Striano, Pasquale

Zuberi, Sameer M.

English

Zuberi S. M.

Striano P.

Archivio istituzionale della ricerca - Università di Genova

The "plus" side of epilepsy phenotyping

Enlighten

EDITORIALSameer M. Zuberi, MDPasquale Striano, MDCorrespondence toDr. Zuberi:sameer.zuberi@nhs.netNeurology® 2017;89:1–2See page 1210The “plus” side of epilepsy phenotypingThe first clinical description of generalized epilepsywith febrile seizures plus (GEFS1) by Scheffer andBerkovic1 in their landmark Brain article of 1997represented a major step forward in the understand-ing of the genetic basis of the epilepsies. Coming2 years after their identification, with collaborators,of the genetic basis for a relatively homogenous syn-drome, autosomal dominant nocturnal frontal lobeepilepsy, the detailed phenotypic description of a sin-gle large Australian family with heterogeneous febrileseizure plus epilepsy phenotypes and a clear dominantpattern of inheritance put a novel perspective ongenotype–phenotype relationships in the epilepsies.2Shortly after, the SCN1A and SCN1B genes werelinked to the syndrome, and subsequently the last2 decades has confirmed that the majority of epilepsygenes show phenotypic heterogeneity and themajority of syndromes reveal genetic heterogeneity.3Why one individual in a GEFS1 family has a severedevelopmental and epileptic encephalopathy such asDravet syndrome and another has simple self-limitedfebrile seizures is unknown, but is likely to be deter-mined by other genetic factors influencing theSCN1A, or other major genes identified in a family.Twenty years later, the Melbourne group has re-visited GEFS1 and further refined the classificationand boundaries of this relatively common familialepilepsy syndrome. In this issue ofNeurology®, Zhanget al.4 analyzed the phenotypic spectrum in over 400affected individuals in 60 (31 previously unreported)families. Clinical information was obtained from pa-rents, spouses, or other eyewitnesses using a validatedseizure questionnaire. Previous medical records werereviewed, including EEG, video-EEG monitoring,and MRI studies. Blood samples and genetic analysiswas performed in the probands and family memberswhere possible. Then the authors performed detailedelectroclinical phenotyping on available affected fam-ilies and compared their phenotypic and genetic datato those published in the literature over the last19 years. By doing so, they have expanded theGEFS1 spectrum and identified new phenotypes,namely focal seizures without preceding febrileseizures and classic genetic generalized epilepsies.As about 9% of affected individuals have focal epilep-sies, the authors suggest that GEFS1 be renamedgenetic epilepsy with febrile seizures plus. Thischange in terminology is already widely accepted fol-lowing several articles reporting focal seizures andepilepsies in GEFS1 families.5,6 In addition, the phe-notypic overlap between GEFS1 and the classicgeneralized epilepsies is considerably greater than pre-viously reported. The authors coin the term early-onset genetic generalized epilepsies for a small subsetof patients. Whether this term has clinical andresearch utility will require further validation.In their study, the authors report genetic variantsin 11/31 GEFS1 families. SCN1A was reported in3 families and the relevance of some of the othervariants, notably SCN9A, in terms of pathogenicityin GEFS1 remains debatable. The report of SCN8Aand PRRT2 is worthy of scrutiny. The PRRT2 var-iants segregate with self-limited infantile seizures inthis family and are not seen with other phenotypes.The SCN8A variant segregates within a family toa child with a severe SCN8A developmental and epi-leptic encephalopathy and to a mosaic father.The 2017 International League Against EpilepsyClassification of Seizure Types and the Epilepsies re-flects scientific advances over the last 3 decades byincorporating an etiologic classification alongsidethe electroclinical phenotype.7,8 This approachfocuses the clinician on stratifying treatment whenpossible based on etiology. Well-described epilepsysyndromes, such as Ohtahara and Lennox-Gastautsyndromes, which had established electroclinical phe-notypes, are now regarded as of diminished clinicalutility unless they are also classified by their structuralor genetic etiology. Zhang et al. present a large housefor GEFS1 and it is likely that to define prognosis forthe individual and aid genetic counseling, detailedgenetic classification will be needed alongside preci-sion phenotyping; at present, this is only possible fora minority of GEFS1 cases. This article is an impor-tant addition to the literature, providing clarificationon several details of the phenotypic spectrum andFrom the Paediatric Neurosciences Research Group (S.M.Z.), Royal Hospital for Children & University of Glasgow, UK; and Pediatric Neurologyand Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (P.S.), Uni-versity of Genoa, “G. Gaslini” Institute, Italy.Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial.© 2017 American Academy of Neurology 1ª 2017 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Published Ahead of Print on August 25, 2017 as 10.1212/WNL.0000000000004399raising more questions about the role and relevance ofgenetic heterogeneity.STUDY FUNDINGNo targeted funding reported.DISCLOSURES.M. Zuberi receives research funding from Epilepsy Research UK,Dravet Syndrome UK, Glasgow Children’s Hospital Charity, and UCBPharma. He has attended advisory boards and received speaker’s hono-raria paid to his institution’s charitable fund from Zogenix, GW Pharma,and Biocodex. P. Striano received honoraria from FB Health, Kolfarmasrl, and Eisai Inc., and research support from the Italian Ministry ofHealth. Go to Neurology.org for full disclosures.REFERENCES1. Scheffer IE, Berkovic SF. Generalized epilepsy with febrileseizures plus: a genetic disorder with heterogeneous clinicalphenotypes. Brain 1997;120:479–490.2. A missense mutation in the neuronal nicotinic acetylcholinereceptor alpha 4 subunit is associated with autosomaldominant nocturnal frontal lobe epilepsy. Nat Genet1995;11:201–203.3. Orsini A, Zara F, Striano P. Recent advances in epilepsygenetics. Neurosci Lett 2017;S0304–3940:30402–0.4. Zhang Y-H, Burgess R, Malone JP, et al. Genetic epilepsywith febrile seizures plus: refining the spectrum. Neurology2017;89:1210–1219.5. Abou-Khalil B, Ge Q, Desai R, et al. Partial and generalizedepilepsy with febrile seizures plus and a novel SCN1A muta-tion. Neurology 2001;57:2265–2272.6. Scheffer IE, Harkin LA, Grinton BE, et al. Temporal lobeepilepsy and GEFS1 phenotypes associated with SCN1Bmutations. Brain 2007;130:100–109.7. Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classifica-tion of the epilepsies: position paper of the ILAE Commis-sion for Classification and Terminology. Epilepsia 2017;58:512–521.8. Fisher RS, Cross JH, French JA, et al. Operational classifi-cation of seizure types by the International League AgainstEpilepsy: position paper of the ILAE Commission for Clas-sification and Terminology. Epilepsia 2017;58:522–530.2 Neurology 89 September 19, 2017ª 2017 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.DOI 10.1212/WNL.0000000000004399 published online August 25, 2017Neurology Sameer M. Zuberi and Pasquale StrianoThe ''plus'' side of epilepsy phenotypingThis information is current as of August 25, 2017ServicesUpdated Information & 004399.full.htmlhttp://www.neurology.org/content/early/2017/08/24/WNL.0000000000including high resolution figures, can be found at:Subspecialty Collections http://www.neurology.org//cgi/collection/partial_seizuresPartial seizures http://www.neurology.org//cgi/collection/generalized_seizuresGeneralized seizures http://www.neurology.org//cgi/collection/all_epilepsy_seizuresAll Epilepsy/Seizures http://www.neurology.org//cgi/collection/all_clinical_neurologyAll Clinical Neurologyfollowing collection(s): This article, along with others on similar topics, appears in the  Permissions & Licensing http://www.neurology.org/misc/about.xhtml#permissionsits entirety can be found online at:Information about reproducing this article in parts (figures,tables) or in  Reprints http://www.neurology.org/misc/addir.xhtml#reprintsusInformation about ordering reprints can be found online:rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.1951, it is now a weekly with 48 issues per year. Copyright © 2017 American Academy of Neurology. All ® is the official journal of the American Academy of Neurology. Published continuously sinceNeurology 

The "plus" side of epilepsy phenotyping

Abstract

Similar works

Full text

Available Versions

Archivio istituzionale della ricerca - Università di Genova

Enlighten

Crossref