#80 Neuromuscular Junction Dysfunction

Question 1

Mechanism in myasthenia gravis

Answer 1

Auto-antibodies bind to and destroy the acetylcholine receptor on the muscle plate
NOTE: ab’s can also target other proteins, but it is rare.

Question 2

2 factors that explain the fatigable nature of weakness in myasthenia gravis

Answer 2

1) decreased Ach release with successive motor nerve action potentials in normal mm
2) loss of safety factor due to lost receptors.

Question 3

What are the main 2 pre-synaptic neuromuscular junction disorders?

Answer 3

Lambert-Eaton myasthenic syndrome
AND
botulism

Question 4

T/F - pre-synaptic neuromuscular junction diseases are fatigable

Answer 4

False! THey are the opposite - may be improved by exercise

Question 5

Why do pre-synaptic neuromuscular junction disorder symptoms improve with exercise?

Answer 5

Rapid motor nerve firing results in calcium accumulation in the axon terminal and increased ACh release

Question 6

2 causes of cholinesterase deficiency, leading to excess ACh in the NMJ

Answer 6

acquired - organophosphate/ drug toxicity

hereditary- COLQ mutations

Question 7

Main symptoms of acquired cholinesterase deficiency

Answer 7

musle twitching and cramping due to muscle hyperexcitability.

Question 8

Main symptoms of long term (hereditary) cholinesterase deficiency.

Answer 8

muscle weakness.

Question 9

symptoms of myasthenia gravis

Answer 9

-limited mvmt of eyes, 
weakness of grip
-cannot raise herself in bed
-fatigable weakness
-asymmetric effects
-difficulty talking.

Question 10

reflexes in myasthenia gravis

Answer 10

depressed to absent

Question 11

basic process by which vesicles of ACh is released and triggers end plate potential.

Answer 11

ACh binds receptors, receptors allow Na to enter/ depolarize muscle
cell

Question 12

Which 3 proteins mediate ACh vesicle docking/release?

Answer 12

SNARE Proteins

• synaptobrevin
• SNAP-25
• Syntaxin

Question 13

Case - 15 year old girl, for two months, she had trouble playing the clarinet, and speaking (better with rest)
For the last 3 days, her eye has been dropping, double vision when she looks to one side, and choking and coughing on food.

Answer 13

Classic case of Myasthenia Gravis.

Question 14

Clinical presentation of myasthenia gravis - 4 characteristics

Answer 14

-often asymmetric
-fatigable weakness
-ocular, bulbar, facial mm most affected, as well as proximal limbs
-respiratory failure (is a major
cause of mortality)

Question 15

3 mechanisms by which antibodies mess up the NM junction in myasthenia gravis

Answer 15

1- bind to AChReceptors, disturbing function
2-Cross linking of AChRs –> endocytosis and degradation

3- Complement mediated damage to muscle endplate –> loss of junctional folds.

Question 16

What are useful diagnostic tests for myasthenia gravis?

Answer 16

1-put icepack on affected muscle OR inject tensilon - these should improve function by inhibiting AchEsterase

2- Antibody studies
3-Nerve stimulation - shows decremental response.

Question 17

Treatment for myasthenia gravis

Answer 17

1- Pyridostigmine (ACh inhibitor)

2- IVIG or plasmapheresis - removes/dilutes the antibodies

3 - immunosuppression

4-Thymectomy - T cells contribute to pathogenesis

Question 18

2 types of myasthenic syndromes that present in infants

Answer 18

1- congenital myasthenia gravis - not severe, passes after mom’s ab’s are gone

2- congenital myasthenic syndromes - mutations in genes coding MNJ components - Rare but severe

Question 19

Case - 67 yo female. Bilateral leg weakness, gets BETTER with exercise, speech slurred, double vision, 20 lb weight loss. Diagnosis??

Answer 19

Lambert-Eaton syndrome!

Question 20

Clinical characteristics of Lambert Eaton Myasthenic Syndrome (LEMS)

Answer 20

• symmetric muscle weakness, better w/ exercise
• absent reflexes which become present after exercise
• paraneoplastic syndrome - 50% of patients with LEMS have cancer!

Question 21

pathophysiology of LEMS Lambert Eaton Myasthenic Syndrome

Answer 21

antibodies target voltage gated calcium channels on the pre-synaptic neuron. Decreased Ca influx–> decreased ACh released–> no end plate potential.

Question 22

How fast does muscle have to fire to build up calcium in LEMS?

Answer 22

faster than 10 Hz –> Ca accumulation in muscle

Question 23

Treatment for LEMS (Lambert Eaton Myasthenic Syndrome )

Answer 23

*** Treat underlying malignancy!! Many times, this will cure the disease.

1- Pyridostigmine - acetylcholinesterase inhibitor

2- 3,4 DAP - acts on K channels to lengthen depolarization –> increase calcium influx.

3- Immunosuppression

Question 24

Case - baby was fine until 2 days ago. Then stopped pooping, very weak in all limbs, pupils dilated, not reacting to light. Eyelids drooping equally. Diagnosis?

Answer 24

Botulinum toxin

Question 25

Pathophysiology of botulinum poisoning

Answer 25

TLDR - cleaves SNARE Proteins

Botulism toxin arrives in the pre-synaptic neuron by binding receptors. Once inside, it splits and the light chain cleaves snare proteins!! having an irreversible effect. To heal, one must regenerate axon terminals.

Question 26

Diagnosis of botulism

Answer 26

• stool culture and toxin detection

- electrodiagnostic testing

Question 27

Treatment of botulism

Answer 27

Supportive care - ventilation and tube feeding.

Infants - IVIG
Foodborne - Antitoxin

Question 28

pathophysiology of COLQ mutation

Answer 28

Collagen Q anchors AchEsterase in the junction.

mutation –> deficiency of AChesterase in the NM junction. Long term excess ACh causes weakness

Question 29

Case: Old man, rapid onset muscle twitching/cramping, bradycardia, hypotension, peed his pants. He is a farmer and was spraying pesticides earlier today. Diagnosis?

Answer 29

Organophosphate poisoning.

Question 30

Pathophysiology of organophosphate poisoning.

Answer 30

It hangs around in synapses and inhibits ACh esterase, leading to excess ACh