Journal ArticleDOI
KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy.
Sarah Weckhuysen,Simone Mandelstam,Arvid Suls,Dominique Audenaert,Dominique Audenaert,Tine Deconinck,L Claes,Liesbet Deprez,Katrien Smets,D. Hristova,Iglika Yordanova,Albena Jordanova,Berten Ceulemans,An Jansen,D. Hasaerts,Filip Roelens,Lieven Lagae,Simone C. Yendle,Thorsten Stanley,Sarah E. Heron,John C. Mulley,Samuel F. Berkovic,Ingrid E. Scheffer,Ingrid E. Scheffer,Peter De Jonghe +24 more
TLDR
This study investigated whether KCNQ2/3 mutations are a frequent cause of epileptic encephalopathies with an early onset and whether a recognizable phenotype exists.Abstract:
OBJECTIVE: KCNQ2 and KCNQ3 mutations are known to be responsible for benign familial neonatal seizures (BFNS). A few reports on patients with a KCNQ2 mutation with a more severe outcome exist, but a definite relationship has not been established. In this study we investigated whether KCNQ2/3 mutations are a frequent cause of epileptic encephalopathies with an early onset and whether a recognizable phenotype exists. METHODS: We analyzed 80 patients with unexplained neonatal or early-infantile seizures and associated psychomotor retardation for KCNQ2 and KCNQ3 mutations. Clinical and imaging data were reviewed in detail. RESULTS: We found 7 different heterozygous KCNQ2 mutations in 8 patients (8/80; 10%); 6 mutations arose de novo. One parent with a milder phenotype was mosaic for the mutation. No KCNQ3 mutations were found. The 8 patients had onset of intractable seizures in the first week of life with a prominent tonic component. Seizures generally resolved by age 3 years but the children had profound, or less frequently severe, intellectual disability with motor impairment. Electroencephalography (EEG) at onset showed a burst-suppression pattern or multifocal epileptiform activity. Early magnetic resonance imaging (MRI) of the brain showed characteristic hyperintensities in the basal ganglia and thalamus that later resolved. INTERPRETATION: KCNQ2 mutations are found in a substantial proportion of patients with a neonatal epileptic encephalopathy with a potentially recognizable electroclinical and radiological phenotype. This suggests that KCNQ2 screening should be included in the diagnostic workup of refractory neonatal seizures of unknown origin.read more
Citations
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ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology.
Ingrid E. Scheffer,Samuel F. Berkovic,Giuseppe Capovilla,Mary B. Connolly,Jacqueline A. French,Laura Maria de Figueiredo Ferreira Guilhoto,Edouard Hirsch,Satish Jain,Gary W. Mathern,Solomon L. Moshé,Douglas R. Nordli,Emilio Perucca,Torbjörn Tomson,Samuel Wiebe,Yuehua Zhang,Sameer M. Zuberi,Sameer M. Zuberi +16 more
TL;DR: The International League Against Epilepsy (ILAE) Classification of the Epilepsies has been updated to reflect our gain in understanding of the epilepsies and their underlying mechanisms following the major scientific advances that have taken place since the last ratified classification in 1989 as mentioned in this paper.
Journal ArticleDOI
Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.
Anita Rauch,Dagmar Wieczorek,Elisabeth Graf,Thomas Wieland,Sabine Endele,Thomas Schwarzmayr,Beate Albrecht,Deborah Bartholdi,Jasmin Beygo,Nataliya Di Donato,Andreas Dufke,Kirsten Cremer,Maja Hempel,Denise Horn,Juliane Hoyer,Pascal Joset,Albrecht Röpke,Ute Moog,Angelika Riess,Christian Thiel,Andreas Tzschach,Antje Wiesener,Eva Wohlleber,Christiane Zweier,Arif B. Ekici,Alexander M. Zink,Andreas Rump,Christa Meisinger,Harald Grallert,Heinrich Sticht,Annette Schenck,Hartmut Engels,Gudrun A. Rappold,Evelin Schröck,Peter Wieacker,Olaf Riess,Thomas Meitinger,André Reis,Tim M. Strom +38 more
TL;DR: The large number of de-novo variants in known intellectual disability genes is only partially attributable to known non-specific phenotypes, suggesting a strong bias in present clinical syndrome descriptions.
Journal ArticleDOI
Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1
Gemma L. Carvill,Sinéad Heavin,Simone C. Yendle,Jacinta M McMahon,Brian J. O'Roak,Joseph Cook,Adiba Khan,Michael O. Dorschner,Michael O. Dorschner,Molly Weaver,Molly Weaver,Sophie Calvert,Stephen M. Malone,Geoffrey Wallace,Thorsten Stanley,Ann M. E. Bye,Andrew Bleasel,Katherine B. Howell,Sara Kivity,Mark T Mackay,Victoria Rodriguez-Casero,Richard Webster,Amos D. Korczyn,Zaid Afawi,Nathanel Zelnick,Tally Lerman-Sagie,Tally Lerman-Sagie,Dorit Lev,Rikke S. Møller,Deepak Gill,Danielle M. Andrade,Jeremy L. Freeman,Lynette G. Sadleir,Jay Shendure,Samuel F. Berkovic,Ingrid E. Scheffer,Heather C Mefford +36 more
TL;DR: Target massively parallel resequencing of 19 known and 46 candidate genes for epileptic encephalopathy in 500 affected individuals (cases) to identify new genes involved and to investigate the phenotypic spectrum associated with mutations in known genes.
Journal ArticleDOI
Detection of Clinically Relevant Genetic Variants in Autism Spectrum Disorder by Whole-Genome Sequencing
Yong-hui Jiang,Ryan K. C. Yuen,Xin Jin,Xin Jin,Mingbang Wang,Nong Chen,Xueli Wu,Jia Ju,Junpu Mei,Yujian Shi,Mingze He,Guangbiao Wang,Jieqin Liang,Zhe Wang,Dandan Cao,Melissa T. Carter,Christina Chrysler,Irene Drmic,Jennifer L. Howe,Lynette Lau,Christian R. Marshall,Christian R. Marshall,Daniele Merico,Thomas Nalpathamkalam,Bhooma Thiruvahindrapuram,Ann Thompson,Mohammed Uddin,Susan Walker,J. Luo,Evdokia Anagnostou,Lonnie Zwaigenbaum,Robert H. Ring,Jian Wang,Clara Lajonchere,Jun Wang,Andy Shih,Peter Szatmari,Huanming Yang,Geraldine Dawson,Geraldine Dawson,Yingrui Li,Stephen W. Scherer,Stephen W. Scherer +42 more
TL;DR: Results suggest that WGS and thorough bioinformatic analyses for de novo and rare inherited mutations will improve the detection of genetic variants likely to be associated with ASD or its accompanying clinical symptoms.
Journal ArticleDOI
The genetic landscape of the epileptic encephalopathies of infancy and childhood
Amy McTague,Amy McTague,Katherine B. Howell,Katherine B. Howell,J. Helen Cross,J. Helen Cross,Manju A. Kurian,Manju A. Kurian,Ingrid E. Scheffer +8 more
TL;DR: Gene discovery provides the basis for neurobiological insights, often showing convergence of mechanistic pathways that underpin the development of targeted therapies, which are essential to improve the outcome of these devastating disorders.
References
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Journal ArticleDOI
A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns
Nanda A. Singh,Carole Charlier,Dora Stauffer,Barbara R. DuPont,Robin J. Leach,Roberta Melis,Gabriel M. Ronen,I. Bjerre,Thomas G. Quattlebaum,J. V. Murphy,M. L. McHarg,David R. Gagnon,T. O. Rosales,Andy Peiffer,V. E. Anderson,Mark Leppert +15 more
TL;DR: A sub-microscopic deletion of chromosome 20q13.3 that co-segregates with seizures in a BFNC family is identified, identifying one encoding a novel voltage-gated potassium channel, KCNQ2, which belongs to a new KQT-like class of potassium channels.
Journal ArticleDOI
A Potassium Channel Mutation in Neonatal Human Epilepsy
Christian Biervert,Björn C. Schroeder,Björn C. Schroeder,Björn C. Schroeder,Christian Kubisch,Christian Kubisch,Christian Kubisch,Samuel F. Berkovic,Samuel F. Berkovic,Samuel F. Berkovic,Peter Propping,Peter Propping,Peter Propping,Thomas J. Jentsch,Thomas J. Jentsch,Thomas J. Jentsch,Ortrud K. Steinlein,Ortrud K. Steinlein,Ortrud K. Steinlein +18 more
TL;DR: Impairment of potassium-dependent repolarization is likely to cause this age-specific epileptic syndrome.
Journal ArticleDOI
A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family.
Carole Charlier,Nanda A. Singh,Stephen G. Ryan,Tracey B. Lewis,B. E. Reus,Robin J. Leach,Mark Leppert +6 more
TL;DR: KCNQ2, KCNQ3 and undiscovered genes of the same family of K+ channels are strong candidates for other IGEs, and a missense mutation in the critical pore region in perfect co-segregation with the BFNC phenotype is found.
Journal ArticleDOI
Patterns of brain injury in term neonatal encephalopathy
Steven P. Miller,Vijay Ramaswamy,David Michelson,A. James Barkovich,Barbara A. Holshouser,Nathaniel D. Wycliffe,David V. Glidden,Douglas D Deming,J. Colin Partridge,Yvonne W. Wu,Stephen Ashwal,Donna M. Ferriero +11 more
TL;DR: The basal ganglia/thalamus pattern was associated with the most impaired motor and cognitive outcome at 30 months in term neonatal encephalopathy, and measured prenatal risk factors did not predict the pattern of brain injury.
Journal ArticleDOI
KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: expansion of the functional and mutation spectrum
Nanda A. Singh,Peter D. Westenskow,Carole Charlier,Chris Pappas,Jonathan D. Leslie,Jessica Dillon,V. Elving Anderson,Michael C. Sanguinetti,Mark Leppert +8 more
TL;DR: The first dominant negative mutation in KCNQ2 that has a phenotype of neonatal seizures without permanent clinical CNS impairment is reported here, and it is shown that only KCNZ2 is deleted.
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