Immature end-plates and utrophin deficiency in congenital myasthenic syndrome caused by epsilon-AChR subunit truncating mutations.

Congenital myasthenic syndromes (CMS) are inborn disorders due to presynaptic, synaptic, or postsynaptic defects of neuromuscular transmission. Some previously described kinships with typical signs of CMS showed a marked deficiency of acetylcholine receptors (AChR) and utrophin at the neuromuscular junctions. Additionally, the end-plate ultrastructure was immature, with reduced enfolding of the postsynaptic membrane. In two such families, we found truncating mutations of the epsilon-AChR subunit. In family 1, both affected siblings were heteroallelic for a epsilon911delT and a epsilonIVS4+1G-->A mutation within the AChR epsilon-subunit gene (CHRNE). In the affected member of family 2, a epsilon1030delC mutation and a previously described epsilonR64X mutation were found. These deleterious epsilonAChR mutations not only result in AChR deficiency, but also affect end-plate maturation, including the formation of secondary synaptic clefts during ontogenesis.