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 presynapt ic, synaptic, or postsynaptic defects of neuromuscular transmission. Some p reviously described kinships with typical signs of CMS showed a marked defi ciency of acetylcholine receptors (AChR) and utrophin at the neuromuscular junctions. Additionally, the end-plate ultrastructure was immature, with re duced enfolding of the postsynaptic membrane. In two such families, we foun d truncating mutations of the epsilon-AChR subunit. In family 1, both affec ted siblings were heteroallelic for a epsilon 911delT and a epsilon IVS4+1G -->A mutation within the AChR epsilon-subunit gene (CHRNE). In the affected member of family 2, a epsilon 1030delC mutation and a previously described epsilon R64X mutation were found. These deleterious epsilon AChR mutations not only result in AChR deficiency. but also affect end-plate maturation, including the formation of secondary synaptic clefts during ontogenesis.