Abstract
Congenital myasthenic syndromes are rare genetic disorders compromising neuromuscular transmission. The defects are mainly mutations in the muscle acetylcholine receptor, or associated proteins rapsyn and Dok-7. We analyzed three unrelated Italian patients with typical clinical features of congenital myasthenic syndrome, who all benefitted from cholinesterase inhibitors. We found five mutations: a previously unreported homozygous αG378D mutation in the CHRNA1 gene, a previously unreported heterozygous εY8X mutation associated with a known heterozygous εM292del deletion in the CHRNE gene, and the common heterozygous N88K mutation associated with a previously unreported heterozygous IVS1 + 2T > G splice site mutation in the RAPSN gene. All three patients had two mutant alleles; parents or offspring with a single mutated allele were asymptomatic, thus all mutations exerted their effects recessively. The previously unreported mutations are likely to reduce the number of AChRs at the motor endplate, although the αG378D mutation might produce a mild fast channel syndrome. The αG378D mutation was recessive, but recessive CHRNA1 mutations have rarely been reported previously, so studies on the effect of this mutation at the cellular level would be of interest.
Similar content being viewed by others
References
Beeson D, Hantaï D, Lochmüller H, Engel AG (2005) 126th International Workshop: congenital myasthenic syndromes, 24–26 September 2004, Naarden, The Netherlands. Neuromuscul Disord 15:498–512
Hantaï D, Richard P, Koenig J, Eymard B (2004) Congenital myasthenic syndromes. Curr Opin Neurol 17:539–551
Ohno K, Engel AG (2004) Congenital myasthenic syndromes: gene mutations. Neuromuscul Disord 14:117–122
Müller JS, Mildner G, Müller-Felber W et al (2003) Rapsyn N88K is a frequent cause of congenital myasthenic syndromes in European patients. Neurology 60:1805–1810
Cossins J, Burke G, Maxwell S et al (2006) Diverse molecular mechanisms involved in AChR deficiency due to rapsyn mutations. Brain 129:2773–2783
Müller SJ, Herczegfalvi A, Vilchez JJ et al (2007) Phenotypical spectrum of DOK7 mutations in congenital myasthenic syndromes. Brain 130:1497–1506
Nichols P, Croxen R, Vincent A et al (1999) Mutation of the acetylcholine receptor ε-subunit promoter in congenital myasthenic syndrome. Ann Neurol 45:439–443
Unwin N (2005) Refined structure of the nicotinic acetylcholine receptor at 4 Å resolution. J Mol Biol 346:967–989
Burke G, Cossins J, Maxwell S et al (2004) Distinct phenotypes of congenital acetylcholine receptor deficiency. Neuromuscul Disord 14:356–364
Croxen R, Vincent A, Newsom-Davis J, Beeson D (2002) Myasthenia gravis in a woman with congenital AChR deficiency due to ε-subunit mutations. Neurology 58:1563–1565
Ohno K, Tsujino A, Shen XM et al (2005) Spectrum of splicing errors caused by CHRNE mutations affecting introns and intron/exon boundaries. J Med Genet 42:e53
Acknowledgments
The authors thank Don Ward for help with the English.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Brugnoni, R., Maggi, L., Canioni, E. et al. Identification of previously unreported mutations in CHRNA1, CHRNE and RAPSN genes in three unrelated Italian patients with congenital myasthenic syndromes. J Neurol 257, 1119–1123 (2010). https://doi.org/10.1007/s00415-010-5472-0
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00415-010-5472-0