophy
5. congenital myopathy
- central core disease
- nemaline myopathy
- centronuclear myopathy
6. metabolic myopathy
statins: rare complication
antibodies against FMG CoA reductase → myonecrosis
- idiopathic infl myopathy
triad of findings
-
muscle weakness
- proximal, symmetric → DM and PM
- distal UE, proximal LE and asymmetric → IBM
- histo path evidence of muscle inflammation
- elevated conc of muscle-derived proteins (ex. creatine kinase)
DM = dermatomyositis
PM = polymyositis
IBM = inclusion body myositis
dermatomyositis
basics
cardinal manifestations
cutaneous manifestations
- affects adults (but juv form also exists)
- autoantibodies assoc with clinical features of disease:
- *anti-Mi2 (helicase; rash)
-
*anti-Jo1 (histidyl RNA synthetase)
- interstitial lung disease & mechanics hands
- anti-P155/P140 (transcr regulators; JDM)
- distinct histopath:
- CD4+ T cells in perimysium
- perifascicular atrophy
*assoc w malignancy → ovarian, breast, colon, NHL (thorough eval for next 3-5 years)
**pathology targets BLOOD VESSELS
- infl exudate is in perimysium area
- antibodies → activation of MAC → cap damage/perifascicular atrophy
cardinal manifestations
- proximal symmetric muscle weakness (large muscles of arms, legs, trunk)
- neck extensor muscles → “head drop”
- pharyngeal muscles → dysphagia
- ocular muscles spared
cutaneous manifestations
- Gottron papules “70%)
- heliotrope rash (over eyelids + periorbital edema)
- “V neck” or “shawl” pattern rash (sun-exposed areas: upper chest, back, base of neck)
systemic involvement
- interstitial lung disease
- upper 1/3 of esoph
- joint manifestations
- cutaneous calcinosis (kids)
DM lab findings
- elevated muscle enzymes
- CK >10x normal
- lactate dehydrogenase
- autoantibodies
- Mi2: nuclear helicase, specific to DM
- Jo1 (aminoacyl tRNA synthetase): in CM/PM
- SRP (signal recog particle)
- elevated serum and urine myoglobin
graphic
Question
(DM)
polymyositis
rare as a standalone disorder
*NO SKIN MANIFESTATIONS
**pathology targets MUSCLE
histopath
- CD8+ T lymphocytes (predom endomysial dist)
- CD8+ T cells, macrophages surround/invade non-necrotic muscle fibers
- MHC I being expressed on muscle cells → not normal
inclusion body myositis
- common: older men 65+
- most autoantibodies absent
- similar to PM: CD8+ T cells in endomysium
specific to IBM:
- abnl cytoplasmic inclusions
- inclusions contain proteins assoc with neurodegen disease
DM vs PM vs IBM
muscular dystrophies
common type?
key gene/protein
two types
inherited disorders of skm characterized by progressive muscle damage
sx: between childhood and adulthood
- DON’T present in infancy
- most common* : X linked muscular dystrophies (mutations in dystrophin protein)
- fx: major component of dystrophin-glycoprotein complex
- links actin cytoskeleton to ECM → mechanical stability to myofiber
-
Duchenne MD (severe, progressive phenotype)
- complete absence of protein
-
Becker MD
- __truncated protein → still retains fx
muscular dystrophy: morphology
histology
- segmental myofiber degen → regen with atrophic myofibers
- fatty replacement of muscle tissue
immunohisto staining
- DMD: absence ofnormal sarcolemmal staining pattern of dystrophin (attached pic)
- BMD: reduced staining
muscular dystrophies
features
DMD vs BMD
WEAKNESS
- dx: age 2-7
- proximal before distal, lower before upper
- delayed devpt
- clumsiness, difficulty climbing/running/jumping
**calf pseudohypertrophy is a key feature
extramuscular features
- cardiac dysfx
- mild cog impairment
- dx: incr CPK, muscle biopsy
what about Becker? later age of onset, milder sx
myotonic dystrophy
phenotypes
mechanisms of disease
most common adult-onset MD
- auto dom → unstable expansion of CTG in 3’ untranslated region of DMPK gene (dystrophia myotonia protein kinase)
- full mutation is > 50 repeats
- pronounced genetic anticipation
- dad will not transmit greater than 1000 repeats. mom will → congenital? almost always from mom
key features
- myotonia
- DM2
- cardiomyopathy
three overlapping phenotypes:
- mild: 50-150
- classic: 150-1000
- severe (congenital): 1000+
mechanism: RNA-mediated toxicity → sequesters all the splicing proteins to that abnormal gene
- improper splicing in muscle
TNR featuers
trinucleotide repeats!
ex. Huntington’s → extra Glu
myotonic dystrophy summary
