Chapter 27: Diseases of the NMJ and Skeletal Muscle

Question 1

Disorders of NMJs present with what?

Answer 1

Painless muscle weakness

Question 2

Myastheina Gravis is associated with autoantibodies against what?

Answer 2

• ACh receptors on post-synaptic membrane (85% cases)
• Muscle-specific receptor tyrosine kinase (15%)

Question 3

There is a strong association with tht AChR autoantibodies seen in Myathenia Gravis and which abnormalities?

Answer 3

Thymic abnormalities: Thymoma and Thymic hyperplasia

Question 4

Myasthenia gravis patients with AChR autoantibodies usually present with what signs/sx’s?

Answer 4

• Fluctuating weakness that worsens with exertion and over course of day
• Diplopia** and **ptosis due to involvement of extra-ocular muscles

Question 5

What electrophysiologic findings help distinguish Myasthenia Gravis and Lambert-Eaton Myasthenic Syndrome?

Answer 5

• M.G. = Diminished muscle responses after repeated stimulation
• L.E.M.S = Increased muscle response after repeated stimulation

Question 6

What is 1st line tx for Myasthenia Gravis and what other tx’s can be used to control the sx’s?

Answer 6

• 1st line = Acetylcholinesterase inhibitors
• Plasmapheresis and immunosuppressives (glucocorticoids, cyclosporine, rituximab) –> ↓ autoAb titers

Question 7

Lambert-Eaton Myasthenic Syndrome is an autoimmune disorder due to what?

Answer 7

Antibodies block ACh release by inhibiting pre-synaptic Ca²⁺ channel

Question 8

50% of Lambert-Eaton Myasthenic Syndrome cases are associated with what underlying condition?

Answer 8

Malignancy; most often small-cell carcinoma of lung

Question 9

Pt’s with Lambert-Eaton Myasthenic Syndrome typically present with what sx’s?

Answer 9

Weakness of the extremities and autonomic dysfunction

Question 10

Type II fiber atrophy with sparing of type I fibers is seen with what?

Answer 10

Prolonged corticosteroid therapy or disuse

Question 11

Regenerating myofibers are rich in what and stain how in H&E stained sections; characteristic nuclei and nucleoli that are seen?

Answer 11

• RNA and stain basophilic
• Enlarged nuclei and prominent nucleoli

Question 12

Which autoantibody type in Dermatomyositis is associated with prominent Gottron papules and heliotrope rash?

Answer 12

Anti-Mi2 antibodies

Question 13

Which autoantibody type in Dermatomyositis is associated with interstitial lung disease, non-erosive arthritis, and a rash known as “mechanic’s hands?”

Answer 13

Anti-Jo1 antibodies

Question 14

Which autoantibody type in Dermatomyositis is associated with paraneoplastic and juvenile cases?

Answer 14

Anti-P155/P140 antibodies

Question 15

Myofiber atrophy accentuated at the periphery of fascicles known as perfascicular atrophy is seen with what disorder?

Answer 15

Dermatomyositis

Question 16

Biopsies and immunohistochemical studies of muscle and skin in Dermatomyositis will show deposition of what?

Answer 16

Complement MAC (C5b-9) within capillary beds + infiltrate rich in CD4+ T helper cells

Question 17

What are the signs and sx’s of dermatomyositis and some complications which may be seen?

Answer 17

• Slow onset symmetric muscle weakness often w/ myalgias affecting the proximal ms. 1st
• 10% of pt’s have dysphagia and another 10% with interstitial lung disease —> can cause death
• Cardiac involvement = common, rarely leads to failure

Question 18

What is the most common inflammatory myopathy in children and average age of onset?

Answer 18

Juvenile Dermatomyositis; average age 7 y/o

Question 19

Juvenile Dermatomyositis is more likely to have what findings compared to the adult-type; how does this affect prognosis?

Answer 19

Calcinosis and lipodystrophy; have a better prognosis

Question 20

Various rashes have been described in Dermatomyositis, but which 2 are the most characteristic?

Answer 20

• Heliotrope rash: Lilac colored discoloration of upper eyelids assoc. w/ periorbital edema
• Gottron papules: scaling erythematous eruption or dusky patches over knuckles, elbows and knees

Question 21

Which inflammatory myopathy is more associated with perimysial infiltration vs. endomysial infilatration?

Answer 21

• Dermatomyositis = perimysial (CD4+ T cells)
• Polymyositis and Inclusion body myositis = endomysial (CD8+ T cells)

Question 22

When is the onset of Polymyositis and what are the signs/sx’s; how is it distinguished from Dermatomyositis?

Answer 22

• Adult onset w/ myalgia and weakness; NO cutaneous features
• Symmetrical proximal muscle involvement

Question 23

When does Inclusion Body Myositis typically present?

Answer 23

• Disease of late adulthood; typically >50 y/o
• Most common cause of inflammatory myopathy in pt’s >65 y/o

Question 24

What are the typical signs/sx’s of Inclusion Body Myositis?

Answer 24

• Slowly progressive muscle weakness most severe in quadriceps and distal upper extremities; asymmetric
• Dysphagia is not uncommon

Question 25

What are 4 morphological changes that are specific for Inclusion Body Myositis?

Answer 25

• Abnormal cytoplasmic inclusions, “rimmed vacuoles”
• Tubulofilamentous inclusions in myofibers
• Cytoplasmic inclusions containing beta-amyloid, TDP-43, and ubiquitin
• Endomysial fibrosis and fatty replacement

Question 26

What is the first-line tx for inflammatory myopathies (i.e., dermatomyositis and polymyositis)?

Answer 26

Corticosteroids

Question 27

Which drugs are associated with slowly progressive muscle weakness which predominantly affects type I fibers?

Answer 27

Chloroquine and hydroxychloroquine

Question 28

How do the type of mutations of Dystrophin differ between Duchenne and Becker muscular dystrophy?

Answer 28

• Duchenne: deletions or frame shift mutations –> total absence
• Becker: synthesis of a truncated version, which retains some function

Question 29

What will immunohistochemical staining for dystrophin show in Duchenne vs. Becker muscular dystrophy?

Answer 29

• Duchenne: absence of normal sarcolemmal staining pattern
• Becker: shows reduced staining

Question 30

What morphological changes are seen with disease progression in Duchenne and Becker muscular dystrophy?

Answer 30

Muscle tissue is replaced by collagen and fat cells = Fatty replacement or change”

Question 31

Where does weakness associated with Duchenne muscular dystrophy begin and how does it progress?

Answer 31

• Begins in pelvic girdles —> extends to shoulder girdles
• Pseudohypertrophy of calves often present
• Wheel-chair bound around age 9.5

Question 32

Which lab value can aid in the diagnosis of Duchenne and Becker muscular dystrophy?↑↑

Answer 32

↑↑↑ CK

Question 33

What is a key feature of Myotonic Dystrophy?

Answer 33

Myotonia: sustained involuntary contraction of a group of muscles; can be elicited by percussion on thenar eminence

Question 34

Myotonic dystrophy is caused by what?

Answer 34

Expansions of CTG triplet repeats in 3’-noncoding region of DMPK gene

Question 35

How does Myotonic Dystrophy present signs and sx’s?

Answer 35

Gait, then atrophy of facial muscles = ptosis and “hatchet face,” frontal balding, cataracts, cardiomyopathy

Question 36

Carnitine palmitoyltransferase II deficiency is associated with what pattern of muscle damage?

Answer 36

• Episodic muscle damage with exercise and fasting
• Defect in transport of FFAs —> mitochondria

Question 37

Milder deficiencies of acid maltase lead to what type of myopathy in adults?

Answer 37

Myopathy preferentially involving respiratory and truncal muscles

Question 38

Skeletal muscle involvement in Mitochondrial Myopathies can manifest with what findings; involvement of what is common and can be a clue to the diagnosis?

Answer 38

• Weakness + ↑ CKorrhabdomyolysis
• Extraocular muscle involvement = common and clue to dx
• Chronic progressive external opthalmoplegia = common feature

Question 39

Morphologically what is the most consistent pathologic change seen in skeletal muscle of the Mitochondrial Myopathies; which stain can be used?

Answer 39

• Abnormal aggregates of mitochondria under the sarcolemma producing appearance of “ragged red fibers”
• Trimchrome stain*

Question 40

Wernig-Hoffman (SMA type 1) is due to destruction of what and what is the presentation?

Answer 40

• Destruction of anterior horn cells in the spinal cord
• Onset at birth, floppy baby, death <3 yo
• Muscle weakness of truncal and extremity ms. initially; followed by chewing, swallowing and breathing difficulties

Question 41

What are the characteristic morphological changes seen with Spinal Muscular Atrophy (SMA)?

Answer 41

Large zones of severely atrophic myofibers mixed with scattered normal sized fibers or hypertrophied myofibers, found individually or in small groups

Question 42

RYR1 mutations are associated with what?

Answer 42

Malignant hyperthermia –> hypermetabolic state: tachycardia + tachypnea + muscle spasms and later hyperpyrexia