From the Guidelines
Myasthenia gravis (MG) pathophysiology involves three main autoantibody targets: AChR, MuSK, and LRP4, each with distinct mechanisms that affect morbidity, mortality, and quality of life in different ways. The pathophysiology of MG is complex and involves the disruption of normal neuromuscular junction function.
- AChR antibodies, found in about 80-85% of MG patients, directly attack acetylcholine receptors at the neuromuscular junction, causing receptor degradation, complement-mediated damage, and physical blockade of acetylcholine binding sites, resulting in the classic fluctuating muscle weakness pattern 1.
- MuSK antibodies, present in approximately 5-8% of MG patients, target the muscle-specific kinase protein that's essential for clustering AChRs at the neuromuscular junction, disrupting the agrin-LRP4-MuSK signaling pathway necessary for proper neuromuscular junction formation, and often present with more pronounced bulbar, facial, and respiratory muscle weakness 1.
- LRP4 antibodies, the most recently discovered and least common (found in 1-3% of seronegative MG patients), target the low-density lipoprotein receptor-related protein 4, which serves as the agrin receptor in the neuromuscular junction, disrupting the interaction between agrin and LRP4, preventing proper MuSK activation and subsequent AChR clustering 1. Understanding these distinct pathophysiological mechanisms is crucial for proper diagnosis and targeted treatment approaches in different MG subtypes, ultimately improving patient outcomes in terms of morbidity, mortality, and quality of life. The diagnosis of MG can be confirmed by the presence of antiacetylcholine receptor antibody (AChR-Ab-binding, blocking, or modulating), although about 20% of patients with generalized myasthenia and about half of those with ocular myasthenia are seronegative, and may require further testing such as repetitive nerve stimulation testing or single fiber electromyography 1. In clinical practice, the treatment of MG should be tailored to the individual patient's needs, taking into account the specific autoantibody target and the severity of symptoms, with the goal of minimizing morbidity, mortality, and improving quality of life.
From the Research
Pathophysiology of Myasthenia Gravis (MG)
The pathophysiology of MG differs among Acetylcholine Receptor (AChR), Muscle-Specific Kinase (MuSK), and Low-Density Lipoprotein Receptor-Related Protein 4 (LRP4) due to distinct antibody-mediated mechanisms.
- AChR-MG is characterized by immunoglobulin (Ig)G1 and IgG3 antibodies to the AChR, leading to complement fixation and damage to the neuromuscular junction 2.
- MuSK-MG is characterized by IgG4 antibodies that interfere with the interaction between MuSK and LRP4, preventing MuSK activation and leading to the dispersal of AChR clusters 2, 3.
- LRP4 is involved in the pathogenesis of MuSK-MG, as it interacts with MuSK and agrin to regulate the development and maintenance of postsynaptic AChR clusters at the neuromuscular junction 3.
Clinical Features and Treatment
The clinical features and treatment of MG also vary among AChR, MuSK, and LRP4.
- AChR-MG is the most prevalent form of MG and is often associated with thymus involvement and distinct HLA alleles 2.
- MuSK-MG is characterized by predominantly focal muscle weakness, particularly in the bulbar and respiratory muscles, and is often resistant to classical treatment options such as IVIG 2, 3.
- Treatment of MuSK-MG often requires prolonged and high doses of steroids, as well as other immunosuppressants, and may involve novel therapeutic approaches such as plasmapheresis, rituximab, and chimeric antigen receptor T cell-based therapies 2, 4.
Serological Diagnosis
Serological tests are crucial for the diagnosis and treatment of MG, as they can detect the presence of specific antibodies such as anti-AChR, anti-MuSK, and anti-LRP4 5.