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.
