Recessive inheritance and variable penetrance of slow-channel congenital myasthenic syndromes

Background: Slow-channel congenital myasthenic syndromes (SCCMS) typically show dominant inheritance. They are caused by missense mutations within the subunits of muscle nicotinic acetylcholine receptors (AChR) that result in prolonged ion channel activations. SCCMS mutations within the AChR a subunit are located in various functional domains, whereas fully described mutations in AChR non-a subunits have, thus far, been located only in the M2 channel-lining domain. The authors identified and characterized two E-subunit mutations, located outside M2, that underlie SCCMS in three kinships. In two of the three kinships, the syndrome showed an atypical inheritance pattern. Methods: These methods included clinical diagnosis, mutation detection, haplotype analysis, and functional expression studies using single-channel recordings of mutant AChR transiently transfected into HEK293 cells. Results: The authors identified two SCCMS mutations in the AChR E Subunit, epsilonL78P and epsilonL221F. Both mutations prolonged ACh-induced ion channel activations. epsilonL78P is present in a consanguineous family and appears to be pathogenic only when present on both alleles, and epsilonL221F shows variable penetrance in one of the two families that were identified harboring this mutation. Conclusion: SCCMS mutations may show a recessive inheritance pattern and variable penetrance. A diagnosis of SCCMS should not be ruled out in cases of CMS with an apparent recessive inheritance pattern.