Exploration of the Genetic Architecture of Idiopathic Generalized Epilepsies
Authors: Hempelmann, Anne; Taylor, Kirsten P.; Heils, Armin1; Lorenz, Susanne; Prud'Homme, Jean-Francois2; Nabbout, Rima3; Dulac, Olivier3; Rudolf, Gabrielle4; Zara, Federico5; Bianchi, Amedeo6; Robinson, Robert7; Gardiner, R. Mark7; Covanis, Athanasios8; Lindhout, Dick9; Stephani, Ulrich10; Elger, Christian E.1; Weber, Yvonne G.11; Lerche, Holger11; Nürnberg, Peter12; Kron, Katherine L.13; Scheffer, Ingrid E.13; Mulley, John C.14; Berkovic, Samuel F.13; Sander, Thomas
Source: Epilepsia, Volume 47, Number 10, October 2006 , pp. 1682-1690(9)
Publisher: Blackwell Publishing
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Abstract:
Summary: Purpose: Idiopathic generalized epilepsy (IGE) accounts for ∼20% of all epilepsies and affects about 0.2% of the general population. The etiology of IGE is genetically determined, but the complex pattern of inheritance suggests an involvement of a large number of susceptibility genes. The objective of the present study was to explore the genetic architecture of common IGE syndromes and to dissect out susceptibility loci predisposing to absence or myoclonic seizures. Methods: Genome-wide linkage scans were performed in 126 IGE-multiplex families of European origin ascertained through a proband with idiopathic absence epilepsy or juvenile myoclonic epilepsy. Each family had at least two siblings affected by IGE. To search for seizure type-related susceptibility loci, linkage analyses were carried out in family subgroups segregating either typical absence seizures or myoclonic and generalized tonic-clonic seizures on awakening. Results: Nonparametric linkage scans revealed evidence for complex and heterogeneous genetic architectures involving linkage signals at 5q34, 6p12, 11q13, 13q22-q31, and 19q13. The signal patterns differed in their composition, depending on the predominant seizure type in the families. Conclusions: Our results are consistent with heterogeneous configurations of susceptibility loci associated with different IGE subtypes. Genetic determinants on 11q13 and 13q22-q31 seem to predispose preferentially to absence seizures, whereas loci on 5q34, 6p12, and 19q13 confer susceptibility to myoclonic and generalized tonic-clonic seizures on awakening.Keywords: Idiopathic generalized epilepsy; Complex inheritance; Absence seizure; Myoclonic seizure; Linkage
Document Type: Research article
DOI: 10.1111/j.1528-1167.2006.00677.x
Affiliations: 1: Clinic of Epileptology and Institute of Human Genetics, Rheinische Friedrich-Wilhelms-University, Bonn, Germany 2: Généthon, Evry 3: Département de Neurologie Pédiatrique et de Maladies Métaboliques, Hopital Necker-Enfants Malades, APHP, Paris 4: Clinique Neurologique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France 5: Laboratory of Neurogenetics, U.O. Neuromuscular and Neurodegenerative Disease, Istituto Gaslini, University of Genova, Genova 6: Epilepsy Centre, Department of Neurology, San Donato Hospital, Arezzo, Italy 7: Department of Pediatrics and Child Health, The Rayne Institute, Royal Free and University College Medical School, London, United Kingdom 8: Department of Neurology, The Children's Hospital “Agia Spohia,” Athens, Greece 9: Complex Genetics Section, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands 10: Clinic for Neuropaediatrics, University Clinics Schleswig Holstein, Kiel 11: Departments of Neurology and Applied Physiology, University of Ulm, Ulm 12: Cologne Center for Genomics and Institute for Genetics, University of Cologne, Cologne, Germany 13: Epilepsy Research Centre and Department of Medicine (Neurology), University of Melbourne and Austin Health and Repatriation Medical Centre, Heidelberg, Victoria 14: Department of Genetic Medicine, Women's and Children's Hospital and School of Molecular and Biomedical Sciences, University of Adelaide, South Australia, Australia
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