Generalized epilepsy with febrile seizures plus Further heterogeneity in a 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, myoclonic, 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 (β 1 -subunit) and two in SCN1A (α-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 phenotypes occurred predominantly during childhood. Only four individuals showed the FS or FS + phenotype. The others presented with different combinations of GTCS, tonic seizures, atonic seizures, and absences, only in part associated 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-and-wave discharges of 2.5 to 5 Hz in eight cases and additional focal parietal discharges in one case. Linkage analysis excluded the previously described loci on chromosomes 2q21-33 and 19q13. All other chromosomal regions containing known genes encoding neuronal Na + channel subunits on chromosomes 3p21-24, 11q23, and 12q13 and described loci for febrile convulsions on chromosomes 5q14-15, 8q13-21, and 19p13.3 were also excluded. Conclusion: These results indicate further clinical and genetic heterogeneity in GEFS + .