Myasthenia gravis and related disorders

Myasthenia gravis (MG) and the Lambert-Eaton myasthenic syndrome (LEMS) are the prototypical autoimmune channelopathies of the peripheral nervous system. The predominant neuromuscular junction (NMJ) antigenic targets are either postsynaptic [MG; nicotinic acetylcholine receptor (AChR)] or presynaptic [LEMS; voltage-gated calcium channel (VGCC)]. Over the last 35 years, the development of active immunization, passive transfer models, and use of transgenic animals has greatly enhanced our understanding of the biology of these disorders. The search for other antibodies in previously “seronegative” MG cases has led to the recognition of antibodies against muscle-specific kinase (MuSK) and low-density lipoprotein receptor related protein 4 (LRP4). The pathogenic mechanisms that underlie MuSK antibodies are particularly interesting as these antibodies are predominantly IgG4 that is functionally monovalent and does not activate complement; the antibodies appear to act mainly by inhibiting the MuSK phosphorylation and downstream activation of AChR clustering at the NMJ. Whilst MG is clearly an antibody mediated disorder, AChR-specific T lymphocytes and the thymus are critical to the autoimmune pathogenesis and a recent randomized clinical trial supports the use of thymectomy in patients with early-onset MG. This chapter aims to summarize the important clinical, immunological, and therapeutic aspects of MG and to a lesser extent LEMS, and highlight some of the relevant developments in the field.