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https://www.readbyqxmd.com/read/28139826/neonatal-nonepileptic-myoclonus-is-a-prominent-clinical-feature-of-kcnq2-gain-of-function-variants-r201c-and-r201h
#1
Sarah B Mulkey, Bruria Ben-Zeev, Joost Nicolai, John L Carroll, Sabine Grønborg, Yong-Hui Jiang, Nishtha Joshi, Megan Kelly, David A Koolen, Mohamad A Mikati, Kristen Park, Phillip L Pearl, Ingrid E Scheffer, Rebecca C Spillmann, Maurizio Taglialatela, Silvia Vieker, Sarah Weckhuysen, Edward C Cooper, Maria Roberta Cilio
OBJECTIVE: To analyze whether KCNQ2 R201C and R201H variants, which show atypical gain-of-function electrophysiologic properties in vitro, have a distinct clinical presentation and outcome. METHODS: Ten children with heterozygous, de novo KCNQ2 R201C or R201H variants were identified worldwide, using an institutional review board (IRB)-approved KCNQ2 patient registry and database. We reviewed medical records and, where possible, interviewed parents and treating physicians using a structured, detailed phenotype inventory focusing on the neonatal presentation and subsequent course...
January 31, 2017: Epilepsia
https://www.readbyqxmd.com/read/28133863/genetics-and-genotype-phenotype-correlations-in-early-onset-epileptic-encephalopathy-with-burst-suppression
#2
Heather E Olson, McKenna Kelly, Christopher M LaCoursiere, Rebecca Pinsky, Dimira Tambunan, Catherine Shain, Sriram Ramgopal, Masanori Takeoka, Mark H Libenson, Kristina Julich, Tobias Loddenkemper, Eric D Marsh, Devorah Segal, Susan Koh, Michael S Salman, Alex R Paciorkowski, Edward Yang, Ann M Bergin, Beth Rosen Sheidley, Annapurna Poduri
OBJECTIVE: We sought to identify genetic causes of early onset epileptic encephalopathies with burst suppression (Ohtahara syndrome and early myoclonic encephalopathy) and evaluate genotype-phenotype correlations. METHODS: We enrolled 33 patients with a referral diagnosis of Ohtahara syndrome or early myoclonic encephalopathy without malformations of cortical development. We performed detailed phenotypic assessment including seizure presentation, EEG, and MRI. We confirmed burst suppression in 28 out of 33 patients...
January 30, 2017: Annals of Neurology
https://www.readbyqxmd.com/read/28125509/kcnq2-3-channel-agonist-flupirtine-reduces-cocaine-place-preference-in-rats
#3
James Mooney, Scott M Rawls
The efficacy of KCNQ2/3 channel agonists against drug reward has not been defined despite their ability to reduce locomotor-stimulant and dopamine-activating effects of psychostimulants. We tested the hypothesis that flupirtine (FLU) (2.5, 10, 20 mg/kg), a KCNQ2/3 agonist, reduces cocaine (15 mg/kg) conditioned place preference. FLU (20 mg/kg), injected concurrently with cocaine during conditioning, reduced the development of cocaine conditioned place preference. FLU (20 mg/kg) also reduced cocaine locomotor activation without affecting baseline activity...
January 25, 2017: Behavioural Pharmacology
https://www.readbyqxmd.com/read/28100740/epilepsy-associated-kcnq2-channels-regulate-multiple-intrinsic-properties-of-layer-2-3-pyramidal-neurons
#4
Zachary Niday, Virginia E Hawkins, Heun Soh, Daniel K Mulkey, Anastasios V Tzingounis
: KCNQ2 potassium channels are critical for normal brain function, as both loss-of-function and gain-of-function KCNQ2 variants can lead to various forms of neonatal epilepsy. Despite recent progress, the full spectrum of consequences as a result of KCNQ2 dysfunction in neocortical pyramidal neurons is still unknown. Here, we report that conditional ablation of Kcnq2 from mouse neocortex leads to hyperexcitability of layer 2/3 (L2/3) pyramidal neurons, exhibiting an increased input resistance and action potential frequency, as well as a reduced medium afterhyperpolarization (mAHP), a conductance partly mediated by KCNQ2 channels...
January 18, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28038823/a-kcnq2-e515d-mutation-associated-with-benign-familial-neonatal-seizures-and-continuous-spike-and-waves-during-slow-wave-sleep-syndrome-in-taiwan
#5
Inn-Chi Lee, Jiann-Jou Yang, Shuan-Yow Li
BACKGROUND/PURPOSE: Pediatric epilepsy caused by a KCNQ2 gene mutation usually manifests as benign familial neonatal seizures (BFNS) during the 1(st) week of life. However, the exact mechanism, phenotype, and genotype of the KCNQ2 mutation are unclear. METHODS: We studied the KCNQ2 genotype from 75 nonconsanguineous patients with childhood epilepsy without an identified cause (age range: from 2 days to 18 years) and from 55 healthy adult controls without epilepsy...
December 27, 2016: Journal of the Formosan Medical Association, Taiwan Yi Zhi
https://www.readbyqxmd.com/read/27994149/fgf14-is-a-regulator-of-kcnq2-3-channels
#6
Juan Lorenzo Pablo, Geoffrey S Pitt
KCNQ2/3 (Kv7.2/7.3) channels and voltage-gated sodium channels (VGSCs) are enriched in the axon initial segment (AIS) where they bind to ankyrin-G and coregulate membrane potential in central nervous system neurons. The molecular mechanisms supporting coordinated regulation of KCNQ and VGSCs and the cellular mechanisms governing KCNQ trafficking to the AIS are incompletely understood. Here, we show that fibroblast growth factor 14 (FGF14), previously described as a VGSC regulator, also affects KCNQ function and localization...
January 3, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27965589/m-currents-kv7-2-7-3-kcnq2-kcnq3-are-responsible-for-dysfunctional-autonomic-control-in-hypertensive-rats
#7
Torill Berg
: Autonomic dysfunctions play important roles in hypertension, heart failure and arrhythmia, often with a detrimental and fatal effect. The present study analyzed if these dysfunctions involved M-channels (members of the Kv7/KNCQ family) in spontaneously hypertensive rats (SHR). Cardiac output and heart rate (HR) were recorded by a flow probe on the ascending aorta in anesthetized SHR and normotensive rats (WKY), and blood pressure (BP) by a femoral artery catheter. Total peripheral vascular resistance (TPR) was calculated...
2016: Frontiers in Physiology
https://www.readbyqxmd.com/read/27920148/epilepsy-associated-kcnq2-channels-regulate-multiple-intrinsic-properties-of-layer-2-3-pyramidal-neurons
#8
Zachary Niday, Virginia E Hawkins, Heun Soh, Daniel K Mulkey, Anastasios V Tzingounis
: KCNQ2 potassium channels are critical for normal brain function, as both loss- and gain-of-function KCNQ2 variants can lead to various forms of neonatal epilepsy. Despite recent progress, the full spectrum of consequences as a result of KCNQ2 dysfunction in neocortical pyramidal neurons is still unknown. Here, we report that conditional ablation of Kcnq2 from mouse neocortex leads to hyperexcitability of layer 2/3 (L2/3) pyramidal neurons, exhibiting an increased input resistance and action potential frequency, as well as a reduced medium afterhyperpolarization (mAHP), a conductance partly mediated by KCNQ2 channels...
December 5, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27888506/rapid-and-safe-response-to-low-dose-carbamazepine-in-neonatal-epilepsy
#9
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...
December 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
#10
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, epilepsy onset occurred before the age of 6 months. The 95-genes panel allowed a genetic diagnosis in 22 (6...
February 2017: 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
#11
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...
January 2017: 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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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)...
January 2017: 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
#18
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
#19
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
#20
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...
November 15, 2016: European Journal of Pharmacology
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