Myasthenia gravis

Associated with Thymoma.

Pathophysiology

Muscle-like (myoid) cells in the thymus express AChR → autoreactive targeting by T cells → production of acetylcholine receptor antibodies (AChR antibodies)

Responsible for inhibition of signal transduction at the neuromuscular junction (NMJ)
Antibodies target postsynaptic AChRs of normal muscle cells → competitive inhibition of acetylcholine (ACh) → AChR decay through receptor internalization (↓ receptor density at the postsynaptic membrane) and activation of complement (→ muscle cell lysis) → impaired signal transduction at the NMJ → skeletal muscle weakness and fatigue
- Seropositive MG (80–90% of cases): positive assays for antibodies (in blood) against the acetylcholine receptor (AChR-Ab)
- Seronegative MG (10–20% of cases): negative for AChR antibodies, but may be positive for muscle-specific tyrosine kinase antibodies (MuSK antibodies)

Warning

Because MG and LEMS are neuromuscular junction disorders, muscle biopsy of these conditions will be normal. Unlike in myopathies (e.g. Polymyositis, Dermatomyositis, Mitochondrial myopathies)

Etiology
- Paraneoplastic: associated with small-cell lung carcinoma (in ⅔ of patients with LEMS)
Pathophysiology: autoantibodies directed against presynaptic voltage-gated calcium channels (anti-VGCC antibodies) → ↓ Ca²⁺ influx → ↓ presynaptic vesicle fusion → impaired acetylcholine release in the NMJ

Tip

Extraocular muscles: move frequently, so they are first affected.
MG: Repeated nerve stimulation → decreasing ACh release (as the storage is limited) → worsen symptoms
LEMS: More depolarization → more ACh release → improved symptoms