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Nicole A Hawkins, Nicole J Zachwieja, Alison R Miller, Lyndsey L Anderson, Jennifer A Kearney
A substantial number of mutations have been identified in voltage-gated sodium channel genes that result in various forms of human epilepsy. SCN1A mutations result in a spectrum of severity ranging from mild febrile seizures to Dravet syndrome, an infant-onset epileptic encephalopathy. Dravet syndrome patients experience multiple seizures types that are often refractory to treatment, developmental delays, and elevated risk for SUDEP. The same sodium channel mutation can produce epilepsy phenotypes of varying clinical severity...
October 2016: PLoS Genetics
Sarenur Gokben, Huseyin Onay, Sanem Yilmaz, Tahir Atik, Gul Serdaroglu, Hande Tekin, Ferda Ozkinay
We investigated the genetic background of early-onset epileptic encephalopathy (EE) using targeted next generation sequencing analysis. Thirty sporadic or familial cases associated with early-onset EE were included. An early-onset EE gene panel including sixteen genes (ARX, CDKL5, CNTNAP2, FOLR1, FOXG1, LAMC3, MBD5, MECP2, NTNG1, PCDH19, PNKP, SCN1A, SCN1B, SCN2A, STXBP1, KCNQ2) was constituted. Nine definite and three potential causal mutations in 30 cases (40 %) were identified. All mutations presented heterozygously except one...
October 12, 2016: Acta Neurologica Belgica
Eric Segal, Helio Pedro, Karen Valdez-Gonzalez, Sarah Parisotto, Felicia Gliksman, Stephen Thompson, Jomard Sabri, Evan Fertig
BACKGROUND: When no chromosomal variations are identified, patients with suspected genetic etiologies can be tested using next-generation sequencing utilizing epilepsy panels. The primary objective of this study was to analyze the diagnostic yield of next-generation sequencing epilepsy panels in medication-resistant epilepsy subjects with non-clinically significant comparative genomic hybridization microarray results. METHODS: We completed a single-center retrospective review of the diagnostic yield of next-generation sequencing epilepsy panels in medication-resistant epilepsy subjects aged 18 years or less who had non-clinically significant comparative genomic hybridization microarray results from January 2011 to December 2014...
July 1, 2016: Pediatric Neurology
Ellen V S Hessel, Hein A van Lith, Inge G Wolterink-Donselaar, Marina de Wit, Marian J A Groot Koerkamp, Frank C P Holstege, Martien J H Kas, Cathy Fernandes, Pierre N E de Graan
Febrile seizures (FS) are the most common seizure type in children. Recurrent FS are a risk factor for developing temporal lobe epilepsy later in life and are known to have a strong genetic component. Experimental FS (eFS) can be elicited in mice by warm-air induced hyperthermia. We used this model to screen the chromosome substitution strain (CSS) panel derived from C57BL/6J and A/J for FS susceptibility and identified C57BL/6J-Chr2(A) /NaJ (CSS2), as the strain with the strongest FS susceptibility phenotype...
September 30, 2016: European Journal of Neuroscience
Lawrence J Jennings, Dawn Kirschmann
Investigators from the EuroEPINOMICS rare epilepsy syndromes Dravet working group performed whole-exome sequencing on 31 trios that had been reported negative for SCN1A mutations by Sanger sequencing.
September 2016: Pediatric neurology briefs
Fiona M Baumer, Jurriaan M Peters, Christelle M El Achkar, Phillip L Pearl
Voltage-gated sodium channels (Nav) are critical regulators of neuronal excitability. Genes for the α-subunits of three sodium channel subtypes-SCN1A, SCN2A, and SCN3A-are all located on chromosome 2q24. A full-term boy with an unremarkable birth history presented at 1 month of age with unusual movements that had started on day of life 2. Exam was notable for lack of visual attention, hypotonia, and hyperreflexia. Electroencephalogram (EEG) showed an invariant burst suppression with multifocal spikes, ictal episodes with bicycling movements associated with buildups of rhythmic activity, and epileptic spasms...
March 2016: Journal of Pediatric Epilepsy
C Peters, R E Rosch, E Hughes, P C Ruben
Dravet syndrome is the prototype of SCN1A-mutation associated epilepsies. It is characterised by prolonged seizures, typically provoked by fever. We describe the evaluation of an SCN1A mutation in a child with early-onset temperature-sensitive seizures. The patient carries a heterozygous missense variant (c3818C > T; pAla1273Val) in the NaV1.1 brain sodium channel. We compared the functional effects of the variant vs. wild type NaV1.1 using patch clamp recordings from channels expressed in Chinese Hamster Ovary Cells at different temperatures (32, 37, and 40 °C)...
2016: Scientific Reports
Toru Takaori, Akira Kumakura, Atsushi Ishii, Shinichi Hirose, Daisuke Hata
BACKGROUND: SCN1A is the gene that codes for the neuronal voltage-gated sodium-channel alpha-subunit 1. It is generally considered that an SCN1A truncating mutation causes the severe phenotype of Dravet syndrome. PATIENTS: We describe 11- and 4-year-old male patients presenting with mild Dravet syndrome with a truncating mutation of SCN1A. The former patient showed moderate mental retardation; however, seizure was controlled to almost one incident a year by levetiracetam and topiramate...
August 17, 2016: Brain & Development
M Saitoh, K Kobayashi, I Ohmori, Y Tanaka, K Tanaka, T Inoue, A Horino, K Ohmura, A Kumakura, Y Takei, S Hirabayashi, M Kajimoto, T Uchida, S Yamazaki, T Shiihara, T Kumagai, M Kasai, H Terashima, M Kubota, M Mizuguchi
Febrile infection-related epilepsy syndrome (FIRES), or acute encephalitis with refractory, repetitive partial seizures (AERRPS), is an epileptic encephalopathy beginning with fever-mediated seizures. The etiology remains unclear. To elucidate the genetic background of FIRES/AERRPS (hereafter FIRES), we recruited 19 Japanese patients, genotyped polymorphisms of the IL1B, IL6, IL10, TNFA, IL1RN, SCN1A and SCN2A genes, and compared their frequency between the patients and controls. For IL1RN, the frequency of a variable number of tandem repeat (VNTR) allele, RN2, was significantly higher in the patients than in controls (p=0...
September 15, 2016: Journal of the Neurological Sciences
Aijie Liu, Xiaojing Xu, Xiaoling Yang, Yuwu Jiang, Zhixian Yang, Xiaoyan Liu, Ye Wu, Xiru Wu, Liping Wei, Yuehua Zhang
Mutations in PCDH19, which encodes protocadherin 19, have been identified in epilepsy, mainly in affected females. We summarized the clinical spectrum of female epilepsy patients with PCDH19 mutations in a Chinese population. We screened for PCDH19 mutations in 75 girls diagnosed as Dravet Syndrome (DS) without a SCN1A mutation and 29 girls with fever-sensitive and cluster seizures. We identified 11 novel and 7 reported mutations in 21 of 104 probands (20.2%), including 6 (6/75, 8%) DS girls and 15 (15/29, 51...
August 16, 2016: Clinical Genetics
Yoshinori Kobayashi, Yoshiyuki Hanaoka, Tomoyuki Akiayma, Iori Ohmori, Mamoru Ouchida, Toshiyuki Yamamoto, Makio Oka, Harumi Yoshinaga, Katsuhiro Kobayashi
We report a female patient with Dravet syndrome (DS) with erratic segmental myoclonus, the origin of which was first identified in the cerebral cortex by the detection of myoclonus-associated cortical discharges. The discharges were disclosed through jerk-locked back-averaging of electroencephalogram (EEG) data using the muscle activity of myoclonus as triggers. The detected spikes on the contralateral parieto-central region preceded myoclonic muscle activity in the forearms by 28-46ms. The patient was six months old at the time of examination, and was developing normally before seizure onset at two months of age...
August 11, 2016: Brain & Development
Wafaa Moustafa M Abo El Fotoh, Sameh Abd Allah Abd El Naby, Mona Salah El-Din Habib, Abeer Ahmed ALrefai, Zeinab A Kasemy
PURPOSE: Despite the advances in the pharmacological treatment of epilepsy, pharmacoresistance still remains challenging. Understanding of the pharmacogenetic causes is critical to predict drug response hence providing a basis for personalized medications. Genetic alteration in activity of drug target and drug metabolizing proteins could explain the development of pharmacoresistant epilepsy. So the aim of this study was to explore whether SCN1A c.3184 A/G (rs2298771) and CYP3A5*3 (rs776746) polymorphisms could serve as genetic based biomarkers to predict pharmacoresistance among Egyptian epileptic children...
October 2016: Seizure: the Journal of the British Epilepsy Association
Tian Li, Yaoyun Kuang, Bin Li
BACKGROUND: mRNA expression in a cell or subcellular organelle is precisely regulated for the purpose of gene function regulation. The 3' untranslated region (3'UTR) of mRNA is the binding target of microRNA and RNA binding proteins. Their interactions regulate mRNA level in specific subcellular regions and determine the intensity of gene repression. The mutations in the coding region of voltage-gated sodium channel alpha 1 subunit gene, SCN1A, were identified in epileptic patients and confirmed as causative factors of epilepsy...
2016: BMC Genetics
Tania Djémié, Sarah Weckhuysen, Sarah von Spiczak, Gemma L Carvill, Johanna Jaehn, Anna-Kaisa Anttonen, Eva Brilstra, Hande S Caglayan, Carolien G de Kovel, Christel Depienne, Eija Gaily, Elena Gennaro, Beatriz G Giraldez, Padhraig Gormley, Rosa Guerrero-López, Renzo Guerrini, Eija Hämäläinen, Corinna Hartmann, Laura Hernandez-Hernandez, Helle Hjalgrim, Bobby P C Koeleman, Eric Leguern, Anna-Elina Lehesjoki, Johannes R Lemke, Costin Leu, Carla Marini, Jacinta M McMahon, Davide Mei, Rikke S Møller, Hiltrud Muhle, Candace T Myers, Caroline Nava, Jose M Serratosa, Sanjay M Sisodiya, Ulrich Stephani, Pasquale Striano, Marjan J A van Kempen, Nienke E Verbeek, Sunay Usluer, Federico Zara, Aarno Palotie, Heather C Mefford, Ingrid E Scheffer, Peter De Jonghe, Ingo Helbig, Arvid Suls
BACKGROUND: Sanger sequencing, still the standard technique for genetic testing in most diagnostic laboratories and until recently widely used in research, is gradually being complemented by next-generation sequencing (NGS). No single mutation detection technique is however perfect in identifying all mutations. Therefore, we wondered to what extent inconsistencies between Sanger sequencing and NGS affect the molecular diagnosis of patients. Since mutations in SCN1A, the major gene implicated in epilepsy, are found in the majority of Dravet syndrome (DS) patients, we focused on missed SCN1A mutations...
July 2016: Molecular Genetics & Genomic Medicine
Yishan Sun, Sergiu P Paşca, Thomas Portmann, Carleton Goold, Kathleen A Worringer, Wendy Guan, Karen C Chan, Hui Gai, Daniel Vogt, Ying-Jiun J Chen, Rong Mao, Karrie Chan, John Lr Rubenstein, Daniel V Madison, Joachim Hallmayer, Wendy M Froehlich-Santino, Jonathan A Bernstein, Ricardo E Dolmetsch
Dravet Syndrome is an intractable form of childhood epilepsy associated with deleterious mutations in SCN1A, the gene encoding neuronal sodium channel Nav1.1. Earlier studies using human induced pluripotent stem cells (iPSCs) have produced mixed results regarding the importance of Nav1.1 in human inhibitory versus excitatory neurons. We studied a Nav1.1 mutation (p.S1328P) identified in a pair of twins with Dravet Syndrome and generated iPSC-derived neurons from these patients. Characterization of the mutant channel revealed a decrease in current amplitude and hypersensitivity to steady-state inactivation...
2016: ELife
Thomas Friedrich, Neslihan N Tavraz, Cornelia Junghans
Mutations in four genes have been identified in familial hemiplegic migraine (FHM), from which CACNA1A (FHM type 1) and SCN1A (FHM type 3) code for neuronal voltage-gated calcium or sodium channels, respectively, while ATP1A2 (FHM type 2) encodes the α2 isoform of the Na(+),K(+)-ATPase's catalytic subunit, thus classifying FHM primarily as an ion channel/ion transporter pathology. FHM type 4 is attributed to mutations in the PRRT2 gene, which encodes a proline-rich transmembrane protein of as yet unknown function...
2016: Frontiers in Physiology
Paola De Liso, Nicole Chemaly, Jacques Laschet, Christine Barnerias, Marie Hully, Dorothée Leunen, Isabelle Desguerre, Catherine Chiron, Olivier Dulac, Rima Nabbout
OBJECTIVE: The aim of this study was to assess outcome and seizure response to treatment with stiripentol (STP) associated to valproate (VPA) and clobazam (CLB), which we have used in our center since the 1990s, in patients with Dravet syndrome (DS). METHODS: We performed a cross-sectional study of all DS patients with SCN1A mutations who had at least one visit to our center in 2013. A total of 54 patients were included (32 males, 22 females), whose ages ranged from 2...
September 2016: Epilepsy Research
J Hsiao, T Y Yuan, M S Tsai, C Y Lu, Y C Lin, M L Lee, S W Lin, F C Chang, H Liu Pimentel, C Olive, C Coito, G Shen, M Young, T Thorne, M Lawrence, M Magistri, M A Faghihi, O Khorkova, C Wahlestedt
Dravet syndrome is a devastating genetic brain disorder caused by heterozygous loss-of-function mutation in the voltage-gated sodium channel gene SCN1A. There are currently no treatments, but the upregulation of SCN1A healthy allele represents an appealing therapeutic strategy. In this study we identified a novel, evolutionary conserved mechanism controlling the expression of SCN1A that is mediated by an antisense non-coding RNA (SCN1ANAT). Using oligonucleotide-based compounds (AntagoNATs) targeting SCN1ANAT we were able to induce specific upregulation of SCN1A both in vitro and in vivo, in the brain of Dravet knock-in mouse model and a non-human primate...
July 2016: EBioMedicine
Cyril Gitiaux, Nicole Chemaly, Susana Quijano-Roy, Christine Barnerias, Isabelle Desguerre, Marie Hully, Catherine Chiron, Olivier Dulac, Rima Nabbout
OBJECTIVE: Since SCN1A is expressed in the motor neuron initial segment, we explored whether motor neuron dysfunction could contribute to gait disturbance and orthopedic misalignment in patients with Dravet syndrome due to SCN1A mutations. METHODS: We assessed 12 consecutive patients who presented to our institution between January and March 2013. All of them were older than 2 years and were positive for the SCN1A mutation. We performed nerve conduction velocity studies and needle EMG recordings...
July 19, 2016: Neurology
Miriam H Meisler, Guy Helman, Michael F Hammer, Brandy E Fureman, William D Gaillard, Alan L Goldin, Shinichi Hirose, Atsushi Ishii, Barbara L Kroner, Christoph Lossin, Heather C Mefford, Jack M Parent, Manoj Patel, John Schreiber, Randall Stewart, Vicky Whittemore, Karen Wilcox, Jacy L Wagnon, Phillip L Pearl, Adeline Vanderver, Ingrid E Scheffer
On April 21, 2015, the first SCN8A Encephalopathy Research Group convened in Washington, DC, to assess current research into clinical and pathogenic features of the disorder and prepare an agenda for future research collaborations. The group comprised clinical and basic scientists and representatives of patient advocacy groups. SCN8A encephalopathy is a rare disorder caused by de novo missense mutations of the sodium channel gene SCN8A, which encodes the neuronal sodium channel Nav 1.6. Since the initial description in 2012, approximately 140 affected individuals have been reported in publications or by SCN8A family groups...
July 2016: Epilepsia
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