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https://www.readbyqxmd.com/read/27784474/-clinical-features-and-gene-mutations-in-epilepsy-of-infancy-with-migrating-focal-seizures
#1
K W Shang, Y H Zhang, X L Yang, A J Liu, Z X Yang, X Y Liu, Y W Jiang, X R Wu
Objective: To summarize the clinical features and gene mutations of epilepsy of infancy with migrating focal seizures (EIMFS). Method: Clinical features and electroencephalograms(EEG)of 9 patients with EIMFS of Peking University First Hospital from May 2015 to January 2016 were analyzed. Candidate gene mutations were screened by next generation sequencing. Result: Among the 9 patients, 3 were males and 6 were females. Two patients had family history. Seizure onset age was 2 days to 3 months after birth (median age 35 days)...
October 2, 2016: Zhonghua Er Ke za Zhi. Chinese Journal of Pediatrics
https://www.readbyqxmd.com/read/27730449/integrated-transcriptome-analysis-of-human-ips-cells-derived-from-a-fragile-x-syndrome-patient-during-neuronal-differentiation
#2
Ping Lu, Xiaolong Chen, Yun Feng, Qiao Zeng, Cizhong Jiang, Xianmin Zhu, Guoping Fan, Zhigang Xue
Fragile X syndrome (FXS) patients carry the expansion of over 200 CGG repeats at the promoter of fragile X mental retardation 1 (FMR1), leading to decreased or absent expression of its encoded fragile X mental retardation protein (FMRP). However, the global transcriptional alteration by FMRP deficiency has not been well characterized at single nucleotide resolution, i.e., RNA-seq. Here, we performed in-vitro neuronal differentiation of human induced pluripotent stem (iPS) cells that were derived from fibroblasts of a FXS patient (FXS-iPSC)...
October 11, 2016: Science China. Life Sciences
https://www.readbyqxmd.com/read/27578169/quinidine-therapy-for-west-syndrome-with-kcnti-mutation-a-case-report
#3
Masataka Fukuoka, Ichiro Kuki, Hisashi Kawawaki, Shin Okazaki, Kiyohiro Kim, Yuka Hattori, Hitomi Tsuji, Megumi Nukui, Takeshi Inoue, Yoko Yoshida, Takehiro Uda, Sadami Kimura, Yukiko Mogami, Yasuhiro Suzuki, Nobuhiko Okamoto, Hirotomo Saitsu, Naomichi Matsumoto
The KCNT1 gene encodes the sodium-dependent potassium channel, with quinidine being a partial antagonist of the KCNT1 channel. Gain-of-function KCNT1 mutations cause early onset epileptic encephalopathies including migrating partial seizures of infancy (MPSI). At 5months of age, our patient presented with epileptic spasms and hypsarrhythmia by electroencephalogram. Psychomotor retardation was observed from early infancy. The patient was diagnosed with West syndrome. Consequently, various anti-epileptic drugs, adrenocorticotropic hormone therapy (twice), and ketogenic diet therapy were tried...
August 28, 2016: Brain & Development
https://www.readbyqxmd.com/read/27123484/paroxysmal-hypnogenic-dyskinesia-is-associated-with-mutations-in-the-prrt2-gene
#4
Xiao-Rong Liu, Dan Huang, Jie Wang, Yi-Fan Wang, Hui Sun, Bin Tang, Wen Li, Jin-Xing Lai, Na He, Mei Wu, Tao Su, Heng Meng, Yi-Wu Shi, Bing-Mei Li, Bei-Sha Tang, Wei-Ping Liao
OBJECTIVE: To explore the potential causative genes of paroxysmal hypnogenic dyskinesia (PHD), which was initially considered a subtype of paroxysmal dyskinesia and has been recently considered a form of nocturnal frontal lobe epilepsy (NFLE). METHODS: Eleven patients with PHD were recruited. Mutations in proline-rich region transmembrane protein-2 (PRRT2), myofibrillogenesis regulator 1 (MR-1), solute carrier family 2, member 1 (SLC2A1), calcium-activated potassium channel alpha subunit (KCNMA1), cholinergic receptor, nicotinic, alpha 4 (CHRNA4), cholinergic receptor, nicotinic, beta 2 (CHRNB2), cholinergic receptor, nicotinic, alpha 2 (CHRNA2), and potassium channel subfamily T member 1 (KCNT1) were screened by direct sequencing...
April 2016: Neurol Genet
https://www.readbyqxmd.com/read/27029629/a-targeted-resequencing-gene-panel-for-focal-epilepsy
#5
Michael S Hildebrand, Candace T Myers, Gemma L Carvill, Brigid M Regan, John A Damiano, Saul A Mullen, Mark R Newton, Umesh Nair, Elena V Gazina, Carol J Milligan, Christopher A Reid, Steven Petrou, Ingrid E Scheffer, Samuel F Berkovic, Heather C Mefford
OBJECTIVES: We report development of a targeted resequencing gene panel for focal epilepsy, the most prevalent phenotypic group of the epilepsies. METHODS: The targeted resequencing gene panel was designed using molecular inversion probe (MIP) capture technology and sequenced using massively parallel Illumina sequencing. RESULTS: We demonstrated proof of principle that mutations can be detected in 4 previously genotyped focal epilepsy cases...
April 26, 2016: Neurology
https://www.readbyqxmd.com/read/26993267/improving-diagnosis-and-broadening-the-phenotypes-in-early-onset-seizure-and-severe-developmental-delay-disorders-through-gene-panel-analysis
#6
Natalie Trump, Amy McTague, Helen Brittain, Apostolos Papandreou, Esther Meyer, Adeline Ngoh, Rodger Palmer, Deborah Morrogh, Christopher Boustred, Jane A Hurst, Lucy Jenkins, Manju A Kurian, Richard H Scott
BACKGROUND: We sought to investigate the diagnostic yield and mutation spectrum in previously reported genes for early-onset epilepsy and disorders of severe developmental delay. METHODS: In 400 patients with these disorders with no known underlying aetiology and no major structural brain anomaly, we analysed 46 genes using a combination of targeted sequencing on an Illumina MiSeq platform and targeted, exon-level microarray copy number analysis. RESULTS: We identified causative mutations in 71/400 patients (18%)...
May 2016: Journal of Medical Genetics
https://www.readbyqxmd.com/read/26802095/multiplex-families-with-epilepsy-success-of-clinical-and-molecular-genetic-characterization
#7
Zaid Afawi, Karen L Oliver, Sara Kivity, Aziz Mazarib, Ilan Blatt, Miriam Y Neufeld, Katherine L Helbig, Hadassa Goldberg-Stern, Adel J Misk, Rachel Straussberg, Simri Walid, Muhammad Mahajnah, Tally Lerman-Sagie, Bruria Ben-Zeev, Esther Kahana, Rafik Masalha, Uri Kramer, Dana Ekstein, Zamir Shorer, Robyn H Wallace, Marie Mangelsdorf, James N MacPherson, Gemma L Carvill, Heather C Mefford, Graeme D Jackson, Ingrid E Scheffer, Melanie Bahlo, Jozef Gecz, Sarah E Heron, Mark Corbett, John C Mulley, Leanne M Dibbens, Amos D Korczyn, Samuel F Berkovic
OBJECTIVE: To analyze the clinical syndromes and inheritance patterns of multiplex families with epilepsy toward the ultimate aim of uncovering the underlying molecular genetic basis. METHODS: Following the referral of families with 2 or more relatives with epilepsy, individuals were classified into epilepsy syndromes. Families were classified into syndromes where at least 2 family members had a specific diagnosis. Pedigrees were analyzed and molecular genetic studies were performed as appropriate...
February 23, 2016: Neurology
https://www.readbyqxmd.com/read/26785903/usefulness-of-ketogenic-diet-in-a-girl-with-migrating-partial-seizures-in-infancy
#8
Tatsuo Mori, Katsumi Imai, Taikan Oboshi, Yuh Fujiwara, Saoko Takeshita, Hirotomo Saitsu, Naomichi Matsumoto, Yukitoshi Takahashi, Yushi Inoue
Migrating partial seizures in infancy (MPSI) are an age-specific epilepsy syndrome characterized by migrating focal seizures, which are intractable to various antiepileptic drugs and cause severe developmental delay. We report a case of MPSI with heterozygous missense mutation in KCNT1, which was successfully managed by ketogenic diet. At age 2months, the patient developed epilepsy initially manifesting focal seizures with eye deviation and apnea, then evolving to secondarily generalized clonic convulsion. Various antiepileptic drugs including phenytoin, valproic acid, zonisamide, clobazam, levetiracetam, vitamin B6, and carbamazepine were not effective, but high-dose phenobarbital allowed discontinuation of midazolam infusion...
June 2016: Brain & Development
https://www.readbyqxmd.com/read/26784557/characterization-of-two-de-novokcnt1-mutations-in-children-with-malignant-migrating-partial-seizures-in-infancy
#9
Francesca Rizzo, Paolo Ambrosino, Anna Guacci, Massimiliano Chetta, Giovanna Marchese, Teresa Rocco, Maria Virginia Soldovieri, Laura Manocchio, Ilaria Mosca, Gianluca Casara, Marilena Vecchi, Maurizio Taglialatela, Giangennaro Coppola, Alessandro Weisz
The KCNT1 gene encodes for subunits contributing to the Na(+)-activated K(+) current (KNa), expressed in many cell types. Mutations in KCNT1 have been found in patients affected with a wide spectrum of early-onset epilepsies, including Malignant Migrating Partial Seizures in Infancy (MMPSI), a severe early-onset epileptic encephalopathy characterized by pharmacoresistant focal seizures migrating from one brain region or hemisphere to another and neurodevelopment arrest or regression, resulting in profound disability...
April 2016: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/26740507/kcnt1-mutations-in-seizure-disorders-the-phenotypic-spectrum-and-functional-effects
#10
REVIEW
Chiao Xin Lim, Michael G Ricos, Leanne M Dibbens, Sarah E Heron
Mutations in the sodium-gated potassium channel subunit gene KCNT1 have recently emerged as a cause of several different epileptic disorders. This review describes the mutational and phenotypic spectrum associated with the gene and discusses the comorbidities found in patients, which include intellectual disability and psychiatric features. The gene may also be linked with cardiac disorders. KCNT1 missense mutations have been found in 39% of patients with the epileptic encephalopathy malignant migrating focal seizures of infancy (MMFSI), making it the most significant MMFSI disease-causing gene identified to date...
April 2016: Journal of Medical Genetics
https://www.readbyqxmd.com/read/26725113/epilepsy-related-slack-channel-mutants-lead-to-channel-over-activity-by-two-different-mechanisms
#11
Qiong-Yao Tang, Fei-Fei Zhang, Jie Xu, Ran Wang, Jian Chen, Diomedes E Logothetis, Zhe Zhang
Twelve sodium-activated potassium channel (KCNT1, Slack) genetic mutants have been identified from severe early-onset epilepsy patients. The changes in biophysical properties of these mutants and the underlying mechanisms causing disease remain elusive. Here, we report that seven of the 12 mutations increase, whereas one mutation decreases, the channel's sodium sensitivity. Two of the mutants exhibit channel over-activity only when the intracellular Na(+) ([Na(+)]i) concentration is ∼80 mM. In contrast, single-channel data reveal that all 12 mutants increase the maximal open probability (Po)...
January 5, 2016: Cell Reports
https://www.readbyqxmd.com/read/26648591/unexplained-early-onset-epileptic-encephalopathy-exome-screening-and-phenotype-expansion
#12
Nicholas M Allen, Judith Conroy, Amre Shahwan, Bryan Lynch, Raony G Correa, Sergio D J Pena, Dara McCreary, Tiago R Magalhães, Sean Ennis, Sally A Lynch, Mary D King
Early onset epileptic encephalopathies (EOEEs) represent a significant diagnostic challenge. Newer genomic approaches have begun to elucidate an increasing number of responsible single genes as well as emerging diagnostic strategies. In this single-center study, we aimed to investigate a cohort of children with unexplained EOEE. We performed whole-exome sequencing (WES), targeting a list of 137 epilepsy-associated genes on 50 children with unexplained EOEE. We characterized all phenotypes in detail and classified children according to known electroclinical syndromes where possible...
January 2016: Epilepsia
https://www.readbyqxmd.com/read/26597493/genetic-heterogeneity-in-26-infants-with-a-hypomyelinating-leukodystrophy
#13
Natsuko Arai-Ichinoi, Mitsugu Uematsu, Ryo Sato, Tasuku Suzuki, Hiroki Kudo, Atsuo Kikuchi, Naomi Hino-Fukuyo, Mitsuyo Matsumoto, Kazuhiko Igarashi, Kazuhiro Haginoya, Shigeo Kure
T2 hyperintensity of brain white matter lesions detected by magnetic resonance imaging (MRI) are characteristic of a heterogeneous group of diseases. Persistent T2 high intensity in combination with T1 iso- or high intensity of white matter in infants indicates a lack of normal myelination, that is, hypomyelination. However, the precise diagnosis of hypomyelinating leukodystrophy based solely on MRI findings can be difficult, especially in the early stage of the disease. We studied 26 patients who were diagnosed with hypomyelinating leukodystrophy according to MRI findings and clinical features to uncover their genetic etiology through chromosomal analyses, targeted gene analyses, and an array comparative genomic hybridization (aCGH) assay...
January 2016: Human Genetics
https://www.readbyqxmd.com/read/26587966/differential-distribution-of-the-sodium-activated-potassium-channels-slick-and-slack-in-mouse-brain
#14
Sandra Rizzi, Hans-Günther Knaus, Christoph Schwarzer
The sodium-activated potassium channels Slick (Slo2.1, KCNT2) and Slack (Slo2.2, KCNT1) are high-conductance potassium channels of the Slo family. In neurons, Slick and Slack channels are involved in the generation of slow afterhyperpolarization, in the regulation of firing patterns, and in setting and stabilizing the resting membrane potential. The distribution and subcellular localization of Slick and Slack channels in the mouse brain have not yet been established in detail. The present study addresses this issue through in situ hybridization and immunohistochemistry...
July 1, 2016: Journal of Comparative Neurology
https://www.readbyqxmd.com/read/26559620/knockout-of-slo2-2-enhances-itch-abolishes-kna-current-and-increases-action-potential-firing-frequency-in-drg-neurons
#15
Pedro L Martinez-Espinosa, Jianping Wu, Chengtao Yang, Vivian Gonzalez-Perez, Huifang Zhou, Hongwu Liang, Xiao-Ming Xia, Christopher J Lingle
Two mammalian genes, Kcnt1 and Kcnt2, encode pore-forming subunits of Na(+)-dependent K(+) (KNa) channels. Progress in understanding KNa channels has been hampered by the absence of specific tools and methods for rigorous KNa identification in native cells. Here, we report the genetic disruption of both Kcnt1 and Kcnt2, confirm the loss of Slo2.2 and Slo2.1 protein, respectively, in KO animals, and define tissues enriched in Slo2 expression. Noting the prevalence of Slo2.2 in dorsal root ganglion, we find that KO of Slo2...
November 11, 2015: ELife
https://www.readbyqxmd.com/read/26369628/quinidine-in-the-treatment-of-kcnt1-positive-epilepsies
#16
Mohamad A Mikati, Yong-Hui Jiang, Michael Carboni, Vandana Shashi, Slave Petrovski, Rebecca Spillmann, Carol J Milligan, Melody Li, Annette Grefe, Allyn McConkie, Samuel Berkovic, Ingrid Scheffer, Saul Mullen, Melanie Bonner, Steven Petrou, David Goldstein
We report 2 patients with drug-resistant epilepsy caused by KCNT1 mutations who were treated with quinidine. Both mutations manifested gain of function in vitro, showing increased current that was reduced by quinidine. One, who had epilepsy of infancy with migrating focal seizures, had 80% reduction in seizure frequency as recorded in seizure diaries, and partially validated by objective seizure evaluation on EEG. The other, who had a novel phenotype, with severe nocturnal focal and secondary generalized seizures starting in early childhood with developmental regression, did not improve...
December 2015: Annals of Neurology
https://www.readbyqxmd.com/read/26140313/de-novo-kcnt1-mutations-in-early-onset-epileptic-encephalopathy
#17
Chihiro Ohba, Mitsuhiro Kato, Nobuya Takahashi, Hitoshi Osaka, Takashi Shiihara, Jun Tohyama, Shin Nabatame, Junji Azuma, Yuji Fujii, Munetsugu Hara, Reimi Tsurusawa, Takahito Inoue, Reina Ogata, Yoriko Watanabe, Noriko Togashi, Hirofumi Kodera, Mitsuko Nakashima, Yoshinori Tsurusaki, Noriko Miyake, Fumiaki Tanaka, Hirotomo Saitsu, Naomichi Matsumoto
KCNT1 mutations have been found in epilepsy of infancy with migrating focal seizures (EIMFS; also known as migrating partial seizures in infancy), autosomal dominant nocturnal frontal lobe epilepsy, and other types of early onset epileptic encephalopathies (EOEEs). We performed KCNT1-targeted next-generation sequencing (207 samples) and/or whole-exome sequencing (229 samples) in a total of 362 patients with Ohtahara syndrome, West syndrome, EIMFS, or unclassified EOEEs. We identified nine heterozygous KCNT1 mutations in 11 patients: nine of 18 EIMFS cases (50%) in whom migrating foci were observed, one of 180 West syndrome cases (0...
September 2015: Epilepsia
https://www.readbyqxmd.com/read/26122718/mutations-in-kcnt1-cause-a-spectrum-of-focal-epilepsies
#18
Rikke S Møller, Sarah E Heron, Line H G Larsen, Chiao Xin Lim, Michael G Ricos, Marta A Bayly, Marjan J A van Kempen, Sylvia Klinkenberg, Ian Andrews, Kent Kelley, Gabriel M Ronen, David Callen, Jacinta M McMahon, Simone C Yendle, Gemma L Carvill, Heather C Mefford, Rima Nabbout, Annapurna Poduri, Pasquale Striano, Maria G Baglietto, Federico Zara, Nicholas J Smith, Clair Pridmore, Elena Gardella, Marina Nikanorova, Hans Atli Dahl, Pia Gellert, Ingrid E Scheffer, Boudewijn Gunning, Bente Kragh-Olsen, Leanne M Dibbens
Autosomal dominant mutations in the sodium-gated potassium channel subunit gene KCNT1 have been associated with two distinct seizure syndromes, nocturnal frontal lobe epilepsy (NFLE) and malignant migrating focal seizures of infancy (MMFSI). To further explore the phenotypic spectrum associated with KCNT1, we examined individuals affected with focal epilepsy or an epileptic encephalopathy for mutations in the gene. We identified KCNT1 mutations in 12 previously unreported patients with focal epilepsy, multifocal epilepsy, cardiac arrhythmia, and in a family with sudden unexpected death in epilepsy (SUDEP), in addition to patients with NFLE and MMFSI...
September 2015: Epilepsia
https://www.readbyqxmd.com/read/26105150/rare-and-low-frequency-variants-and-their-association-with-plasma-levels-of-fibrinogen-fvii-fviii-and-vwf
#19
Jennifer E Huffman, Paul S de Vries, Alanna C Morrison, Maria Sabater-Lleal, Tim Kacprowski, Paul L Auer, Jennifer A Brody, Daniel I Chasman, Ming-Huei Chen, Xiuqing Guo, Li-An Lin, Riccardo E Marioni, Martina Müller-Nurasyid, Lisa R Yanek, Nathan Pankratz, Megan L Grove, Moniek P M de Maat, Mary Cushman, Kerri L Wiggins, Lihong Qi, Bengt Sennblad, Sarah E Harris, Ozren Polasek, Helene Riess, Fernando Rivadeneira, Lynda M Rose, Anuj Goel, Kent D Taylor, Alexander Teumer, André G Uitterlinden, Dhananjay Vaidya, Jie Yao, Weihong Tang, Daniel Levy, Melanie Waldenberger, Diane M Becker, Aaron R Folsom, Franco Giulianini, Andreas Greinacher, Albert Hofman, Chiang-Ching Huang, Charles Kooperberg, Angela Silveira, John M Starr, Konstantin Strauch, Rona J Strawbridge, Alan F Wright, Barbara McKnight, Oscar H Franco, Neil Zakai, Rasika A Mathias, Bruce M Psaty, Paul M Ridker, Geoffrey H Tofler, Uwe Völker, Hugh Watkins, Myriam Fornage, Anders Hamsten, Ian J Deary, Eric Boerwinkle, Wolfgang Koenig, Jerome I Rotter, Caroline Hayward, Abbas Dehghan, Alex P Reiner, Christopher J O'Donnell, Nicholas L Smith
Fibrinogen, coagulation factor VII (FVII), and factor VIII (FVIII) and its carrier von Willebrand factor (vWF) play key roles in hemostasis. Previously identified common variants explain only a small fraction of the trait heritabilities, and additional variations may be explained by associations with rarer variants with larger effects. The aim of this study was to identify low-frequency (minor allele frequency [MAF] ≥0.01 and <0.05) and rare (MAF <0.01) variants that influence plasma concentrations of these 4 hemostatic factors by meta-analyzing exome chip data from up to 76,000 participants of 4 ancestries...
September 10, 2015: Blood
https://www.readbyqxmd.com/read/26100633/transcriptional-regulation-of-the-sodium-activated-potassium-channel-slick-kcnt2-promoter-by-nuclear-factor-%C3%AE%C2%BAb
#20
Danielle L Tomasello, Amy M Gancarz-Kausch, David M Dietz, Arin Bhattacharjee
Although recent studies have shown the sodium-activated potassium channel SLACK (KCNT1) can contribute to neuronal excitability, there remains little information on the physiological role of the closely related SLICK (KCNT2) channel. Activation of SLICK channels may be important during pathological states such as ischemia, in which an increase in intracellular sodium and chloride can perturb membrane potential and ion homeostasis. We have identified two NFκB-binding sites within the promoter region of the human SLICK (KCNT2) and orthologous rat Slick (Kcnt2) genes, suggesting that conditions in which NFκB transcriptional activity is elevated promote expression of this channel...
July 24, 2015: Journal of Biological Chemistry
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