Abstracts

Rationale: To determine if specific epilepsy syndromic features aggregate within families and establish whether these aggregation patterns constitute distinct "familial syndromes," which likely differ in their genetic influences. Methods: Families (n=303) with three or more individuals affected with non-acquired epilepsy or unprovoked seizures were analysed across multiple centres using a standardized protocol. Affected individuals were classified as genetic generalised epilepsy (GGE), non-acquired focal epilepsy (NAFE), mixed generalized and focal epilepsy, febrile seizures plus (FS+), or unclassified epilepsy. Families were classified based on broad syndromic groupings of individuals: GGE, NAFE, mixed GGE and NAFE, or genetic epilepsy with febrile seizures plus (GEFS+). Results: There were 1269 affected individuals phenotyped in 303 families; 118 families had GGE. Absence epilepsies predominantly aggregated independently of other GGE syndromes (e.g., Juvenile Myoclonic Epilepsy). Early onset absence epilepsy with onset under 4 years was frequent (n=64). Severe GGE syndromes such as epilepsy with myoclonic-atonic seizures and eyelid myoclonia with absences generally occurred in families with early childhood-onset absence epilepsies. Familial NAFE was identified in 63 families; 25 with temporal lobe epilepsy, and 3 with frontal lobe epilepsy. Two unrecognised familial focal syndrome patterns emerged. Seventeen families had posterior quadrant epilepsies including 10 with occipito-temporal localization and 7 with temporo-parietal foci. Four families displayed familial childhood epilepsy with centro-temporal spikes with multiple affected siblings suggesting recessive inheritance. Ninety-three families were classified as having mixed generalized and focal epilepsy. Forty-four families were mainly GGE or NAFE with an incidental family member who had a different broad classification. A total of 51 individuals had features of both generalized and focal seizure activity. Twenty-nine families were categorised as GEFS+ and displayed the most heterogeneous phenotypes. Conclusions: Two key findings emerged. First, whilst generalized and focal epilepsies commonly segregate separately, families and indeed individuals were frequently observed with both major forms. Secondly, specific patterns of syndromic aggregation were seen, including newly recognized forms of familial focal epilepsy. This carefully phenotyped collection of multiplex families forms the substrate for a detailed molecular interrogation of the genetic basis of common familial epilepsies that is the next phase of the Epi4K project. Funding: NIH Grant number:U01NS077367