Abstracts

RATIONALE: The relationships among epilepsy syndromes and seizure types and their underlying genetic mechanisms are poorly understood. We have previously found evidence for distinct genetic contributions to generalized and localization-related epilepsy. Here we use similar methods to examine the shared vs. distinct genetic contributions to two generalized seizure subtypes: absence and myoclonic seizures. At the end of this activity the participants should be able to understand the role of family studies in examining genetic contributions to different seizure types, and the genetic influences on myocolonic and absence seizures in particular.
METHODS: We examined concordance of myoclonic and absence seizures in families containing multiple individuals with idiopathic generalized epilepsy. To evaluate whether or not the number of concordant families exceeded that expected by chance, we compared the observed number to the number expected from the distribution of absence and myoclonic seizures in the study families, using a permutation test. The rationale for this test is that if some of the genetic influences on myoclonic and absence seizures are distinct (i.e., they raise risk for one seizure type without raising risk for the other), familial concordance is expected to exceed that expected by chance, whereas if none of the genetic influences is distinct (i.e., each raises risk for both seizure types to the same degree), concordance is expected to be consistent with that expected by chance.
RESULTS: The analysis included 24 families containing 63 individuals with either myoclonic seizures alone (N=27, 43%), absence seizures alone (N=18, 29%), or both seizure types (N=18, 29%). Overall, 15 of the 24 families (63%) were concordant for seizure type. In 9 families all individuals with generalized epilepsy had absence seizures only, in 3 families all had myoclonic seizures only, and in 3 families all had both absence and myoclonic seizures. The observed number of concordant families was significantly greater than that expected (15 vs. 6, Z=4.508, p[lt]0.0001). To evaluate evidence for independent genetic effects on myoclonic seizures occurring alone and absence seizures occurring alone, we excluded the individuals with both seizure types. In this analysis, the observed number of concordant families remained greater than expected (14 vs. 7.87, Z=2.946, p[lt]0.0016).
CONCLUSIONS: These results provide evidence for distinct genetic effects on absence and myoclonic seizures. The approach used here can be used to guide linkage analysis by allowing rational subdivision of epilepsy syndromes into groups likely to share susceptibility genes. This may help solve the problem of phenotype definition in linkage studies of the idiopathic generalized epilepsy syndromes, suggesting that a focus on seizure type rather than syndrome may be fruitful. The results also give insight into the mechanisms by which genes cause epilepsy-- raising the risk not only for epilepsy overall but for its specific clinical features.
[Supported by: NIH Grants R01 NS20656 and K23 NS02211]