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A Twin Study of Genetic Influences on Epilepsy Outcome
- Michael R. Johnson, Roger L. Milne, Yvonne Torn-Broers, John L. Hopper, Ingrid E. Scheffer, Samuel F. Berkovic
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- Journal:
- Twin Research / Volume 6 / Issue 2 / 01 April 2003
- Published online by Cambridge University Press:
- 21 February 2012, pp. 140-146
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The identification of genetic factors that confer susceptibility to the epilepsies has to date been the focus of genetic efforts in this field. Few studies have assessed the genetic contribution to disease course in epilepsy, yet an understanding of the genetic influences on epilepsy outcome is key to developing new therapeutic strategies. The aim of this study was to assess the genetic contributions to epilepsy outcome in twin pairs concordant for epilepsy. We studied 37 epilepsy concordant twin pairs (27 monozygotic, 10 dizygotic) in whom there were no recognized environmental contributions (e.g., acquired brain injury) to epilepsy, and in whom the most likely cause for epilepsy was a shared genetic susceptibility. Clinical outcome was determined using the binary measure of Seizure Status (seizure remission or recurrence) and on a six-category ordinal Outcome Scale. Epilepsy outcome was independent of age of seizure onset, age at assessment and major epilepsy syndrome diagnosis. The proportion of twin pairs concordant for Seizure Status was 0.81 (22/27) for monozygous and 1.0 (10/10) for dizygous pairs, p = 0.3. Within-pair correlation in outcome (Outcome Scale) was 0.60 (95% CI: 0.32, 0.78) in monozygous and 0.78 (0.48, 0.92) in dizygous pairs. These data provide no evidence for genetic influences on epilepsy outcome independent of those that contribute to disease susceptibility. The observed high correlations for outcome suggest that, for epilepsy, susceptibility genes also have a major influence on outcome.
Cyclin-Dependent Kinase-Like 5 (CDKL5) Mutation Screening in Rett Syndrome and Related Disorders
- Rose White, Gladys Ho, Swetlana Schmidt, Ingrid E. Scheffer, Alexandra Fischer, Simone C. Yendle, Thierry Bienvenu, Juliette Nectoux, Carolyn J. Ellaway, Artur Darmanian, XingZhang Tong, Desiree Cloosterman, Bruce Bennetts, Veena Kalra, Tod Fullston, Jozef Gecz, Timothy C. Cox, John Christodoulou
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- Journal:
- Twin Research and Human Genetics / Volume 13 / Issue 2 / 01 April 2010
- Published online by Cambridge University Press:
- 21 February 2012, pp. 168-178
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Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting females almost exclusively and is characterized by a wide spectrum of clinical manifestations. Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene have been found in up to 95% of classical RTT cases and a lesser proportion of atypical cases. Recently, mutations in another X-linked gene, CDKL5 (cyclin-dependent kinase-like 5) have been found to cause atypical RTT, in particular the early onset seizure (Hanefeld variant) and one female with autism. In this study we screened several cohorts of children for CDKL5 mutations, totaling 316 patients, including individuals with a clinical diagnosis of RTT but who were negative for MECP2 mutations (n = 102), males with X-linked mental retardation (n = 9), patients with West syndrome (n = 52), patients with autism (n = 59), patients with epileptic encephalopathy (n = 33), patients with Aicardi syndrome (n = 7) and other patients with intellectual disability with or without seizures (n = 54). In all, seven polymorphic variations and four de novo mutations (c.586C>T [p.S196L]; c.58G>C [p.G20R]; c.2504delC [p.P835fs]; deletion of exons 1 - 3) were identified, and in all instances of the latter the clinical phenotype was that of an epileptic encephalopathy. These results suggest that pathogenic CDKL5 mutations are unlikely to be identified in the absence of severe early-onset seizures and highlight the importance of screening for large intragenic and whole gene deletions.
Contributors
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- By Jane E. Adcock, Yahya Aghakhani, A. Anand, Eva Andermann, Frederick Andermann, Alexis Arzimanoglou, Sandrine Aubert, Nadia Bahi-Buisson, Carman Barba, Agatino Battaglia, Geneviève Bernard, Nadir E. Bharucha, Laurence A. Bindoff, William Bingaman, Francesca Bisulli, Thomas P. Bleck, Stewart G. Boyd, Andreas Brunklaus, Harry Bulstrode, Jorge G. Burneo, Laura Canafoglia, Laura Cantonetti, Roberto H. Caraballo, Fernando Cendes, Kevin E. Chapman, Patrick Chauvel, Richard F. M. Chin, H. T. Chong, Fahmida A. Chowdhury, Catherine J. Chu-Shore, Rolando Cimaz, Andrew J. Cole, Bernard Dan, Geoffrey Dean, Alessio De Ciantis, Fernando De Paolis, Rolando F. Del Maestro, Irissa M. Devine, Carlo Di Bonaventura, Concezio Di Rocco, Henry B. Dinsdale, Maria Alice Donati, François Dubeau, Michael Duchowny, Olivier Dulac, Monika Eisermann, Brent Elliott, Bernt A. Engelsen, Kevin Farrell, Natalio Fejerman, Rosalie E. Ferner, Silvana Franceschetti, Robert Friedlander, Antonio Gambardella, Hector H. Garcia, Serena Gasperini, Lorenzo Genitori, Gioia Gioi, Flavio Giordano, Leif Gjerstad, Daniel G. Glaze, Howard P. Goodkin, Sidney M. Gospe, Andrea Grassi, William P. Gray, Renzo Guerrini, Marie-Christine Guiot, William Harkness, Andrew G. Herzog, Linda Huh, Margaret J. Jackson, Thomas S. Jacques, Anna C. Jansen, Sigmund Jenssen, Michael R. Johnson, Dorothy Jones-Davis, Reetta Kälviäinen, Peter W. Kaplan, John F. Kerrigan, Autumn Marie Klein, Matthias Koepp, Edwin H. Kolodny, Kandan Kulandaivel, Ruben I. Kuzniecky, Ahmed Lary, Yolanda Lau, Anna-Elina Lehesjoki, Maria K. Lehtinen, Holger Lerche, Michael P. T. Lunn, Snezana Maljevic, Mark R. Manford, Carla Marini, Bindu Menon, Giulia Milioli, Eli M. Mizrahi, Manish Modi, Márcia Elisabete Morita, Manuel Murie-Fernandez, Vivek Nambiar, Lina Nashef, Vincent Navarro, Aidan Neligan, Ruth E. Nemire, Charles R. J. C. Newton, John O'Donavan, Hirokazu Oguni, Teiichi Onuma, Andre Palmini, Eleni Panagiotakaki, Pasquale Parisi, Elena Parrini, Liborio Parrino, Ignacio Pascual-Castroviejo, M. Scott Perry, Perrine Plouin, Charles E. Polkey, Suresh S. Pujar, Karthik Rajasekaran, R. Eugene Ramsey, Rahul Rathakrishnan, Roberta H. Raven, Guy M. Rémillard, David Rosenblatt, M. Elizabeth Ross, Abdulrahman Sabbagh, P. Satishchandra, Swati Sathe, Ingrid E. Scheffer, Philip A. Schwartzkroin, Rod C. Scott, Frédéric Sedel, Michelle J. Shapiro, Elliott H. Sherr, Michael Shevell, Simon D. Shorvon, Adrian M. Siegel, Gagandeep Singh, S. Sinha, Barbara Spacca, Waney Squier, Carl E. Stafstrom, Bernhard J. Steinhoff, Andrea Taddio, Gianpiero Tamburrini, C. T. Tan, Raymond Y. L. Tan, Erik Taubøll, Robert W. Teasell, Mario Giovanni Terzano, Federica Teutonico, Suzanne A. Tharin, Elizabeth A. Thiele, Pierre Thomas, Paolo Tinuper, Dorothée Kasteleijn-Nolst Trenité, Sumeet Vadera, Pierangelo Veggiotti, Jean-Pierre Vignal, J. M. Walshe, Elizabeth J. Waterhouse, David Watkins, Ruth E. Williams, Yue-Hua Zhang, Benjamin Zifkin, Sameer M. Zuberi
- Edited by Simon D. Shorvon, Frederick Andermann, Renzo Guerrini
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- Book:
- The Causes of Epilepsy
- Published online:
- 05 March 2012
- Print publication:
- 14 April 2011, pp ix-xvi
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Chapter 9 - Genetic epilepsy with febrile seizures plus
- from Section 2 - Idiopathic epilepsy
- Edited by Simon D. Shorvon, Frederick Andermann, Renzo Guerrini
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- Book:
- The Causes of Epilepsy
- Published online:
- 05 March 2012
- Print publication:
- 14 April 2011, pp 74-77
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Summary
The genetic epilepsy with febrile seizures plus (GEFS+) spectrum is a complex concept to understand and derives from clinical genetic studies. In GEFS+, the clinician needs to understand the presentations that form part of the phenotypic spectrum to consider a familial epilepsy syndrome diagnosis of GEFS+. The characteristic electroencephalograph (EEG) signature is of irregular generalized spike-wave activity; however, this is not present in all affected individuals. All individuals with GEFS+ have seizures, although some have simple febrile seizures whilst others have more severe phenotypes. The main risk factor is fever in infancy and early childhood, however, some family members also have afebrile seizures of various types. As with all forms of epilepsy, seizures are more likely if the patient is tired or stressed. In the more severe phenotypes, multiple antiepileptic agents may be necessary. Often valproate and lamotrigine are useful for myoclonic-astatic epilepsy (MAE).
15 - Opercular epilepsies with oromotor dysfunction
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- By Javier Salas-Puig, Department of Neurology, Hospital General de Asturias, Oviedo, Spain, Angeles Pérez-Jiménez, Department of Neurology, Hospital General de Asturias, Oviedo, Spain, Pierre Thomas, Department of Neurology, CHU, Nice, France, Ingrid I. E. Scheffer, Department of Neurology, Austin and Repatriation Medical Centre, University of Melbourne, Heidelberg, Victoria, Australia, Bernardo Dalla Bernardina, Neuropediatric Department, Borgo Roma Hospital, Verona, Italy, Renzo Guerrini, Neurosciences Unit, Institute of Child Health, The Wolfson Centre, London, UK
- Edited by Renzo Guerrini, University of London, Jean Aicardi, Hôpital Robert-Debré, Paris, Frederick Andermann, Montreal Neurological Institute & Hospital, Mark Hallett, National Institutes of Health, Baltimore
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- Book:
- Epilepsy and Movement Disorders
- Published online:
- 03 May 2010
- Print publication:
- 13 December 2001, pp 251-268
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Summary
Introduction
The term operculum insulae denotes the cortical region that covers the insulae Reili. It is made up of frontal, parietal, and temporal cortical convolutions. A bilateral structural or functional disturbance of the cortical motor areas of the anterior part (frontal) operculum, including the inferior rolandic area, and their corticonuclear projections to the nuclei of the 5th, 7th, 9th, and 10th cranial nerves, causes a unique clinical picture of a supranuclear (pseudobulbar) palsy. It presents with swallowing difficulties, anarthria or severe dysarthria, and loss of the ability to imitate oral gestures, resulting from a central disturbance of volitional control of the facio-linguo-glosso-pharyngo-masticatory muscles, while preserving automatic, involuntary, emotional innervation, and reflex motor activity. Pathological crying and laughing are conspicuously absent. It is also designated Foix–Chavany–Marie Syndrome (FCMS), in honour of the authors who described it in 1926, in two adults with bilateral infarction of the anterior operculum (Foix et al., 1926). Bilateral cortical impairment underlies the symptomatology of FCMS as lower cranial nerve brainstem receive innervation from both hemispheres.
The best known form of the syndrome is the classical FCMS due to serial strokes in adults with cerebrovascular disease (Bruyn & Gathier, 1969). FCMS can also occur in infancy and childhood, in relation to diverse etiologies and different clinical evolutions. It can be permanent, secondary to congenital malformation or to acquired structural lesion in early life, or can have an intermittent or reversible expression in the background of certain epileptic disorders involving the perisylvian regions (Christen et al., 2000).