Molecular characterisation of congenital myasthenic syndromes in Southern Brazil

Abstract

Objective To perform genetic testing of patients with congenital myasthenic syndromes (CMS) from the Southern Brazilian state of Parana. Patients and methods Twenty-five CMS patients from 18 independent families were included in the study. Known CMS genes were sequenced and restriction digest for the mutation RAPSN p.N88K was performed in all patients. Results We identified recessive mutations of CHRNE in ten families, mutations in DOK7 in three families and mutations in COLQ, CHRNA1 and CHRNB1 in one family each. The mutation CHRNE c.70insG was found in six families. We have repeatedly identified this mutation in patients from Spain and Portugal and haplotype studies indicate that CHRNE c.70insG derives from a common ancestor. Conclusions Recessive mutations in CHRNE are the major cause of CMS in Southern Brazil with a common mutation introduced by Hispanic settlers. The second most common cause is mutations in DOK7. The minimum prevalence of CMS in Parana is 0.18/100 000.

Clinical and genetic basis of congenital myasthenic syndromes

“…The genes encoding the α (CHRNA1 gene, 2q31.1), δ (CHRND gene, 2q37.1) and γ (CHRNG gene, 2q37.1) chains are located on the long arm of chromosome 2 at different genetic loci, while the genes encoding the β chain (CHRNB1 gene) and ε (CHRNE gene) are located in different loci on the short arm of chromosome 17p13.2 2,4 . In southern Brazil, as a consequence of founder effect mutations of Hispanic settlers origin, CHRNE gene recessive mutations represent the main cause of CMS 9 . Mutations in genes encoding the acetylcholine receptor subunits can produce CMS by means of three mechanisms: (1) reducing the number of acetylcholine receptors in the postsynaptic membrane; (2) extended opening called the slow-channel syndrome; (3) short opening of the receptors known as the fast-channel syndrome.…”

“…In southern Brazil, in the state of Paraná, a minimum prevalence of 0.18/100.000 of CMS is estimated 9 .…”

Congenital myasthenic syndromes and myasthenia gravis are challenging diagnoses in neurological practice

“…The authors estimated a minimum prevalence of 0.18 cases per 100.000 in the State of Parana and the most frequent mutation was in CHRNE gene, which is responsible for coding the εAChR subunit. The second mutation in frequency was documented in DOK7 gene 8 . Interestingly, the same mutation was observed in Spain and Portugal, nations with significant role in the immigration process of the mentioned area.…”

“…In 2009 a Brazilian case-report of end-plate acetylcholinesterase deficiency with proven genetic mutation was published 6 , and a year later, a CMS series of cases came from the Southern region 8 . The authors estimated a minimum prevalence of 0.18 cases per 100.000 in the State of Parana and the most frequent mutation was in CHRNE gene, which is responsible for coding the εAChR subunit.…”

“…Considering the importance of genetic testing in the final diagnose of CMS 8,9 and that it is costly and only available in few centers of Brazil, it seems to be of a high demand to reverse this situation. Early and definite diagnoses in CMS lead to a better rational therapeutic choice in benefit to patients.…”