Genetic epilepsy with febrile seizures plus: Refining the spectrum

Yue-Hua Zhang; Rosemary Burgess; Jodie P Malone; Georgie C Glubb; Katherine L Helbig; Lata Vadlamudi; Sara Kivity; Zaid Afawi; Andrew Bleasel; Padraic Grattan-Smith; Bronwyn E Grinton; Susannah T Bellows; Danya F Vears; John A Damiano; Hadassa Goldberg-Stern; Amos D Korczyn; Leanne M Dibbens; Elizabeth K Ruzzo; Michael S Hildebrand; Samuel F Berkovic; Ingrid E Scheffer

doi:10.1212/WNL.0000000000004384

Genetic epilepsy with febrile seizures plus: Refining the spectrum

Neurology. 2017 Sep 19;89(12):1210-1219. doi: 10.1212/WNL.0000000000004384. Epub 2017 Aug 25.

Authors

Yue-Hua Zhang¹, Rosemary Burgess¹, Jodie P Malone¹, Georgie C Glubb¹, Katherine L Helbig¹, Lata Vadlamudi¹, Sara Kivity¹, Zaid Afawi¹, Andrew Bleasel¹, Padraic Grattan-Smith¹, Bronwyn E Grinton¹, Susannah T Bellows¹, Danya F Vears¹, John A Damiano¹, Hadassa Goldberg-Stern¹, Amos D Korczyn¹, Leanne M Dibbens¹, Elizabeth K Ruzzo¹, Michael S Hildebrand¹, Samuel F Berkovic¹, Ingrid E Scheffer²

Affiliations

¹ From the Epilepsy Research Centre, Department of Medicine (Y.-H.Z., R.B., J.P.M., G.C.G., K.L.H., L.V., B.E.G., S.T.B., D.F.V., J.A.D., M.S.H., S.F.B., I.E.S.), The University of Melbourne, Austin Health, Australia; Department of Pediatrics (Y.-H.Z.), Peking University First Hospital, Beijing, China; Department of Neurology (L.V.), The University of Queensland Centre for Clinical Research, Royal Brisbane and Women's Hospital, Australia; Schneider Children's Medical Center of Israel (S.K., H.G.-S.), Petach Tikvah; Department of Neurology (Z.A.), Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel; Westmead Hospital (A.B.), New South Wales, Australia; Department of Neurology (P.G.-S.), Sydney Children's Hospital, Australia; Department of Neurology (A.D.K.), Tel Aviv University, Israel; Women's and Children's Hospital (L.M.D.), University of Adelaide, South Australia; Center for Neurobehavioral Genetics (E.K.R.), Semel Institute, David Geffen School of Medicine, University of California, Los Angeles; Department of Paediatrics (I.E.S.), The University of Melbourne, Royal Children's Hospital, Victoria; and The Florey Institute of Neurosciences and Mental Health (I.E.S.), Melbourne, Australia.
² From the Epilepsy Research Centre, Department of Medicine (Y.-H.Z., R.B., J.P.M., G.C.G., K.L.H., L.V., B.E.G., S.T.B., D.F.V., J.A.D., M.S.H., S.F.B., I.E.S.), The University of Melbourne, Austin Health, Australia; Department of Pediatrics (Y.-H.Z.), Peking University First Hospital, Beijing, China; Department of Neurology (L.V.), The University of Queensland Centre for Clinical Research, Royal Brisbane and Women's Hospital, Australia; Schneider Children's Medical Center of Israel (S.K., H.G.-S.), Petach Tikvah; Department of Neurology (Z.A.), Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel; Westmead Hospital (A.B.), New South Wales, Australia; Department of Neurology (P.G.-S.), Sydney Children's Hospital, Australia; Department of Neurology (A.D.K.), Tel Aviv University, Israel; Women's and Children's Hospital (L.M.D.), University of Adelaide, South Australia; Center for Neurobehavioral Genetics (E.K.R.), Semel Institute, David Geffen School of Medicine, University of California, Los Angeles; Department of Paediatrics (I.E.S.), The University of Melbourne, Royal Children's Hospital, Victoria; and The Florey Institute of Neurosciences and Mental Health (I.E.S.), Melbourne, Australia. scheffer@unimelb.edu.au.

PMID: 28842445
DOI: 10.1212/WNL.0000000000004384

Abstract

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.

MeSH terms

Adolescent
Adult
Age of Onset
Child
Child, Preschool
Epilepsies, Partial / genetics
Epilepsies, Partial / physiopathology*
Epilepsy, Generalized / genetics
Epilepsy, Generalized / physiopathology*
Female
Humans
Infant
Male
Middle Aged
Pedigree
Phenotype
Seizures, Febrile / genetics
Seizures, Febrile / physiopathology*
Young Adult