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  • Precision Medicine & Epilepsy

    YuwuJiang

    Dept.ofPediatrics&PediatricEpilepsyCenterPekingUniversityFirstHospital

  • Disclosures

    NoConflictsofInterest

    2

  • Outline

    Precisionmedicine:whyepilepsy?

    Precisionmedicine:practiceinepilepsydiagnosisandtreatment

    3

  • OutlinePrecisionmedicine:whyepilepsy?

    Precisionmedicine:practiceinepilepsydiagnosisandtreatment

    4

  • 5

    Epidemiology

    1. CamfieldP.EpilepticDisord2015;17:1171232. WilmshurstJM,etal.Epilepsia2015;56:11851197

    Incidenceofepilepsyinchildren 41187/100,0001

    consistentlyreportedtobehighestinthefirstyearoflife2

    Prevalencerangesfrom: 3.25.5/1,000indevelopedcountries1

    3.644/1,000inunderdevelopedcountries1(~10millioninChina,7/1000)

    Totally,~1/3refractory

  • GeneticEpilepsyEtiologyGenetic

    MonogenicSinglegene,Mendelian

    RarevariantsCopynumbervariations(CNVs)

    Common/ComplexepilepsiesMultigenicmultiplegenes,nonMendelian

    EtiologyStructure/Metabolic

    AcomponentofthephenotypespectrumforotherMendeliansyndromeswithbrainstructureormetabolicabnormalitiesduetogeneticdisease

    7

  • PrecisionMedicine&Epilepsy

    8

    Aftercancer,epilepsyoffersoneofthepossiblybestmodeltoachieveprecisionmedicine

    Therapidprogressinepilepsygenediscovery

    Theexistenceofgoodanimalandinvitromodelsallowingthedevelopmentofmedicationstailoredtogeneticallydefinedsubtypesofepilepsy

    Theabilitytoassessefficacyofexperimentaltargetedtreatmentsincosteffective,small,briefclinicaltrials

    National/Internationallargescalemulticentertrailgraduallyestablished

    NEnglJMed2015;372:793795

  • PrecisionMedicine&Epilepsy

    9NEnglJMed2015;372:793795

    Alltypesofnonacquiredepilepsywillbeassessed,andbasic,clinical,andtranslationalsciencewillbecloselyintegratedtodrivethedevelopmentofprecisiontherapies

  • OutlinePrecisionmedicine:whyepilepsy?

    Precisionmedicine:practiceinepilepsydiagnosisandtreatment

    10

  • Detectionrate:18% (84/467) 84patientswereidentifiedwithcausativemutations 34 genesinvolved 63noveland26reportedmutations 39severemutationsand49missensemutations SCN1Amutationaccountedforthelargestproportion

    (15/84),followedbySCN8A (10/84)andKCNQ2 (5/84) 53%(18/34)ofthemutatedgenesoccurred onlyinone

    case

    Num

    bero

    fpatients

    EpilepsywithID ourdata

  • TreatmentGuidedbyGeneticTesting

    Case1

    Male,4yrs

    Afebrileconvulsionoccurredat3monthsafterbirth,staringtooneside,developtofocalseizureswithgeneralization.Seizurefrequencyincreasedgradually.Seizuresoccurredeverytimeduringfeverorgettingcold,whichwerealwaysstatusepilepticus

    12

  • TreatmentGuidedbyGeneticTesting

    Case1

    Treatedbyantiepilepticdrugssince1yr

    Seizuresnotcontrolledwellbyvalproate,topiramateandoxcarbazepine.Duringhisbesttime,nofevernoseizures

    Nervoussystemexamination(),cranialMRI(),biochemicalexamination(),blood(urine)metabolismscreening()

    EEG:normalatonset;multifocalspikes,withslowbackgroundatlatestage

    13

  • Case1

    Dravetsyndromeclinically

    But,genemutationscreeningofSCN1A

    Diagnose?FurtherTreatment?

    14

    TreatmentGuidedbyGeneticTesting

  • Case1

    Dravetsyndromeclinically

    Targetedepilepsygenespanel

    ALDH7A1c.1553G>C/p.Arg518Thr,hetero, paternal;c.1061A>G/p.Tyr354Cys,hetero,maternal

    Diagnosis:pyridoxinedependentseizures

    TreatedbyvitaminB650mg,tidsince2yrs,graduallytaperedAEDs,seizurefreeforover2yrs (noseizureseveninfever)

    15

    TreatmentGuidedbyGeneticTesting

  • Case2

    male4 yrs

    Seizuresoccurredat2yrs,allduringsleep,occurredalmosteverynight,multipleseizureseachsleep,asymmetrictonicseizures,10sec(duration),poorsleepwhenseizuresoccurred frequently

    Ineffective:oxcarbazepine,levetiracetam,valproate

    16

    TreatmentGuidedbyGeneticTesting

  • Case2

    Nervoussystemexamination(),cranialMRI(),

    biochemicalexamination(),blood(urine)

    metabolismscreening()

    EEG:paroxysmalslowwavesatbilateralfrontal

    lobesinterictal

    17

    TreatmentGuidedbyGeneticTesting

  • Case2

    Targetedepilepsygenespanel

    KCNT1, c.1058G>A/p.Arg353Gln,denovo, notfoundinhisparents

    Diagnosis:Nocturnalfrontallobeepilepsy,KCNT1mutationinduced

    Treatedbyquinidine

    KCNT1 gainoffunctioninepilepsyreversedbyquinidine

    AnnNeurol.2014Apr;75(4):58190

    18

    TreatmentGuidedbyGeneticTesting

  • 0

    5

    10

    15

    20

    25

    30

    35

    K+ channel gene mutations

    Num

    bero

    fpatients

    32

    21

    9

    3 3 31 1 1 1

    75 K+ channelgenemutationsinvolved72 patients

    54 noveland21 reportedmutations

    KCNQ2mutationsaccountedforthelargestpopulation(42.7%,32/75),followedbyKCNT1(28.0%,21/75),andKCNMA1(12.0%,9/75)2casesreported

    All themutationsaredenovo

  • Precisionmedicineinepilepsy

    20

    AEDschoicebasedongene,notonclinic

    SCN8AmutationsinChinesechildrenwithearlyonsetepilepsyandintellectualdisability.OXC

    Epilepsia.2015;56(3):4318.

    EarlyandeffectivetreatmentofKCNQ2 encephalopathy.CBZPHT

    Epilepsia.2015;56(5):68591.

    STXBP1 relatedepilepticencephalopathyLEV

    BrainDev.2016Jan;38(1):12831.

  • Num

    bero

    fpatients

    362 Na+ channelgenemutationsinvolved362 patients

    277 noveland85 reportedmutations

    SCN1Amutationsaccountedforthelargest

    population(81.8%,296/362),followedbySCN2A(8.6%,

    31/362),andSCN8A(8.0%,29/362)

    All themutationsaredenovo

  • Precisionmedicineinepilepsy

    22

    Repurposeddrugchoicetreatmenttrialsbasedonmutationrealted mechanism KCNT1gainoffunctionin2epilepsyphenotypesisreversedby

    quinidine. AnnNeurol.2014;75(4):58190.

    GRIN2Amutationandearlyonsetepilepticencephalopathy:personalizedtherapywithmemantine. AnnClin Transl Neurol.2014;1(3):190198.

    SCN1AmutatedepilepsyClemizole (histamineantagonist), arepurposeddrugfromavailablelibraryof300compounds Neurobiol Dis.2015;79:13549

  • PredictSevereAEDsinducedcutaneousreactionsGeneticTest?

    HLAB*1502allele:highlyassociatedwithcarbamazepineinducedStevensJohnsonsyndrome(SJS)inHanChinese(Taiwan,HongKong,Mainland),aswellasphenytoin,andlamotrigineinducedSJS;notassociatedwithmaculopapularexanthema(MPE).NotfoundinCaucasiancases(butinCaucasianwithAsianancestry)indicatetheroleofethnicityCommercialdetectingkitisavailable

    Epilepsia. 2007;48(5):1015-8; Pharmacogenomics J. 2006;6(4):265-8

    23

  • PredictSevereAEDsinducedcutaneousreactions

    N Engl J Med 2011;364:1126-33

    24

  • N Engl J Med 2011;364:1126-33

    25

    PredictSevereAEDsinducedcutaneousreactions

  • PrecisionmedicinerelatedmaincompaniesinChina

    Equipment Service

    Comprehensive

    SpecializedReagnents

    Domestic

    Foreign

    Imported

    Domestic

    Bioinformatic

  • WhatsnextforPMinepilepsy?Largescale(national&international)cohortandregistrationstudyforallnonacquiredepilepsy

    Morefast,convenientandeconomicgenetictest:nextgenerationsequence

    Enhancingbioinformaticscapacityfordataanalysistoimprovetheaccuracyofriskassessmentandgeneticcounseling

    Betterfunctionalstudyforpathogenicvariation

    Developingmorespecific/tailoredAEDstherapy,evengenetherapythroughspecificgeneticmarkersortargets,orbasedoncertainpathogenicpathway

    27

  • WhatsnextforPM?

    28

    Clinicalpractice

    Geneticandmolecular

    Investigation

    Clinicaltrial&

    Bigdata

    Mutual&activeinteractioninhealthcarewholeprocess

    e.g.ourJIprojectforepilepsy

  • 29

    Thanks!jiangyuwu@bjmu.edu.cn