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Tariq Zaman, Ingo Helbig, Ivana Babić Božović, Suzanne D DeBrosse, A Christina Bergqvist, Kimberly Wallis, Livija Medne, Aleš Maver, Borut Peterlin, Katherine L Helbig, Xiaohong Zhang, Ethan M Goldberg
OBJECTIVE: Voltage-gated sodium (Na+ ) channels underlie action potential generation and propagation and hence are central to the regulation of excitability in the nervous system. Mutations in the genes SCN1A, SCN2A, and SCN8A, encoding the Na+ channel pore-forming (α) subunits Nav1.1, 1.2, and 1.6, respectively, and SCN1B, encoding the accessory subunit β1 , are established causes of genetic epilepsies. SCN3A, encoding Nav1.3, is known to be highly expressed in brain, but has not previously been linked to early infantile epileptic encephalopathy...
February 21, 2018: Annals of Neurology
Ara Ko, Song Ee Youn, Se Hee Kim, Joon Soo Lee, Sangwoo Kim, Jong Rak Choi, Heung Dong Kim, Seung-Tae Lee, Hoon-Chul Kang
OBJECTIVE: We performed targeted gene-panel sequencing for children with developmental and epileptic encephalopathy (DEE) and evaluated the clinical implications of genotype-phenotype correlations. METHODS: We assessed 278 children with DEE using a customized gene panel that included 172 genes, and extensively reviewed their clinical characteristics, including therapeutic efficacy, according to genotype. RESULTS: In 103 (37.1%) of the 278 patients with DEE, 35 different disease-causing monogenic mutations were identified...
February 12, 2018: Epilepsy Research
Juliet K Knowles, Jonathan D Santoro, Brenda E Porter, Fiona M Baumer
Primary familial brain calcification (PFBC), otherwise known as Fahr's disease, is a rare autosomal dominant condition with manifestations of movement disorders, neuropsychiatric symptoms, and epilepsy in a minority of PFBC patients. The clinical presentation of epilepsy in PFBC has not been described in detail. We present a paediatric patient with PFBC and refractory focal epilepsy based on seizure semiology and ictal EEG, but with generalized interictal EEG abnormalities. The patient was found to have a SLC20A2 mutation known to be pathogenic in PFBC, as well as a variant of unknown significance in SCN2A...
February 6, 2018: Seizure: the Journal of the British Epilepsy Association
P Zhou, N He, J-W Zhang, Z-J Lin, J Wang, L-M Yan, H Meng, B Tang, B-M Li, X-R Liu, Y-W Shi, Q-X Zhai, Y-H Yi, W-P Liao
Epileptic encephalopathies are severe epilepsy disorders with strong genetic bases. We performed targeted next-generation sequencing (NGS) in 70 patients with epileptic encephalopathies. The likely pathogenicity of variants in candidate genes was evaluated by American College of Medical Genetics and Genomics (ACMG) scoring taken together with the accepted clinical presentation. Thirty-three candidate variants were detected after population filtration and computational prediction. According to ACMG, 21 candidate variants, including 18 de novo variants, were assessed to be pathogenic/likely pathogenic with clinical concordance...
January 4, 2018: Genes, Brain, and Behavior
Jun Xiang, Fang Wen, Lingyun Zhang, Yu Zhou
The expression of sodium voltage-gated channel alpha subunit 2 (SCN2A) is closely related to the development of epilepsy. This study investigated regulatory element of the SCN2A gene involved in epilepsy. An intractable epilepsy cell model was constructed using hippocampal primary neurons and the SH-SY5Y cell line. SCN2A protein and gene expression in cells as well as the level of lactic acid dehydrogenase (LDH) in the cell culture supernatants was detected. Potential regulatory factors of SCN2A and its upstream regulatory elements were identified using the dual-luciferase reporter assay...
December 28, 2017: Experimental Neurology
Qi Zeng, Xiaoling Yang, Jing Zhang, Aijie Liu, Zhixian Yang, Xiaoyan Liu, Ye Wu, Xiru Wu, Liping Wei, Yuehua Zhang
Benign familial epilepsies that present themselves in the first year of life include benign familial neonatal epilepsy (BFNE), benign familial neonatal-infantile epilepsy (BFNIE) and benign familial infantile epilepsy (BFIE). We used Sanger sequencing and targeted next-generation sequencing to detect gene mutations in a Chinese cohort of patients with these three disorders. A total of 79 families were collected, including 4 BFNE, 7 BFNIE, and 68 BFIE. Genetic testing led to the identification of gene mutations in 60 families (60 out of 79, 75...
January 2018: Journal of Human Genetics
Xiaolin Zhu, Raghavendra Padmanabhan, Brett Copeland, Joshua Bridgers, Zhong Ren, Sitharthan Kamalakaran, Ailbhe O'Driscoll-Collins, Samuel F Berkovic, Ingrid E Scheffer, Annapurna Poduri, Davide Mei, Renzo Guerrini, Daniel H Lowenstein, Andrew S Allen, Erin L Heinzen, David B Goldstein
Trio exome sequencing has been successful in identifying genes with de novo mutations (DNMs) causing epileptic encephalopathy (EE) and other neurodevelopmental disorders. Here, we evaluate how well a case-control collapsing analysis recovers genes causing dominant forms of EE originally implicated by DNM analysis. We performed a genome-wide search for an enrichment of "qualifying variants" in protein-coding genes in 488 unrelated cases compared to 12,151 unrelated controls. These "qualifying variants" were selected to be extremely rare variants predicted to functionally impact the protein to enrich for likely pathogenic variants...
November 2017: PLoS Genetics
Michael F Hammer, Alejandra D C Encinas
Investigators from the University of British Columbia, Great Ormond Street Hospital for Children, and the National Hospital reported their findings on neurotransmitter deficiencies in two patients with mutations in voltage-gated sodium genes ( SCN2A and SCN8A ) discovered by whole exome sequencing.
November 2017: Pediatric Neurology Briefs
X Yang, G Pan, W H Li, L M Zhang, B B Wu, H J Wang, P Zhang, S Z Zhou
Objective: To summarize the gene mutation of early onset epileptic spasm with unknown reason. Method: In this prospective study, data of patients with early onset epileptic spasm with unknown reason were collected from neurological department of Children's Hospital of Fudan University between March 2016 and December 2016. Patients with known disorders such as infection, metabolic, structural, immunological problems and known genetic mutations were excluded. Patients with genetic disease that can be diagnosed by clinical manifestations and phenotypic characteristics were also excluded...
November 2, 2017: Zhonghua Er Ke za Zhi. Chinese Journal of Pediatrics
Kameryn M Butler, Cristina da Silva, John J Alexander, Madhuri Hegde, Andrew Escayg
BACKGROUND: The contribution of genetic factors to epilepsy has long been recognized and has been estimated to play a role in 70% to 80% of cases. Identification of a pathogenic variant can help families to better cope with the disorder, allows for genetic counseling to determine recurrence risk, and in some cases, can directly influence treatment options. In this study, we determined the diagnostic yield of a clinical gene panel applied to an unselected cohort of epilepsy patients. METHODS: Variant reports from 339 clinically referred epilepsy patients screened using a 110-gene panel were retrospectively reviewed...
December 2017: Pediatric Neurology
Philipp Follwaczny, Rico Schieweck, Therese Riedemann, Antonia Demleitner, Tobias Straub, Anna H Klemm, Martin Bilban, Bernd Sutor, Bastian Popper, Michael A Kiebler
Epilepsy is a neurological disease that is caused by abnormal hypersynchronous activities of neuronal ensembles leading to recurrent and spontaneous seizures in human patients. Enhanced neuronal excitability and a high level of synchrony between neurons seem to trigger these spontaneous seizures. The molecular mechanisms, however, regarding the development of neuronal hyperexcitability and maintenance of epilepsy are still poorly understood. Here, we show that pumilio RNA-binding family member 2 (Pumilio2; Pum2) plays a role in the regulation of excitability in hippocampal neurons of weaned and 5-month-old male mice...
November 1, 2017: Disease Models & Mechanisms
Shruti Bagla, Daniela Cukovic, Eishi Asano, Sandeep Sood, Aimee Luat, Harry T Chugani, Diane C Chugani, Alan A Dombkowski
Tuberous sclerosis complex (TSC) is characterized by hamartomatous lesions in various organs and arises due to mutations in the TSC1 or TSC2 genes. TSC mutations lead to a range of neurological manifestations including epilepsy, cognitive impairment, autism spectrum disorders (ASD), and brain lesions that include cortical tubers. There is evidence that seizures arise at or near cortical tubers, but it is unknown why some tubers are epileptogenic while others are not. We have previously reported increased tryptophan metabolism measured with α[(11)C]-methyl-l-tryptophan (AMT) positron emission tomography (PET) in epileptogenic tubers in approximately two-thirds of patients with tuberous sclerosis and intractable epilepsy...
October 7, 2017: Neurobiology of Disease
Nataraj S Pagadala, Trent C Bjorndahl, Michael Joyce, David S Wishart, Khajamohiddin Syed, Abdolamir Landi
Prion diseases are fatal neurodegenerative disorders of the central nervous system characterized by the accumulation of a protease resistant form (PrP(Sc)) of the cellular prion protein (PrP(C)) in the brain. Two types of cellular prion (PrP(C)) compounds have been identified that appear to affect prion conversion are known as Effective Binders (EBs) and Accelerators (ACCs). Effective binders shift the balance in favour of PrP(C), whereas Accelerators favour the formation of PrP(Sc). Molecular docking indicates EBs and ACCs both bind to pocket-D of the SHaPrP(C) molecule...
September 19, 2017: Bioorganic & Medicinal Chemistry
Dora Steel, Joseph D Symonds, Sameer M Zuberi, Andreas Brunklaus
OBJECTIVE: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy characterized by the onset of prolonged febrile and afebrile seizures in infancy, and evolving to drug-resistant epilepsy with accompanying cognitive, behavioral, and motor impairment. Most cases are now known to be caused by pathogenic variants in the sodium channel gene SCN1A, but several other genes have also been implicated. This review examines current understanding of the role of non-SCN1A genes in DS, and what is known about phenotypic similarities and differences...
November 2017: Epilepsia
Deidre R Krupp, Rebecca A Barnard, Yannis Duffourd, Sara A Evans, Ryan M Mulqueen, Raphael Bernier, Jean-Baptiste Rivière, Eric Fombonne, Brian J O'Roak
Genetic risk factors for autism spectrum disorder (ASD) have yet to be fully elucidated. Postzygotic mosaic mutations (PMMs) have been implicated in several neurodevelopmental disorders and overgrowth syndromes. By leveraging whole-exome sequencing data on a large family-based ASD cohort, the Simons Simplex Collection, we systematically evaluated the potential role of PMMs in autism risk. Initial re-evaluation of published single-nucleotide variant (SNV) de novo mutations showed evidence consistent with putative PMMs for 11% of mutations...
September 7, 2017: American Journal of Human Genetics
Mary Beth Stosser, Amanda S Lindy, Elizabeth Butler, Kyle Retterer, Caitlin M Piccirillo-Stosser, Gabriele Richard, Dianalee A McKnight
PurposeMosaicism probably represents an underreported cause of genetic disorders due to detection challenges during routine molecular diagnostics. The purpose of this study was to evaluate the frequency of mosaicism detected by next-generation sequencing in genes associated with epilepsy-related neurodevelopmental disorders.MethodsWe conducted a retrospective analysis of 893 probands with epilepsy who had a multigene epilepsy panel or whole-exome sequencing performed in a clinical diagnostic laboratory and were positive for a pathogenic or likely pathogenic variant in one of nine genes (CDKL5, GABRA1, GABRG2, GRIN2B, KCNQ2, MECP2, PCDH19, SCN1A, or SCN2A)...
August 24, 2017: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Jinchen Li, Lin Wang, Hui Guo, Leisheng Shi, Kun Zhang, Meina Tang, Shanshan Hu, Shanshan Dong, Yanling Liu, Tianyun Wang, Ping Yu, Xin He, Zhengmao Hu, Jinping Zhao, Chunyu Liu, Zhong Sheng Sun, Kun Xia
Autism spectrum disorder (ASD) represents a set of complex neurodevelopmental disorders with large degrees of heritability and heterogeneity. We sequenced 136 microcephaly or macrocephaly (Mic-Mac)-related genes and 158 possible ASD-risk genes in 536 Chinese ASD probands and detected 22 damaging de novo mutations (DNMs) in 20 genes, including CHD8 and SCN2A, with recurrent events. Nine of the 20 genes were previously reported to harbor DNMs in ASD patients from other populations, while 11 of them were first identified in present study...
September 2017: Molecular Psychiatry
Theodora U J Bruun, Caro-Lyne DesRoches, Diane Wilson, Vann Chau, Tadashi Nakagawa, Masahiro Yamasaki, Shinya Hasegawa, Toshiyuki Fukao, Christian Marshall, Saadet Mercimek-Andrews
PurposeNeonatal encephalopathy, which is characterized by a decreased level of consciousness, occurs in 1-7/1,000 live-term births. In more than half of term newborns, there is no identifiable etiological factor. To identify underlying genetic defects, we applied whole-exome sequencing (WES) in term newborns with neonatal encephalopathy as a prospective cohort study.MethodsTerm newborns with neonatal encephalopathy and no history of perinatal asphyxia were included. WES was performed using patient and both parents' DNA...
August 17, 2017: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Elaine T Lim, Mohammed Uddin, Silvia De Rubeis, Yingleong Chan, Anne S Kamumbu, Xiaochang Zhang, Alissa M D'Gama, Sonia N Kim, Robert Sean Hill, Arthur P Goldberg, Christopher Poultney, Nancy J Minshew, Itaru Kushima, Branko Aleksic, Norio Ozaki, Mara Parellada, Celso Arango, Maria J Penzol, Angel Carracedo, Alexander Kolevzon, Christina M Hultman, Lauren A Weiss, Menachem Fromer, Andreas G Chiocchetti, Christine M Freitag, George M Church, Stephen W Scherer, Joseph D Buxbaum, Christopher A Walsh
We systematically analyzed postzygotic mutations (PZMs) in whole-exome sequences from the largest collection of trios (5,947) with autism spectrum disorder (ASD) available, including 282 unpublished trios, and performed resequencing using multiple independent technologies. We identified 7.5% of de novo mutations as PZMs, 83.3% of which were not described in previous studies. Damaging, nonsynonymous PZMs within critical exons of prenatally expressed genes were more common in ASD probands than controls (P < 1 × 10-6 ), and genes carrying these PZMs were enriched for expression in the amygdala (P = 5...
September 2017: Nature Neuroscience
Jao-Shwann Liang, Li-Ju Lin, Ming-Tao Yang, Jinn-Shyan Wang, Jyh-Feng Lu
Epileptic encephalopathies are highly heterogeneous and phenotypical disorders with different underlying genetic defects. Mutations in the SCN2A gene cause different epilepsy syndromes, including epilepsy of infancy with migrating focal seizures, Ohtahara syndrome, and West syndrome. We utilized a targeted next generation sequencing (NGS) approach on a girl with early-onset seizures and Rett-like features, including autistic behavior, limited hand function with chorea, and profound intellectual disability, to identify novel missense mutation (c...
November 2017: Brain & Development
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