Presynaptic Congenital Myasthenic Syndromes

Presynaptic congenital myasthenic syndromes (CMS) encompass a large number of rare neurologic disorders caused by impaired release of acetylcholine (ACh) from motor nerve terminals. There are two main groups of presynaptic CMS: one in which the amount of ACh in synaptic vesicles (SV) is diminished and another in which the mechanism of synaptic vesicle release is impaired. The latter is often referred to as a congenital Lambert-Eaton myasthenic syndrome (LEMS). Presynaptic CMS, like other forms of CMS, is primarily characterized by muscle weakness and fatigue, but is often associated with additional manifestations of central and autonomic nervous system involvement, including episodic apneas, cognitive delay, seizures, and gastrointestinal complications. The most common causes of presynaptic CMS are recessive and dominant mutations in genes encoding proteins participating in the mechanisms of ACh synthesis and SV release. However, at times gene mutations can result in more complex pathogenic mechanisms. The most effective treatment of these conditions is prevention of potentially fatal episodes of apnea and other respiratory complications resulting from bulbar weakness. Pharmacologic treatments are also useful; however, in many cases the response is incomplete, and in other mild cases there is improvement with age that obviates the need for pharmacologic interventions. Preclinical studies in animal models of presynaptic CMS using targeted gene therapies are promising but these new therapies will not be available in the near future.