From the Guidelines
Myasthenia gravis is an autoimmune disorder where antibodies attack and destroy acetylcholine receptors at the neuromuscular junction, causing variable weakness exacerbated by fatigue, as described in the most recent study 1. The primary mechanism involves the production of autoantibodies, most commonly against the nicotinic acetylcholine receptor (AChR) on the postsynaptic membrane of skeletal muscles.
- These antibodies bind to the receptors, causing their degradation, cross-linking, and internalization, which reduces the number of functional receptors available.
- Additionally, the antibodies can activate complement, leading to damage of the postsynaptic membrane.
- In some cases, antibodies target muscle-specific kinase (MuSK) or lipoprotein receptor-related protein 4 (LRP4) instead of AChR, but the end result is similar. This interference with neuromuscular transmission causes the characteristic fluctuating muscle weakness and fatigue seen in myasthenia gravis, typically worsening with repeated use and improving with rest, as noted in 1. The thymus gland often plays a role in the pathogenesis, with thymic hyperplasia or thymoma present in many patients, suggesting it may be the site where the autoimmune response is initiated, and thymectomy is indicated in certain cases, as discussed in 1.
- The patient population includes adults with myasthenia gravis without geographic or racial predilection.
- Patients are at risk for having or developing thymoma, and proper medical and surgical treatment, including short-term and subsequent long-term management of associated ptosis and strabismus, is essential.
From the Research
Mechanism of Myasthenia Gravis Pathology
The pathology of myasthenia gravis (MG) is primarily caused by autoantibodies targeting proteins of the neuromuscular junction, leading to skeletal muscle weakness and fatigability 2, 3, 4. The main autoantibodies involved in MG are:
- Autoantibodies against the muscle acetylcholine receptor (AChR-MG), found in approximately 85% of MG patients 2, 4
- Autoantibodies against the muscle-specific kinase (MuSK-MG), found in about 5% of MG patients 2, 4
- Autoantibodies against the low-density lipoprotein receptor-related protein 4 (LRP4), found in some MG patients 2, 3, 5
Pathogenic Effects of Autoantibodies
These autoantibodies disrupt cholinergic transmission between nerve terminals and muscle fibers by:
- Causing downregulation, destruction, or functional blocking of AChRs 4
- Disrupting the clustering of AChRs in the postsynaptic membrane 4
- Inhibiting the binding of LRP4 to its ligand, leading to dysfunction of the neuromuscular endplate 5
Clinical Manifestations
The clinical manifestations of MG vary according to the type of autoantibody and whether a thymoma is present 4. The core clinical manifestation of MG is fatigable muscle weakness, which may affect:
- Ocular muscles
- Bulbar muscles
- Respiratory muscles
- Limb muscles
Diagnostic Challenges and Treatment Strategies
Diagnostic challenges and treatment strategies for MG are complex and depend on the specific autoantibody profile of the patient 2, 3, 6. The development of novel sensitive autoantibody detection assays and antigen-specific therapies is crucial for improving MG management and patient quality of life 2, 6.