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https://www.readbyqxmd.com/read/27888506/rapid-and-safe-response-to-low-dose-carbamazepine-in-neonatal-epilepsy
#1
Tristan T Sands, Martina Balestri, Giulia Bellini, Sarah B Mulkey, Olivier Danhaive, Eliza Hayes Bakken, Maurizio Taglialatela, Michael S Oldham, Federico Vigevano, Gregory L Holmes, Maria Roberta Cilio
OBJECTIVE: To evaluate treatment responses in benign familial neonatal epilepsy (BFNE). METHODS: We recruited patients with BFNE through a multicenter international collaboration and reviewed electroclinical and genetic details, and treatment response. All patients were tested at minimum for mutations/deletions in the KCNQ2, KCNQ3, and SCN2A genes. RESULTS: Nineteen patients were included in this study. A family history of neonatal seizures was positive in 16 patients, and one additional patient had a family history of infantile seizures...
November 26, 2016: Epilepsia
https://www.readbyqxmd.com/read/27864847/diagnostic-targeted-resequencing-in-349-patients-with-drug-resistant-pediatric-epilepsies-identifies-causative-mutations-in-30-different-genes
#2
Elena Parrini, Carla Marini, Davide Mei, Anna Galuppi, Elena Cellini, Daniela Pucatti, Laura Chiti, Domenico Rutigliano, Claudia Bianchini, Simona Virdò, Dalila De Vita, Stefania Bigoni, Carmen Barba, Francesco Mari, Martino Montomoli, Tiziana Pisano, Anna Rosati, Renzo Guerrini
Targeted resequencing gene panels are used in the diagnostic setting to identify gene defects in epilepsy. We performed targeted resequencing using a 30-genes panel and a 95-genes panel in 349 patients with drug-resistant epilepsies beginning in the first years of life. We identified 71 pathogenic variants, 42 of which novel, in 30 genes, corresponding to 20.3% of the probands. In 66% of mutation positive patients seizures onset occurred before age 6 months. The 95-genes panel allowed a genetic diagnosis in 22 (6...
November 19, 2016: Human Mutation
https://www.readbyqxmd.com/read/27861786/infantile-spasms-and-encephalopathy-without-preceding-neonatal-seizures-caused-by-kcnq2-r198q-a-gain-of-function-variant
#3
John J Millichap, Francesco Miceli, Michela De Maria, Cynthia Keator, Nishtha Joshi, Baouyen Tran, Maria Virginia Soldovieri, Paolo Ambrosino, Vandana Shashi, Mohamad A Mikati, Edward C Cooper, Maurizio Taglialatela
Variants in KCNQ2 encoding for Kv 7.2 neuronal K(+) channel subunits lead to a spectrum of neonatal-onset epilepsies, ranging from self-limiting forms to severe epileptic encephalopathy. Most KCNQ2 pathogenic variants cause loss-of-function, whereas few increase channel activity (gain-of-function). We herein provide evidence for a new phenotypic and functional profile in KCNQ2-related epilepsy: infantile spasms without prior neonatal seizures associated with a gain-of-function gene variant. With use of an international registry, we identified four unrelated patients with the same de novo heterozygous KCNQ2 c...
November 9, 2016: Epilepsia
https://www.readbyqxmd.com/read/27857203/rapid-and-efficient-crispr-cas9-gene-inactivation-in-human-neurons-during-human-pluripotent-stem-cell-differentiation-and-direct-reprogramming
#4
Alicia Rubio, Mirko Luoni, Serena G Giannelli, Isabella Radice, Angelo Iannielli, Cinzia Cancellieri, Claudia Di Berardino, Giulia Regalia, Giovanna Lazzari, Andrea Menegon, Stefano Taverna, Vania Broccoli
The CRISPR/Cas9 system is a rapid and customizable tool for gene editing in mammalian cells. In particular, this approach has widely opened new opportunities for genetic studies in neurological disease. Human neurons can be differentiated in vitro from hPSC (human Pluripotent Stem Cells), hNPCs (human Neural Precursor Cells) or even directly reprogrammed from fibroblasts. Here, we described a new platform which enables, rapid and efficient CRISPR/Cas9-mediated genome targeting simultaneously with three different paradigms for in vitro generation of neurons...
November 18, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27781560/precision-medicine-in-genetic-epilepsies-break-of-dawn
#5
Philipp Sebastian Reif, Meng-Han Tsai, Ingo Helbig, Felix Rosenow, Karl Martin Klein
Therapy with current antiepileptic drugs aims at reducing the likelihood of seizure occurrence rather than influencing the underlying disease process. Therefore, antiepileptic drugs have an anticonvulsant rather than antiepileptic property. Areas covered: The increasing identification of genetic causes for epilepsy over the recent years improves the understanding of the underlying epileptogenic process and allows for the possibility of directed therapeutic approaches. An ideal antiepileptic therapy consists of a drug which is able to influence the functional changes caused by a specific pathogenic variant...
November 10, 2016: Expert Review of Neurotherapeutics
https://www.readbyqxmd.com/read/27781029/novel-kcnq3-mutation-in-a-large-family-with-benign-familial-neonatal-epilepsy-a-rare-cause-of-neonatal-seizures
#6
Snezana Maljevic, Sabina Vejzovic, Matthias K Bernhard, Astrid Bertsche, Sebastian Weise, Miriam Döcker, Holger Lerche, Johannes R Lemke, Andreas Merkenschlager, Steffen Syrbe
Benign familial neonatal seizures (BFNS) present a rare familial epilepsy syndrome caused by genetic alterations in the voltage-gated potassium channels Kv7.2 and Kv7.3, encoded by KCNQ2 and KCNQ3. While most BFNS families carry alterations in KCNQ2, mutations in KCNQ3 appear to be less common. Here, we describe a family with 6 individuals presenting with neonatal focal and generalized seizures. Genetic testing revealed a novel KCNQ3 variant, c.835G>T, cosegregating with seizures in 4 tested individuals...
September 2016: Molecular Syndromology
https://www.readbyqxmd.com/read/27779742/gene-mutation-analysis-of-175-chinese-patients-with-early-onset-epileptic-encephalopathy
#7
Qingping Zhang, Jiarui Li, Ying Zhao, Xinhua Bao, Liping Wei, Jiaping Wang
To investigate the genetic characteristics and clinical features of a cohort of Chinese patients with early-onset epileptic encephalopathies (EOEEs). Targeted next-generation sequencing (NGS), focusing on 17 genes, was performed on 175 Chinese patients with EOEEs to screen gene mutations. The mutation rate was 32% (56/175). All mutations were de novo and heterozygous, including 41 novel and 15 reported mutations. Patients with cyclin-dependent kinase-like 5 (CDKL5) gene mutation accounted for the largest proportion-13...
October 25, 2016: Clinical Genetics
https://www.readbyqxmd.com/read/27734276/targeted-next-generation-sequencing-the-diagnostic-value-in-early-onset-epileptic-encephalopathy
#8
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
https://www.readbyqxmd.com/read/27693347/genome-wide-association-study-identifies-african-specific-susceptibility-loci-in-african-americans-with-inflammatory-bowel-disease
#9
Steven R Brant, David T Okou, Claire L Simpson, David J Cutler, Talin Haritunians, Jonathan P Bradfield, Pankaj Chopra, Jarod Prince, Ferdouse Begum, Archana Kumar, Chengrui Huang, Suresh Venkateswaran, Lisa W Datta, Zhi Wei, Kelly Thomas, Lisa J Herrinton, Jan-Micheal A Klapproth, Antonio J Quiros, Jenifer Seminerio, Zhenqiu Liu, Jonathan S Alexander, Robert N Baldassano, Sharon Dudley-Brown, Raymond K Cross, Themistocles Dassopoulos, Lee A Denson, Tanvi A Dhere, Gerald W Dryden, John S Hanson, Jason K Hou, Sunny Z Hussain, Jeffrey S Hyams, Kim L Isaacs, Howard Kader, Michael D Kappelman, Jeffry Katz, Richard Kellermayer, Barbara S Kirschner, John F Kuemmerle, John H Kwon, Mark Lazarev, Ellen Li, David Mack, Peter Mannon, Dedrick E Moulton, Rodney D Newberry, Bankole O Osuntokun, Ashish S Patel, Shehzad A Saeed, Stephan R Targan, John F Valentine, Ming-Hsi Wang, Martin Zonca, John D Rioux, Richard H Duerr, Mark S Silverberg, Judy H Cho, Hakon Hakonarson, Michael E Zwick, Dermot P B McGovern, Subra Kugathasan
BACKGROUND & AIMS: The inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn's disease (CD) cause significant morbidity and are increasing in prevalence among all populations, including African Americans. More than 200 susceptibility loci have been identified in populations of predominantly European ancestry, but few loci have been associated with IBD in other ethnicities. METHODS: We performed 2 high-density, genome-wide scans comprising 2345 cases of African Americans with IBD (1646 with CD, 583 with UC, and 116 inflammatory bowel disease unclassified) and 5002 individuals without IBD (controls, identified from the Health Retirement Study and Kaiser Permanente database)...
September 28, 2016: Gastroenterology
https://www.readbyqxmd.com/read/27607834/pharmacophore-modeling-3d-qsar-and-in-silico-adme-prediction-of-n-pyridyl-and-pyrimidine-benzamides-as-potent-antiepileptic-agents
#10
Ruchi Malik, Pakhuri Mehta, Shubham Srivastava, Bhanwar Singh Choudhary, Manish Sharma
Biological mechanism attributing mutations in KCNQ2/Q3 results in benign familial neonatal epilepsy (BFNE), a rare form of epilepsy and thus neglected. It offers a potential target for antiepileptic drug discovery. In the present work, a pharmacophore-based 3D-QSAR model was generated for a series of N-pyridyl and pyrimidine benzamides possessing KCNQ2/Q3 opening activity. The pharmacophore model generated contains one hydrogen bond donor (D), one hydrophobic (H), and two aromatic rings (R). They are the crucial molecular write-up detailing predicted binding efficacy of high affinity and low affinity ligands for KCNQ2/Q3 opening activity...
September 8, 2016: Journal of Receptor and Signal Transduction Research
https://www.readbyqxmd.com/read/27602407/kcnq2-encephalopathy-features-mutational-hot-spots-and-ezogabine-treatment-of-11-patients
#11
John J Millichap, Kristen L Park, Tammy Tsuchida, Bruria Ben-Zeev, Lionel Carmant, Robert Flamini, Nishtha Joshi, Paul M Levisohn, Eric Marsh, Srishti Nangia, Vinodh Narayanan, Xilma R Ortiz-Gonzalez, Marc C Patterson, Phillip L Pearl, Brenda Porter, Keri Ramsey, Emily L McGinnis, Maurizio Taglialatela, Molly Tracy, Baouyen Tran, Charu Venkatesan, Sarah Weckhuysen, Edward C Cooper
OBJECTIVE: To advance the understanding of KCNQ2 encephalopathy genotype-phenotype relationships and to begin to assess the potential of selective KCNQ channel openers as targeted treatments. METHODS: We retrospectively studied 23 patients with KCNQ2 encephalopathy, including 11 treated with ezogabine (EZO). We analyzed the genotype-phenotype relationships in these and 70 previously described patients. RESULTS: The mean seizure onset age was 1...
October 2016: Neurology. Genetics
https://www.readbyqxmd.com/read/27590358/a-novel-muscarinic-receptor-independent-mechanism-of-kcnq2-3-potassium-channel-blockade-by-oxotremorine-m
#12
Ruud Zwart, Hannah Reed, Sophie Clarke, Emanuele Sher
Inhibition of KCNQ (Kv7) potassium channels by activation of muscarinic acetylcholine receptors has been well established, and the ion currents through these channels have been long known as M-currents. We found that this cross-talk can be reconstituted in Xenopus oocytes by co-transfection of human recombinant muscarinic M1 receptors and KCNQ2/3 potassium channels. Application of the muscarinic acetylcholine receptor agonist Oxotremorine-methiodide (Oxo-M) between voltage pulses to activate KCNQ2/3 channels caused inhibition of the subsequent KCNQ2/3 responses...
August 31, 2016: European Journal of Pharmacology
https://www.readbyqxmd.com/read/27535030/clinical-and-genetic-features-of-13-spanish-patients-with-kcnq2-mutations
#13
Montesclaros Hortigüela, Ana Fernández-Marmiesse, Verónica Cantarín, Sofía Gouveia, Juan J García-Peñas, Carmen Fons, Judith Armstrong, Desirée Barrios, Felícitas Díaz-Flores, Pilar Tirado, María L Couce, Luis G Gutiérrez-Solana
The KCNQ2 gene codifies a subunit of the voltage-gated potassium M channel underlying the neuronal M-current. Classically, mutations in this gene have been associated with benign familial neonatal seizures, however, in recent years KCNQ2 mutations have been reported associated to early-onset epileptic encephalopathy. In this work, detailed familiar, clinical and genetic data were collected for 13 KCNQ2-positive patients revealed among a cohort of 80 epileptic pediatric probands from Spain who were analyzed through a targeted next-generation sequencing assay for 155 epilepsy-associated genes...
August 18, 2016: Journal of Human Genetics
https://www.readbyqxmd.com/read/27506413/sequence-determinants-of-subtype-specific-actions-of-kcnq-channel-openers
#14
Alice W Wang, Runying Yang, Harley T Kurata
Retigabine is the first approved anti-epileptic drug that acts via activation of voltage-gated potassium channels, targeting KCNQ channels that underlie the neuronal M-current. Retigabine exhibits little specificity between KCNQ2-5, due to conservation of a Trp residue in the pore domain that binds to the drug. The retigabine analog ICA-069673 ('ICA73') exhibits much stronger effects on KCNQ2 channels, including a large hyperpolarizing shift of the voltage-dependence of activation, roughly two-fold enhancement of peak current, and pronounced subtype specificity for KCNQ2 over KCNQ3...
August 9, 2016: Journal of Physiology
https://www.readbyqxmd.com/read/27466704/protein-arginine-methylation-facilitates-kcnq-channel-pip2-interaction-leading-to-seizure-suppression
#15
Hyun-Ji Kim, Myong-Ho Jeong, Kyung-Ran Kim, Chang-Yun Jung, Seul-Yi Lee, Hanna Kim, Jewoo Koh, Tuan Anh Vuong, Seungmoon Jung, Hyunwoo Yang, Su-Kyung Park, Dahee Choi, Sung Hun Kim, KyeongJin Kang, Jong-Woo Sohn, Joo Min Park, Daejong Jeon, Seung-Hoi Koo, Won-Kyung Ho, Jong-Sun Kang, Seong-Tae Kim, Hana Cho
KCNQ channels are critical determinants of neuronal excitability, thus emerging as a novel target of anti-epileptic drugs. To date, the mechanisms of KCNQ channel modulation have been mostly characterized to be inhibitory via Gq-coupled receptors, Ca(2+)/CaM, and protein kinase C. Here we demonstrate that methylation of KCNQ by protein arginine methyltransferase 1 (Prmt1) positively regulates KCNQ channel activity, thereby preventing neuronal hyperexcitability. Prmt1+/- mice exhibit epileptic seizures. Methylation of KCNQ2 channels at 4 arginine residues by Prmt1 enhances PIP2 binding, and Prmt1 depletion lowers PIP2 affinity of KCNQ2 channels and thereby the channel activities...
July 28, 2016: ELife
https://www.readbyqxmd.com/read/27450567/suppression-of-kv7-kcnq-potassium-channel-enhances-neuronal-differentiation-of-pc12-cells
#16
Najing Zhou, Sha Huang, Li Li, Dongyang Huang, Yunli Yan, Xiaona Du, Hailin Zhang
Membrane potential shift driven by electrical activity is critical in determining the cell fate of proliferation or differentiation. As such, the ion channels that underlie the membrane electrical activity play an important role in cell proliferation/differentiation. KV7/KCNQ potassium channels are critical in determining the resting membrane potentials in many neuronal cells. However, the role of these channels in cell differentiation is not well studied. In the present study, we used PC12 cells as well as primary cultured rat cortical neurons to study the role and mechanism of KV7/KCNQ in neuronal differentiation...
October 1, 2016: Neuroscience
https://www.readbyqxmd.com/read/27217553/osmoregulatory-inositol-transporter-smit1-modulates-electrical-activity-by-adjusting-pi-4-5-p2-levels
#17
Gucan Dai, Haijie Yu, Martin Kruse, Alexis Traynor-Kaplan, Bertil Hille
Myo-inositol is an important cellular osmolyte in autoregulation of cell volume and fluid balance, particularly for mammalian brain and kidney cells. We find it also regulates excitability. Myo-inositol is the precursor of phosphoinositides, key signaling lipids including phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. However, whether myo-inositol accumulation during osmoregulation affects signaling and excitability has not been fully explored. We found that overexpression of the Na(+)/myo-inositol cotransporter (SMIT1) and myo-inositol supplementation enlarged intracellular PI(4,5)P2 pools, modulated several PI(4,5)P2-dependent ion channels including KCNQ2/3 channels, and attenuated the action potential firing of superior cervical ganglion neurons...
June 7, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27030113/a-kv7-2-mutation-associated-with-early-onset-epileptic-encephalopathy-with-suppression-burst-enhances-kv7-m-channel-activity
#18
Jérôme Devaux, Affef Abidi, Agathe Roubertie, Florence Molinari, Hélène Becq, Caroline Lacoste, Laurent Villard, Mathieu Milh, Laurent Aniksztejn
Mutations in the KCNQ2 gene encoding the voltage-gated potassium channel subunit Kv7.2 cause early onset epileptic encephalopathy (EOEE). Most mutations have been shown to induce a loss of function or to affect the subcellular distribution of Kv7 channels in neurons. Herein, we investigated functional consequences and subcellular distribution of the p.V175L mutation of Kv7.2 (Kv7.2(V175L) ) found in a patient presenting EOEE. We observed that the mutation produced a 25-40 mV hyperpolarizing shift of the conductance-voltage relationship of both the homomeric Kv7...
May 2016: Epilepsia
https://www.readbyqxmd.com/read/27005699/synthesis-and-evaluation-of-potent-kcnq2-3-specific-channel-activators
#19
Manoj Kumar, Nicholas Reed, Ruiting Liu, Elias Aizenman, Peter Wipf, Thanos Tzounopoulos
KQT-like subfamily (KCNQ) channels are voltage-gated, noninactivating potassium ion channels, and their down-regulation has been implicated in several hyperexcitability-related disorders, including epilepsy, neuropathic pain, and tinnitus. Activators of these channels reduce the excitability of central and peripheral neurons, and, as such, have therapeutic utility. Here, we synthetically modified several moieties of the KCNQ2-5 channel activator retigabine, an anticonvulsant approved by the U.S. Food and Drug Administration...
June 2016: Molecular Pharmacology
https://www.readbyqxmd.com/read/26993565/severe-neonatal-seizures-from-molecular-diagnosis-to-precision-therapy
#20
REVIEW
M Milh, P Cacciagli, C Ravix, C Badens, A Lépine, N Villeneuve, L Villard
Early onset epileptic encephalopathies (EOEE) are heterogeneous group of severe epilepsies that still need to be better defined and characterized. On a genetic point of view, several dozen of genes have been associated with EOEE, and to date, it is difficult to find a common mechanism to explain EOEE. In this short review, we show that two mains genes are involved in EOEE: STXBP1 and KCNQ2. Focusing on KCNQ2 related EOEE, we show that a relatively similar phenotype can be related to various consequences of mutations on a single gene...
March 2016: Revue Neurologique
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