Human Molecular Genetics Advance Access published online on July 27, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi250
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1 Program in Genetics and Genomic Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada
* To whom correspondence should be addressed. Neurons throughout the brain suddenly discharging synchronously and recurrently cause primarily generalized seizures. Discharges localized awhile in one part of the brain cause focal-onset seizures. A genetically determined generalized hyperexcitability had been predicted in the former, but surprisingly the first epilepsy gene discovered, CHRNA4, was in a focal (frontal lobe)-onset syndrome. Another surprise with CHRNA4 was its encoding an ion channel present throughout the brain. Why CHRNA4 causes focal-onset seizures is unknown. Recently, a second focal (temporal lobe)-onset epilepsy gene, LGI1 (unknown function), was discovered. CHRNA4 led the way to mutation identifications in 15 ion channel genes, most causing primarily generalized epilepsies. Potassium channel mutations cause Benign Familial Neonatal Convulsions. Sodium channel mutations cause Generalized Epilepsy with Febrile Seizures Plus or, if more severe, Severe Myoclonic Epilepsy of Infancy. Chloride and calcium channel mutations are found in rare families with the common syndromes Childhood Absence Epilepsy and Juvenile Myoclonic Epilepsy (JME). Mutations in the EFHC1 gene (unknown function) occur in other rare JME families, and in yet other families associations are present between JME (or other generalized epilepsies) and single nucleotide polymorphisms in the BRD2 (unknown function) and the malic enzyme 2 (ME2) genes. Hippocrates predicted the genetic nature of the "sacred" disease. Genes underlying the "malevolent" forces seizing one percent of humans have now been revealed. These, however, still account for a mere fraction of the genetic contribution to epilepsy. Exciting years are ahead, in which the genetics of this extremely common, and debilitating, neurological disorder will be solved.
Received June 15, 2005
Accepted July 8, 2005
Article
Sacred Disease Secrets Revealed: The Genetics of Human Epilepsy
2 Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, 48109-0618, USA
3 Center for the Study of Brain Diseases, Centre Hospitalier de l'Université de Montréal - Notre Dame Hospital, Montreal, Quebec, H2L 4M1, Canada
4 Epilepsy Center of Excellence, Greater Los Angeles VA Healthcare System, Los Angeles, California, 90073, USA
5 Program in Genetics and Genomic Biology and Department of Paediatrics (Neurology), The Hospital for Sick Children, Toronto M5G 1X8, Canada
Berge A. Minassian, E-mail: bminass{at}sickkids.ca
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