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Gain of function SCN1A disease‐causing variants: Expanding the phenotypic spectrum and functional studies guiding the choice of effective antiseizure medication.

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Title: Gain of function SCN1A disease‐causing variants: Expanding the phenotypic spectrum and functional studies guiding the choice of effective antiseizure medication.
Authors: Matricardi, Sara (AUTHOR), Cestèle, Sandrine (AUTHOR), Trivisano, Marina (AUTHOR), Kassabian, Benedetta (AUTHOR), Leroudier, Nathalie (AUTHOR), Vittorini, Roberta (AUTHOR), Nosadini, Margherita (AUTHOR), Cesaroni, Elisabetta (AUTHOR), Siliquini, Sabrina (AUTHOR), Marinaccio, Cristina (AUTHOR), Longaretti, Francesca (AUTHOR), Podestà, Barbara (AUTHOR), Operto, Francesca Felicia (AUTHOR), Luisi, Concetta (AUTHOR), Sartori, Stefano (AUTHOR), Boniver, Clementina (AUTHOR), Specchio, Nicola (AUTHOR), Vigevano, Federico (AUTHOR), Marini, Carla (AUTHOR), Mantegazza, Massimo (AUTHOR)
Source: Epilepsia (Series 4). May2023, Vol. 64 Issue 5, p1331-1347. 17p.
Subjects: Epilepsy, Sodium channel blockers, Partial epilepsy, Febrile seizures, Disabilities
Abstract: Objective: This study was undertaken to refine the spectrum of SCN1A epileptic disorders other than Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS+) and optimize antiseizure management by correlating phenotype–genotype relationship and functional consequences of SCN1A variants in a cohort of patients. Methods: Sixteen probands carrying SCN1A pathogenic variants were ascertained via a national collaborative network. We also performed a literature review including individuals with SCN1A variants causing non‐DS and non‐GEFS+ phenotypes and compared the features of the two cohorts. Whole cell patch clamp experiments were performed for three representative SCN1A pathogenic variants. Results: Nine of the 16 probands (56%) had de novo pathogenic variants causing developmental and epileptic encephalopathy (DEE) with seizure onset at a median age of 2 months and severe intellectual disability. Seven of the 16 probands (54%), five with inherited and two with de novo variants, manifested focal epilepsies with mild or no intellectual disability. Sodium channel blockers never worsened seizures, and 50% of patients experienced long periods of seizure freedom. We found 13 SCN1A missense variants; eight of them were novel and never reported. Functional studies of three representative variants showed a gain of channel function. The literature review led to the identification of 44 individuals with SCN1A variants and non‐DS, non‐GEFS+ phenotypes. The comparison with our cohort highlighted that DEE phenotypes are a common feature. Significance: The boundaries of SCN1A disorders are wide and still expanding. In our cohort, >50% of patients manifested focal epilepsies, which are thus a frequent feature of SCN1A pathogenic variants beyond DS and GEFS+. SCN1A testing should therefore be included in the diagnostic workup of pediatric, familial and nonfamilial, focal epilepsies. Alternatively, non‐DS/non‐GEFS+ phenotypes might be associated with gain of channel function, and sodium channel blockers could control seizures by counteracting excessive channel function. Functional analysis evaluating the consequences of pathogenic SCN1A variants is thus relevant to tailor the appropriate antiseizure medication. [ABSTRACT FROM AUTHOR]
Copyright of Epilepsia (Series 4) is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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  Data: Gain of function SCN1A disease‐causing variants: Expanding the phenotypic spectrum and functional studies guiding the choice of effective antiseizure medication.
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  Data: <searchLink fieldCode="JN" term="%22Epilepsia+%28Series+4%29%22">Epilepsia (Series 4)</searchLink>. May2023, Vol. 64 Issue 5, p1331-1347. 17p.
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  Data: <searchLink fieldCode="DE" term="%22Epilepsy%22">Epilepsy</searchLink><br /><searchLink fieldCode="DE" term="%22Sodium+channel+blockers%22">Sodium channel blockers</searchLink><br /><searchLink fieldCode="DE" term="%22Partial+epilepsy%22">Partial epilepsy</searchLink><br /><searchLink fieldCode="DE" term="%22Febrile+seizures%22">Febrile seizures</searchLink><br /><searchLink fieldCode="DE" term="%22Disabilities%22">Disabilities</searchLink>
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  Label: Abstract
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  Data: Objective: This study was undertaken to refine the spectrum of SCN1A epileptic disorders other than Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS+) and optimize antiseizure management by correlating phenotype–genotype relationship and functional consequences of SCN1A variants in a cohort of patients. Methods: Sixteen probands carrying SCN1A pathogenic variants were ascertained via a national collaborative network. We also performed a literature review including individuals with SCN1A variants causing non‐DS and non‐GEFS+ phenotypes and compared the features of the two cohorts. Whole cell patch clamp experiments were performed for three representative SCN1A pathogenic variants. Results: Nine of the 16 probands (56%) had de novo pathogenic variants causing developmental and epileptic encephalopathy (DEE) with seizure onset at a median age of 2 months and severe intellectual disability. Seven of the 16 probands (54%), five with inherited and two with de novo variants, manifested focal epilepsies with mild or no intellectual disability. Sodium channel blockers never worsened seizures, and 50% of patients experienced long periods of seizure freedom. We found 13 SCN1A missense variants; eight of them were novel and never reported. Functional studies of three representative variants showed a gain of channel function. The literature review led to the identification of 44 individuals with SCN1A variants and non‐DS, non‐GEFS+ phenotypes. The comparison with our cohort highlighted that DEE phenotypes are a common feature. Significance: The boundaries of SCN1A disorders are wide and still expanding. In our cohort, >50% of patients manifested focal epilepsies, which are thus a frequent feature of SCN1A pathogenic variants beyond DS and GEFS+. SCN1A testing should therefore be included in the diagnostic workup of pediatric, familial and nonfamilial, focal epilepsies. Alternatively, non‐DS/non‐GEFS+ phenotypes might be associated with gain of channel function, and sodium channel blockers could control seizures by counteracting excessive channel function. Functional analysis evaluating the consequences of pathogenic SCN1A variants is thus relevant to tailor the appropriate antiseizure medication. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
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  Data: <i>Copyright of Epilepsia (Series 4) is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1111/epi.17509
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        Text: English
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