title: Mutations in the sodium channel gene SCN2A cause neonatal epilepsy with late-onset episodic ataxia.
abstract: Mutations in SCN2A cause epilepsy syndromes of variable severity including neonatal-infantile seizures. In one case, we previously described additional childhood-onset episodic ataxia. Here, we corroborate and detail the latter phenotype in three further cases. We describe the clinical characteristics, identify the causative SCN2A mutations and determine their functional consequences using whole-cell patch-clamping in mammalian cells. In total, four probands presented with neonatal-onset seizures remitting after five to 13 months. In early childhood, they started to experience repeated episodes of ataxia, accompanied in part by headache or back pain lasting minutes to several hours. In two of the new cases, we detected the novel mutation p.Arg1882Gly. While this mutation occurred de novo in both patients, one of them carries an additional known variant on the same SCN2A allele, inherited from the unaffected father (p.Gly1522Ala). Whereas p.Arg1882Gly alone shifted the activation curve by -4 mV, the combination of both variants did not affect activation, but caused a depolarizing shift of voltage-dependent inactivation, and a significant increase in Na(+) current density and protein production. p.Gly1522Ala alone did not change channel gating. The third new proband carries the same de novo SCN2A gain-of-function mutation as our first published case (p.Ala263Val). Our findings broaden the clinical spectrum observed with SCN2A gain-of-function mutations, showing that fairly different biophysical mechanisms can cause a convergent clinical phenotype of neonatal seizures and later onset episodic ataxia.
authors.affiliation: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Schwarz
authors.affiliation: Department of Neuropediatrics, University Medical Clinic Giessen, Giessen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Hahn
authors.affiliation: Epilepsy Center Kork, Kehl-Kork, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Bast
authors.affiliation: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Müller
authors.affiliation: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Löffler
authors.affiliation: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Maljevic
authors.affiliation: Department of Pediatric Neurology, Children's Hospital, Helsinki University Hospital, Helsinki, Finland.
authors.forename: E
authors.initials: E
authors.lastname: Gaily
authors.affiliation: CeGaT GmbH, University of Tübingen, Tübingen, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Prehl
authors.affiliation: CeGaT GmbH, University of Tübingen, Tübingen, Germany.|Department of Neurology with focus on Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.|German Center for Neurodegenerative Diseases (DZNE) Tübingen, Tübingen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Biskup
authors.affiliation: Folkhälsan Institute of Genetics, Neuroscience Center and Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.
authors.forename: T
authors.initials: T
authors.lastname: Joensuu
authors.affiliation: Folkhälsan Institute of Genetics, Neuroscience Center and Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.
authors.forename: A-E
authors.initials: AE
authors.lastname: Lehesjoki
authors.affiliation: Department of Neuropediatrics, University Medical Clinic Giessen, Giessen, Germany.
authors.forename: B A
authors.initials: BA
authors.lastname: Neubauer
authors.affiliation: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany. holger.lerche@uni-tuebingen.de.
authors.forename: H
authors.initials: H
authors.lastname: Lerche
authors.affiliation: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.
authors.forename: U B S
authors.initials: UBS
authors.lastname: Hedrich
mesh_terms: D001259:Ataxia / Q000235:genetics*; D001483:Base Sequence; D015153:Blotting, Western; D004252:DNA Mutational Analysis; D004827:Epilepsy / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D062551:NAV1.2 Voltage-Gated Sodium Channel / Q000235:genetics*; D018408:Patch-Clamp Techniques; D010375:Pedigree; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D062551:NAV1.2 Voltage-Gated Sodium Channel; C568251:SCN2A protein, human
keywords: Ataxia; Channelopathy; Epilepsy; Genetics; Sodium channel