Mutations in the ε-acetylcholine receptor (AChRε) subunit gene cause congenital myasthenic syndromes (CMS) with postsynaptic neural transmission defects. We present 3 male and 2 female patients from three unrelated Croatian, Hungarian, and Russian families with autosomal recessive CMS. All patients manifested with variable degrees of ophthalmoparesis and generalized, fatiguable muscle weakness since birth or early infancy. Electrophysiological studies showed a decremental response in all patients indicating a neuromuscular transmission defect. Pyridostigmine treatment improved the proximal muscle weakness whereas the ophthalmoparesis remained unchanged in all patients. Analysis of the AChRε subunit gene showed homozygosity for a novel splice site mutation of intron 7 ε(IVS7-2A/G) in the two Croatian siblings. ε-mRNA analysis by RT-PCR and direct sequencing revealed that exon 7 was spliced directly to exon 9 with skipping of exon 8. The Hungarian and Russian patients were heteroallelic carriers of the same mutation ε(IVS7-2A/G) and of a frameshiffing mutation ε70insG and ε1293insG, respectively. We hypothesize that altered splice products may not be expressed as functional receptors at the cell surface. A haplotype analysis with polymorphic markers revealed a high degree of similarity for the ε(IVS7-2A/G) carrying allele in all families and may therefore indicate a common origin of the mutation.
- AChR Deficiency
- AChRε Subunit
- Congenital Myasthenic Syndrome (CMS)
- Splice Site Mutation
ASJC Scopus subject areas
- Pediatrics, Perinatology, and Child Health
- Clinical Neurology