Biological concepts in human sodium channel epilepsies and their relevance in clinical practice

Autor: Andreas Brunklaus, David Baez-Nieto, Matthieu Milh, Bertrand Isidor, Hilde Van Esch, Joseph D. Symonds, Ingo Helbig, Stephanie Schorge, Arthur J. Campbell, Annapurna Poduri, Jen Q. Pan, Ismael I. Ghanty, Dana Craiu, Haoran Wang, Jordane Dimidschstein, Felix Steckler, Dennis Lal, Tiffany Busa, Heather E. Olson, Andrew J. Allen, Katrine M. Johannesen, Sarah Weckhuysen, Holger Lerche, Christel Depienne, Peter DeJonge, Beth Rosen Sheidley, Henrike O. Heyne, Christina Fenger, Rikke S. Møller, Sameer M. Zuberi, Juanjiangmeng Du, Stephen Sanders
Přispěvatelé: University of Glasgow, University Hospital of Cologne [Cologne], University of Southern Denmark (SDU), Danish Epilepsy Center Filadelfia, University College of London [London] (UCL), Massachusetts Institute of Technology (MIT), Harvard University [Cambridge], University of Tübingen, University of California (UC), Boston Children's Hospital, Harvard Medical School [Boston] (HMS), University of Medicine and Pharmacy 'Carol Davila' Bucharest (UMPCD), Antwerp University Hospital [Edegem] (UZA), University of Pennsylvania, Kiel University, University Hospitals Leuven [Leuven], Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Nantes (CHU Nantes), University Children's Hospital of Essen [Essen, Germany], University of Cologne, Caugant, Julien, Harvard University, University of California, University of Pennsylvania [Philadelphia]
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Male
Autism Spectrum Disorder
[SDV]Life Sciences [q-bio]
Medizin
Gene Expression
Sodium Channels
Epilepsy
SCN3A
0302 clinical medicine
Sodium channel blocker
Loss of Function Mutation
Gene Duplication
NAV1.3 Voltage-Gated Sodium Channel
Missense mutation
Copy-number variation
SCN1A
Age of Onset
Child
Genetics
NAV1.2 Voltage-Gated Sodium Channel
neurodevelopmental disorders
Gene Expression Regulation
Developmental
Electroencephalography
Phenotype
[SDV] Life Sciences [q-bio]
Neurology
Codon
Nonsense
Child
Preschool
Gain of Function Mutation
Female
Sodium Channel Blockers
SCN8A
DNA Copy Number Variations
Genotype
Mutation
Missense
Biology
03 medical and health sciences
Dravet syndrome
medicine
Humans
Sodium channel
Infant
Newborn
Infant
medicine.disease
NAV1.1 Voltage-Gated Sodium Channel
030104 developmental biology
NAV1.6 Voltage-Gated Sodium Channel
Neurodevelopmental Disorders
epilepsy
Neurology (clinical)
Human medicine
SCN2A
Epileptic Syndromes
030217 neurology & neurosurgery
Gene Deletion
Zdroj: Epilepsia
Epilepsia, 2020, 61, pp.387-399. ⟨10.1111/epi.16438⟩
Brunklaus, A, Du, J, Steckler, F, Ghanty, I I, Johannesen, K M, Fenger, C D, Schorge, S, Baez-Nieto, D, Wang, H R, Allen, A, Pan, J Q, Lerche, H, Heyne, H, Symonds, J D, Zuberi, S M, Sanders, S, Sheidley, B R, Craiu, D, Olson, H E, Weckhuysen, S, DeJonge, P, Helbig, I, Van Esch, H, Busa, T, Milh, M, Isidor, B, Depienne, C, Poduri, A, Campbell, A J, Dimidschstein, J, Møller, R S & Lal, D 2020, ' Biological concepts in human sodium channel epilepsies and their relevance in clinical practice ', Epilepsia, vol. 61, no. 3, pp. 387-399 . https://doi.org/10.1111/epi.16438
Epilepsia, Wiley, 2020, 61, pp.387-399. ⟨10.1111/epi.16438⟩
ISSN: 0013-9580
Popis: International audience; ObjectiveVoltage‐gated sodium channels (SCNs) share similar amino acid sequence, structure, and function. Genetic variants in the four human brain‐expressed SCN genes SCN1A/2A/3A/8A have been associated with heterogeneous epilepsy phenotypes and neurodevelopmental disorders. To better understand the biology of seizure susceptibility in SCN‐related epilepsies, our aim was to determine similarities and differences between sodium channel disorders, allowing us to develop a broader perspective on precision treatment than on an individual gene level alone.MethodsWe analyzed genotype‐phenotype correlations in large SCN‐patient cohorts and applied variant constraint analysis to identify severe sodium channel disease. We examined temporal patterns of human SCN expression and correlated functional data from in vitro studies with clinical phenotypes across different sodium channel disorders.ResultsComparing 865 epilepsy patients (504 SCN1A, 140 SCN2A, 171 SCN8A, four SCN3A, 46 copy number variation [CNV] cases) and analysis of 114 functional studies allowed us to identify common patterns of presentation. All four epilepsy‐associated SCN genes demonstrated significant constraint in both protein truncating and missense variation when compared to other SCN genes. We observed that age at seizure onset is related to SCN gene expression over time. Individuals with gain‐of‐function SCN2A/3A/8A missense variants or CNV duplications share similar characteristics, most frequently present with early onset epilepsy (
Databáze: OpenAIRE
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