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

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

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

Answer 17

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

Question 18

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

Answer 18

• 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 19

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

Answer 19

Juvenile Dermatomyositis; average age 7 y/o

Question 20

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

Answer 20

Calcinosis and lipodystrophy; have a better prognosis

Question 21

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

Answer 21

• 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 22

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

Answer 22

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

Question 23

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

Answer 23

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

Question 24

When does Inclusion Body Myositis typically present?

Answer 24

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

Question 25

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

Answer 25

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

Question 26

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

Answer 26

- Abnormal cytoplasmic inclusions, **_"rimmed vacuoles"_** - **Tubulofilamentous** **inclusions** in **myofibers** - Cytoplasmic inclusions containing **beta-amyloid**, **TDP-43**, and **ubiquitin** - **Endomysial fibrosis** and **fatty replacement**

Question 27

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

Answer 27

**Corticosteroids**

Question 28

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

Answer 28

**Chloroquine** and **hydroxychloroquine**

Question 29

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

Answer 29

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

Question 30

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

Answer 30

- **Duchenne**: deletions _or_ frame shift mutations --\> **total absence** - **Becker**: synthesis of a _truncated_ version, which retains some function

Question 31

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

Answer 31

- **Duchenne**: absence of _normal_ **sarcolemmal** staining pattern - **Becker**: shows _reduced_ staining

Question 32

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

Answer 32

**Muscle tissue** is _replaced_ by **collagen** and **fat cells** = **Fatty replacement** or **change"**

Question 33

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

Answer 33

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

Question 34

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

Answer 34

↑↑↑ **CK**

Question 35

What is a key feature of Myotonic Dystrophy?

Answer 35

**Myotonia**: sustained involuntary contraction of a group of muscles; can be elicited by **_percussion on thenar eminence_**

Question 36

Myotonic dystrophy is caused by what?

Answer 36

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

Question 37

How does Myotonic Dystrophy present signs and sx's?

Answer 37

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

Question 38

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

Answer 38

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

Question 39

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

Answer 39

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

Question 40

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

Answer 40

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

Question 41

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

Answer 41

Myopathy preferentially involving **respiratory** and **truncal** muscles

Question 42

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 42

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

Question 43

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

Answer 43

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

Question 44

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

Answer 44

**Kearns-Sayre syndrome**

Question 45

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

Answer 45

- **Myoclonic epilepsy** w/ **ragged red fibers** - **Leber hereditary optic neuropathy**

Question 46

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

Answer 46

- 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 47

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

Answer 47

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

Question 48

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

Answer 48

**Hypokalmemic** paralysis

Question 49

RYR1 mutations are associated with what?

Answer 49

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