title: Remarkable Phenytoin Sensitivity in 4 Children with SCN8A-related Epilepsy: A Molecular Neuropharmacological Approach.
abstract: Mutations in SCN8A are associated with epilepsy and intellectual disability. SCN8A encodes for sodium channel Nav1.6, which is located in the brain. Gain-of-function missense mutations in SCN8A are thought to lead to increased firing of excitatory neurons containing Nav1.6, and therefore to lead to increased seizure susceptibility. We hypothesized that sodium channel blockers could have a beneficial effect in patients with SCN8A-related epilepsy by blocking the overactive Nav1.6 and thereby counteracting the effect of the mutation. Herein, we describe 4 patients with a missense SCN8A mutation and epilepsy who all show a remarkably good response on high doses of phenytoin and loss of seizure control when phenytoin medication was reduced, while side effects were relatively mild. In 2 patients, repeated withdrawal of phenytoin led to the reoccurrence of seizures. Based on the findings in these patients and the underlying molecular mechanism we consider treatment with (high-dose) phenytoin as a possible treatment option in patients with difficult-to-control seizures due to an SCN8A mutation.
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Ragna S
authors.initials: RS
authors.lastname: Boerma
authors.affiliation: Department of Pediatric Neurology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Kees P
authors.initials: KP
authors.lastname: Braun
authors.affiliation: Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Marcel P H
authors.initials: MP
authors.lastname: van den Broek
authors.affiliation: Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Maarten P H
authors.initials: MP
authors.lastname: van de Broek
authors.affiliation: Department of Pediatric Neurology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Frederique M C
authors.initials: FM
authors.lastname: van Berkestijn
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Marielle E
authors.initials: ME
authors.lastname: Swinkels
authors.affiliation: Department of Neurology, University Medical Centre Groningen, Groningen, The Netherlands.
authors.forename: Eveline O
authors.initials: EO
authors.lastname: Hagebeuk
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: Lindhout
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Marjan
authors.initials: M
authors.lastname: van Kempen
authors.affiliation: Department of Pediatric Neurology, Stichting Epilepsie Instellingen Nederland, Zwolle, The Netherlands.
authors.forename: Maartje
authors.initials: M
authors.lastname: Boon
authors.affiliation: Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands.|Epilepsy Center Kempenhaeghe, Heeze, The Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: Nicolai
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Carolien G
authors.initials: CG
authors.lastname: de Kovel
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Eva H
authors.initials: EH
authors.lastname: Brilstra
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands. b.p.c.koeleman@umcutrecht.nl.
authors.forename: Bobby P C
authors.initials: BP
authors.lastname: Koeleman
mesh_terms: D000927:Anticonvulsants / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004827:Epilepsy / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D020125:Mutation, Missense / Q000235:genetics; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000187:drug effects / Q000235:genetics*; D010672:Phenytoin / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000927:Anticonvulsants; D062557:NAV1.6 Voltage-Gated Sodium Channel; C100681:SCN8A protein, human; D010672:Phenytoin
keywords: SCN8A; epileptic encephalopathy; phenytoin; sodium channel blockers