Chapter 27: Diseases of the NMJ and Skeletal Muscle

Question 1

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

Answer 1

Chloroquine and hydroxychloroquine

Question 2

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

Answer 2

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

Question 3

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

Answer 3

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

Question 4

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

Answer 4

Dermatomyositis

Question 5

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

Answer 5

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

Question 6

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

Answer 6

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

Question 7

Which syndrome due to deletions or duplications in mtDNA is characterized by ophthalmoplegia, pigmentary degeneration of the retina, and complete heart block?

Answer 7

Kearns-Sayre syndrome

Question 8

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

Answer 8

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

Question 9

Clusters or groups of atrophic skeletal muscle fibers are seen in which disorders?

Answer 9

Neurogenic diseases

Question 10

How does Myotonic Dystrophy present signs and sx’s?

Answer 10

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

Question 11

Point mutations in mtDNA can lead to which two mitochondrial myopathies?

Answer 11

• Myoclonic epilepsy w/ ragged red fibers
• Leber hereditary optic neuropathy

Question 12

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

Answer 12

↑↑↑ CK

Question 13

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

Answer 13

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

Question 14

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

Answer 14

Malignancy; most often small-cell carcinoma of lung

Question 15

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

Answer 15

Myopathy preferentially involving respiratory and truncal muscles

Question 16

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

Answer 16

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

Question 17

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

Answer 17

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

Question 18

Myotonic dystrophy is caused by what?

Answer 18

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

Question 19

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

Answer 19

• 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 20

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

Answer 20

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

Question 21

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

Answer 21

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

Question 22

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

Answer 22

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

Question 23

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

Answer 23

Weakness of the extremities and autonomic dysfunction

Question 24

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

Answer 24

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

Question 25

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

Answer 25

**Juvenile Dermatomyositis**; average age **7 y/o**

Question 26

Missense mutations in CACNA1S (subunit of muscle Ca²⁺ channel) are the most common cause of what?

Answer 26

**Hypokalmemic** paralysis

Question 27

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

Answer 27

- **_Episodic_** muscle damage with **exercise** and **fasting** - **Defect** in transport of **FFAs** ---\> **mitochondria**

Question 28

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

Answer 28

**Calcinosis** and **lipodystrophy**; have a _better_ prognosis

Question 29

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 29

- **Weakness** + ↑ **C****K**or**rhabdomyolysis** - **Extraocular muscle involvement** = common and _clue_ to dx - **Chronic progressive external opthalmoplegia** = _common feature_

Question 30

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

Answer 30

- _Slowly_ progressive muscle weakness **_most_** severe in **quadriceps** and **_distal_ upper extremities**; _asymmetric_ - **Dysphagia** is not uncommon

Question 31

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

Answer 31

- _**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 32

RYR1 mutations are associated with what?

Answer 32

**Malignant hyperthermia** --\> _**hypermetabolic state**:_ tachycardia + tachypnea + muscle spasms and later **hyperpyrexia**

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

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

Answer 34

**Corticosteroids**

Question 35

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

Answer 35

- **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 36

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

Answer 36

**Thymic abnormalities**: **Thymoma** and **Thymic hyperplasia**

Question 37

Ullrich congenital muscular dystophy (UCMD) is due to mutations in what; what is a morphological hallmark?

Answer 37

- Mutations in one of thre **collagen VI alpha genes** - **Hallmark**: mismatched expression of normally co-localized matrix proteins **perlecan** and **collagen VI**

Question 38

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

Answer 38

- **RNA** and stain **basophilic** - **Enlarged nuclei** and _prominent_ **nucleoli**

Question 39

What is the triad of findings seen with Emery-Dreifuss Muscular Dystrophy?

Answer 39

1) _Slowly_ progressive **humeroperoneal** weakness 2) **Cardiomyopathy** w/ _conduction_ defects 3) **Early contractures** of the **achilles**, **spine**, and **elbows**

Question 40

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

Answer 40

**Anti-Jo1** antibodies

Question 41

When does Inclusion Body Myositis typically present?

Answer 41

- Disease of **late adulthood**; typically **\>50 y/o** - **_Most common_** cause of **inflammatory myopathy** in pt's **\>65 y/o**

Question 42

Myastheina Gravis is associated with autoantibodies against what?

Answer 42

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

Question 43

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

Answer 43

**Large zones** of _severely_ **atrophic** myofibers _mixed_ with scattered _normal sized_ fibers or _hypertrophied_ myofibers, found individually or in small groups

Question 44

Emery-Dreifuss Muscular Dystrophy is due to mutations in genes that encode what and what is the inheritance of EMD1 and EMD2?

Answer 44

- Genes that encode **nuclear _lamina_ proteins** - **X-linked** = **EMD1** - **Autosomal dominant** = **EMD2**

Question 45

Disorders of NMJs present with what?

Answer 45

**_Painless_** muscle **weakness**

Question 46

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

Answer 46

**Prolonged corticosteroid therapy** or **disuse**

Question 47

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

Answer 47

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

Question 48

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

Answer 48

**Anti-P155/P140** antibodies

Question 49

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

Answer 49

**Anti-Mi2** antibodies