Chapter 22: Myasthenia Gravis & Other Disorders of the Neuromuscular Junction

NEUROMUSCULAR TRANSMISSION

The neuromuscular junction is the synaptic connection formed between a motor neuron axon and the muscle fiber it innervates. The transmitter used at the neuromuscular junction, acetylcholine, is stored in the presynaptic motor nerve terminals. The postsynaptic muscle membrane has many folds in which receptors for acetylcholine are located. When a motor nerve action potential reaches the presynaptic nerve terminal, there is a resultant increase in calcium conductance through voltage-gated calcium channels. This increase in intracellular calcium leads to the fusion of acetylcholine-filled presynaptic vesicles with the plasma membrane of the motor nerve terminal. Acetylcholine is subsequently released into the synaptic cleft by exocytosis.

The acetylcholine diffuses across the synapse and binds to the acetylcholine receptors on the postsynaptic muscle membrane. The binding of acetylcholine to these receptors facilitates increased conduction of sodium and potassium. This leads to transient depolarization of the postjunctional muscle membrane known as an end-plate potential. This depolarization allows for the generation and propagation of action potentials in the postsynaptic muscle cell. These processes initiate a chain of events in the muscle cell that culminates in muscle contraction. Disorders of the neuromuscular junction result from a disruption of this series of events.

MYASTHENIA GRAVIS (AUTOIMMUNE MYASTHENIA)

General Considerations

Myasthenia gravis (MG), the most common of the neuromuscular junction disorders, is an acquired, predominantly antibody-mediated autoimmune disease. In this disorder, antibodies are often targeted against the nicotinic acetylcholine receptor (AChR) at the neuromuscular junction, resulting in an overall reduction in the number of AChRs and damage to the postsynaptic membrane. However, other associated antibodies have also been identified, as discussed below.

The prevalence of autoimmune MG is estimated at 1 case in 10,000–20,000 people. Women are affected more often in the second and third decades of life, and men more often in the fifth and sixth decades. Associated autoimmune diseases are present in approximately 5% of patients, and comorbid thyroid disease occurs in more than 10%.

Pathogenesis

The AChR, located on the postsynaptic membrane, is a ligand-gated ion channel composed of five subunits, including α₂βγδ in the developing fetus and α₂βεδ in the adult receptor. AChR autoantibodies most often target the α subunit, and these tend to be more pathogenic than those targeting other subunits. In generalized MG, AChR antibodies are detected in up to 90% of patients, whereas in purely ocular MG, only about 50% of patients are antibody positive. Furthermore, they can be found in individuals with early and late onset disease. Three subtypes of AChR antibodies have been identified: binding, blocking, and modulating. All of ...