Generalized epilepsy with febrile seizures plus Further heterogeneity in a large family H. Lerche, MD*; Y.G. Weber, MD*; H. Baier, MD; K. Jurkat–Rott, MD; O. Kraus de Camargo, MD; A.C. Ludolph, MD; H. Bode, MD; and F. Lehmann–Horn, MD Article abstract—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 ( 1 -subunit) and two in SCN1A (-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 + . NEUROLOGY 2001;57:1191–1198 Genetic analyses of Mendelian forms of epilepsy provide an excellent tool to study the etiology and pathophysiology of neuronal hyperexcitability in molecular detail. In particular, ion channel defects can cause inherited idiopathic epileptic syndromes, as has been found recently for autosomal dominant nocturnal frontal lobe epilepsy (ADFNLE), 1 benign familial neonatal convulsions (BFNC), 2-4 and gener- alized epilepsy with febrile seizures plus (GEFS + ). 5,6 Concepts derived from studies of these rare epileptic disorders may contribute to find new therapeutic strategies as has been shown recently for retigabine. This novel antiepileptic drug activates KCNQ K + channels, which are mutated in BFNC. 7 GEFS + was first described in 1997 and 1999 by Scheffer et al. 8,9 as a syndrome featuring febrile con- vulsions and a variety of afebrile epileptic seizure types within the same pedigree showing autosomal dominant inheritance. Most common was the febrile convulsion syndrome (FS), often with febrile seizures persisting after the 6th year of life or in combination with afebrile generalized tonic-clonic seizures (called FS + ). The phenotypes FS and FS + were found in about two thirds of affected individuals. According to the additional seizure types occurring in the remain- ing third of the patients, phenotypes such as “FS + with absences,” “FS + with myoclonic seizures,” or “FS + with atonic seizures” were described. The most severe phenotype was myoclonic astatic epilepsy (MAE). Also, partial epilepsies occurred in rare cases (“FS + with temporal lobe epilepsy”). The penetrance was about 60%. Voltage-gated sodium channels consist of one - and at least one -subunit. The -subunit alone forms normally functioning channels when ex- pressed in mammalian cells. It contains all main structural features such as the ion-conducting pore, voltage sensors, and the activation and inactivation Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Con- tents for the October 9 issue to find the title link for this article. *Both authors contributed equally to this study. From the Departments of Neurology (Drs. Lerche, Weber, Baier, and Ludolph), Applied Physiology (Drs. Lerche, Jurkat–Rott, and Lehmann–Horn), and Pediatrics (Drs. Kraus de Camargo and Bode), University of Ulm, Germany. Supported by the Bundesministerium für Bildung und Forschung (BMBF)/Interdisziplinäres Zentrum für Klinische Forschung (IZKF) Ulm, projects B1 (F.L.H. and K.J.R.) and B8 (H.L.). Received December 6, 2000. Accepted in final form May 24, 2001. Address correspondence to Dr. Holger Lerche, Departments of Neurology and Applied Physiology, University of Ulm Zentrum Klinische Forschung, Helmholtzstr. 8/1, D-89081 Ulm, Germany; e-mail: holger.lerche@medizin.uni-ulm.de Copyright © 2001 by AAN Enterprises, Inc. 1191