Far Eastern University – Nicanor Reyes Medical Foundation MECHANISM OF TRANSMISSION OF THE NTA

PHYSIO – B: MYASTHENIA GRAVIS – 2020 1. Neurotransmitters are synthesized in the neuron and stored in the
A 67-year-old male presented to the urgent care optometry clinic
complaining of sudden onset right eye ptosis and binocular, vertical,
diplopia, worse at the end of the day, of one week duration. The patient
denied difficulty swallowing, breathing, hoarseness or generalized
weakness. Past medical history showed hypertension, atrial fibrillation
and high cholesterol with regular intake of atenolol, simvastatin,
Niaspan, and coumadin as medications. He was a non-smoker and had
no drug allergies. He was oriented to person, place and time.
Due to the variable and fatigable ptosis and diplopia, which improved
with ice pack testing, and without symptoms of generalized
involvement, the patient was subjected to Tensilon Test. The result was
positive. The following blood work was ordered: acetylcholine receptor
antibody (AchR) test and thyroid function tests (T3, T4 and TSH). A chest
CT was also ordered to rule out thymus gland abnormality. AchR
antibody testing was positive and thyroid function tests returned
normal. The chest CT was normal, with no evidence of thymoma. The
patient was referred to a neurologist, who prescribed a course of oral
pyridostigmine, which lead to complete symptom resolution.
CLINICAL MANIFESTATIONS:
• Past Health History:
o Hypertension
o Atrial fibrillation
o High cholesterol
• Present Illness:
o Sudden onset of right eye ptosis
o (1 week) Binocular, vertical, diplopia, worse at the end of the
day
• Medications taken: (regularly)
o Atenolol
o Simvastatin
o Niaspan
o Coumadin
• Diagnostic Test Results:
o (+) Tensilon Test
o (+) Acetylcholine receptor antibody (AchR) Test
o Normal Thyroid function tests (T3, T4, and TSH)
o Normal Chest CT (with no evidence of thymoma)
vesicles.
2. Action Potential reaches the Axon Terminal
3. Depolarization of the presynaptic terminal causes voltage-gated Ca++
channels open causing Calcium Influx
4. Calcium together with the SNARE protein, synaptotagmin binds with
the vesicle to allow the effective movement or fusion of the vesicle
to the presynaptic membrane
• Synaptotagmin: Ca++ sensor that triggers the actual fusion
event.
• Local high Ca++ concentration allows the rapid binding of Ca++
that causes conformational change in synaptotagmin
triggering the fusion of a docked vesicle.
5. When the vesicle reached the membrane, they bind to the
synaptobrevin, a Vesicle Associated Membrane Protein (VAMP),
and interact with t-SNAREs, Syntaxin and SNAP25, to have an
exocytosis of the NTA.
• Synaptotagmin and Synaptobravin form the v-SNAREs
• t-SNAREs (Syntaxin and SNAP 25) are important for the
communication of the pre and postsynaptic nerve
6. NTA is released towards the synaptic cleft by exocytosis (KINESINS
are needed if it involves activation of microtubules)
7. NTAs affects ionotropic receptors in the postsynaptic membrane
that causes electrical changes at the postsynaptic nerve
• For instance, Ach triggers a conformational change in a
channel protein which allows Na+ ions to enter the cell,
causing depolarization.
8. Generates either:
• Excitatory Postsynaptic potential if an excitatory agent
• Inhibitory Postsynaptic potential if an inhibitory agent

REVIEW
NEURON – Basic unit of the nervous system
- Three mains parts:
• Axon: conduct impulse
o Axon hillock
o Axon terminal - where NTAs are located and released in
the synapse
• Soma: contain organelles
• Dendrites: contains the receptor

How to remember
these four SNARE
proteins?

Two longest word

belongs to the vesicle
SNARE.

The other two with

shorter name
classified as target
SNARE.

1
STEPS IN EXCITATION–CONTRACTION COUPLING IN SKELETAL MUSCLE PATHOPHYSIOLOGY
1. Release of acetylcholine by the axon motor neuron crosses the cleft MYASTHENIA GRAVIS
and binds to the recetor on motor end plate - “Muscle weakness” + “Grave”
2. Action potentials is generated in the muscle cell membrane that will - Autoimmune disease
initiate depolarization of the T tubules. - Antibodies targeting nicotinic acetylcholine receptors in post-
3. Depolarization of the T tubules causes a conformational change in its synaptic / neuromuscular junction (connections of skeletal muscles)
dihydropyridine receptor, which opens Ca2+ release channels o Anti-acetylcholine receptor antibodies block or destroy Ach
(ryanodine receptors) in the nearby SR, causing release of Ca2+ from receptors
the SR into the intracellular fluid. o Thereby:
4. Intracellular [Ca2+] increases.  Decreasing the number of sites available for Ach binding
5. Ca2+ binds to troponin C on the thin filaments, causing a  Disrupting their functionality and causing them to be
conformational change in troponin that moves tropomyosin out of more rapidly degraded.
the way. The cross-bridge cycle begins:  Size of the End Plate Potential (EPP) is reduced
a. At first, no ATP is bound to myosin (A), and myosin is tightly • Mostly too weak to initiate opening of the
attached to actin. In rapidly contracting muscle, this stage is voltage gated Na channels to cause muscle
brief. In the absence of ATP, this state is permanent (i.e., rigor). depolarization
b. ATP then binds to myosin (B), producing a conformational o Leading to skeletal muscle weakness, fatigability & subsequent
change in myosin that causes myosin to be released from paralysis
actin.
c. Myosin is displaced toward the plus end of actin. There is
hydrolysis of ATP to ADP and inorganic phosphate (Pi). ADP
remains attached to myosin (C).
d. Myosin attaches to a new site on actin, which constitutes the
power (force-generating) stroke (D). ADP is then released,
returning myosin to its rigor state.
e. The cycle repeats as long as Ca2+ is bound to troponin C. Each
cross-bridge cycle “walks” myosin further along the actin
filament.
6. Relaxation occurs when Ca2+ is reaccumulated by the SR Ca2+-
ATPase (SERCA). Intracellular Ca2+ concentration decreases, Ca2+ is
released from troponin C, and tropomyosin again blocks the myosin-
binding site on actin. As long as intracellular Ca2+ concentration is
low, cross-bridge cycling cannot occur.
7. Mechanism of tetanus. A single action potential causes the release
of a standard amount of Ca2+ from the SR and produces a single
twitch. However, if the muscle is stimulated repeatedly, more Ca2+
is released from the SR and there is a cumulative increase in
intracellular [Ca2+], extending the time for cross-bridge cycling. The
muscle does not relax (tetanus).
ANTIBODIES MAY VARY:
• ACH Antibodies – main (dito sa case, blocked receptors)
• Muscle specific kinase (MUSK)
• Low Density Lipoprotein Receptor Related Protein (LRP4)
• MUSK and LRP4 – affect the proteins that make up the framework of
receptors.

3 Mechanisms of the ACh Receptor Bodies

• Directly alters function by BLOCKING Ach binding and Ach receptor
activation
• Promote endocytosis of Ach - resulting to degradation
• Destroys postsynaptic surface (lower receptors = less sensitivity)

2 Major Clinical Forms:

• Ocular MG: PX has predominantly ocular symptoms; weakness
isolated to the EOMs, levator, and orbicularis oculi (ptosis, diplopia,
or blurred vision)
• Generalized MG: PX develops generalized proximal weakness
(bulbar, limb, and respiratory muscles)

RATIONALE OF ITS MANIFESTATION

Sudden onset of right Weakened Levator palpebrae superioris
eye ptosis
Binocular, vertical Weakened extraocular muscles
diplopia, worse at the
end of the day
(+) Tensilon Test Tensilon Test: temporarily blocks the
breakdown of acetylcholine, and briefly
relieves weakness. When weakness is
caused by MG, improvement in muscle
function occurs after administration. Uses
10mg edrophonium hydrochloride

Procedure: Patient will repetitively do

movements such as blinking multiple times,

2
 look upwards for a period of time, or even
repeatedly abduct and adduct
shoulder/arm. Patient will now feel fatigue,
then will be given the 10mg edrophonium
hydrochloride. If the patient recovers, the
test is POSITIVE.

** Edrophonium allows accumulation of

acetylcholine (ACh) in the neuromuscular
junctions, and makes more Ach available to
the muscle receptors, thereby increasing
muscle strength in myasthenia gravis
(+) Acetycholine Detection of antiacetylcholine antibodies
receptor antibody present in the circulating blood
(AchR) test
Normal Thyroid ** done to rule out Graves’ Disease or
Function Test hyperthyroidism
Normal Chest CT Scan ** done to rule out thymoma or thymic
enlargement. (especially in older
individuals)

Why are the eye muscles frequently involved in myasthenia gravis?

Extraocular muscles (EOMs) are more commonly affected as twitch

fibers in EOMs develop tension faster and have a higher frequency of
synaptic firing than limb muscles. This makes them more susceptible to
fatigue. Furthermore, tonic muscle fibers are necessary to sustain the
gaze in any direction. This type of fiber has fewer ACh receptors, which
makes them more susceptible to receptor loss or damage.

Treatment:
• Acetylcholinesterase inhibitors – relieve muscle weakness
• Corticosteroids – immunosuppression
• Plasmapheresis and intravenous immunoglobulin (blood)
• Thymectomy (again correlation bet. MG and thymomas)
• Neostigmine and Pyridostigmine (parasymppathomimetic)

SOURCE:
1. Botulism Trans – Nerve & Mechanism of NTAs
2. Primary Hyperkalemic – Excitation Contraction Coupling in Skeletal
Muscle
3. Previous Trans
4. Q&A with friends