Pharmacological approaches in drug-resistant pediatric epilepsies caused by pathogenic variants in potassium channel genes
Variants in genes encoding for voltage-gated K+ (Kv) channels are frequent cause of drug-resistant pediatric epilepsies. Obtaining a molecular diagnosis gives the opportunity to assess the efficacy of pharmacological strategies based on in vitro features of mutant channels. In this retrospective obs...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fncel.2024.1512365/full |
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| author | Ilaria Filareto Ilaria Mosca Elena Freri Francesca Ragona Laura Canafoglia Roberta Solazzi Barbara Castellotti Giuliana Messina Cinzia Gellera Maria Virginia Soldovieri Paolo Ambrosino Maurizio Taglialatela Jacopo C. DiFrancesco Tiziana Granata |
| author_facet | Ilaria Filareto Ilaria Mosca Elena Freri Francesca Ragona Laura Canafoglia Roberta Solazzi Barbara Castellotti Giuliana Messina Cinzia Gellera Maria Virginia Soldovieri Paolo Ambrosino Maurizio Taglialatela Jacopo C. DiFrancesco Tiziana Granata |
| author_sort | Ilaria Filareto |
| collection | DOAJ |
| description | Variants in genes encoding for voltage-gated K+ (Kv) channels are frequent cause of drug-resistant pediatric epilepsies. Obtaining a molecular diagnosis gives the opportunity to assess the efficacy of pharmacological strategies based on in vitro features of mutant channels. In this retrospective observational study, we selected patients with drug-resistant pediatric epilepsies caused by variants in potassium channel encoding genes, followed at the Fondazione IRCCS Istituto Neurologico Carlo Besta of Milan, Italy. After the experimental characterization of variants’ functional properties in transiently transfected Chinese Hamster Ovary (CHO) cells, we identified drugs to be used as pharmacological approaches. We recruited six patients carrying different missense variants in four Kv channels (Kv7.2, Kv7.3, Kv3.1, and KNa1.1). In vitro experiments demonstrated that variants in Kv7 channels induced loss-of-function (LoF) effects, while those affecting Kv3.1 or KNa1.1 led to gain-of-function (GoF). Moreover, we found that the Kv7 channels activator gabapentin was able to revert the LoF effects caused by Kv7.2/Kv7.3 variants, and the potassium channel-blocker fluoxetine counteracted the GoF effects in Kv3.1 or KNa1.1 variants. According to experimental data, patients carrying Kv7 variants were treated with gabapentin. While this treatment resulted successful in two patients (#1, Kv7.2 G310S variant; #3, Kv7.3 V359L + Kv7.3 D542N), it resulted detrimental in the remaining case (#2, Kv7.2 D535E), requiring drug withdrawal. The application in vivo of fluoxetine to counteract GoF effects induced by Kv3.1 or KNa1.1 variants determined a significant reduction of both seizure frequency and behavior disturbances in patient #4 (Kv3.1 V425M), and in both subjects carrying KNa1.1 variants (#5, S937G and #6, R262Q). However, for the latter case, this drug was halted due to severe behavioral side effects. For most of the patients herein reported, pharmacological strategies, selected according to the in vitro functional properties of Kv-channels pathogenic variants, resulted in a significant improvement of both epileptic and cognitive features. |
| format | Article |
| id | doaj-art-15c01910f40e42d2806566a4ce1adaf6 |
| institution | Kabale University |
| issn | 1662-5102 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Cellular Neuroscience |
| spelling | doaj-art-15c01910f40e42d2806566a4ce1adaf62025-01-24T07:13:29ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022025-01-011810.3389/fncel.2024.15123651512365Pharmacological approaches in drug-resistant pediatric epilepsies caused by pathogenic variants in potassium channel genesIlaria Filareto0Ilaria Mosca1Elena Freri2Francesca Ragona3Laura Canafoglia4Roberta Solazzi5Barbara Castellotti6Giuliana Messina7Cinzia Gellera8Maria Virginia Soldovieri9Paolo Ambrosino10Maurizio Taglialatela11Jacopo C. DiFrancesco12Tiziana Granata13Department of Medical and Surgical Sciences of the Mothers, Children and Adults, University of Modena and Reggio Emilia, Modena, ItalyDepartment of Medicine and Health Sciences “Vincenzo Tiberio”, University of Molise, Campobasso, ItalyDepartment of Pediatric Neuroscience, member of the European Reference Network EPIcare, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalyDepartment of Pediatric Neuroscience, member of the European Reference Network EPIcare, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalyDepartment of Epileptology, member of the European Reference Network EPIcare, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalyDepartment of Pediatric Neuroscience, member of the European Reference Network EPIcare, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalyUnit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalyUnit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalyUnit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalyDepartment of Medicine and Health Sciences “Vincenzo Tiberio”, University of Molise, Campobasso, ItalyDepartment of Science and Technology, University of Sannio, Benevento, ItalyDepartment of Neuroscience, University of Naples “Federico II”, Naples, ItalyDepartment of Neurology, Fondazione IRCCS S. Gerardo dei Tintori, Monza, ItalyDepartment of Pediatric Neuroscience, member of the European Reference Network EPIcare, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalyVariants in genes encoding for voltage-gated K+ (Kv) channels are frequent cause of drug-resistant pediatric epilepsies. Obtaining a molecular diagnosis gives the opportunity to assess the efficacy of pharmacological strategies based on in vitro features of mutant channels. In this retrospective observational study, we selected patients with drug-resistant pediatric epilepsies caused by variants in potassium channel encoding genes, followed at the Fondazione IRCCS Istituto Neurologico Carlo Besta of Milan, Italy. After the experimental characterization of variants’ functional properties in transiently transfected Chinese Hamster Ovary (CHO) cells, we identified drugs to be used as pharmacological approaches. We recruited six patients carrying different missense variants in four Kv channels (Kv7.2, Kv7.3, Kv3.1, and KNa1.1). In vitro experiments demonstrated that variants in Kv7 channels induced loss-of-function (LoF) effects, while those affecting Kv3.1 or KNa1.1 led to gain-of-function (GoF). Moreover, we found that the Kv7 channels activator gabapentin was able to revert the LoF effects caused by Kv7.2/Kv7.3 variants, and the potassium channel-blocker fluoxetine counteracted the GoF effects in Kv3.1 or KNa1.1 variants. According to experimental data, patients carrying Kv7 variants were treated with gabapentin. While this treatment resulted successful in two patients (#1, Kv7.2 G310S variant; #3, Kv7.3 V359L + Kv7.3 D542N), it resulted detrimental in the remaining case (#2, Kv7.2 D535E), requiring drug withdrawal. The application in vivo of fluoxetine to counteract GoF effects induced by Kv3.1 or KNa1.1 variants determined a significant reduction of both seizure frequency and behavior disturbances in patient #4 (Kv3.1 V425M), and in both subjects carrying KNa1.1 variants (#5, S937G and #6, R262Q). However, for the latter case, this drug was halted due to severe behavioral side effects. For most of the patients herein reported, pharmacological strategies, selected according to the in vitro functional properties of Kv-channels pathogenic variants, resulted in a significant improvement of both epileptic and cognitive features.https://www.frontiersin.org/articles/10.3389/fncel.2024.1512365/fullepilepsypotassium channelfunctional studygabapentin (GBP)fluoxetine (FLX) |
| spellingShingle | Ilaria Filareto Ilaria Mosca Elena Freri Francesca Ragona Laura Canafoglia Roberta Solazzi Barbara Castellotti Giuliana Messina Cinzia Gellera Maria Virginia Soldovieri Paolo Ambrosino Maurizio Taglialatela Jacopo C. DiFrancesco Tiziana Granata Pharmacological approaches in drug-resistant pediatric epilepsies caused by pathogenic variants in potassium channel genes Frontiers in Cellular Neuroscience epilepsy potassium channel functional study gabapentin (GBP) fluoxetine (FLX) |
| title | Pharmacological approaches in drug-resistant pediatric epilepsies caused by pathogenic variants in potassium channel genes |
| title_full | Pharmacological approaches in drug-resistant pediatric epilepsies caused by pathogenic variants in potassium channel genes |
| title_fullStr | Pharmacological approaches in drug-resistant pediatric epilepsies caused by pathogenic variants in potassium channel genes |
| title_full_unstemmed | Pharmacological approaches in drug-resistant pediatric epilepsies caused by pathogenic variants in potassium channel genes |
| title_short | Pharmacological approaches in drug-resistant pediatric epilepsies caused by pathogenic variants in potassium channel genes |
| title_sort | pharmacological approaches in drug resistant pediatric epilepsies caused by pathogenic variants in potassium channel genes |
| topic | epilepsy potassium channel functional study gabapentin (GBP) fluoxetine (FLX) |
| url | https://www.frontiersin.org/articles/10.3389/fncel.2024.1512365/full |
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