Gardella, Elena ORCID: 0000-0002-7138-6022, Becker, Felicitas, Moller, Rikke S., Schubert, Julian, Lemke, Johannes R., Larsen, Line H. G., Eiberg, Hans, Nothnagel, Michael ORCID: 0000-0001-8305-7114, Thiele, Holger, Altmueller, Janine, Syrbe, Steffen, Merkenschlager, Andreas, Bast, Thomas, Steinhoff, Bernhard, Nuernberg, Peter, Mang, Yuan, Moller, Louise Bakke, Gellert, Pia, Heron, Sarah E., Dibbens, Leanne M., Weckhuysen, Sarah ORCID: 0000-0003-2878-1147, Dahl, Hans Atli, Biskup, Saskia, Tommerup, Niels ORCID: 0000-0003-2304-0112, Hjalgrim, Helle, Lerche, Holger, Beniczky, Sandor ORCID: 0000-0002-6035-6581 and Weber, Yvonne G. (2016). Benign Infantile Seizures and Paroxysmal Dyskinesia Caused by an SCN8A Mutation. Ann. Neurol., 79 (3). S. 428 - 437. HOBOKEN: WILEY. ISSN 1531-8249

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Abstract

Objective: Benign familial infantile seizures (BFIS), paroxysmal kinesigenic dyskinesia (PKD), and their combination-known as infantile convulsions and paroxysmal choreoathetosis (ICCA)-are related autosomal dominant diseases. PRRT2 (proline-rich transmembrane protein 2 gene) has been identified as the major gene in all 3 conditions, found to be mutated in 80 to 90% of familial and 30 to 35% of sporadic cases. Methods: We searched for the genetic defect in PRRT2-negative, unrelated families with BFIS or ICCA using whole exome or targeted gene panel sequencing, and performed a detailed cliniconeurophysiological workup. Results: In 3 families with a total of 16 affected members, we identified the same, cosegregating heterozygous missense mutation (c.4447G> A; p.E1483K) in SCN8A, encoding a voltage-gated sodium channel. A founder effect was excluded by linkage analysis. All individuals except 1 had normal cognitive and motor milestones, neuroimaging, and interictal neurological status. Fifteen affected members presented with afebrile focal or generalized tonic-clonic seizures during the first to second year of life; 5 of them experienced single unprovoked seizures later on. One patient had seizures only at school age. All patients stayed otherwise seizure-free, most without medication. Interictal electroencephalogram (EEG) was normal in all cases but 2. Five of 16 patients developed additional brief paroxysmal episodes in puberty, either dystonic/dyskinetic or shivering attacks, triggered by stretching, motor initiation, or emotional stimuli. In 1 case, we recorded typical PKD spells by video-EEG-polygraphy, documenting a cortical involvement. Interpretation: Our study establishes SCN8A as a novel gene in which a recurrent mutation causes BFIS/ICCA, expanding the clinical-genetic spectrum of combined epileptic and dyskinetic syndromes.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Gardella, ElenaUNSPECIFIEDorcid.org/0000-0002-7138-6022UNSPECIFIED
Becker, FelicitasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moller, Rikke S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schubert, JulianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lemke, Johannes R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Larsen, Line H. G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eiberg, HansUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nothnagel, MichaelUNSPECIFIEDorcid.org/0000-0001-8305-7114UNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Syrbe, SteffenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Merkenschlager, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bast, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Steinhoff, BernhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mang, YuanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moller, Louise BakkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gellert, PiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heron, Sarah E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dibbens, Leanne M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weckhuysen, SarahUNSPECIFIEDorcid.org/0000-0003-2878-1147UNSPECIFIED
Dahl, Hans AtliUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Biskup, SaskiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tommerup, NielsUNSPECIFIEDorcid.org/0000-0003-2304-0112UNSPECIFIED
Hjalgrim, HelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lerche, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beniczky, SandorUNSPECIFIEDorcid.org/0000-0002-6035-6581UNSPECIFIED
Weber, Yvonne G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-283568
DOI: 10.1002/ana.24580
Journal or Publication Title: Ann. Neurol.
Volume: 79
Number: 3
Page Range: S. 428 - 437
Date: 2016
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1531-8249
Language: English
Faculty: Faculty of Mathematics and Natural Sciences
Divisions: Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
SODIUM-CHANNEL SCN8A; EPILEPTIC ENCEPHALOPATHY; KINESIGENIC CHOREOATHETOSIS; MOLECULAR ANALYSIS; INACTIVATION GATE; PRRT2 MUTATIONS; PROTEIN; CONVULSIONS; FAMILYMultiple languages
Clinical Neurology; NeurosciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/28356

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