Skeletal muscle and peripheral nerve path Flashcards
Normal muscle on H and E
Peripheral nuclei, behive, polyglonal fiber shape
Muscle contractions
depolarization down the t tuble, Sarcoplasmic reticulum releases calcium,
Actin and myosin
tropomyosin blocks myosin, tropomyosin has Ca receptors on it
Basic pathologic reactions of muscle
Changes in fiber size- Hypertrophy (increased load on fibers due to exercise or pathologic conditions) , atrophy denervation disuse or myopathic conditions)
Changes in fiber shape- angular fibers (denervation, rounded fibers (myopathic)
Changes in nuclei- internal nuclei (myopathic), nuclear clumps (denervation)
Changes in fiber type distribution (fiber type grouping reinnervation)
Degeneration and regeneration of muscle
Degeneration- Necrosis (pale staining fibers, stimulates infiltration by phagocytic cells), Ragged red fibers ( subsarcolemmal proliferation of abnormal mitochondriat, mitochondrial myopathies
Regeneration- proliferation of satellite cells around necrotic fiber, basophilic fiber with enlarged vesicular
myopathic vs neuropathic muscle disease
Myopathic- small rounded fibers, widely ranging fiber, size variability, nuclei are increased internal, necrosis and regen is common, fiber type distribution is normal or type predominance
Neuropathic- small angular fibers, bimodal fiber size distribution, group atrophy, pyknotic nuclear clumps of atrophied fibers, rare necrosis, type grouping
Neurogenic chnages in muscle
Denervation atrophy (neurogenic atrophy)- atrophic fibers with angulated edges, pyknotic nuclear clumps (severly atrophic fibers), devervation of one motor unit (one motor nerve) results in widely scattered and clustered small angular fibers, denervation or multiple motor units produces group atrophy of intermingled type 1 and type 2 fibers
Reinnervation- neighboting axons sprout and reinnervate denervated fibers, reinnervated fiber assumes fiber type conferred by the neighboring axon, results in fiber type grouping
ALS
Progressive, neurodegenerative disorder, upper and lower motor neuron degenration, normal sensation
Onset 50-60y of age, 5-10% are familial types of ALS, weakness (muscle atrophy, dysphagia, dysarria), fasciculations (affected body part, tongue) spasticity, executive dysfunction
Spinal muscular atrophy
Degenerative lower motor neuron disorder of childhood»adulthood
2nd most common autosomal recessive disorder, most commonly due to homozygous deletion of exon 7 of SMN 1 (survival motor neuron) gene
3 deffernt subtypes- Type 1 (Werdnig Hoffman)- severe infantile, never able to sit Type 2 - late infantile, able to sit not stand type 3 (Kugelberg- welander)-- onset 2nd yr of life to adulthood, achieve ambulation
Symmetric proximal > distal weakness, areflexic
Dysphagia, respiratory weakness, sparing of facial muscles
Normal intellect, sensation intact
Congenital muscle disease
muscle disease occurring due to mutations in genes that are necessart for muscl estructure of function
Dystrophies- caused by mutations in genes required for stabilizing muscle fibers
Congenital myopathies- caused by mutations in genes required for muscle contraction
Dystrophin proteinq
stabilizes act to sarcolemma
Duchenne/becker muscular dystrophy
Mutation in DMD gene (X p21), encodes dystrophin
DMD–>99% have no or almost no dystrophin
BMD–>80% have abnormal dystrophin in reduced quantity, 20% have normal dystrophin in reduced quantity
DMD clinical presentation
Usually marked by gait symptoms (delayed onset, toe walking, waddling, gowers maneuver) at 3-5 yrs , ambulation lost at 7-12 yrs of age, often death by late 20s
Dilated cardiomyopathy (100% after age 18 yrs), CK is elevated 50-100x with elevations in AST and ALT (from muscle not liver), some cases have intellectual impairment
Becker muscular dystrophy
later onset, milder limb girdle weakness, calf hypertrophy, wheelchair dependent after 15 yrs, wildely phenotype (onset in childhood to late adulthood), cramp-myalgia syndrome, exercise- induced rhabdomyolysis, quadriceps myopathy, asymptomatic hyper CKema variants, cardiac involvement in most, mean age death by mid 40s
Increased spectrin and utrophin
Congenital myopathy
Typically onset early in life with hypotonia and weakness, relatively nonprogressive, wide variation in clinical severity within each subtype
Distinctive and specific morphologic abnormalities in skeletal muscle as a main pathological feature
nemaline myopathy
Clinically variable, typical form has proximal weakness, respiratory insufficiency facial weakness, extra ocular sparing
Genetically heterogenous
Nemalin rods and bodies are the key diagnostic feature
Rods can also be found in normal muscle with increasing age, there is no association between rod burden and severity
Thin filament gene is messeed up
Centronuclear myopathy
excessive internalized/centralized nucleation without other evidence of degenerative or regenerative changes
Can be caused by RYR1, MTM1, DNM2, BIN 1, and TTN mutation
These genes (except TTN) are all involved in endocytic trafficking and or excitation/contraction coupling
x linked myotubular myopathy XLMTM
congenital myopathy, incidence 1/50k live born maales, born floppy with severe global muscle weakness, hypotonia, respiratory insufficiency, ophthalmoplegia
50% mortality in first 18 months
Myotonic
most common muscular dystrophy in adults, autosomal dominant, DM1 = dystrophia myotonica type 1
CTG repeat exmansion in DMPK gene on ch 19, normal 5- 34 repeats, full mutation is >50 repeats 35 -49 premutation , genetic anticipation
DM1 clinical
weakness (distal hands and feet–> grip and foot drop, proximal muscles, thin elingated myopathic face, temporal wasting balding and ptosis, GI smooth muscle involvement, endocrine abnormalities (hypogonadism), insulin resistance/diabetes, thyroid disorders, hyperparathyroidism, premature cataracts, cardiac arythmias 90% of pts, less common dilated cardiomyopathy, decreased intelligence
They cant hold a pen longer
metabolic myopathies
Hereditary muscle disorders caused by specific enzymatic defects resulting in abnormalities of muscle energy metabolism
Glycogen storage diseases- hereditary deficiency of enzymes involved in synthesis or breakdown of glycogen
Lipid storage disorders- disorders of fatty acid metabolism, disorders of purine nucleotide metabolism
glycogen storage diseases
3 major subgroups-
hepatic forms
Myopathic forms- exercise intolerance with myalgias, cramps, and intermittent rhabdomyolyisis
Phosphorylase deficiency= type 5 glycogenosis- mcardle disease
Generalized storage- many organs, acid maltas deficieny type 2 glycogenosis= pompe disease, adult onset pompe is primarily myopathic
Generalized glycogen storage diseases
type2= pompe disease,
acid maltase= acid alpha- glucosidase GAA deficiency
Lysosomal enzymes
Classic infantile pompe- glycogen storage in many organs,die in the 1st yr of life from hypertrophic cardiomyopathy
Late onset= after age 1, progressive weakness and respiratory failure, with or without hepatomegaly, cardiomegaly, in kids and juveniles
Muscle biopsy shows vacuolar myopathy with glycogen storage and autophagic features
Diagnosis- GAA enzyme activity in dried blood spot, enzyme replacement therapy-rhGAA
Mitochondrial myopathies
Heterogenous group of disorders caused by mutations in mitochondrial (mt) or nuclear genes involved in oxidative phosphorylation
Multisystem diseases in which clinical or morphological evidence of myopathy not always present
cells contain 100s-1000s copies of mtDNA (encodes 13 subunits of ox phos system, 22 tRNAs and 2 rRNAs( lots of mito proteins encoded by nuclear genes)
Diseases caused by nuclear gene mutations show mendalian inheritance, those caused by mt DNA mutations are sporadic or show maternal inheritance (mtDNA transmitted only from mother to child)
MELAS
Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (oxygen is messed up but not due to vasculature)
MtDNA mutation, mutation codes for tRNA(leu), most common mutation m3243A>G
Criteria of MELAS- stroke like episodes (under 40 non vascular), encephalopathy Seizures or dementia, lactic acidosis or ragged-red fibers
Inflammatory myopathies
Idiopathic inflammatory myopathies- sporadic inclusion body myositis, dermatomyositis, polymyositis
all 3 types feature- feature necrotic/regenerating fibers and inflammation in muscle bx, T cells B cells and macrophages
autoimmune necrotizing myopathies- sparse inflammation
Polymyositis
Clinical- Subacute progressive symmetric proximal weakness, no rash, adult F>M, elevated CK, No or weak association with malignancy (< dermatomyositis), overlap syndromes- association with other autoimmune diseases, SLE MCTD, Sjorgrens systemic sclerosis RA
Inflammatory infliltrates: Predominantly T cells (Cd8+ > CD4+ ) and macrophages, cells are endomysial= surround individual muscle fibers, autoinvasion of non-necrotic fibers
Dermatomyositis
Pathology- microvasculature attacked by complement, perivascular inflammation in perimysium, Primarity B cells and CD4+ plasmacytoid plasma cells
Perifascucular atrophy (and regenerating fibers), punched out fiber)
Steroid induced myopathy
Proximal weakness, high dose, prolonged use of steroids, pathology type 2 B atrophy
Statin myopathy
Statin myopathy, statin myopathy syndromes, myalgias- uncertain mechanism may not be myotoxocity, up to 10-20% in observational studies
Progressive proximal weakness with elevated CK- uncertain incidence, Rhabdomyolysis- incidence .3-1.6 per 10000 pt- with atorvastatin simvastatin, pravastatin, lovastatin, fluvastatin
Trigger necrotizing autoimmune myopathy- HMG CR antibodies, incidence unknown , rare
Clues for the identication of disease class
Dystrophy- presentation after infancy (except in CMD) , and progressive weakness, may have characteristic extramuscular findings, elevated CK characteristic biopsy
Congenital myopathy- presentation in infancy, often including characteristic facies, ophthalmoplegia, and relatively non prgressive weakness, normal CK and characteristic biopsy findings
Nuerogenic- primary (screening tests, EMG, muscle biopsy, Myasthenia - EMG clinical testing)
Metabolic- severe cases usually have extramuscular involvement, less severe causes have exertion- related symptoms
inflammatory- elevated serum inflammatory markers or Abs, imaging characteristic skin findings
PNS
motro autonomic, sensory neurons extending outside CNS, many diseases affect PNS specifically, PNS is able to regenerate unlike CNS
Terminology- Motor unit, axon etc
Vasculitis
Multiple mononeuropathy
Ischemic injury of peripheral nerves, distal sciatic –> foor drop, ulnar in mid arm–> hand weakness, immune mediated diagnosis, by nerve biopsy, inflammation of nerve vascular necrosis
Leprosy
M. leprae, route of transmission is unknown, nasal droplet, infected soil contact with infected, 5-7 y incubation period, bacilli invade nerves and skin–> inflammation and granuloma, 2 forms of disease TB- host mounts t cell response, lepromatous - host is anergic
Grows best in cooler regions of body: skin, nerves, anterior chamber of eye, testes, upper respiratory tract
Hypopigmented lesions - well defined, anesthetic anhidrosis
Nerve enlarged- destruction –> anesthesis–> autoamputation
herpes zoster
VZV reactivtion (dormant in satellite cells, dorsal root gan DRG), VZV travels down axon from dorsal root ganglion –> rash
Pain and sensory loss in dermatomal distribution
Post-herpetic neuralgiain -10%>3 months
Immunosuppressed, elderly
Hereditary Neuropathy CMT
Chacot marie tooth type 1A,
Gradual myelin loss-> 2’ axonal degeneration
duplication or point mutation in PMP22
AD, Demyelinating disease, onset in early mid teens
Longest nerves- Foot drop, inverted champagne bottles, stork legs, tripping, falling, clumsy walk, claw hands, ataxia loss of proprioception, pes cavus, hammer toes
diabetic neuropathy
axonal degeneration- 2’ demyelination
Diabetic polyneuropathy- most common 50% pts, slowly progressive, stocking glove distribution length dependent or distal symmetric, sensory motor but sensory predominant (numbness, tingling, pain> weakness), severe proprioceptive loss of foot drop unusual /late findings
Associated with severity and duration of diabetes
Carpal tunnel syndrome
Median nerve at wrist, pain, numbness, tingling in median distribution, worse at night or when wrist flexed/extended
Tx- wrist splints at night, carpal tunnel release surgery
