## Seronegative Myasthenia Gravis Pathophysiology **Key Point:** Seronegative MG (negative for anti-AChR antibodies) accounts for ~50% of generalized MG cases and ~90% of ocular MG cases. The primary mechanism in most seronegative cases involves antibodies against muscle-specific kinase (MuSK). ### MuSK Antibodies in Seronegative MG MuSK is a receptor tyrosine kinase essential for: - Clustering and stabilization of acetylcholine receptors (AChRs) at the neuromuscular junction - Maintenance of the postsynaptic apparatus - Signal transduction for neuromuscular junction development Anti-MuSK antibodies disrupt this process, leading to: 1. Loss of AChR clustering 2. Reduced number of functional AChRs 3. Impaired neuromuscular transmission ### Clinical Features of MuSK-Positive Seronegative MG | Feature | Anti-MuSK MG | Anti-AChR MG | |---------|--------------|---------------| | Antibody prevalence in seronegative | 40–50% | — | | Ocular involvement | Less common | More common | | Bulbar symptoms | Prominent | Variable | | Neck/respiratory weakness | More severe | Variable | | Thymic abnormality | Rare | Common (70%) | | Response to immunosuppression | Good | Good | | Thymectomy benefit | Minimal | Significant | **High-Yield:** Anti-MuSK antibodies are found in approximately 40–50% of seronegative MG patients. The remaining seronegative patients may have antibodies against other neuromuscular junction proteins (e.g., LRP4, agrin) or truly double-seronegative disease. **Clinical Pearl:** Patients with anti-MuSK MG often present with more severe bulbar and respiratory symptoms compared to anti-AChR MG, and thymectomy is typically NOT beneficial in anti-MuSK disease. [cite:Harrison 21e Ch 385]
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