In myasthenia gravis, the fatigable weakness is due to antibody-mediated destruction of nicotinic ACh receptors (nAChRs) at the neuromuscular junction. The electrophysiological finding on repetitive nerve stimulation (RNS) is a decremental response because:

• A Reduced functional nAChRs cause EPPs that fall below threshold after successive stimuli as quantal ACh content per vesicle decreases with stimulation
• B With fewer functional receptors, the safety factor at the NMJ is reduced; successive EPPs fail to reach threshold as ACh stores deplete (presynaptic exhaustion) ✓
• C Antibodies block voltage-gated Ca²⁺ channels at the presynaptic terminal, reducing ACh release per stimulus progressively
• D IgG antibodies against nAChR activate complement-mediated lysis of the presynaptic terminal, reducing ACh synthesis

Explanation

Each neuromuscular junction has a 'safety factor' — the excess of ACh released over the minimum needed to reach action potential threshold. In MG, anti-nAChR antibodies reduce functional receptor number, shrinking this safety factor. At low stimulation rates, each EPP may still reach threshold. However, during repetitive stimulation at 3 Hz, normal presynaptic quantal release decreases (normal short-term depression), and with the already-reduced postsynaptic receptor complement, successive EPPs fall below threshold — producing decremental CMAP amplitude of >10%. The quantal ACh content per vesicle does not decrease; it is presynaptic ACh depletion combined with postsynaptic receptor deficit that reveals the reduced safety margin.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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