Brunklaus, Andreas ORCID: 0000-0002-7728-6903, Bruenger, Tobias, Feng, Tony, Fons, Carmen, Lehikoinen, Anni, Panagiotakaki, Eleni ORCID: 0000-0003-2611-0227, Vintan, Mihaela-Adela, Symonds, Joseph ORCID: 0000-0002-2141-4216, Andrew, James, Arzimanoglou, Alexis, Delima, Sarah, Gallois, Julie, Hanrahan, Donncha, Lesca, Gaetan, MacLeod, Stewart, Marjanovic, Dragan, McTague, Amy, Nunez-Enamorado, Noemi, Perez-Palma, Eduardo ORCID: 0000-0003-0546-5141, Scott Perry, M., Pysden, Karen, Russ-Hall, Sophie J., Scheffer, Ingrid E., Sully, Krystal, Syrbe, Steffen, Vaher, Ulvi, Velayutham, Murugan, Vogt, Julie, Weiss, Shelly, Wirrell, Elaine, Zuberi, Sameer M., Lal, Dennis, Moller, Rikke S. ORCID: 0000-0002-9664-1448, Mantegazza, Massimo ORCID: 0000-0002-1070-7929 and Cestele, Sandrine (2022). The gain of function SCN1A disorder spectrum: novel epilepsy phenotypes and therapeutic implications. Brain, 145 (11). S. 3816 - 3832. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2156

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Abstract

Brain voltage-gated sodium channel Na(V)1.1 (SCN1A) loss-of-function variants cause the severe epilepsy Dravet syndrome, as well as milder phenotypes associated with genetic epilepsy with febrile seizures plus. Gain of function SCN1A variants are associated with familial hemiplegic migraine type 3. Novel SCN1A-related phenotypes have been described including early infantile developmental and epileptic encephalopathy with movement disorder, and more recently neonatal presentations with arthrogryposis. Here we describe the clinical, genetic and functional evaluation of affected individuals. Thirty-five patients were ascertained via an international collaborative network using a structured clinical questionnaire and from the literature. We performed whole-cell voltage-clamp electrophysiological recordings comparing sodium channels containing wild-type versus variant Na(V)1.1 subunits. Findings were related to Dravet syndrome and familial hemiplegic migraine type 3 variants. We identified three distinct clinical presentations differing by age at onset and presence of arthrogryposis and/or movement disorder. The most severely affected infants (n = 13) presented with congenital arthrogryposis, neonatal onset epilepsy in the first 3 days of life, tonic seizures and apnoeas, accompanied by a significant movement disorder and profound intellectual disability. Twenty-one patients presented later, between 2 weeks and 3 months of age, with a severe early infantile developmental and epileptic encephalopathy and a movement disorder. One patient presented after 3 months with developmental and epileptic encephalopathy only. Associated SCN1A variants cluster in regions of channel inactivation associated with gain of function, different to Dravet syndrome variants (odds ratio = 17.8; confidence interval = 5.4-69.3; P = 1.3 x 10(-7)). Functional studies of both epilepsy and familial hemiplegic migraine type 3 variants reveal alterations of gating properties in keeping with neuronal hyperexcitability. While epilepsy variants result in a moderate increase in action current amplitude consistent with mild gain of function, familial hemiplegic migraine type 3 variants induce a larger effect on gating properties, in particular the increase of persistent current, resulting in a large increase of action current amplitude, consistent with stronger gain of function. Clinically, 13 out of 16 (81%) gain of function variants were associated with a reduction in seizures in response to sodium channel blocker treatment (carbamazepine, oxcarbazepine, phenytoin, lamotrigine or lacosamide) without evidence of symptom exacerbation. Our study expands the spectrum of gain of function SCN1A-related epilepsy phenotypes, defines key clinical features, provides novel insights into the underlying disease mechanisms between SCN1A-related epilepsy and familial hemiplegic migraine type 3, and identifies sodium channel blockers as potentially efficacious therapies. Gain of function disease should be considered in early onset epilepsies with a pathogenic SCN1A variant and non-Dravet syndrome phenotype. Brunklaus et al. describe a spectrum of novel SCN1A epilepsy phenotypes with gain of function properties ranging from neonatal developmental and epileptic encephalopathy with movement disorder and arthrogryposis, to early onset developmental and epileptic encephalopathies with and without movement disorder, which respond to sodium channel blocking therapies.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Brunklaus, AndreasUNSPECIFIEDorcid.org/0000-0002-7728-6903UNSPECIFIED
Bruenger, TobiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Feng, TonyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fons, CarmenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lehikoinen, AnniUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Panagiotakaki, EleniUNSPECIFIEDorcid.org/0000-0003-2611-0227UNSPECIFIED
Vintan, Mihaela-AdelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Symonds, JosephUNSPECIFIEDorcid.org/0000-0002-2141-4216UNSPECIFIED
Andrew, JamesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Arzimanoglou, AlexisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Delima, SarahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gallois, JulieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hanrahan, DonnchaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lesca, GaetanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
MacLeod, StewartUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marjanovic, DraganUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McTague, AmyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nunez-Enamorado, NoemiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perez-Palma, EduardoUNSPECIFIEDorcid.org/0000-0003-0546-5141UNSPECIFIED
Scott Perry, M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pysden, KarenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Russ-Hall, Sophie J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scheffer, Ingrid E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sully, KrystalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Syrbe, SteffenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vaher, UlviUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Velayutham, MuruganUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vogt, JulieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weiss, ShellyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wirrell, ElaineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zuberi, Sameer M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lal, DennisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moller, Rikke S.UNSPECIFIEDorcid.org/0000-0002-9664-1448UNSPECIFIED
Mantegazza, MassimoUNSPECIFIEDorcid.org/0000-0002-1070-7929UNSPECIFIED
Cestele, SandrineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-698768
DOI: 10.1093/brain/awac210
Journal or Publication Title: Brain
Volume: 145
Number: 11
Page Range: S. 3816 - 3832
Date: 2022
Publisher: OXFORD UNIV PRESS
Place of Publication: OXFORD
ISSN: 1460-2156
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
SEVERE MYOCLONIC EPILEPSY; SODIUM-CHANNEL SCN1A; HEMIPLEGIC MIGRAINE; GABAERGIC INTERNEURONS; ILAE COMMISSION; POSITION PAPER; MOUSE MODEL; MUTATION; ENCEPHALOPATHY; MECHANISMSMultiple languages
Clinical Neurology; NeurosciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69876

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