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Myasthenia Gravis

Bio 231: A&P 1


J. Siclon
29 July 2014

Outline
Define Myasthenia Gravis
A & P of Normal Neuromuscular Junction
(NMJ)
A & P of NMJ affected by Myasthenia
Gravis
Clinical Aspect (by Silvia)

What is Myasthenia Gravis?


it is an autoimmune disorder
o the antibodies attack the nicotinic acetylcholine
receptors (AChRs)
the postsynaptic membrane is attacked by these
antibodies
o this is the location of AChRs, junctional folds, and
terminal expansion
characterized by weakness and fatigability of voluntary
muscles (e.g. ptosis - drooping of eyelid)

http://www.nhs.uk/conditions/Myasthenia-gravis/Pages/Introduction.aspx

Schema of normal neuromuscular junction.

presynaptic membrane

synaptic cleft:

primary
postsynaptic
membrane

secondary

Thanvi B R , and Lo T C N Postgrad Med J 2004;80:690-700

Copyright The Fellowship of Postgraduate Medicine. All rights reserved.

Characteristic of Normal Postsynaptic Membrane


Normal junctional fold
o slender stalk
o has peaks (called terminal expansion)
Acetylcholine receptors (AChRs) are concentrated at
the peaks of the junctional folds
Acetylcholinesterase (AChE) is highly concentrated in
the secondary clefts

Major Abnormalities of Postsynaptic Membrane in


Myasthenia Gravis
reduced number of AChRs
o leading to reduced length of postsynaptic membrane

shortening of the synaptic folds


o due to destruction of the terminal expansions

widening of the (secondary) synaptic clefts


o caused by shortening of the junctional folds

Schema of neuromuscular junction in myasthenia gravis (note: widened synaptic cleft, reduced number
of acetylcholine receptors, and simplification of postsynaptic membrane).

Thanvi B R , and Lo T C N Postgrad Med J 2004;80:690-700

Copyright The Fellowship of Postgraduate Medicine. All rights reserved.

Thanvi B R , and Lo T C N Postgrad Med J 2004;80:690-700

Thanvi B R , and Lo T C N Postgrad Med J 2004;80:690-700

Mechanism for Destruction of


Postsynaptic Membrane
Antibodies cross linking (formation of covalent bonds)
with the AChR - complement
o accelerates endocytosis and degradation of AChR
by the muscle cell
Antibody blocking the binding sites of AChR (the two
alpha subunits) - neutralization
Complement-mediated destruction of junctional folds of
the postsynaptic membrane

REVIEW:

Mariebs Anatomy and Physiology (9th),


Fig 21.15, p. 782

Schema of the acetylcholine (ACh) receptor.

antibodies cross-link at the two


alpha subunits of the ACh receptor

Thanvi B R , and Lo T C N Postgrad Med J 2004;80:690-700

Copyright The Fellowship of Postgraduate Medicine. All rights reserved.

Result of the destruction of the postsynaptic


membrane? muscle weakness and fatigue
The action potential is an all-or-nothing event:
o When the stimulus fails to produce depolarization
that exceeds the threshold value, no action potential
results
o However, when threshold potential is exceeded,
complete depolarization occurs
In MG, the safety factor (=EPP/threshold potential) is
reduced thus causing muscle weakness
very high neuronal stimulation frequency causes fatigue

http://www.cliffsnotes.com/sciences/anatomy-and-physiology/nervous-tissue/transmission-of-nerve-impulses

Axon terminal
Open Na+
Channel
Synaptic
cleft

Closed K+
Channel

Na
+

ACh

Na K
+

ACh

Na K
+

1 Local depolarization:

generation of the end


plate potential on the
sarcolemma
Sarcoplasm of muscle fiber

K+

+
+ ++++

Action potential

+++++
+

2 Generation and propagation of

the action potential (AP)


Closed Na+
Channel

Open K+
Channel

Na
+

K+

3 Repolarization
Figure 9.9 Marieb

Miscellaneous
10%-20% of myasthenia gravis patients do
not have anti-AChR antibodies - they are
called seronegative.
however, these patients have antibodies that
bind to MuSK (muscle-specific protein
kinase).
MuSK is involved in anchoring and clustering
of AChRs at the postsynaptic membrane