Congenital myasthenic syndromes (CMS) constitute a rare (1/500.000 subjects) heterogeneous group of inherited neuromuscular disorders associated with distinctive clinical, electrophysiological, ultrastructural and genetic abnormalities. These genetic defects, affecting different proteins of the neuromuscular junction, impair neuromuscular transmission and cause muscle weakness.

The neuromuscular junction is a specialized synapse with a complex molecular architecture, which serves to achieve reliable transmission between the nerve terminal and muscle fiber. It is composed of three main compartments: the presynaptic part formed by the nerve terminal is responsible for acetylcholine synthesis, storage and release. The synaptic cleft contains the basal lamina, which constitutes a sound extracellular matrix, both structurally and functionally. This maintains proper adhesion between the synaptic membranes and facilitates neuromuscular communication. The post-synaptic muscle membrane, also known as endplate, shows several folds, which contains several acetylcholine receptors clustered on its surface. Depolarization at the nerve terminal opens the presynaptic voltage-gated calcium channels allowing influx of ions into the pre-synaptic nerve bud, triggering the release of acetylcholine vesicles of by exocytosis. Acetylcholine diffuses across the synaptic space and binds to the acetylcholine receptors. This in turn results in influx of cations, which induces depolarization of the muscle endplate and ultimately muscle contraction.

The base phenotype of CMSs is characterized by congenital onset, eye muscle involvement with ophtalmoplegia and/or ptosis, muscle weakness and occurrence of apneic attacks and joint contractures. The severity of these diseases is variable and is worsened by infections and fever episodes, which may cause respiratory impairments.

CMSs can be recessively or dominantly inherited and to date at least 16 different genes have been associated with these disorders, most frequently:

1. Presynaptic: CHAT
2. Synaptic: COLQ
3. Postsynaptic: CHRNE, CHRNA1, CHRNB1, CHRND, RAPSN
4. Defects in the mechanisms of neuromuscular junction development and maintenance: DOK7, MUSK, GFPT1