This study will use parametric and non-parametric linkage analysis to look for the genetic influences on childhood absence epilepsy (CAE). We will use strategies which we have successfully applied to unravel some of the genetic contributions to juvenile onset idiopathic generalized epilepsy (IGE), including juvenile myoclonic epilepsy (JME) on chromosome 6p and non-JME forms of IGE on chromosome 8. IGEs are one of the most common forms of epilepsy and have a prominent genetic component. We have shown that a major confound factor in study the complex genetic influences in IGE is heterogeneity. We will recruit families through our referral network through the East Cost of the US and obtain detailed clinical and family histories from probands and family members. We will perform EEGs on healthy family members to identify subclinically affected members with spike-wave in the EEG. The families will be typed for markers through the genome and we will use parametric- and non-parametric linkage analysis to identify loci that contribute to the expression of CAE. We are aware of the problem of heterogeneity in genetic analysis and will minimize it by strict phenotype definition and stringent patient selection criteria. This strategy has been shown to be the key issue in our success in JME. Once we have evidence for linkage, we will also investigate whether bursts of generalized rhythmical 3Hz waves without interposed spikes is a 'form fruste' of the classical 3Hz spike-and-wave complex and whether it is also associated with the epileptic genotype in CAE. We will further test for heterogeneity in CAE by using clinical criteria to separate possibly genetically different groups of CAE patients. Clinically, the distinction can be made between CAE patients with only absence seizures and additional generalized tonic clonic seizures (GTCS). We will use the criteria of GTCS to differentiate CAE patients, analyze them separately and look for genetic differences in these two groups. The knowledge and experience from our previous studies together with the availability of the infrastructure and environment of a well established neuropsychiatric genetics group will contribute to the success of the study and with this to an enhanced understanding of the differences in the genetic basis of idiopathic generalized epilepsies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG4-EDC-2 (02))
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Fureman, Brandy E
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Columbia University (N.Y.)
Biostatistics & Other Math Sci
Schools of Public Health
New York
United States
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Wittkowski, Knut M; Sonakya, Vikas; Song, Tingting et al. (2013) From single-SNP to wide-locus: genome-wide association studies identifying functionally related genes and intragenic regions in small sample studies. Pharmacogenomics 14:391-401
Vierck, Esther; Cauley, Ryan; Kugler, Steven L et al. (2010) Polyspike and waves do not predict generalized tonic-clonic seizures in childhood absence epilepsy. J Child Neurol 25:475-81
Chioza, Barry A; Aicardi, Jean; Aschauer, Harald et al. (2009) Genome wide high density SNP-based linkage analysis of childhood absence epilepsy identifies a susceptibility locus on chromosome 3p23-p14. Epilepsy Res 87:247-55
Everett, Kate; Chioza, Barry; Aicardi, Jean et al. (2007) Linkage and mutational analysis of CLCN2 in childhood absence epilepsy. Epilepsy Res 75:145-53
Pal, Deb K; Durner, Martina; Klotz, Irene et al. (2006) Complex inheritance and parent-of-origin effect in juvenile myoclonic epilepsy. Brain Dev 28:92-8
Greenberg, David A; Cayanis, Eftihia; Strug, Lisa et al. (2005) Malic enzyme 2 may underlie susceptibility to adolescent-onset idiopathic generalized epilepsy. Am J Hum Genet 76:139-46
Pal, Deb K; Evgrafov, Oleg V; Tabares, Paula et al. (2003) BRD2 (RING3) is a probable major susceptibility gene for common juvenile myoclonic epilepsy. Am J Hum Genet 73:261-70
Durner, M; Keddache, M A; Tomasini, L et al. (2001) Genome scan of idiopathic generalized epilepsy: evidence for major susceptibility gene and modifying genes influencing the seizure type. Ann Neurol 49:328-35
Pal, D K; Durner, M; Greenberg, D A (2001) Effect of misspecification of gene frequency on the two-point LOD score. Eur J Hum Genet 9:855-9
Greenberg, D A; Durner, M; Keddache, M et al. (2000) Reproducibility and complications in gene searches: linkage on chromosome 6, heterogeneity, association, and maternal inheritance in juvenile myoclonic epilepsy. Am J Hum Genet 66:508-16