title: Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders.
abstract: Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, 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 (≥3 months of age) occur almost as often as those with an early infantile onset (<3 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 (<3 months), whereas other antiepileptic drugs were less effective. In contrast, sodium channel blockers were rarely effective in epilepsies with later onset (≥3 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.
authors.affiliation: Department of Pediatric Neurology and Developmental Medicine, University Children's Hospital, Tübingen, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Wolff
authors.affiliation: The Danish Epilepsy Centre, Dianalund, Denmark.|Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
authors.forename: Katrine M
authors.initials: KM
authors.lastname: Johannesen
authors.affiliation: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Ulrike B S
authors.initials: UBS
authors.lastname: Hedrich
authors.affiliation: Department of Brain and Behavior, University of Pavia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Masnada
authors.affiliation: The Danish Epilepsy Centre, Dianalund, Denmark.|University of Copenhagen, Copenhagen, Denmark.
authors.forename: Guido
authors.initials: G
authors.lastname: Rubboli
authors.affiliation: The Danish Epilepsy Centre, Dianalund, Denmark.|Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
authors.forename: Elena
authors.initials: E
authors.lastname: Gardella
authors.affiliation: Department of Genetics, Lyon University Hospital, Lyon, France.|Claude Bernard Lyon I University, Lyon, France.|Lyon Neuroscience Research Centre, CNRS UMRS5292, INSERM U1028, Lyon, France.
authors.forename: Gaetan
authors.initials: G
authors.lastname: Lesca
authors.affiliation: Department of Pediatric Neurology and Reference Center for Rare Children Epilepsy and Tuberous Sclerosis, Hôpital Femme Mere Enfant, Centre Hospitalier Universitaire de Lyon, HCL, France.
authors.forename: Dorothée
authors.initials: D
authors.lastname: Ville
authors.affiliation: APHM Service de neurologie pédiatrique, Marseille, France.|Aix Marseille Univ, Inserm, GMGF, UMR-S 910, Marseille, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Milh
authors.affiliation: Aix Marseille Univ, Inserm, GMGF, UMR-S 910, Marseille, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Villard
authors.affiliation: AP-HP, Unité de Gènètique Clinique, Hôpital Armand Trousseau, Groupe Hospitalier Universitaire de l'Est Parisien, Paris, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Afenjar
authors.affiliation: AP-HP, Unité de Gènètique Clinique, Hôpital Armand Trousseau, Groupe Hospitalier Universitaire de l'Est Parisien, Paris, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Chantot-Bastaraud
authors.affiliation: AP-HP, Département de Génétique; Centre de Référence Défiences Intellectuelles de Causes Rares; Groupe de Recherche Clinique UPMC "Déficiences Intellectuelles et Autisme" GH Pitié-Salpêtrère, Paris, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Mignot
authors.affiliation: Service de Pediatrie neonatale et Réanimation - Neuropediatrie, 76000 Rouen, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Lardennois
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Inserm U 1127, CNRS UMR 7225, ICM, France.|Department of Genetics, Pitié-Salpêtrière Hospital, AP-HP, F-75013 Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Nava
authors.affiliation: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Niklas
authors.initials: N
authors.lastname: Schwarz
authors.affiliation: Service de Génétique Clinique, CHU Caen, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Gérard
authors.affiliation: Department of Genetics, Robert Debré Hospital, AP-HP, Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Perrin
authors.affiliation: AP-HP, Service de Neuropédiatrie, Hôpital Trousseau, Paris, France.
authors.forename: Diane
authors.initials: D
authors.lastname: Doummar
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, INSERM UMR1141, Paris, France.|AP-HP, Hôpital Robert Debré, Service de Neurologie Pédiatrique, Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Auvin
authors.affiliation: Department of Pediatrics, Herlev University Hospital, Herlev, Denmark.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Miranda
authors.affiliation: Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Maja
authors.initials: M
authors.lastname: Hempel
authors.affiliation: Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Eva
authors.initials: E
authors.lastname: Brilstra
authors.affiliation: Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Nine
authors.initials: N
authors.lastname: Knoers
authors.affiliation: Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Nienke
authors.initials: N
authors.lastname: Verbeek
authors.affiliation: Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Marjan
authors.initials: M
authors.lastname: van Kempen
authors.affiliation: Department of Pediatric Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, The Netherlands.
authors.forename: Kees P
authors.initials: KP
authors.lastname: Braun
authors.affiliation: Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Grazia
authors.initials: G
authors.lastname: Mancini
authors.affiliation: CeGaT - Center for Genomics and Transcriptomics, Tübingen, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: Biskup
authors.affiliation: CeGaT - Center for Genomics and Transcriptomics, Tübingen, Germany.
authors.forename: Konstanze
authors.initials: K
authors.lastname: Hörtnagel
authors.affiliation: CeGaT - Center for Genomics and Transcriptomics, Tübingen, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Döcker
authors.affiliation: Epilepsy Center Kork, Kehl, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bast
authors.affiliation: Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Harvard Medical School, Boston MA, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Loddenkemper
authors.affiliation: Division of Child and Adolescent Neurology, Department of Neurology, Mayo Clinic, Rochester MN, USA.
authors.forename: Lily
authors.initials: L
authors.lastname: Wong-Kisiel
authors.affiliation: Children's Hospital, RoMed Klinikum, Rosenheim, Germany.
authors.forename: Friedrich M
authors.initials: FM
authors.lastname: Baumeister
authors.affiliation: Pediatric Neurology, University Hospital Cologne, Germany.
authors.forename: Walid
authors.initials: W
authors.lastname: Fazeli
authors.affiliation: Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health, University of Genoa 'G. Gaslini' Institute, Genova, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Striano
authors.affiliation: Servizio di Epilettologia e Neurofisiopatologia Pediatrica, UO Neurofisiopatologia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy.
authors.forename: Robertino
authors.initials: R
authors.lastname: Dilena
authors.affiliation: Centro di Diagnosi e Cura delle Epilessie Infantili, Azienda Ospedaliera -Policlinico Gianbattista Rossi, Verona, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Fontana
authors.affiliation: Laboratory of Neurogenetics and Neuroscience, Department of Neuroscience, "G. Gaslini" Institute, Genova, Italy.
authors.forename: Federico
authors.initials: F
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authors.affiliation: Department of Pediatric Neurology, University Children's Hospital, Münster, Germany.
authors.forename: Gerhard
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authors.lastname: Kurlemann
authors.affiliation: Children's Hospital, Klinikum Aschaffenburg, Germany.
authors.forename: Joerg
authors.initials: J
authors.lastname: Klepper
authors.affiliation: University of Michigan, Pediatric Genetics, Ann Arbor, MI USA.
authors.forename: Jess G
authors.initials: JG
authors.lastname: Thoene
authors.affiliation: Division of Pediatric Neurology and Epilepsy - Beaumont Children's Hospital, William Beaumont Oakland University School of Medicine, Royal Oak, Michigan, USA.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Arndt
authors.affiliation: Department of Neurology, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Deconinck
authors.affiliation: Children's Hospital Lucerne, Luzerner Kantonsspital, Kinderspital Luzern, CH-6000 Luzern 16, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schmitt-Mechelke
authors.affiliation: Department of child neurology, Children's Hospital, St. Gallen, Switzerland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Maier
authors.affiliation: Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian-Albrechts University, Kiel, Germany.
authors.forename: Hiltrud
authors.initials: H
authors.lastname: Muhle
authors.affiliation: Gillette Children's Specialty Healthcare, Saint Paul, MN, USA.
authors.forename: Beverly
authors.initials: B
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authors.affiliation: Klinik für Kinder- und Jugendmedizin, Elisabeth-Krankenhaus, Essen, Germany.
authors.forename: Claudio
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authors.affiliation: Wangen, Germany.
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authors.affiliation: Pediatric Practice University Medical Center for Children and Adolescents, Angelika Lautenschläger Children's Hospital, Heidelberg, Germany.
authors.forename: Joachim
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authors.affiliation: Klinik für Kinder- und Jugendmedizin, Klinikum Lippe GmbH, Detmold, Germany.
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authors.affiliation: Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
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authors.affiliation: Department of Pediatrics, Aarhus University hospital, Aarhus, Denmark.
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authors.initials: KM
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authors.affiliation: Department of Genetics and Cytogenetics, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière Charles-Foix, Paris, France.
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authors.affiliation: Institute of Genetics, University Hospital, Heidelberg, Germany.
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authors.initials: U
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authors.affiliation: Children's Clinic, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
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authors.initials: E
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authors.affiliation: Department of Pediatrics and Mercy Kids Autism Center, Mercy Children's Hospital, St. Louis, Missouri, USA.
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authors.initials: JF
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authors.affiliation: Department of Pediatrics and Neurology, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Kristen
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authors.affiliation: Centre de Génétique Humaine, Institut de Pathologie et Génétique, Gosselies, Belgium.
authors.forename: Marie
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authors.affiliation: Centre de Génétique Humaine, Institut de Pathologie et Génétique, Gosselies, Belgium.
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authors.affiliation: Centre de Génétique Humaine, Institut de Pathologie et Génétique, Gosselies, Belgium.
authors.forename: Sandrine
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authors.affiliation: Pediatric Neurology Unit, Pediatric Department, Centre Hospitalier de Luxembourg, Luxembourg.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Scalais
authors.affiliation: Department of Pediatrics, Pediatric Neurology and Neurometabolic Unit, Cairo University Children Hospital, Cairo, Egypt.
authors.forename: Laila
authors.initials: L
authors.lastname: Selim
authors.affiliation: Department of Pediatrics, Division of Pediatric Neurology and Metabolism, Ghent University Hospital, Ghent, Belgium.
authors.forename: Rudy
authors.initials: R
authors.lastname: Van Coster
authors.affiliation: Department of Development and Regeneration, Section Pediatric Neurology, University Hospital KU Leuven, Leuven, Belgium.
authors.forename: Lieven
authors.initials: L
authors.lastname: Lagae
authors.affiliation: The Danish Epilepsy Centre, Dianalund, Denmark.
authors.forename: Marina
authors.initials: M
authors.lastname: Nikanorova
authors.affiliation: The Danish Epilepsy Centre, Dianalund, Denmark.|Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
authors.forename: Helle
authors.initials: H
authors.lastname: Hjalgrim
authors.affiliation: Zentrum für Kinder- und Jugendmedizin (Elisabeth Kinderkrankenhaus), Klinik für Neuropädiatrie u. Angeborene, Stoffwechselerkrankungen, Oldenburg, Germany.
authors.forename: G Christoph
authors.initials: GC
authors.lastname: Korenke
authors.affiliation: Neurology Unit, Department of Neuroscience, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Trivisano
authors.affiliation: Neurology Unit, Department of Neuroscience, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Specchio
authors.affiliation: Paediatric Neurology University Hospital and University of Antwerp, Wilrijkstraat 10, 2650 Edegem, Belgium.
authors.forename: Berten
authors.initials: B
authors.lastname: Ceulemans
authors.affiliation: Swiss Epilepsy Center, Zurich, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dorn
authors.affiliation: Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Helbig
authors.affiliation: Neurogenetics Group, Center for Molecular Neurology, VIB, Antwerp, Belgium.|Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Katia
authors.initials: K
authors.lastname: Hardies
authors.affiliation: Neurogenetics Group, Center for Molecular Neurology, VIB, Antwerp, Belgium.|Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.|Division of Neurology, University Hospital Antwerp (UZA), Antwerp, Belgium.
authors.forename: Hannah
authors.initials: H
authors.lastname: Stamberger
authors.affiliation: Neurogenetics Group, Center for Molecular Neurology, VIB, Antwerp, Belgium.|Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.|Division of Neurology, University Hospital Antwerp (UZA), Antwerp, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: de Jonghe
authors.affiliation: Neurogenetics Group, Center for Molecular Neurology, VIB, Antwerp, Belgium.|Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.|Division of Neurology, University Hospital Antwerp (UZA), Antwerp, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Weckhuysen
authors.affiliation: Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
authors.forename: Johannes R
authors.initials: JR
authors.lastname: Lemke
authors.affiliation: Department of Pediatric Neurology and Developmental Medicine, University Children's Hospital, Tübingen, Germany.
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Krägeloh-Mann
authors.affiliation: Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian-Albrechts University, Kiel, Germany.|Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, USA.
authors.forename: Ingo
authors.initials: I
authors.lastname: Helbig
authors.affiliation: Neuropediatric Clinic and Clinic for Neurorehabilitation, Epilepsy Center for Children and Adolescents, Schoen Klinik, Vogtareuth, Germany.|PMU Salzburg, Austria.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Kluger
authors.affiliation: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Lerche
authors.affiliation: The Danish Epilepsy Centre, Dianalund, Denmark.|Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
authors.forename: Rikke S
authors.initials: RS
authors.lastname: Møller
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D003718:Denmark / Q000453:epidemiology; D004827:Epilepsy / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology*; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D062551:NAV1.2 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000502:physiology*; D065886:Neurodevelopmental Disorders / Q000235:genetics*; D010641:Phenotype; D026941:Sodium Channel Blockers / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D062551:NAV1.2 Voltage-Gated Sodium Channel; C568251:SCN2A protein, human; D026941:Sodium Channel Blockers
keywords: SCN2A; epilepsy; epilepsy genetics; sodium channel blockers; treatment response