Nocturnal frontal lobe epilepsy with paroxysmal arousals due to CHRNA2 loss of function

Neurology
Valerio ContiRenzo Guerrini

Abstract

We assessed the mutation frequency in nicotinic acetylcholine receptor (nAChR) subunits CHRNA4, CHRNB2, and CHRNA2 in a cohort including autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and sporadic nocturnal frontal lobe epilepsy (NFLE). Upon finding a novel mutation in CHRNA2 in a large family, we tested in vitro its functional effects. We sequenced all the coding exons and their flanking intronic regions in 150 probands (73 NFLE, 77 ADNFLE), in most of whom diagnosis had been validated by EEG recording of seizures. Upon finding a missense mutation in CHRNA2, we measured whole-cell currents in human embryonic kidney cells in both wild-type and mutant α2β4 and α2β2 nAChR subtypes stimulated with nicotine. We found a c.889A>T (p.Ile297Phe) mutation in the proband (≈0.6% of the whole cohort) of a large ADNFLE family (1.2% of familial cases) and confirmed its segregation in all 6 living affected individuals. Video-EEG studies demonstrated sleep-related paroxysmal epileptic arousals in all mutation carriers. Oxcarbazepine treatment was effective in all. Whole-cell current density was reduced to about 40% in heterozygosity and to 0% in homozygosity, with minor effects on channel permeability and sensitivity to nicotine. ...Continue Reading

Citations

Jun 15, 2015·Journal of Neuroscience Methods·Morgane Boillot, Stéphanie Baulac
Jul 16, 2016·Journal of Neurology·Omar TorrianiFabienne Picard
Dec 22, 2017·Pharmacological Reviews·Julia OyrerChristopher A Reid
Jun 17, 2020·The Canadian Journal of Neurological Sciences. Le Journal Canadien Des Sciences Neurologiques·Maxime Cadieux-DionDang Khoa Nguyen
Feb 23, 2017·Proceedings of the National Academy of Sciences of the United States of America·Franziska WielaenderHannes Lohi
Apr 27, 2020·Cellular and Molecular Neurobiology·Kamilla MussinaOlena Filchakova
Oct 29, 2020·Cell Reports·Margarida Cardoso-MoreiraHenrik Kaessmann
Jun 29, 2021·Frontiers in Neurology·Susan HarveyKathleen M Gorman

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