#80 Neuromuscular Junction Dysfunction Flashcards
Mechanism in myasthenia gravis
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.
2 factors that explain the fatigable nature of weakness in myasthenia gravis
1) decreased Ach release with successive motor nerve action potentials in normal mm
2) loss of safety factor due to lost receptors.
What are the main 2 pre-synaptic neuromuscular junction disorders?
Lambert-Eaton myasthenic syndrome
AND
botulism
T/F - pre-synaptic neuromuscular junction diseases are fatigable
False! THey are the opposite - may be improved by exercise
Why do pre-synaptic neuromuscular junction disorder symptoms improve with exercise?
Rapid motor nerve firing results in calcium accumulation in the axon terminal and increased ACh release
2 causes of cholinesterase deficiency, leading to excess ACh in the NMJ
acquired - organophosphate/ drug toxicity
hereditary- COLQ mutations
Main symptoms of acquired cholinesterase deficiency
musle twitching and cramping due to muscle hyperexcitability.
Main symptoms of long term (hereditary) cholinesterase deficiency.
muscle weakness.
symptoms of myasthenia gravis
-limited mvmt of eyes, weakness of grip -cannot raise herself in bed -fatigable weakness -asymmetric effects -difficulty talking.
reflexes in myasthenia gravis
depressed to absent
basic process by which vesicles of ACh is released and triggers end plate potential.
ACh binds receptors, receptors allow Na to enter/ depolarize muscle
cell
Which 3 proteins mediate ACh vesicle docking/release?
SNARE Proteins
- synaptobrevin
- SNAP-25
- Syntaxin
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.
Classic case of Myasthenia Gravis.
Clinical presentation of myasthenia gravis - 4 characteristics
-often asymmetric
-fatigable weakness
-ocular, bulbar, facial mm most affected, as well as proximal limbs
-respiratory failure (is a major
cause of mortality)
3 mechanisms by which antibodies mess up the NM junction in myasthenia gravis
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.
What are useful diagnostic tests for myasthenia gravis?
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.
Treatment for myasthenia gravis
1- Pyridostigmine (ACh inhibitor)
2- IVIG or plasmapheresis - removes/dilutes the antibodies
3 - immunosuppression
4-Thymectomy - T cells contribute to pathogenesis
2 types of myasthenic syndromes that present in infants
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
Case - 67 yo female. Bilateral leg weakness, gets BETTER with exercise, speech slurred, double vision, 20 lb weight loss. Diagnosis??
Lambert-Eaton syndrome!
Clinical characteristics of Lambert Eaton Myasthenic Syndrome (LEMS)
- symmetric muscle weakness, better w/ exercise
- absent reflexes which become present after exercise
- paraneoplastic syndrome - 50% of patients with LEMS have cancer!
pathophysiology of LEMS Lambert Eaton Myasthenic Syndrome
antibodies target voltage gated calcium channels on the pre-synaptic neuron. Decreased Ca influx–> decreased ACh released–> no end plate potential.
How fast does muscle have to fire to build up calcium in LEMS?
faster than 10 Hz –> Ca accumulation in muscle
Treatment for LEMS (Lambert Eaton Myasthenic Syndrome )
*** 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
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?
Botulinum toxin
