This chapter discusses the newly recognized congenital myasthenic syndromes—namely, (1) congenital paucity of synaptic vesicles and reduced quantal release, (2) high-conductance fast-channel syndrome, (3) abnormal acetylcholine receptor (AChR) interaction with acetylcholine, and (4) AChR deficiency and short channel-open time. In the congenital myasthenic syndromes, the safety margin of neuromuscular transmission is compromised by one or more specific mechanisms. The recognition and characterization of these diseases requires the combined use of clinical, electromyographic (EMG), in vitro electrophysiological and morphological data. The syndromes that are adequately characterized to date include congenital neuromuscular junction (NMJ) and acetylcholinesterase (AChE) deficiency. The findings are consistent with a functionally abnormal AChR ion channel because of a mutation in an AChR subunit. Site-directed mutagenesis studies indicate that single amino acid substitutions in any subunit that alter the distribution of negative or positive charges close to the external or cytoplasmic vestibule of the ion channel affect the cation flux through the channel. The high channel conductance is associated with a shorter than normal channel lifetime indicates that the mutation has a dual affect on the kinetic properties of the ion channel.
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