Martin: 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

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

Answer 11

Neurogenic diseases

Question 12

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

Answer 12

• RNA and stain basophilic
• Enlarged nuclei and prominent nucleoli

Question 13

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

Answer 13

Anti-Mi2 antibodies

Question 14

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

Answer 14

Anti-Jo1 antibodies

Question 15

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

Answer 15

Anti-P155/P140 antibodies

Question 16

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

Answer 16

Dermatomyositis

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

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 37

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

Question 38

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

Answer 38

- _Abnormal_ aggregates of **mitochondria** under the sarcolemma producing appearance of **"ragged red fibers"** - **Trimchrome stain\***

Question 39

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

Answer 39

- 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 40

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

Answer 40

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

Question 41

RYR1 mutations are associated with what?

Answer 41

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

Question 42

What disease has the triad of **humeroperoneal** weakness, **cardiomyopathy**, and early **contracture** of the Achilles' tendon?

Answer 42

Question 43

Answer 43

Limb-Girdle MD