Skeletal muscle and peripheral nerve path

Question 1

Normal muscle on H and E

Answer 1

Peripheral nuclei, behive, polyglonal fiber shape

Question 2

Muscle contractions

Answer 2

depolarization down the t tuble, Sarcoplasmic reticulum releases calcium,

Actin and myosin
tropomyosin blocks myosin, tropomyosin has Ca receptors on it

Question 3

Basic pathologic reactions of muscle

Answer 3

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)

Question 4

Degeneration and regeneration of muscle

Answer 4

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

Question 5

myopathic vs neuropathic muscle disease

Answer 5

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

Question 6

Neurogenic chnages in muscle

Answer 6

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

Question 7

ALS

Answer 7

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

Question 8

Spinal muscular atrophy

Answer 8

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

Question 9

Congenital muscle disease

Answer 9

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

Question 10

Dystrophin proteinq

Answer 10

stabilizes act to sarcolemma

Question 11

Duchenne/becker muscular dystrophy

Answer 11

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

Question 12

DMD clinical presentation

Answer 12

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

Question 13

Becker muscular dystrophy

Answer 13

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

Question 14

Congenital myopathy

Answer 14

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

Question 15

nemaline myopathy

Answer 15

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

Question 16

Centronuclear myopathy

Answer 16

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

Question 17

x linked myotubular myopathy XLMTM

Answer 17

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

Question 18

Myotonic

Answer 18

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

Question 19

DM1 clinical

Answer 19

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

Question 20

metabolic myopathies

Answer 20

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

Question 21

glycogen storage diseases

Answer 21

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

Question 22

Generalized glycogen storage diseases

Answer 22

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

Question 23

Mitochondrial myopathies

Answer 23

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)

Question 24

MELAS

Answer 24

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

Question 25

Inflammatory myopathies

Answer 25

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

Question 26

Polymyositis

Answer 26

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

Question 27

Dermatomyositis

Answer 27

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)

Question 28

Steroid induced myopathy

Answer 28

Proximal weakness, high dose, prolonged use of steroids, pathology type 2 B atrophy

Question 29

Statin myopathy

Answer 29

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

Question 30

Clues for the identication of disease class

Answer 30

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

Question 31

PNS

Answer 31

motro autonomic, sensory neurons extending outside CNS, many diseases affect PNS specifically, PNS is able to regenerate unlike CNS

Terminology- Motor unit, axon etc

Question 32

Vasculitis

Answer 32

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

Question 33

Leprosy

Answer 33

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

Question 34

herpes zoster

Answer 34

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

Question 35

Hereditary Neuropathy CMT

Answer 35

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

Question 36

diabetic neuropathy

Answer 36

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

Question 37

Carpal tunnel syndrome

Answer 37

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