Wolff, Markus ORCID: 0000-0001-5640-0888, Johannesen, Katrine M., Hedrich, Ulrike B. S., Masnada, Silvia ORCID: 0000-0003-3850-8849, Rubboli, Guido ORCID: 0000-0002-5309-2514, Gardella, Elena ORCID: 0000-0002-7138-6022, Lesca, Gaetan ORCID: 0000-0001-7691-9492, Ville, Dorothee, Milh, Mathieu, Villard, Laurent ORCID: 0000-0001-6657-5008, Afenjar, Alexandra, Chantot-Bastaraud, Sandra, Mignot, Cyril, Lardennois, Caroline, Nava, Caroline ORCID: 0000-0003-1272-0518, Schwarz, Niklas, Gerard, Marion, Perrin, Laurence, Doummar, Diane, Auvin, Stephane, Miranda, Maria J., Hempel, Maja, Brilstra, Eva, Knoers, Nine, Verbeek, Nienke, van Kempen, Marjan, Braun, Kees P., Mancini, Grazia, Biskup, Saskia, Hoertnagel, Konstanze, Doecker, Miriam, Bast, Thomas, Loddenkemper, Tobias ORCID: 0000-0003-2074-0674, Wong-Kisiel, Lily, Baumeister, Friedrich M., Fazeli, Walid, Striano, Pasquale ORCID: 0000-0002-6065-1476, Dilena, Robertino ORCID: 0000-0003-1064-1840, Fontana, Elena ORCID: 0000-0002-4553-2452, Zara, Federico ORCID: 0000-0001-9744-5222, Kurlemann, Gerhard, Klepper, Joerg, Thoene, Jess G., Arndt, Daniel H., Deconinck, Nicolas, Schmitt-Mechelke, Thomas, Maier, Oliver, Muhle, Hiltrud, Wical, Beverly, Finetti, Claudio, Brueckner, Reinhard, Pietz, Joachim, Golla, Guenther, Jillella, Dinesh ORCID: 0000-0002-5399-0170, Linnet, Karen M., Charles, Perrine, Moog, Ute, Oiglane-Shlik, Eve, Mantovani, John F., Park, Kristen, Deprez, Marie, Lederer, Damien, Mary, Sandrine, Scalais, Emmanuel, Selim, Laila, Van Coster, Rudy, Lagae, Lieven, Nikanorova, Marina, Hjalgrim, Helle, Korenke, G. Christoph, Trivisano, Marina, Specchio, Nicola, Ceulemans, Berten, Dorn, Thomas, Helbig, Katherine L., Hardies, Katia, Stamberger, Hannah, de Jonghe, Peter, Weckhuysen, Sarah ORCID: 0000-0003-2878-1147, Lemke, Johannes R., Kraegeloh-Mann, Ingeborg, Helbig, Ingo ORCID: 0000-0001-8486-0558, Kluger, Gerhard, Lerche, Holger and Moller, Rikke S. (2017). Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders. Brain, 140. S. 1316 - 1337. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2156

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Abstract

Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Na(v)1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (53 months of age) occur almost as often as those with an early infantile onset (53 months), and are thus more frequent than previously reported; (ii) distinct phenotypes can be seen within the late onset group, including myoclonic-atonic epilepsy (two patients), Lennox-Gastaut not emerging from West syndrome (two patients), and focal epilepsies with an electrical status epilepticus during slow sleep-like EEG pattern (six patients); and (iii) West syndrome constitutes a common phenotype with a major recurring mutation (p.Arg853Gln: two new and four previously reported children). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatment regimen and the course of the epilepsy in 66 patients for which well-documented medical information was available. We find that the use of sodium channel blockers was often associated with clinically relevant seizure reduction or seizure freedom in children with early infantile epilepsies (53 months), whereas other antiepileptic drugs were less effective. In contrast, sodium channel blockers were rarely effective in epilepsies with later onset (53 months) and sometimes induced seizure worsening. Regarding the genetic findings, truncating mutations were exclusively seen in patients with late onset epilepsies and lack of response to sodium channel blockers. Functional characterization of four selected missense mutations using whole cell patch-clamping in tsA201 cells-together with data from the literature-suggest that mutations associated with early infantile epilepsy result in increased sodium channel activity with gain-of-function, characterized by slowing of fast inactivation, acceleration of its recovery or increased persistent sodium current. Further, a good response to sodium channel blockers clinically was found to be associated with a relatively small gain-of-function. In contrast, mutations in patients with late-onset forms and an insufficient response to sodium channel blockers were associated with loss-of-function effects, including a depolarizing shift of voltage-dependent activation or a hyperpolarizing shift of channel availability (steady-state inactivation). Our clinical and experimental data suggest a correlation between age at disease onset, response to sodium channel blockers and the functional properties of mutations in children with SCN2A-related epilepsy.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Wolff, MarkusUNSPECIFIEDorcid.org/0000-0001-5640-0888UNSPECIFIED
Johannesen, Katrine M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hedrich, Ulrike B. S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Masnada, SilviaUNSPECIFIEDorcid.org/0000-0003-3850-8849UNSPECIFIED
Rubboli, GuidoUNSPECIFIEDorcid.org/0000-0002-5309-2514UNSPECIFIED
Gardella, ElenaUNSPECIFIEDorcid.org/0000-0002-7138-6022UNSPECIFIED
Lesca, GaetanUNSPECIFIEDorcid.org/0000-0001-7691-9492UNSPECIFIED
Ville, DorotheeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Milh, MathieuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Villard, LaurentUNSPECIFIEDorcid.org/0000-0001-6657-5008UNSPECIFIED
Afenjar, AlexandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chantot-Bastaraud, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mignot, CyrilUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lardennois, CarolineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nava, CarolineUNSPECIFIEDorcid.org/0000-0003-1272-0518UNSPECIFIED
Schwarz, NiklasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gerard, MarionUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perrin, LaurenceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Doummar, DianeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Auvin, StephaneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Miranda, Maria J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hempel, MajaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brilstra, EvaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knoers, NineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Verbeek, NienkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Kempen, MarjanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braun, Kees P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mancini, GraziaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Biskup, SaskiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoertnagel, KonstanzeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Doecker, MiriamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bast, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Loddenkemper, TobiasUNSPECIFIEDorcid.org/0000-0003-2074-0674UNSPECIFIED
Wong-Kisiel, LilyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baumeister, Friedrich M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fazeli, WalidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Striano, PasqualeUNSPECIFIEDorcid.org/0000-0002-6065-1476UNSPECIFIED
Dilena, RobertinoUNSPECIFIEDorcid.org/0000-0003-1064-1840UNSPECIFIED
Fontana, ElenaUNSPECIFIEDorcid.org/0000-0002-4553-2452UNSPECIFIED
Zara, FedericoUNSPECIFIEDorcid.org/0000-0001-9744-5222UNSPECIFIED
Kurlemann, GerhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klepper, JoergUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thoene, Jess G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Arndt, Daniel H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deconinck, NicolasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmitt-Mechelke, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maier, OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muhle, HiltrudUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wical, BeverlyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Finetti, ClaudioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brueckner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pietz, JoachimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Golla, GuentherUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jillella, DineshUNSPECIFIEDorcid.org/0000-0002-5399-0170UNSPECIFIED
Linnet, Karen M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Charles, PerrineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moog, UteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oiglane-Shlik, EveUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mantovani, John F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Park, KristenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deprez, MarieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lederer, DamienUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mary, SandrineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scalais, EmmanuelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Selim, LailaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Van Coster, RudyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lagae, LievenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nikanorova, MarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hjalgrim, HelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Korenke, G. ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trivisano, MarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Specchio, NicolaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ceulemans, BertenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dorn, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Helbig, Katherine L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hardies, KatiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stamberger, HannahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Jonghe, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weckhuysen, SarahUNSPECIFIEDorcid.org/0000-0003-2878-1147UNSPECIFIED
Lemke, Johannes R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kraegeloh-Mann, IngeborgUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Helbig, IngoUNSPECIFIEDorcid.org/0000-0001-8486-0558UNSPECIFIED
Kluger, GerhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lerche, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moller, Rikke S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-233101
DOI: 10.1093/brain/awx054
Journal or Publication Title: Brain
Volume: 140
Page Range: S. 1316 - 1337
Date: 2017
Publisher: OXFORD UNIV PRESS
Place of Publication: OXFORD
ISSN: 1460-2156
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
NEONATAL-INFANTILE SEIZURES; DE-NOVO MUTATIONS; AUTISM SPECTRUM DISORDER; MIGRATING FOCAL SEIZURES; ONSET EPISODIC ATAXIA; SODIUM-CHANNEL; SCN2A MUTATION; EPILEPTIC ENCEPHALOPATHY; INTELLECTUAL DISABILITY; MISSENSE MUTATIONMultiple languages
Clinical Neurology; NeurosciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/23310

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