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Flashcards in P- Neuromuscular Pathology Deck (47):

What are skeletal muscle cells composed of?

The cytoplasm of a myofiber has myofilaments arranged in myofibrils.

Myofibrils are arranged as units of sarcomeres flanked by Z-bands running perpendicular.


What are the major contractile proteins of muscle?
Which make up the think filaments?

Actin = thin filaments
Myosin = thick filaments


Actin thin filament is attached to the __________ and appear as light staining _________.
The Myosin thick filaments are located at the _____________ and partially overlap with actin to form the darker staining ____________.

Actine attaches to the Z-band and appears as light staining I bands

Myosin is located at the center region of the sarcomere and partially overlaps with actin to make the A band


What stimulates muscles to contract? What occurs when the stimulus is received?

1. Motor neuron propogates an AP
2. depolarization of the sarcolema
3. T-tubule --> Ca release from SR
4. Ryanadine receptor
5. exposed Ca binds site on actin
6. myosin head binds sites on actin

The process depends on ATP for energy and controlled ion fluxes [local calcium release and reuptake]


Normal contractile activity of muscle requires the physical interaction between what 3 things?

What protein plays a critical role in the interaction of these three components?

1. contractile proteins
2. muscle fiber membrane [sarcolemma]
3. extracellular connective tissue

Dystrophin [a large membrane associated protein] binds actin on one side and B,A dystophin complex on the other side which attaches to laminin a2 in the basal lamina of the muscle fiber.


What are type 1 and type 2 myofibers?

Type 1 = slow twitch = oxidative enzymes, mitochondria, lipids

Type 2 = fast twitch = glycogen, glycolytic pathway enzymes, fewer mitochondria/fat stores


What determines the metabolic profile of a myofiber?

The spinal motor neuron that innervates it


How does muscle biopsy handling differ from what is used in most biopsy specimen?

1. stains must be done on frozen skeletal muscle
2. stains must be done very shortly after the biopsy is taken

-frozen tissue allows for the evaluation of the activities of various enzymes within the muscle

**tell the pathologist you are taking a muscle biopsy before it is obtained so they can be prepared to work quickly


What 4 muscles do you want to take most biopsies from?

What 2 kinds of muscle should you AVOID taking biopsy from?

1. quads
2 deltoid
3. biceps
4. gastrocnemius

Avoid taking biopsy from
1. "end-stage" muscle because they will be less likely to yield useful info about the CAUSE of the underlying problem
2. muscle that has been used for injection or needle electrode placement


What are the 2 broad categories of muscle disorders?

1. skeletal muscle fiber atrophy
-type 2
2. presence of an intrinsic muscle abnormality [myopathy]


What is the most important stain when looking for type 2 myofiber atrophy?

myosin ATPase


What will the stain look like for type 2 muscle atrophy?
What are the 2 major underlying causes of type 2 muscle atrophy?

There will be randomly distributed angular atrophic fibers that all stain with ATPase [all the dark fibers].

1. disuse atrophy [when you work out, type 2 get bigger, when you don't they get smaller]
2. glucocorticoid levels are elevated [exogenous from treatment or endogenous with Cushing]


You do a muscle biopsy and note:
1. angular, atrophic fibers of type 1 and type 2
2. increased activity of enzymes like esterase
3. clusters of contiguous atrophic fibers [group atrophy]
4. fiber type grouping

What is the likely problem?

Denervating atophy that has regained its nerve supply.

Denervating and NOT type 2 because of the grouping, both 1 and 2 involvement

You know it is re-innervated because of the fiber type grouping


What is fiber type grouping?

when a denervated muscle regains nerve supply, regenerating axonal processes derived from a common LMN attach to contiguous fibers.
Instead of a mosaic of type 1 and type 2, all the fibers will then adopt the metabolic profile determined by the axon that re-innervated it


What are the 3 major disorders of the motor unit that can cause denervation atrophy in skeletal muscle?

1. peripheral nerve disorders
2. anterior spinal nerve roots
3. lower motor neurons in spinal cord or brainstem

**** NMJ disorders do NOT cause dennervation atrophy


Describe amyotrophic lateral sclerosis.

ALS is a degenerative disorder marked by the loss of UMN: spasticity due to sclerotic lateral columns
and LMN: weakness
The patient will experience progressive weakness and eventual death due to respiratory compromise.


Describe infantile spinal muscular atrophy [SMA1, Werdnig-Hoffman]
What gene is mutated?
What is the inheritance pattern?
How does the baby present?
What would a muscle biopsy show?

It is a mutation of SMN1 [survival motor neuron 1] and is an autosomal recessive disorder.

Baby is floppy [neonatal hypotonia] and respiratory compromise

Muscle biopsy shows:
1. atrophic fibers mixed with normal/hypertrophic fibers
2. rounded small fibers [not angular like adult form]
3. involvement of type 1 and 2 fibers


What exactly is a myopathy?
What are the 5 types?

Myopathy is a primary disease of skeletal muscle [not due to disuse or innervation]

1. inflammatory myopathy
2. toxic myopathy
3. muscular dystrophy
4. congenital myopathy
5. metabolic myopathy


What are the 2 major types of inflammatory myopathy?

1. polymyositis
2. dermatomyositis


What is the main cause of toxic myopathy?



What are the 2 main muscular dystrophies?

1. Duchenne
2. Becker


Why is it really important for a physician to differentiate inflammatory myopathies from dystrophies, metabolic disorders, etc?

Because they can be successfully treated with immunosuppressive agents


How do polymyositis and dermatomyositis differ in terms of:
1. cause of inflammation
2. age group affected
3. presentation
4. pathologic hallmarks

1. Polymyositis = cell-mediated attack of skeletal muscle
dermatomyositis = antibody-mediated injury of small blood vessels

2. Polymositis = adults
Dermatomyositis = children AND adults

3. Poly = acute/subacute progression of weakness in proximal muscles, swelling/pain, elevated CK, aldolase
Dermato = muscle weakness, skin rash. In children, ischemic bowel. In adults, underlying visceral malignancy

4. Poly = lymphocytic[CD8] infiltrate in the endomysium between myofibers/invading myofibers

Dermato = selective atrophy of periphery of muscle fascicles [perifasicular atrophy], inflammatory infiltrates around fascicles [perimysial], EM shows endothelial cells with tuboreticular inclusions


Describe the histology seen with polymyositis.

1. lymphocytic [CD8] infiltrates in the endomysial space (between muscle fiber)
2. lymphocytic invasion of viable myofiber [must be differentiated from macrophage invasion of necrotic fiber]


In the childhood form of dermatomyositis, a devastating complication is that they can get ___________________.

In adults, there is a well-documented relationship between dermatomyositis and what?

Children = ischemic injury to the bowel/visceral organs

Adults = associated with visceral malignancies [like GI carcinomas]


Describe the histology of dermatomyositis.

1. perifascicular atrophy - selective atrophy at the periphery of the muscle fiber
2. inflammatory infiltrate are pronounced in the connective tissue around the muscle fascicle [not between individual fibers like polymoysitis]
3. EM will show endothelial cells that have tubuloreticular inclusions


An elderly man presents with weakness and atrophy that is most pronounced in his quads and finger flexors. His CK level is elevated.

What condition are you considering?
What would you see on biopsy?

Inclusion-body myositis

Biopsy shows lymphocytic infiltrate in the endomysium [like polymyositis] except inclusion-body myositis does NOT respond to immunosuppression like poly


What is the effect of excess corticosteroids on muscle?

Corticosteroids ---> type 2 atrophy

Statins[HMG-Coa Reductase inhibitor] --> muscle fiber degeneration, necrosis and regeneration


What cause most/all muscular dystophies?

Genetic mutations in genes encoding intrinsic muscle proteins [particularly those that form or stabilize the cytoskeleton and cell membrane of the muscle fiber


What is the inheritance pattern of Becker and Duchenne muscular dystrophy?
What gene is mutated?

It is X-linked caused by a mutation in the dystrophin gene which encodes the structural protein dystrophin which links actin in the sarcomere to the ECM and stabilizes the myofiber membrane during contraction

Dystrophin is found in: cardiac and smooth muscle, retina, brain, leukocytes and lymphocytes


What is the incidence of Duchenne muscular dystrophy?
What specific genetic mutation is associated with it?
What is the pathophysiology?

It is in 1/3500 live male births
It is an abnormal stop codon that disrupts the reading frame of the dystrophin gene and prevents expression of ALL skeletal muscle dystrophin.

Absence of dystrophin destabilizes the membrane of muscle fibers and results in progressive degeneration and necrosis of myofibers. Muscle is replaced by connective tissue.


What is the presentation of Duchenne muscular dystophy?

1. high CK levels early in life
2. Muscle milestones are delayed
3. develop weakness from proximal to distal muscles
4. wheelchair bound by age 12.
5. cardiac abnormalities [rhythm, conduction, ventricular failure]
6. cognitive impairment
7. death in the 20s due to respiratory insufficiency


Describe what is seen on muscle biopsy for someone with Duchenne's muscular dystrophy.

1. degenerating and regenerating fibers
2. muscle fiber hypertrophy
3. increased connective tissue [collagen & adipose]

Immunohistochemical staining shows complete lack of dystrophin in cell membranes of all muscle fibers


What is the mutation associated with Becker dystrophy?

X-linked mutation that allows dystrophin transcription but the resultant protein is:
1. abnormal configuration
2. transcribed in low amounts


Describe how the presentation of Becker dystrophy differs from Duchenne.

Becker still has small amounts of dystrophin so the progression is slower and the patient will present later [usually around 12, when Duchenne patients are already wheelchair bound].

Both Becker and Duchenne have cardiac problems and cognitive impairment


Describe the muscle biopsy of a patient with Becker dystrophy.

1. myofiber atrophy
2. necrosis and regeneration
3. chronic myopathic change [muscle hypertrophy, connective tissue increase]

Immunohistochemical staining shows dystophin activity in the surviving fibers thought weak and irregular compared to normal muscle fiber


What is congenital myopathy?
What is the cause of most?
How does the presentation compare to muscular dystophies?

Congenital myopathies are defined by the presence of specific histological abnormalities.
The cause of most is hereditary with AD, AR, and X linked patterns all reported.

In general, muscle fiber injury is much less conspicuous for congenital myopathies than for muscular dystophies.


What is the inheritance pattern of central core disease?
What does the mutation cause?

It is autosomal dominant mutation in the gene encoding ryanodine receptors [in the membrane of the SR that plays a role in the regulation of Ca flux and excitation-contraction coupling].


What is seen morphologically for central core disease?

1. Central zone of pallor in muscle fibers that are best seen with stains for mitochondrial and oxidative enzymes

2. little to no muscle fiber destruction


All patients with central core disease should be considered at increased risk for what?

malignant hyperthermia


A patient presents with a history of motor delay and non-progressive weakness that is most pronounced in the pelvic girdle. On biopsy, you note that muscle fibers have central zones of pallor. What drugs should not be given to this patient and why?

Anesthetic agents can provoke malignant hyperthermia where the patient develops hypermetabolic state followed by dramatic elevation of core temp.


What are the 2 main groups of metabolic myopathies?

1. glycogen storage disorders [glycogenoses]
2. lipid myopathies
3. mitochondrial myopathies


What mutation is present in McArdle's disease?
What is the inheritance pattern?
How will the patient present?

It is an autosomal recessive mutation in muscle glycogen phosphorylase.

The absence of this myophosphorylase decreases the amount of energy available to the myofiber via glycolytic pathways.

The patient will present with exercise-induced muscle cramps and weakness [rhabdomyolysis and myoglobinuria may occur]


Describe the appearance of McArdle's disease on muscle biopsy.

Normal on H&E but myofibers contain increase in free glycogen due to the absence of the enzyme to break down glycogen


How does the inheritance pattern differ for mitochondrial myopathies caused by mutations in mitochondrial DNA vs. nuclear DNA?

Mitochondrial DNA = maternal pattern

Nuclear = autosomal dominant or recessive


What are the cardinal features of mitochondrial myopathies on muscle biopsy?

mitochondrial aggregates in affected myofibers-"ragged red fibers"


In addition to muscle, what other tissue are affected by mitochondrial mutations?

1. liver
2. heart
3, inner ear
4. central nervous system