Posted on Authorea 12 May 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162082741.10922171/v1 — This a preprint and has not been peer reviewed. 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McTague Symonds, 2020; al et ¨ odberg 1 n ai Giardino Maria and 1 1 dege al et ¨ odberg Posted on Authorea 12 May 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162082741.10922171/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. fcanlfnto,teciia vdneta h diitaino oimcanlbokr aeseizure made loss blockers causing channel possibly sodium (SCN1A) of channel that to administration sodium discovery evolving the the the Following frequency that of 2018). evidence seizure subunit al clinical alpha1 in et the the increase Lange function, of de an channel mutations 1998; determine of to al, to et in indicated associated avoided potential (Guerrini is reports patients be the clinical DS some should have some encephalo- in (CBZ) identified, they epilepticus epileptic carbamazepine was since status and and cause (LTG) DS developmental genetic lamotrigine with studied the including patients and before blockers Well renowned channel treatment 2019). guides most sodium al aetiology that the genetic et underling (DS) (Mei the Syndrome of (DEE) identification seizure Dravet pathy the - how of of improving that example best is or and first worsening the either of One - modifying ASM known frequency of evidence Clinical-based of impact the to according subtypes four into treatment: patient’s divided real been on have knowledge evidences such tailored current and purposes, specific mechanism academic a pathophysiological For following of findings, implications implementation genetic therapeutic the between ae- the for correlation treatment. multiple discuss environment seizure the ideal will of and We the identification diagnosis approach. drug- provides the genetic intervention medicine new where early precision epilepsies, of preventive for paediatric-onset a development potential on the the mainly and to focuses tiologies contribute review, and present The biology underlying effective the on depends protocols. illuminate treatments well- screening appropriate targeted that a more developing having or systems or of new identifying into importance model causes and the genetic outcomes, emphasise of Translation clinical guidelines assessments. relevant Such issued outcome (FDA) identifying 19). 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All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162082741.10922171/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. ono ydoe eeehprestvt ecin nptet fAinoii Cuge l20) These Stevens- 2004). al carbamazepine-induced et of (Chung additional origin predictive An Asian highly 2014). of is patients al in which et reaction, allele (Hynynen hypersensitivity valproate HLA-B*15:02 severe adverse with a the of syndrome, treated mutations avoidance of Johnson POLG1 when facilitating including that failure example in is recent hepatic role of example fatal number important a develop equally by might illustrated an as who has efficacy, maximising also in epilepsies as treatment). is completely reactions preventive the disappear ASM of in spasms GABAergic section and medicine conventional effective the Precision very a in is (GVG), below TSC, Vigabatrin with (see patients occurring 2018). patients of spasms al most spasms infantile infantile et in and for (Curatolo pathway seizures drug focal infants plasticity. line rapamycin) with first TSC and epilepsy, of the growth, of drug-resistant target survival, and 80% severe proliferation, (mammalian about of cell mTOR in cause including the major functions, a TSC1 of neuronal is either components of TSC in variety important mutations a inactivating are (De regulates by that episodes which caused disorder disease genes multisystem movement TSC2 a the or is al and (TSC) et seizures complex (Marini suppress sclerosis Tuberous seizures to childhood absence effective During very and infants. are migraine 2019). Marini normal Silveira-Moriyama CBZ hemiplegic 2011; Gusmao, otherwise of include al in doses et manifestations years (Chen Small rare choreoathetosis 2012). 2 Additional that kinesigenic age 2012). seizures paroxysmal in by focal al develop variants may onset et disappear Disease-causing patients infantile and some fusion. with outcome adolescence, expressed vesicle interacting or benign clinically synaptic protein are very enables and transmembrane a which haploinsufficiency have presynaptic in complex, a result SNARE gene is the PRRT2 (PRRT2) of seizure 2 early members that protein with suggested 2015). transmembrane been al has proline-rich et it (Pisano and The Pisano patients ASM outcome 2014; these in neurodevelopmental al on improve seizures freedom et also of seizure may (Numis treatment achieve the control patients epilepticus the of Most status for 2015). knowledge with drugs al by presenting first-line et only those as not including recommended KCNQ2-encephalopathy, guided also with is are PHT medication consequences. and ASM functional Carbamazepine The onset best its 2017). the by seizure al also of and et but (Wolff choice function CBZ gene the channel and mutated patients, PHT of some with gain In stopped Larsen a epilepsy. are 2014; seizures to al yet leading et of phenotypes S Ohba mutations severe story 2019). 2015; months, missense Moeller al 3 Gardella, to age et 2017; Pisano before related al 2014; et is al Dilena blockers 2017; et al channel (Numis et PHT Wolff and 2015; CBZ al to et by associated controlled those fully including are DEE well-defined seizures 2021). some seizures al in of when contrary, et induction the (Bleakley paradoxical frequency On a animals seizures in mutant resulted in of model patients mouse induction worsening HCN1 knock-in spiking from genetic especially report and the the clinical in ASM this LTG in with of Consistent to observed administration (LCS). the lacosamide response is and (PHT) the blockers phenytoin with channel shared treated sodium also by correlation aggravation phenotype seizures to of related example DEE discontinuing GABAergic straightforward patients inhibitory, second few of A with enhancement duration tolerated, to and well due concentration (Chiron likely generally effects. peak activity epilepticus adverse are increasing anti-convulsing status for agents including direct reduced 2011).These action a markedly (Fisher of and and neurotransmission mechanisms CLB CLB multiple of and seizure VPA action has convulsive al to in of STP et reduction added 2000). Wirrel 50% the when than 2004; al avoiding cases, greater al et a especially of et with seizures 71% (Ceulemans associated preventing was in DS STP with frequency in 2019). infants (VPA), effective Nabbout in acid and most observed valproic Wirrel complete frequently the 2018, of Although epilepticus, combination is 2019). the status al (STP) into that et stiripentol evolution shown Mei have and 2010; studies (CLB) Marini clinical Mantegazza, attainable, clobazam 2001; rarely al is et control (Claes seizure explained partly was worse SCN2A HCN1 dsaohrlvlo opeiyt aeit con hntetn ain ihagenetic a with patient a treating when account into take to complexity of level another adds eeGy9s uain(aiie l21) w ainswt opeegenotype- complete with patients Two 2018). al et (Marini mutation Gly39Asp gene 3 CN2A SCN2A uain epnet sodium to response mutations and SCN8A eemutations, gene Posted on Authorea 12 May 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162082741.10922171/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. dacsi h dnicto fteudryn asso plpisldt oe hrpui approach therapeutic novel a to led epilepsies of causes underlying the of knowl- identification pathophysiological the from in Advances developed strategies CLB= treatment stiripentol; novel STP= edge medicine: function; of Precision loss 2. LOF= spasms infantile function; IS= of mutation, gain Mut= GOF= clobazam; medication; antiseizure ASM= frequency seizure improving- or worsening - modifying ASM Known examples reported above the summarizes for below, choice. epilepsies here treating available underling Most 1, initial and Table the syndromes. mutations our gene of are and channel channels knowledge ion epilepsies to ion the some related targeting are from of drugs insights gained pathophysiological management greater have obtained therapeutically families we the which and in clinicians mutations much gene how show clearly examples POLG TSC2 & TSC1 HCN1 PRRT2 SCN1A SCN1A SCN8A SCN2A allele HLA-B*15:02 Functional KCNQ2 Gene nciaigGGIpoigI uaooe al et Curatolo IS Improving GVG Inactivating O asodium Na 1 line 1st LOF STP CLB, VPA, CBZ haploinsufficiency LOF O asodium Na LOF nnw achannel Na Unknown O achannel Na GOF eaieeffect negative Dominant effect 4 LCM) LTG, PHT, (CBZ, blockers channel LTG) PHT, (CBZ, blockers channel PHT) (CBZ, blockers PHT) (CBZ, blockers B Stevens- CBZ Reference effect ASM PHT) (CBZ, blockers channel Na ASM P ct liver Acute VPA osnn aiie al et Marini Worsening treatment treatment osnn uriie al et Guerrini Worsening mrvmn asne al et Larsen Improvement mrvmn offe al et Wolff Improvement sa origin Asian in syndrome Johnson al et Numis Improvement failure st line 2018 2018 2019 Moriyama Silveira- Gusmao, De 2018 Nabbout Wirrel, 2017; al et Wirrel ta 2018 al et Lange de 1998; 2018 2017 2004 al et Chung 2015 al et Pisano 2014; 2014 al et Hynynen Posted on Authorea 12 May 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162082741.10922171/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. ewe h g f2ad4yas agaedly oo yfnto n eaiua rbes Long-term problems. behavioural and dysfunction seizures motor by delay, characterized language is years, CLN2 4 2017). and (Markham 2 of (TPP1) age 1 alfa neurodegenerative the the peptidase cerliponase rare between in tripeptidyl with a mutations enzyme disease, therapy recessive CLN2 lysosomal replacement autosomal of the enzyme by treatment as the caused such 2017, for diseases disorder In approved neurodegenerative paediatric been by (CLN2). has caused TPP1) 2 epilepsy human of type (recombinant of treatment lipofuscinosis the regardless ceroid for mg/d important countries.neuronal 5–20 also developed 2012) is at in (Wolf diagnosis birth supplementation disorders Early at activity these biotin screening enzyme both life-long neonatal biotinidase for is of for age Treatment part Testing or is weight confirmatory. life. and pre- is available of clinical readily testing months is classical few Genetic blood disorder, first peripheral neurometabolic the the recessive in in autosomal seizures recurrent rare, includes a methyltetrahydrofolate sentation is 5- deficiency correct and enzyme to calcification, Biotinidase acid 2019). associated ganglia al folinic be basal et may of (Pope bilateral It initiation levels body. changes, includes CSF the Treatment matter of receptor epilepsy. white rest folate the drug-refractory disorder, the in metabolite movement encoding metabolism active delay, gene folate (the developmental FOLR1 normal 5-methyltetrahydrofolate the but of system in levels nervous mutations low the PLP by in dependency and/or characterized folate) lifelong of pyridoxine is a deficiency either with 2021). folate of al condition Cerebral Administration et general are (Coughlin overall genes supply 2019). the PNPO B6 of al vitamin improvement and et on (antiquitin) and caused Wilson resolution ALDH7A1 deficiencies 2013, seizures the (PLP) determine B of phosphate (Plecko mutations pyridoxal frequent heterozygous and relatively compound pyridoxine (van or early neurodegeneration epilepsies homozygous of responsive their by risk vitamin seizures, the the decrease of Amongst to cause or common beyond seizures, common 2018) measures control al most therapeutic to et substitutive the either Karnebeek the essential represent some is for not drugs, since anti-epileptic do importance, utmost metabolism of is of identification effect blood-brain errors neuroprotective the ketone substrate. inborn through a hereditary energetic provides transported in Although alternative this bodies and diet resulting an For Keton synthesis, important low-carbohydrate as 2020). 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All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162082741.10922171/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. htqiiiemyb neetv eiaini uain asn ano ucinlaigt constitutive evidence to leading clinical function first of the gain a reported causing al mutations in et drug- antagonist al medication Bearden and partial effective et a an 2014 severe as (Barcia be In often operates may epilepsy channel. which are quinidine associated drug that potassium epilepsies antimalarial of sodium-activated KCNT1-related and date focal antiarrhythmic type KCNT1 to with migrating Ia evaluated the of associated class variants with of a Seizures gene is infancy irrespective All 2018). 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All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162082741.10922171/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. oigtwrsteftr ht o oecniin saraytepeet ese into step we present, the already is conditions some treatments for progress that, in future and the towards treatments Moving preventive aetiology-based medicine: Precision 3. knowledge pathophysiological from developed strategies treatment Novel 2020). evidences al reported et above Neuray the and summarizes these 2020 in below, and al outcome here KD et clinical 2, of Hardenberg improve Table acid von combination to glutamic shown 2020, A function been al of inhibitory have seizures. et conversion GABAergic availability and (Chatron and impaired the hyperexcitability patients function the catalyses neuronal seizures GABA thus that enhancing underlie function myoclonic both might enzyme of or GVG enzyme excitation an spasms the of encodes loss excess epileptic gene a and with GAD1 epileptic cause Mutations life The and GABA. developmental of to 2020). onset months al randomized infantile second et no syndromic the however, (Chatron a around 2000) cause presenting al GAD1 with encephalopathy et in studies, variants Kerrigan pilot loss-of-function 2007; open-label 2021). 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All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162082741.10922171/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. ullnt rti.Acretciia ra ece t hs rnoie,dul-ln,placebo- double-blind, (randomized, 2 enabling Phase thus its mutations reached gene trial nonsense by clinical caused current (Mork- dystrophy codons A muscular stop Duchenne with premature patients protein. in suppresses in also full-length prescribed which in present effective 2020), at be drug, ous and available brain an Gys1- the The is reach Ataluren thus 2021). al puncture et lumbar (Ahonen via formation patients to body the patients. administered Lafora in epilepsy. of injection be intra-cerebro-ventricular reduction myoclonus could by a ASO progressive administered determined was Treatment devastating brain teenage-onset model. the oligonucleotide mouse in Antisense a mRNA section). disease the previous targeting (see Lafora metformin intra-cerebro-ventricular(Gys1-ASO) including for disappointing treated, very needed is treatment to successfully urgently Current reduced time, weeks also is same 3 injection the cure was from ASO At mice A DS an syndrome 2020). 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Data may be preliminary. r fteaista agtteudryn as n ehnsso plpy vial,commercialised the Available, towards moved epilepsy. have of We and mechanisms epilepsy. treatment and 2011 of epilepsy al cause cause of et underlying the Jozwiak paradigm the of our treatment target in enable that that shift therapies and major of ASM a era beyond identify witnessing to go allowed already that patients, some are therapies very in for epilepsies, now of targets onset is aetiologies sz specific the Research accompanying of to and understanding prior seizures avoided. increased improving Vigabatrin our drugs be Furthermore, disorder/diseases which the should for of thus cure indication effects a identify the side to comorbidities. severe and/or need urgent cause medication also the but or best to prognosis, sensitive frequency the and pathogenic diagnosis seizure of for the worsen selection only identifying might including not that relevant management indicates is patient’s epilepsies clearly genetic for sections with previous patients in individual in discussed variant examples and evidences The TSC1/TSC2 Conclusions seizure sz= oligonucleotide; antisense ASO= teraphy Preventive treatments progress in and treatments preventive Aetiology-based evidences 2021). reported al above et the (Gumusgoz summarizes hurdles below, specificity here might and 3, it efficiency, to therapy,Table delivery, that neurological approach major in hopes alternative promise of the great raising clearance an holds biotechnology the models be CRISPR/Cas9 experimental pending patients. could animal for in available NPY results become of soon promising delivered levels has activity. the therapy seizure Gene Increasing suppress the and resected in effect 2019). surgically al activity slices therapeutic et al epileptiform a hippocampal (Cattaneo induced et achieve in chemically epilepsies (Wickham application, reduces with gyrus NPY significantly patients TLE, that NPY-based dentate of drug-resistant Therefore, demonstrate treatment with 2019 epilepsy. the patients of in for from models al the approach animal et in novel in the Wickham overexpression seizures In a its 2021). suppress represent level. indeed can anticonvulsant, circuit may vectors endogenous to therapy viral an cellular gene of as from the aid act range in the to expressed that with thought pathways neuropeptide brain is a affecting is NPY neuromodulator, epilepsy, NPY a of challenge. as context a acts much very it 2021). still where is al including brain, approach disorders et therapy neurological (Servais gene of the Biogen) et management epilepsy Spinraza- For the (Piguet and for gene Novartis approved suicide silencing, (Zolgensma- therapies of gene gene SMA be expression few for replacement, can or only nervoustwo gene products are phenotype central therapy of There improve for Gene use to 2021). pathways issue research. the al cellular of including major of of focus mechanisms, the passage central modulation pathophysiological the is devel- a transplicing, restricts the Delivery are research barrier solve obstacle brain intensive 2. to this blood and tailored bypass experienced the fre- therapy, to 1 has gene strategies and for phase diseases thus particularly pre-clinical vectors and types neurological in general, for in still deficiency, seizure therapies therapy are (CDKL5) system on gene trials 5 Most years, kinase-like efficacy 10 opment. cyclin-dependent and than or mutation more safety For nonsense the with DS testing in in drug (https://clinicaltrials.gov/ct2/show/NCT02758626). the NCT02758626) of trial, quency clinical controlled 10 lnclogigtilSNAAOSK01hts/daesnrmnw.o/ h OAC ra NT4425 tk Therapeutics Stoke (NCT04442295) 2020 trial al MONARCH et the Lenk https://dravetsyndromenews.com/; ASO/STK-001 ASO SCN1A SCN8A models) animal in only (tested progress In trial ongoing Clinical yeo ramn eesrtg/ramn Reference strategy/treatment gene treatment of type C1 S eke l2020 al et Lenk 2021 al et Ahonen https://clinicaltrials.gov/ct2/show/NCT02758626 https://clinicaltrials.gov/ct2/show/NCT02758626 ASO Gys1-ASO Ataluren EPM2A/EPM2B SCN1A Ataluren 2010 al deficiency et CDKL5 Stockler mutations SCN1A nonsense Pyridoxin administration Maternal epilepsy Pyridoxin-dependent Posted on Authorea 12 May 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162082741.10922171/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. ilgcleprie hscasadfmle r ed n okn owr oti e r fprecision of era new this to forward and looking genetic, and clinical, ready References with are researchers that families development together multi-center, the targets and bring on disorders, new Physicians that medicine. depends rare identifies goals groups with these expertise. studies research have Reaching dealing integrated biological functional who drugs. are and when tailored epilepsy we collaborative and feasible of with since personalized of and of into first third, individuals translated characterization needed and of be epilepsy: are functional genes might cohorts trials in standardized epilepsy large controlled a medicine the enrol randomized, of second precision to each to characterized; in requirement approach genomically mutations Meanwhile, key systematic and a phenotypically comorbidities. a registry, and been for patient’s seizures requirements pathophysiology- is featuring curative, main disorders all more three a of towards are approach evolving there therapeutic rapidly preventive comorbidities. is promote community and and to preventively. scientific seizures order even based whole in including or epilepsy, early the disease epilepsy To of conclusion of of occurrence In causes stages the the epilepsies. early avoid identify monogenic the to to tool is during and to promising epileptologists administered therapies very for approach preventive when a challenge therapeutic effective the be scenario, most to our this seems be In change editing to gene will likely variants, is therapy pathogenic and of gene impact that pathophysiological the focused doubt and reverse still discordant no are are treatments is such Results Moreover There genotypes. medicines. similar precision proposed, carrying seizures. newly others stopping have the in on of drugs not most several for satisfying, and univocal partially patients not only some are in treatments effective aetiology-based proven authorities, the by approved and Gern ,NeesJ o a dacsi plpygntc edt etrtetet n cures? and 2018;47(3):218-226 treatments Med. better Presse progress. to Continuing lead epilepsies: genetics human of epilepsy Genetics in P. advances Szepetowski can 14. How J. Noebels R, clinic. the Guerrini in sequencing 13. generation Next disorders: developmental and Epilepsy McTague. JD, Symonds 12. F1000Resaerch testing. genetic and genomics epilepsy in St advances 11. Recent HC. Mefford M, Hebbar 10. PriiE aiiC e ta.Dansi agtdRsqecn n39Ptet ihDrug- with Patients 349 in Resequencing Targeted Diagnostic in al. strategies et medicine D of precision Mei Diagnosis C, and for preventive Marini Methods predictive, E, Sequencing Parrini of Generation Impact 9. Next M. al Kuchenbuch et R, N, Nabbout Diagnosis the Maksemous 8. on CL, Sequencing Next-Generation of Albury of epilepticus–Report P, Impact status The Dunn of R. 7. classification Guerrini C, and Marini definition E, A Parrini 1973;28:1-9. D, al. Neurol Mei et Arch 6. D primates. Hesdorffer in H, epilepticus status Cock syn- of E, Landau-Kleffner Physiology Trinka AM. RW. Soprano 5. 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