Myasthenia Gravis is a Post-Synaptic Disorder
Myasthenia gravis is definitively a post-synaptic neuromuscular junction disorder where autoantibodies attack components of the post-synaptic membrane, primarily acetylcholine receptors, causing their destruction and reducing their number at the muscle endplate. 1, 2, 3
Mechanism of Post-Synaptic Pathology
The disease operates through a clear post-synaptic mechanism:
Autoantibodies target the post-synaptic nicotinic acetylcholine receptors, causing lytic destruction of the post-synaptic membrane and reducing the number of functional receptors available for neuromuscular transmission. 2, 4
Acetylcholine is normally released from the pre-synaptic motor neuron and crosses the synaptic cleft to reach the post-synaptic muscle membrane, but in myasthenia gravis, the problem lies entirely on the receiving (post-synaptic) side. 1, 5
The antibodies cause complement-mediated damage to the post-synaptic membrane and increase the rate of acetylcholine receptor turnover, both mechanisms resulting in loss of receptors from the post-synaptic surface. 3
Multiple Post-Synaptic Antibody Targets
The post-synaptic nature is confirmed by the various antibody targets, all located on the muscle side of the junction:
Acetylcholine receptor (AChR) antibodies are found in nearly all patients with generalized myasthenia gravis and in 40-77% of patients with ocular myasthenia gravis, representing the most common post-synaptic target. 1, 5
Muscle-specific kinase (MuSK) antibodies account for 5-10% of cases and are predominantly IgG4, causing disassembly of the neuromuscular junction by disrupting post-synaptic MuSK function in synapse maintenance. 6, 3
Low-density lipoprotein receptor-related protein 4 (LRP4) antibodies are found in approximately 50% of double-seronegative patients, representing another post-synaptic target that inhibits agrin-induced aggregation of acetylcholine receptors. 6, 7
Clinical Implications of Post-Synaptic Pathology
Understanding the post-synaptic nature has important clinical ramifications:
Patients with myasthenia gravis show increased sensitivity (down-regulation) to neuromuscular blocking agents used in anesthesia, because the disease already reduces functional post-synaptic receptors. 1
Acetylcholinesterase inhibitors (neostigmine, pyridostigmine, edrophonium) work therapeutically by increasing acetylcholine concentration in the synaptic cleft, allowing the remaining post-synaptic receptors to be more effectively stimulated. 1, 2
The pre-synaptic release mechanism remains intact—the problem is purely that the post-synaptic membrane cannot adequately respond to the acetylcholine that is normally released. 5, 3
Key Distinguishing Feature
- Pupillary function is typically NOT affected in myasthenia gravis, which helps distinguish it from pre-synaptic disorders like Lambert-Eaton myasthenic syndrome or botulism—this is because the post-synaptic defect in myasthenia gravis selectively affects nicotinic receptors at the skeletal neuromuscular junction, not autonomic synapses. 8