Objective: Following our original description of generalized epilepsy with febrile seizures plus (GEFS+) in 1997, we analyze the phenotypic spectrum in 409 affected individuals in 60 families (31 new families) and expand the GEFS+ spectrum. Methods: We performed detailed electroclinical phenotyping on all available affected family members. Genetic analysis of known GEFS+ genes was carried out where possible. We compared our phenotypic and genetic data to those published in the literature over the last 19 years. Results: We identified new phenotypes within the GEFS+ spectrum: Focal seizures without preceding febrile seizures (16/409 [4%]), classic genetic generalized epilepsies (22/409 [5%]), and afebrile generalized tonic-clonic seizures (9/409 [2%]). Febrile seizures remains the most frequent phenotype in GEFS+ (178/409 [44%]), followed by febrile seizures plus (111/409 [27%]). One third (50/163 [31%]) of GEFS+ families tested have a pathogenic variant in a known GEFS+ gene. Conclusion: As 37/409 (9%) affected individuals have focal epilepsies, we suggest that GEFS+ be renamed genetic epilepsy with febrile seizures plus rather than generalized epilepsy with febrile seizures plus. The phenotypic overlap between GEFS+ and the classic generalized epilepsies is considerably greater than first thought. The clinical and molecular data suggest that the 2 major groups of generalized epilepsies share genetic determinants.
|Number of pages||10|
|State||Published - 19 Sep 2017|
Bibliographical noteFunding Information:
Y. Zhang, R. Burgess, J. Malone, G. Glubb, K. Helbig, L. Vadlamudi, S. Kivity, Z. Afawi, A. Bleasel, P. Grattan-Smith, B. Grinton, S. Bellows, D. Vears, J. Damiano, H. Goldberg-Stern, A. Korczyn, L. Dibbens, E. Ruzzo, and M. Hildebrand report no disclosures relevant to the manuscript. S. Berkovic has served on scientific advisory boards for UCB and Janssen-Cilag; serves on the editorial boards of Lancet Neurology and Epileptic Disorders and the Advisory Board of Brain; may accrue future revenue on pending patent WO61/010176: Therapeutic Compound that relates to discovery of PCDH19 gene as the cause of familial epilepsy with mental retardation limited to females; is one of the inventors listed on a patent held by Bionomics Inc. on diagnostic testing of using the SCN1A gene, WO2006/133508; has received speaker honoraria from UCB; has received unrestricted educational grants from UCB, Janssen-Cilag, and Sanofi-Aventis; and receives/has received research support from the National Health and Medical Research Council of Australia and NINDS. I. Scheffer serves on the editorial boards of the Annals of Neurology, Neurology®, and Epileptic Disorders; may accrue future revenue on a pending patent WO61/010176: Therapeutic Compound that relates to discovery of PCDH19 gene as the cause of familial epilepsy with mental retardation limited to females; is one of the inventors listed on a patent held by Bionomics Inc. on diagnostic testing of using the SCN1A gene, WO2006/133508; has received speaker honoraria from Athena Diagnostics, UCB, GSK, and Transgenomics; has received funding for travel from Athena Diagnostics, UCB, and GSK; and receives/has received research support from the National Health and Medical Research Council of Australia and NINDS. Go to Neurology.org for full disclosures.
This work was supported by the National Health and Medical Research Council of Australia (Program Grant 628952, 2011–2015, to S.F.B., I.E. S., L.M.D.; Program Grant 1091593, 2016–2020, to S.F.B. and I.E.S.), Australia Fellowship (466671 to S.F.B.), Senior Practitioner Fellowship (1006110, 2011–2015; 1104831, 2016–2020; to I.E.S.), and Career Development Fellowship (1032603 to LMD and 1063799 to M.S.H.).
© 2017 American Academy of Neurology.