Generalized epilepsy with febrile seizures plus - Further heterogeneity ina large family

Background: Generalized epilepsy with febrile seizures plus (GEFS(+)) is a recently described benign childhood-onset epileptic syndrome with autosomal dominant inheritance. The most common phenotypes are febrile seizures (FS) often with accessory afebrile generalized tonic-clonic seizures (GTCS, FS). In about one third, additional seizure types occur, such as absences, my oclonic, or atonic seizures. So far, three mutations within genes encoding subunits of neuronal voltage-gated Na+ channels have been found in GEFS(+) families, one in SCN1B (beta (1)-subunit) and two in SCN1A (alpha -subunit) . Methods: The authors examined the phenotypic variability of GEFS(+) in a five-generation German family with 18 affected individuals. Genetic linkage analysis was performed to exclude candidate loci. Results: Inheritance was autosomal dominant with a penetrance of about 80%. A variety of epilepsy p henotypes occurred predominantly during childhood. Only four individuals sh owed the FS or FS' phenotype. The others presented with different combinati ons of GTCS, tonic seizures, atonic seizures, and absences, only in part as sociated with fever. The age at onset was 2.8 +/- 1.3 years. Interictal EEG recordings showed rare, 1- to 2-second-long generalized, irregular spike-a nd-wave discharges of 2.5 to 5 Hz in eight cases and additional focal parie tal discharges in one case. Linkage analysis excluded the previously descri bed loci on chromosomes 2q21-33 and 19q13. All other chromosomal regions co ntaining known genes encoding neuronal Na+ channel subunits on chromosomes 3p21-24, 11q23, and 12q13 and described loci for febrile convulsions on chr omosomes 5q14-15, 8q13-21, and 19p13.3 were also excluded. Conclusion: Thes e results indicate further clinical and genetic heterogeneity in GEFS(+).