Abstracts

Rationale: GEFS+ (generalized epilepsy with febrile seizures plus) is a familial epilepsy syndrome characterized by phenotypic heterogeneity that we described in 1997. The GEFS+ spectrum includes Febrile Seizures (FS), Febrile Seizures Plus (FS+), FS/FS+ with generalized and focal seizures, and a range of epileptic encephalopathies including Dravet syndrome and epilepsy with myoclonic-atonic seizures. GEFS+ is infrequently associated with mutations of sodium channel mutations including SCN1A and SCN1B. Less frequently GABA receptor subunit gene mutations have been identified. In addition, susceptibility genes have been found in smaller families. We studied 31 new families and analyzed the phenotypic spectrum in these families and our previously published families. Methods: We performed detailed electro-clinical phenotyping on all available affected family members and reviewed EEG and neuroimaging studies. We report the phenotypic findings on 408 affected individuals in a total of 60 families and compare this data to other GEFS+ studies. Results: New phenotypes in GEFS+ families included focal seizures without preceding FS (16/408, 4% ), classical genetic generalized epilepsies (22/408, 5%) most commonly childhood absence epilepsy, and afebrile generalized tonic-clonic seizures (9/408, 2%). FS remains the most frequent phenotype in GEFS+ (178/408, 44%) followed by FS+ (110/408, 27%). Large GEFS+ families are suggestive of autosomal dominant inheritance. Many smaller families exist where the inheritance pattern is more suggestive of complex inheritance. Conclusions: Initially GEFS+ was conceived as comprising generalized epilepsy phenotypes and identified through large autosomal dominant families. Our data, show that the spectrum of phenotypes within GEFS+ is greater than originally conceived. Focal epilepsies and classical GGE are seen in GEFS+ families. We propose that GEFS+ be renamed "genetic epilepsy with febrile seizures plus" in view of the number of individuals with focal epilepsies. The overlap between GEFS+ and the classical GGE is considerably greater than first thought and suggests that the two major groups of generalized epilepsies have shared genetic determinants.