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Generalized epilepsy with febrile seizures plus

Further heterogeneity in a large family

*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.

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{at}medizin.uni-ulm.de

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 (ß₁-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⁺.

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