GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS - A GENETIC DISORDER WITH HETEROGENEOUS CLINICAL PHENOTYPES

The clinical and genetic relationships of febrile seizures and the gen eralized epilepsies are poorly understood. We ascertained a family wit h genealogical information in 2000 individuals where there was an unus ual concentration of individuals with febrile seizures and generalized epilepsy in one part of the pedigree. We first clarified complex cons anguineous relationships in earlier generations and then systematicall y studied the epilepsy phenotypes in affected individuals. In one bran ch (core family) 25 individuals over four generations were affected Th e commonest phenotype, denoted as 'febrile seizures plus' (FS+), compr ised childhood onset (median 1 year) of multiple febrile seizures, but unlike the typical febrile convulsion syndrome, attacks with fever co ntinued beyond 6 years, or afebrile seizures occurred Seizures usually ceased by mid childhood (median II years). Other phenotypes included FS+ and absences, FS+ and myoclonic seizures, FS+ and atonic seizures, and the most severely affected individual had myoclonic-astatic epile psy (MAE). The pattern of inheritance was autosomal dominant. The larg e variation in generalized epilepsy phenotypes was not explained by ac quired factors. Analysis of this large family and critical review of t he literature led to the concept of a genetic epilepsy syndrome termed generalized epilepsy with febrile seizures phs (GEFS(+)). GEFS(+) has a spectrum of phenotypes including febrile seizures, FS+ and the less common MAE. Recognition of GEFS(+) explains the epilepsy phenotypes o f previously poorly understood benign childhood generalized epilepsies . In individual patients the inherited nature of GEFS(+) may be overlo oked. Molecular genetic study of such large families should allow iden tification of genes relevant to febrile seizures and generalized epile psies.