Congenital myasthenic syndromes.

The neuromuscular junction is a prototypic synapse that has been extensively studied and provides a model for smaller and less accessible central synapses. Central to transmission at the neuromuscular synapse is the muscle acetylcholine receptor cation channel. Studies of the genetic disorders affecting the neuromuscular junction, termed congenital myasthenic syndromes, have illustrated how impaired signal transmission may be caused by a variety of mutations both within the ion channel itself and by the context of the ion channel within the synapse. Thus, multiple pathogenic mutations are also identified in proteins affecting the clustering, location, and density of the receptor within the overall synaptic structure. Disease severity ranges from death in childhood to mild disability throughout life. In addition, in utero, fetal akinesia due to impaired neuromuscular transmission may cause developmental abnormalities. Early studies identified mutations in the genes encoding the acetylcholine receptor subunits that impair ion channel gating or reduce the number of endplate receptors or a combination of the two, giving rise to "slow channel," "fast channel," or deficiency syndromes. Subsequently, it became clear that myasthenic syndromes also stem from mutations in proteins involved in neurotransmitter release, the formation and maintenance of the neuromuscular synapse, or glycosylation. This chapter describes the patient phenotypes, the diverse range of molecular mechanisms for synaptic dysfunction, and the corresponding therapeutic strategies, including drug combinations, that can be tailored to the many subtypes.