Upload
others
View
2
Download
0
Embed Size (px)
Citation preview
1
Genetic counselling and testing for Alzheimer's Disease and Frontotemporal Lobar
Degeneration:anItalianconsensusprotocol
RunningTitle:ItalianDIAfNProtocolforGeneticCounselling
MartinaBocchettaa,b,AnnaMegaa, LiviaBernardic, EmilioDiMariad, LuisaBenussie,GiulianoBinettif,
BarbaraBorronig,RosannaColaoc,GiuseppeDiFedeh, SilviaFostinellie,DanielaGalimbertii,Massimo
Gennarellij, Roberta Ghidonie, Irene Piacerik, Michela Pievania, Corinna Porteril, Veronica Redaellih,
Giacomina Rossih, Silvia Suardih, Claudio Babilonim, Elio Scarpinii, Fabrizio Tagliavinih, Alessandro
Padovanig,BenedettaNacmiask,SandroSorbik,GiovanniB.Frisonia,n,SINdem*,AmaliaC.Brunic.
*SINdemCollaborators:
MarcoBozzalio, Lucilla Parnettip, Carlo Ferrareseq, Stefano F. Cappar, CamilloMarras, CarloMasullot,
InnocenzoRainerou,VincenzoSilaniv,GiuseppeSorrentinow,GiuseppeBrunox,AnnachiaraCagniny.
a)LaboratoryofAlzheimer’sNeuroimagingandEpidemiology,IRCCSIstitutoCentroSanGiovannidiDio
Fatebenefratelli,Brescia,Italy;
b)DepartmentofMolecularandTranslationalMedicine,UniversityofBrescia,Brescia,Italy;
c)CentroRegionalediNeurogenetica,LameziaTerme,Italy;
d)DepartmentofHealthSciences,UniversityofGenovaandDivisionofMedicalGenetics,GallieraHospital,
Genova,Italy;
e)MolecularMarkersLaboratory,IRCCSIstitutoCentroSanGiovannidiDioFatebenefratelli,Brescia,Italy;
f)IRCCSIstitutoCentroSanGiovannidiDioFatebenefratelli,Brescia,Italy;
g)UniversityofBresciaandCentreforAgeingBrainandNeurodegenerativeDisorders,NeurologyUnit,
Brescia,Brescia,Italy;
h)IRCCSFondazioneIstitutoNeurologicoCarloBesta,Milan,Italy;
i)UniversityofMilan,FondazioneCàGranda,IRCCSOspedaleMaggiorePoliclinico,Milan,Italy;
j)GeneticUnit,IRCCSIstitutoCentroSanGiovannidiDioFatebenefratelli,Brescia,Italy;
k) Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence,
Florence,Italy;
l)BioethicsUnit,IRCCSIstitutoCentroSanGiovannidiDioFatebenefratelli,Brescia,Italy;
m)DepartimentofPhysiologyandPharmacology,UniversityofRome“LaSapienza”,Rome,Italy;IRCCS
SanRaffaelePisanaofRome,Italy;
n)MemoryClinicandLANVIE-LaboratoryofNeuroimagingofAging,UniversityHospitalsandUniversity
ofGeneva,Geneva,Switzerland;
o)NeuroimagingLaboratory,IRCCSSantaLuciaFoundation,Rome,Italy;
2
p)SectionofNeurology,DepartmentofMedicine,CentreforMemoryDisturbances,UniversityofPerugia,
Perugia,Italy;
q)SchoolofMedicineandSurgery,MilanCenterforNeuroscience(NeuroMI),UniversityofMilanoBicocca,
Italy;NeurologyUnit,SanGerardoHospital,Monza,Italy;
r)NeTSCenter-IstitutoUniversitariodiStudiSuperiori(IUSS),Pavia,Italy;
s)InstituteofNeurologyandCenterforNeuropsychologicalResearchofthePoliclinicoGemelli,Catholic
UniversityofRome,Italy;
t)DepartmentofNeuroscience,InstitutesofNeurology,CatholicUniversityoftheSacredHeart,Rome;
u)NeurologyI-HeadacheCenter,DepartmentofNeuroscience"RitaLeviMontalcini,UniversityofTorino,
Torino,Italy;
v) Department of Neurology-Stroke Unit and Laboratory of Neuroscience, IRCCS Istituto Auxologico
Italiano, "Dino Ferrari" Centre, Department of Pathophysiology and Transplantation, Universita' degli
StudidiMilano,Milan,Italy;
w)UniversityofNaplesParthenope,Naples,Italy;
x)MemoryClinic,DepartmentofNeurologyandPsychiatry,UniversityofRome"Sapienza",Italy;
y) Department of Neurosciences (DNS), University of Padova, Padua; IRCCS, San Camillo Hospital
Foundation,Venice,Italy.
Corresponding Author: Amalia Cecilia Bruni, MD; Centro Regionale di Neurogenetica, Viale Arturo
Perugini, 88046 Lamezia Terme, Italy; phone: +39 0968 208080; fax: +39 0968 208032; e-mail:
Keywords:Alzheimerdisease;frontotemporaldegeneration;geneticcounselling;genetictesting
3
BACKGROUND Genetic testing of familial Alzheimer’s disease (AD) and frontotemporal lobar
degeneration(FTLD)isattractinginterestthankstoinnovativeprimarypreventionclinicaltrialsand
increased request for information by at-risk individuals. However, ethical, social and psychological
implicationsareparamountandgenetictestingmustbesupportedbystructuredgeneticcounselling.In
Italy,practiceparametersandguidelinesforgeneticcounsellingindementiaarenotavailable.
AIMTodevelopanationallyharmonizedprotocolforgeneticcounsellingandtestingoffamilialADand
FTLD.
METHODSActivitieswerecarriedout inthecontextof theItalianDominantlyInheritedAlzheimer’s
and Frontotemporal Network (IT-DIAfN) project, a national network of centres of excellence with
expertise in managing patients with familial AD and FTLD. A survey of the literature on genetic
counselling protocols and guidelines was conducted. Local protocols for genetic counselling were
surveyed.Differencesandcommonalitiesamongprotocolswereidentifiedanddiscussedamongproject
partners.Consensuswasreachedfollowingimplicitaggregationmethods.
RESULTSConsensuswasreachedonaprotocol forpatientswithclinicallydiagnosed familialADor
FTLDandadistinctprotocol for their at-risk relatives.Genetic counselling shouldbeprovidedby a
multidisciplinary team including a geneticist, a neurologist/geriatrician, and a
psychologist/psychiatrist, according to the following schedule: (i) initial consultation with tailored
informationon thegeneticsof thedementias; (ii) clinical,psychologicalandcognitiveassessment; if
deemedappropriate(iii)genetictestingfollowingastructureddecisiontreeforgenemutationsearch;
(iv)genetictestingresultdisclosure;(v)psychologicalsupportfollow-up.
CONCLUSIONSThisgeneticcounsellingprotocolprovidesItaliancentreswithalineofsharedpractice
for dealingwith the requests for genetic testing for familialAD andFTLD frompatients and at-risk
relatives,whomayalsobeeligibleparticipantsfornovelpreventionclinicaltrials.
4
1.INTRODUCTION
Alzheimer’sDisease(AD)andfrontotemporallobardegeneration(FTLD)aretwoofthemostcommon
formsofdementia.Althoughthemajorityofcasesaresporadic(i.e.withoutafamilyhistory),amarkedly
familialcomponenthasbeenreportedin60%ofearlyonset(<65years)ADpatients[1]andin25-50%
ofFTLDpatients[2,3].Anautosomaldominantmodeofinheritanceisfoundinabout1-5%ofADand
10-50% of FTLD cases [4,5]: specifically, pathogenic AD mutations were identified in the Amyloid
precursorprotein(APP)[6]andthePresenilin(PSEN1andPSEN2)genes[7,8],whilethegenesmainly
involved in FTLD are theMicrotubule associated protein tau (MAPT) [9-11], the Progranulin (GRN)
[12,13] and Chromosome 9 open reading frame 72 (C9orf72) [14,15]. Since the majority of GRN
pathogeneticmutationscauseproteinhaploinsufficiency,thedosageofcirculatingprogranulinhasbeen
proposedasausefultoolforaquickandinexpensivelarge-scalescreeningofGRNmutationscarriers
[16-19].
GenetictestingforADandFTLDischangingrapidlyduetotheincreasingavailabilityofnewandfaster
technologiesforDNAtest,anditisattractinginterestfrompatientsandfamiliesthankstoinnovative
primarypreventionclinicaltrialstargetinggeneticdementiaandtothegrowingrequestforinformation
by at-risk individuals. Two recent innovative clinical trials targeting genetic dementia are the
Dominantly Inherited Alzheimer Network Trial for AD (DIAN-TU,
www.clinicaltrials.gov/show/NCT01760005) and the Presymptomatic Neurodegeneration Initiative
for FTLD (PreNI, www.neurodegenerationresearch.eu/initiatives/jpnd-alignment-
actions/longitudinal-cohorts/call-for-working-groups/call-results/). Genetic mutation carriers, both
symptomaticandasymptomatic,couldthereforebeeligibleparticipantsforthesenovelclinicaltrials.
Genetictestinginsymptomaticpatientsisusedtoconfirmtheclinicaldiagnosis(diagnosticDNAtest);
genetictestingincognitivelyunimpairedrelativesofpatientswithamutationidentifiesthosewhowill
develop the disease in the future (predictive DNA test) [20-23]. In at-risk asymptomatic relatives,
predictivegenetictestingoffersthepossibilityofassessingtheirpersonalrisk,thusallowingthemto
organizetheirlivesandmakeinformedcareerorreproductivechoicesanddecision[23].Undergoing
predictive testsmayhelpat-risk individuals to copeemotionallywith theirgenetic riskby reducing
uncertaintyabouttheirstatusandfocusingonplanningforthefuture[24],assuggestedbyaseminal
5
studyinHuntington'sdisease[25].AscomparedtoAmericans,Italianat-riskrelativesexpressedhigher
intentionstoundergogenetictesting[20].
However, togetherwiththesepotentialadvantages,genetic testshave importantethical,social, legal
and psychological implications for the patients and thewhole family. In fact, the identification of a
geneticmutation inapatient implicitlydefines the risk for theother familymembers,withpossible
implicationfortheirhealthandtheirfuture.Ontheotherhand,informationongeneticstatuscannotbe
sensiblyusedfortherapeuticpurposes,asnoapproveddisease-modifyingtreatmentisavailabletodate.
Inhealthyat-riskindividuals,thereareconcernsthatapositivegenetictestingmaytriggeranegative
psychologicalresponse,suchasseveredepression,anxiety,helplessness,orevensuicidalideation[26].
Fromasocial/legalperspective,theremaybeissuesofpotentialgeneticdiscrimination,difficultiesin
findingajoborserviceassistance(includinginsuranceimplications),andincreatingrelationships[21].
Current guidelines for AD and other inherited dementia recommend that genetic testing should be
offeredwithinapropergeneticcounsellingprocedure[21].Forasymptomaticat-riskindividuals,the
protocolestablishedforHuntington’sdiseaseandrecentlyrevised[27]isrecommended.
Withtheadventofthepreventionclinicaltrialsindementia,suchasDIAN-TUforADinpre-symptomatic
mutationcarriers,disclosureofgeneticstatusisapre-conditiontoparticipateinatrialinItaly.Such
disclosurecannotbemadewithouteffectivepre-andpost-genetictestingsupport[28].
To date, in Italy no practice standards and consensus-based guidelines are available for genetic
counsellingoffamilialADorFTLD.TheIT-DIAfNproject,anetworkofItaliancentresofexcellencewith
recognized experience in managing patients with familial AD and FTLD, aimed at developing a
harmonized and structured protocol for genetic testing and counselling for those families, both for
symptomaticpatientsandat-riskrelatives.AsinheritedADandFTLDaregeneticallyheterogeneousand
symptomsoftenoverlap,wealsogeneratedadecisiontreetoassistclinicians/researchersinmutations
search.
6
2.METHODS
Thisstudywasconductedaspartofthe"ItalianDominantlyInheritedAlzheimer’sandFrontotemporal
Network(IT-DIAfN)",anationalproject fundedby the ItalianMinistryofHealth (RF-2010-2319722,
BandoRicercaFinalizzata2010).ItgatherssixcentresofexcellenceinthestudyofgeneticADandFTLD:
IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli of Brescia, IRCCS Fondazione Istituto
NeurologicoCarloBestaofMilan,UniversityofFlorence,CentroRegionalediNeurogeneticaofLamezia
Terme,UniversityofBrescia,andFondazioneIRCCSCàGrandaOspedaleMaggiorePoliclinicoofMilan.
Aworkinggroupwascomposedbygeneticists,psychologists,neurologists,andbioethicists,withatleast
one representative from each centre, with the collaboration of the Department of Health Sciences,
UniversityofGenovaandDivisionofMedicalGenetics,GallieraHospital,Genova.
Asafirststep,thegroupconductedasurveyofgeneticcounsellingprotocolsapprovedbythelocalethics
committees and in use at each centre. In particular, the group collected information regarding the
professionals involved in the genetic counselling team, tests used for the assessment, phases,
procedures,timelines,informedconsentforms,accesscriteriaandspecificrequestsfromthelocalethics
committees.Moreover,otherspecificissueswereaddressed,suchastheinformedconsent/refusalfor
storageofthebiologicalsamplesinabiobankforpossiblefutureresearchstudies.Literaturesearchand
experiencefromcentreswerecombinedtodevelopadecisiontreetoassistinthesearchofthemutation,
tobemoreaccurate,andtoreducetimeandcost.
Aliteraturesearchwasconductedtoanalyseguidelinesorrecommendationsavailableforothergenetic
diseases,suchasHuntington'sdisease[27,29,30],or inuse inothercountries. Italianregulationsfor
data protection were considered (The Italian Data Protection Authority, General Authorisation No.
8/2014fortheProcessingofGeneticData,doc.webNo.3632835).
InFebruary-March2013theworkinggroupparticipatedinthefirstmeetings(onein-personandonea
remoto, via teleconferences) aimed at identifying and discussing the surveyed differences and
commonalitiesamongprotocols.Thefirstdraftwasdiscussedduringanin-personmeetinginJuly2013
and circulated to the working group in the ensuing months. All comments and feedbacks were
periodicallysummarizedandcollatedbytheProjectCoordinator,whowasinchargeofmoderatingthe
discussion via electronic communication and of reconciling the different viewpoints to reach a
7
consensus.ThefinalconsensuswasreachedinOctober2014followingimplicitaggregationmethods
[31]:thegroupexpertsineachfieldguidedthedecision-makingprocessandthefinalconsensuswas
defined by majority position. Further comments from SINdem (Italian Society for the study of
Dementias)werealsotakenintoaccount.
The harmonized protocol for genetic counselling was approved in February 2015 by the Ethics
CommitteeoftheCoordinatingCentreoftheIT-DIAfNproject(IRCCSIstitutoCentroSanGiovannidiDio
FatebenefratelliofBrescia).
3.RESULTS
3.1Surveyforlocalprotocols
TheresultsofthesurveyarereportedinTable1.Inallcentresgeneticcounsellingwasprovidedbya
multidisciplinary team, including a geneticist, a neurologist, a psychologist or a psychiatrist. The
schedule of the consultation and the procedures varied among centres. Three centres divided the
procedureintothreeconsultations:thefirstwasaninformationalmeeting,wherethefamilyhistorywas
collectedandthesubjectsunderwentaneurologicalandapsychologicalexamination;thesecondwas
thebloodsamplecollection,whilethethirdwasthedisclosureofthegenetictestresults.Theotherthree
centresdividedthepre-testphaseintotwovisits:oneinformationalandonefortheassessmentofthe
patient. The timetable for the visits and for the supportive follow-up varied from centre to centre.
Moreover,somecentresconsideredthefollow-upasnonmandatoryortheyoffereditonlyincaseof
positivityatthetest.Differenttestswereusedtoassessdifferentdomainslocally(Table1).Onlytwo
centres had a specific protocol for symptomatic subjects (diagnostic test), while all centres had a
protocolforat-riskrelatives.
3.2Harmonizedprotocolforgeneticcounselling
3.2.1Targetpopulation
Genetic counselling can be requested (and eventually stopped or suspended at any stage) by (i)
symptomaticpatientswithapositivefamilyhistorysuggestiveofanautosomaldominantgeneticcause
forADandFTLDand(ii)relativesofpatientswithprovengeneticADorFTLD.Eachsubjecthastobe≥
8
18yearsold.Apositivefamilyhistoryisdefinedwithinthegroupbasedonthepresenceofoneofthe
followingcriteria:i)atleastthreeaffectedfirst-degreerelativesintwogenerations,irrespectivelyofthe
ageatonset; ii)at least twoaffectedfirst-degreerelatives intwogenerations,withat leastonewith
onsetat≤65years;oriii)oneaffectedfamilymemberwithonsetat≤60yearsorwithasuggestive
clinicalphenotype(e.g.dementiawithatypicalpresentation[32],recurringpresenceinotherrelatives,
peculiargeographicorigin).
Cognitivelyunimpairedat-riskrelativesenterthecounsellingandareeligibletoundergothegenetic
testingonlyaftertheprovenpresenceofthemutationinafirst-degreesymptomaticrelative.
Twospecificgeneticcounsellingprotocolsweredefined:oneforsymptomaticpatients(Section3.2.4)
andoneforat-riskrelatives,withamorerelaxedandprolongedschedule(Section3.2.5).
3.2.2GeneticCounsellingTeam
Geneticcounsellingisprovidedbyamultidisciplinaryteamofhealthprofessionalswhoworktogether
toprovideanindividualorafamilywithcurrentinformationandsupportivecounsellingaboutgenetic
testing.GeneticcounsellingisstructuredandguidedbyaGeneticistandbyaSpecializedMedicalDoctor
with specific competences in neurodegenerative diseases. The Geneticist is a specialist in medical
geneticswithexpertiseinneurodegenerativediseases,whohadeducationingeneticcounselling.The
SpecializedMedicalDoctor(Neurologist,Geriatrician,and/orPsychiatrist)istheclinicalcontactperson
forthepatient:thisrolecanbealsoplayedbythegeneticist,butonlyifhe/sheisamedicaldoctorwith
a consolidated clinical background for the aforementioned diseases. Beside the Geneticist and the
Specialized Medical Doctor, the multidisciplinary team is composed by other professionals (i.e. a
Psychologistand/oraPsychiatrist),whohaveexpertiseincounselling,andhaveskillsatprovidingon-
goingsupporttoindividualswithpossiblesocio-psychologicalconsequencesassociatedwiththeriskof
beingamutationcarrier.
3.2.3EvaluationTests
Acommonbatteryofclinical,psychologicalandcognitivetestswasdefinedforsymptomaticpatients
andtheirat-riskrelatives.Specifically,thebatteryincludestheMini-MentalStateExamination(MMSE)
9
[33]andtheClinicalDementiaRatingScale(CDR)[34],theQuestionnaireontheHealthStatus-12(SF-
12)[35]andtheWorldHealthOrganizationQualityofLife(WHOQOL)[36],fortheassessmentofquality
oflifeandhealthstatus;theStateTraitAnxietyInventory(STAI-Y)[37],theBeckDepressionInventory
(BDI) [38] and the Hamilton Rating Scale for Depression (HRSD) [39], for anxiety and depression
measurement;theBriefCOPE(BC)[40],theResilienceScaleforAdult(RSA)[41]andtheHealthLocus
ofControl(HLC)[42,43],fortheevaluationofthecopingstyleandthelocusofcontrols.Moreover,a
depth evaluation of the risk of suicide is recommended, if the subject showed suicidal thoughts or
attitudesinthepastoratpresent(item9ofBDIand/oritem3ofHRSD).OnesuggestedscaleistheBeck
HopelessnessScale[44,45].Inadditiontothesetests,theat-riskrelativesarealsoassessedwiththeBig
FiveQuestionnaire(BFQ)forpersonalityassessment[46,47].
Thesubject isassessedatapre-testphase, to investigatehis/herabilitytocopewiththetestresult.
ExceptfortheMMSE,theCDRandtheBFQ,theassessmentwiththeothertestsisrepeatedpost-testat
differenttime-points,tomonitorthepsychologicalstatusofthesubject,asspecifiedlaterinthetextand
inFigure1A-B.
Basedontheprofileofthesubject,themultidisciplinaryteamcansuggesttopostponethegenetictest.
Theteamcontinuestofollowandsupporttheindividualaslongasitisdeemednecessarybytheteam
orrequestedbythesubject.
3.2.4ProtocolforSymptomaticSubjects
Thegenetictestingforsymptomaticsubjectshasadiagnosticpurpose,i.e.toidentifythegeneticcause
ofthediseaseandconfirmthediagnosisofADorFTLD.TheproceduresareillustratedinFigure1Aand
include:atleastonepre-testconsultation,onemeetingforbloodwithdrawalforthegenetictesting,a
post-testconsultation,wherethegeneticstatusisdisclosed(forthosewhowishtoknow)andthenthree
follow-ups.Thenumberoftheconsultationscanbeincreasedandthetimespanrelaxed,ifrequiredby
the patients of if considered appropriate by the team.Genetic counselling for symptomatic patients
shouldbeperformedinthepresenceofthecaregiveraccordingtopatient'swill,andtheindividual’s
legalguardianifappointedfortheindividualpatient,tohelpthepatientinthedecision-makingprocess,
10
specificallytohelpinunderstandingandappreciatingthepurposeandpossibleresultsofthegenetic
testandinexpressingachoice[21,48].
3.2.4.1Firstconsultation:Pre-test
During the first informational visit, the whole multidisciplinary team provides general information
regardingthefamilialformsofdementiaanddetailsaboutgeneticcounselling(i.e.timespan,teamroles,
aimsandprocedures),thereliabilityofthetestandtheinterpretationoftheresults.Theteamshould
explainmedical andgenetic termsandavoid technical jargon.The implicationsofbothpositiveand
negativetestresultarediscussed,aswellas ifandhowtheseresultswillbecommunicatedtoother
familymembers.Patientsandtheirfamiliesshouldunderstandthatmultiplepossibleresultsmaybe
revealed:acausativemutationinoneofthegenes,nomutationinanyofthegenes,avariantofunknown
significance,orevenmutationsorvariants inmore thanonegenes. Supportive information is given
regarding the diagnosis and risk for the genetic disease in the family and its clinical, psychological,
sociological and ethical implications, togetherwith the impact on the familymembers. The specific
implications,prospectivebenefitsandrisksofundergoinggenetictestingarediscussed.Theaimisto
provideasmuchclearinformationaspossible,anddiscussanyquestionordoubt,toallowsubjectsto
takeanautonomousandinformeddecisionwhethertheyarewillingtoundergogeneticcounsellingand
testingandtoknowtheirgeneticstatus.Theteamavoidstoinfluencethedecisionoftheindividualand
thefamily,andaimsatfacilitatingtheirautonomousdecisionmaking.
If agreed, the subject, and/or his/her legal guardian on his/her behalf if appropriated, signs the
informedconsentformforgeneticcounselling.Thecaregiver,ifpresentaccordingtopatient'swishes,
canalsosigntheinformedconsenttoexpressagreement[48].Thefamilyhealthhistoryiscollectedto
constructthefamilypedigreeand,wherepossible,acompletefamilyhistoryshouldbecollectedusing
a structuredquestionnaire.Personal clinicalphenotypeand familyhistorywill beused toguide the
algorithm formutation search (see3.2.6Flowchart for genetic testing) and to evaluatewhether the
genetictestisappropriate(asaguide:[49,50]).
Finally,ifnottooseverelyimpaired,thesubjectisassessedusingthetestdescribedin3.2.3Evaluation
Tests.
11
Aftertheconsultation,theteamprovidesthepatientwithawrittensummaryorbrochurewithallthe
general information discussed in person, to allow their elaboration and comprehension. In case of
doubts,asecondinformationalvisitcanbescheduled.
3.2.4.2Secondconsultation:BloodSampleCollection
At the beginning of the second consultation, thewhole team evaluateswhether all the information
provided during the first visit was fully understood, and it clarifies any remaining doubts or new
questionsthatmayarise.Theresultsoftheassessment(ifdone)arediscussed.Ifthepatientwishesto
proceedwiththetest,thesubject,and/orhis/herlegalguardianonhis/herbehalfifappropriated,signs
the informed consent for genetic testing and blood sample is collected. The caregiver, if present
accordingtopatient'swishes,canalsosigntheinformedconsenttoexpressagreement.Atthisstage,
thepatientcandecidewhetherhis/hersamplecanbestoredinabiobankforpossiblefutureresearch
studiesongeneticformsofdementiaordestroyedafterthecompletionoftheanalyses.
The team informs the patient about the timespan for the completion of molecular genetic analysis
(aroundtwomonths).
3.2.4.3Thirdconsultation:Post-test
Withintwomonthsfromthebloodsamplecollection,theresultsaremadeavailable.Ifthepatientstill
wishes toknow, the genetic test results aredisclosedanddiscussedwith thepatient, andawritten
reportisgiven.Thewholeteamshouldassesstheindividual’sunderstandingofhis/hersituationand
adapt the language to the patient in order to clearly explain themeaning and the implications of a
positive,negative,oruncleartestresult.
Theteamshouldsupportandassistthepatientandthefamilyinexpressingtheiremotionalreactions
to their genetic status. Before leaving the visit, the presence of psychological distress should be
informallyassessed.
3.2.4.4Follow-up
12
Afterthedisclosureoftheresults,theteamofferson-goingsupportandinformation.Threedifferent
timepoints for the follow-upweredefined: after1,6and12months from thedisclosure.The team
collectsinformationaboutanypossiblechangeoccurredinthefamilyandinhis/hereverydaylife.The
patientisqualitativelyassessedabouthis/herpsychologicalconditions,andthetestsdescribedin3.2.3
EvaluationTestsareadministered,wheneverpossible.
3.2.5ProtocolforAt-riskSubjects
Thepredictivetestingeneticcounsellingaimsatconfirmingwhetherthegeneticmutationidentifiedin
thefamilyhasbeeninheritedbytheat-riskrelative,atastagewheretheindividualdoesnotpresent
anysymptom.Thisprotocolarisesmuchmoreethicalandpsychosocialissuesthatthediagnostictestin
symptomaticsubjects,becausethepotentialidentificationasbeingcarrierofanautosomaldominant
mutation almost certainly predicts the future development of the disease in an individual currently
healthy.Undergoingapredictivetestisahighlypersonaldecisionthatdemandsextensivecounselling.
TheproceduresareillustratedinFigure1Banddetailedbelow.Theschedulemainlydiffersfromthe
diagnostictestinprescribingatleasttwopre-testconsultationsbeforethegenetictesting,andinhaving
aphonecalloneweekafterthedisclosureofthegeneticstatus.
3.2.5.1Firstconsultation:Pre-test
Asforthesymptomaticpatients,thefirstconsultationisaninformationalandsupportingvisit,when
thewholeteamcoversspecificissuesofthefamilialformsofdementia,geneticcounsellingandtesting,
and the implications of the results (for further details see 3.2.4.1 First consultation: Pre-test). The
presenceofasupportpersonisencouraged.
If agreed, the subject signs the informed consent form for genetic counselling. Then, there is an
evaluationofthepersonalandfamilialmedicalhistory.
Aftertheconsultation,theteamprovidesthesubjectwithawrittensummaryorbrochurewithallthe
generalinformationdiscussedinperson,toallowtheirelaborationandcomprehension.
3.2.5.2Secondconsultation:Pre-test
13
Afteronemonthfromthefirstvisit,thesecondoneisscheduled,tofurtherdiscussthemotivationfor
thepredictivetestandclarifyanydoubtswhichmayhavearisen.
Thesubjectisassessedusingthetestsdescribedin3.2.3EvaluationTests.
3.2.5.3Thirdconsultation:BloodSampleCollection
Theproceduresarethesameasforthesymptomaticprotocol(see3.2.4.2Secondconsultation:Blood
SampleCollection).
3.2.5.4Fourthconsultation:Post-test
Theproceduresarethesameasforthesymptomaticprotocol(see3.2.4.3Thirdconsultation:Post-test).
3.2.5.5Follow-up
Oneweekafterthedisclosureoftheresults,theteam(specificallythePsychologistand/orPsychiatrist),
contactsthesubjectbyphoneandofferson-goingsupportandinformation.Theotherfollow-upvisits
arethesameasforthesymptomaticprotocol(see3.2.4.4Follow-up).
3.2.6Flowchartforgenetictesting
Adecisiontreewasdevelopedtoassistinthesearchofthemutationinsymptomaticpatients(Figure
2).
IfthepatienthasrecentlyundergonealumbarpunctureandAβandtaulevelsinthecerebrospinalfluid
(CSF)havebeenanalyzed,thismeasureguidesthegeneticscreening.IftheCSFtauandAβ42levelsare
abnormal(i.e.tau/Aβ42>0.52)[51],geneticmutationslinkedtoADaresearchedasfirst.Todetermine
which gene should be sequenced first (i.e., APP, PSEN1, or PSEN2), patient’s age at onset (AAO) is
considered:ifthepatienthasanearlyageatonset(≤65years),APPgene(exons16-17)issequenced;if
negative: all PSEN1 exons and flanking regions; if negative: all PSEN2 exons and flanking regions.
Instead,ifthepatienthasalateageatonset,PSEN2geneisthefirstchoiceforsequencing,andthenAPP
and PSEN1. If all AD genes aremutation-negative, but there is a strong evidence for an autosomal
dominantpattern, thengenes linked toFTLDare screened.Plasmaprogranulindosage forGRN null
14
mutationscreeninghasthepriority:ifthelevelis<61.55ng/ml[19],thepresenceofthecommonItalian
p.L271fs(exon8:c.811_814del,refsequenceNM_002087)mutationisassessed[52];ifnomutationis
found, all other exons are sequenced. Conversely, if the progranulin level is not suggestive for the
presenceofnullmutations (i.e.>61.55ng/ml), the clinicalphenotype is taken intoaccount.C9orf72
genetic screening should have the priority in patientswith FTLD andMotorNeuronDisease (FTD–
MND),behaviouralvariantfrontotemporaldementia(bvFTD)withpsychosis,orFTLDwithcerebellar
features,whileMAPTgene(exons1,9-13,asfirst)shouldbethefirstchoiceinpatientswithbvFTDand
semanticdementia,progressivesopranuclearpalsy(PSP),corticobasalsyndrome(CBS)oranearlyage
atonset(AAO<60years).WhenbothC9orf72andMAPTresultednegative,thenGRNshouldbetested,
givenpossiblefalsenegativeinprogranulinplasmascreening.
WhenCSF tau andAβ levels arenormal ornot available, the algorithm is basedon theprogranulin
dosage,asdescribedpreviously.Whenpatient'slevelofprogranulinisnormal,theclinicalphenotypeis
taken into account for guiding the analysis. If the clinical phenotype is FTD-like, then the priority
betweenC9orf72andMAPT isdefinedaspreviouslydescribed.Iftheclinicalphenotypeisconsistent
with AD, then, according to the age at onset, APP, PSEN1 and PSEN2 are screened as described
previously.Whennomutationisfound,theotherbranchinthediagramisfollowed(Figure2).
Lastly, if theDNAanalysis isdone inanat-risksubject,only themutation found in thesymptomatic
relativeissearchedfor.
4.DISCUSSION
Genetic testinghas ethical, social, legal andpsychological implications for patients and their family:
when handled by an experienced and qualifiedmultidisciplinary team following structured criteria,
these issues can be faced serenely and confidently by families. Here, we present a standard and
structured protocol for genetic testing and counselling for symptomatic and at-risk individuals
belonging to familieswithsuspected formsofautosomaldominantADorFTLD.Thisprotocol isnot
designed for genetic counseling of people who carry susceptibility genetic risk for AD, such as the
ApolipoproteinEe4allele,asthisisonlyariskfactorfordementiaandnodefinitivepredictioncanbe
made about dementia in these subjects. Moreover, based on the current knowledge, wewould not
15
recommendgeneticcounsellingtoallsporadicFTDcasesasthelikelihoodoffindingamutationincases
withanegativefamilyhistoryispresumablylow[49]andwouldthusunnecessarilyincreaseburdento
patientsandtheirfamilies.TheIT-DIAfNprotocolprovidesguidanceontheschedule,theprocedures,
thetestsandtheprofessionalfiguresinvolvedingeneticcounselling,withtheaimtosupportandtake
responsible care of these families. The tests for clinical, cognitive and personality assessmentwere
accuratelychosentoobtainaconcisebutaccurateprofileoftheindividual,helpinginpersonalizingand
adaptingthesupportwithinthecounsellingtohis/herpossiblereactions.
WehavetakenintoaccounttheguidelinesforthegenetictestingofHuntington'sdisease[27,29,30],
whichisconsideredthegoldstandardforgenetictestingforadultonsetdiseases.Asrecommendby
theseguidelines,weusedamultidisciplinaryapproachtofacilitatethesubject'sautonomousdecision
making: theGeneticistas theexpert ingeneticcounselling forADandFTLD, theSpecializedMedical
Doctorastheclinicalcontactpersonofthepatients;andthePsychologist/Psychiatristasthecontact
personforcounselling,psychologicalappraisalandsupport.Thescheduleandtimespanofthevisitsare
similartothosedefinedforHuntington'sdisease:severalsessionsandphases(pre-,post-testingand
follow-ups)arecrucialtoallowfreechoice,withoutrushingintogenetictestingbeforeallthenecessary
explanationsandinformationaregiven.OtherrecommendationsprescribedintheHuntington'sdisease
guidelineswereadoptedhere:i)disclosureofthegeneticstatusisprovidedbothorallyandthrougha
writtenreport; ii)availabilityof the testonly to individualswhohavecomeofage; iii)possibilityof
storingthebiologicalsamplesinabiobankforresearchstudiesaftersigningtheinformedconsent.
AsdescribedinotherexistentcounsellingprotocolsforADandFTLD[21,22],werecommendedthati)
the legal guardian of the symptomatic patient is present during the counselling to help her/him in
understandingitspurposeandpossibleresultsofthegenetictestandinexpressingachoice,andthat
ii)asymptomaticfamilymembershouldbetestedbeforeanat-riskindividual.
TheguidelinesforgeneticcounsellingforADdefinedbytheAmericanCollegeofMedicalGeneticsand
theNational SocietyofGeneticCounsellors [21] specified thatgenetic counselling couldbedone in-
personorthroughvideoconferences.TheHuntington'sdiseaseguidelinesclearlystatedthattheresults
ofthetestshouldberevealedin-person,andnotbyphoneormail[27,30],whilepsychosocialsupport
16
shouldbeavailableclosetotheperson’scommunity,byphoneortelemedicinewherenecessary.Afew
pilotprojectsdemonstratedthattelemedicinecanbeusedtooffermedicalgeneticsserviceonaremote
basis [53]. Preliminary evidence suggests that genetic counselling can be effectively delivered in
underserved areas, also in late-onset genetic disorders such as familial cancer [54]. The advent of
telegenetics could allow the implementation of this genetic counselling protocol in clinical research
centreswithoutloweringtheclinicalstandard;itmayalsofacilitatetheenrolmentinclinicaltrialsof
individualswhocouldnotaccesstotertiarycaregeneticscentres.Nevertheless,itisrecommendedthat
thePsychologist/Psychiatristshouldbealwayspresentinpersonduringthevisits.
We developed two specific paths, one for symptomatic patients and one for asymptomatic at-risk
subjects,beingawareofthedifferenceofthetwoscenarios. Infact, insymptomaticsubjects,genetic
testingisaimedatconfirmingtheclinicaldiagnosisandthegeneticcauseofthedisease.Apositiveresult
canprovokehopelessnessandsenseofguiltyforthepossibilityoftransmissionofthemutationtothe
offspring.Inthecaseofasymptomaticsubjectspsychological,socialandethicalissuesareevenmore
critical,especiallyintheabsenceofpreventionortreatmentoptions:acorrectandcarefulcounselling
willofferthemtheoptionofknowingtheircondition,copepositivelywiththeirfutureandeventually
theymightbeofferedthepossibilitytoenteranovelpreventionclinicaltrial.Itmustbeunderlinedthat
a negative result has differentmeanings according to the twodifferent scenarios: in a symptomatic
subject,thiscouldnotexcludedefinitelythatthediseasehasageneticcause(thusitissporadic),because
an unknown/newmutation could be present but not yet been discovered; in an at-risk relative, a
negative result confirms almostwith absolute certainty that he/she has not inherited the causative
mutationfoundintheaffectedrelativeandthushe/shehasthesameriskofthegeneralpopulationto
developthediseaseinthefuture.
Considering the results reported in Binetti et al., 2006 [20], Italian families with familial dementia
showedpoorknowledgeof thediseaseandpoorawarenessofpersonalriskofdevelopingdementia
duringlifetime.Thismeansthatthefirstconsultationshouldaddresstheseaspectsindetails,guiding
familiestoafreeandinformedchoice.
17
Wedevelopedastep-by-stepalgorithmforguidinggeneticscreeningonthebasisofbiomarkerresults
andclinicaldata,toreducetimeandcostofthelaboratoryanalysis.Specifically,thedecisiontreewas
definedaccordingto(i)theobservedfrequencyofgenesinspecificclinicalphenotypesintheliterature
[49,55-58],andspecificallyinItalianclinicalseries[52,59-65],(ii)thedirectexperienceoftheItalian
centres,and(iii)practicalconsiderations,e.g.thehighspeedandlowcostofagivenscreeningprocedure
(i.e. plasma progranulin dosage). In the future, other biomarkers can be taken into account and
implementedwithintheflowchart,suchastheamyloidPET.
TheresearchprotocolreportedhereinreflectsthecurrentpracticeofItaliancentrestakingparttothe
IT-DIAfN initiative. Should important innovationsbe introduced in the clinicalpracticeaswell as in
laboratoryanalyses,theprotocolwillbeamended.Followingthewideavailabilityofnextgeneration
sequencing (NGS)panels for themolecular genetics analysis, thedecision tree is subject to changes
accordingly.NGSisnotcurrentlyappliedinallcentersparticipatingintotheIT-DIAfNframework,but
appearsastheupcomingtechnologyforthemutationanalysisinheterogeneousgeneticdisorderssuch
asADandFTLD.Todate,theNGSapproachprovidesthesimultaneousanalysisofapanelof17genes
(PRNP, PSEN1, PSEN2, APP, GRN, MAPT, TREM2, CHMP2B, CSF1R, FUS, ITM2B, NOTCH3, SERPINI1,
TARDBP, TYROBP, VCP, SQSTM1). Other experimental panels of additional genes and SNP
polymorphisms are currently under development within the IT-DIAfN group. The mutation search
shouldbecompletedwithtwoPCRanalysesoftheC9orf72hexanucleotiderepeatexpansionandthe
octapeptiderepeatregionofPRNP[66].
Thisprotocol,developedbyexpertsinthefield,providesItaliancentreswithalineofsharedpractice
forofferinggeneticcounsellingtoeligibleindividualswhomaybenefitfromgenetictestingforfamilial
AD and FTLD, and recruit them through a procedure which is compliant with International
recommendationsandgoodpractices.
Future steps will be the validation of the harmonized protocol of genetic counselling. This will be
performedintwosteps:i)afterapprovalbylocalethicscommittees,theprotocolwillbeimplemented
inallcentresparticipatingintotheIT-DIAfNproject;ii)datafromeachcentrewillbecollectedandthe
resultsfromthepilotstagewillbecriticallyreviewedbytheworkinggroupwhodevelopedtheprotocol.
18
Thegeneticcounsellingprotocolwillalsobedisseminatedthroughmedicalsocietiesandproposalsfor
amendmentswillbeacknowledged.
Weare aware that theentireprocedure, including counselling, repeatedassessments and testing, is
highly demanding, especially in terms of human resources. The procedure is expected to be
accomplished within a research environment by a multidisciplinary team in centres with specific
expertise–assuchitwasnotdesignedtobeappliedinroutineclinicalpracticeinitscurrentversion.In
thelightofthesuggestionraisedduringthevalidationphase,anoptimizedprotocolcouldbeeventually
transferred to clinics, provided that evidence of clinical utility has been produced and a health
technologyassessmenthassupporteditsimplementationinclinicalpractice.
5.FUNDING
Thisstudywasfundedthrough"ItalianDominantlyInheritedAlzheimer’sandFrontotemporalNetwork
(IT-DIAfN)", a project funded by the Italian Ministry of Health (RF-2010-2319722, Bando Ricerca
Finalizzata2010)andcoordinatedbyGiovanniB.FrisoniattheIRCCSIstitutoCentroSanGiovannidi
DioFatebenefratelli,Brescia,Italy.
19
6.REFERENCES
1. BirdTD.(2008)GeneticaspectsofAlzheimerdisease.GenetMed.10(4):231-239.
2. RohrerJD,GuerreiroR,VandrovcovaJ,UphillJ,ReimanD,BeckJ,IsaacsAM,AuthierA,FerrariR,
FoxNC,MackenzieIR,WarrenJD,deSilvaR,HoltonJ,ReveszT,HardyJ,MeadS,RossorMN(2009)
Theheritabilityandgeneticsoffrontotemporallobardegeneration.Neurology73:1451-1456.
3. SeelaarH,RohrerJD,PijnenburgYA,FoxNC,vanSwietenJC(2011)Clinical,geneticandpathological
heterogeneityoffrontotemporaldementia:areview.JNeurolNeurosurgPsychiatry82:476-486.
4. BekrisLM,YuCE,BirdTD,TsuangDW(2010)GeneticsofAlzheimerdisease.JGeriatrPsychiatry
Neurol23(4):213-27.
5. WarrenJD,RohrerJD,RossorMN(2013)Clinicalreview.Frontotemporaldementia.BritishMedical
Journal.347:f4827.
6. GoateA,Chartier-HarlinMC,MullanM,BrownJ,CrawfordF,FidaniL,GiuffraL,HaynesA,IrvingN,
JamesL,MantR,NewtonP,RookeK,RoquesP,TalbotC,Pericak-VanceM,RosesA,WilliamsonR,
RossorM,OwenM,HardyJ.(1991)Segregationofamissensemutationintheamyloidprecursor
proteingenewithfamilialAlzheimer'sdisease.Nature.349(6311):704-706.
7. SherringtonR,RogaevEI,LiangY,RogaevaEA,LevesqueG,IkedaM,ChiH,LinC,LiG,HolmanK,
TsudaT,MarL,FoncinJF,BruniAC,MontesiMP,SorbiS,RaineroI,PinessiL,NeeL,ChumakovI,
PollenD,BrookesA,SanseauP,PolinskyRJ,WascoW,DaSilvaHA,HainesJL,Perkicak-VanceMA,
TanziRE,RosesAD,FraserPE,RommensJM,StGeorge-HyslopPH.(1995)Cloningofagenebearing
missensemutationsinearly-onsetfamilialAlzheimer'sdisease.Nature.375(6534):754-760.
8. SherringtonR,FroelichS,SorbiS,CampionD,ChiH,RogaevaEA,LevesqueG,RogaevEI,LinC,Liang
Y,IkedaM,MarL,BriceA,AgidY,PercyME,Clerget-DarpouxF,PiacentiniS,MarconG,NacmiasB,
AmaducciL,FrebourgT,LannfeltL,RommensJM,StGeorge-HyslopPH.(1996)Alzheimer'sdisease
associatedwithmutationsinpresenilin2israreandvariablypenetrant.HumMolGenet.5(7):985-
988.
9. HuttonM,LendonCL,RizzuP,BakerM,FroelichS,HouldenH,Pickering-BrownS,ChakravertyS,
IsaacsA,GroverA,HackettJ,AdamsonJ,LincolnS,DicksonD,DaviesP,PetersenRC,StevensM,de
GraaffE,WautersE,vanBarenJ,HillebrandM,JoosseM,KwonJM,NowotnyP,CheLK,NortonJ,
20
MorrisJC,ReedLA,TrojanowskiJ,BasunH,LannfeltL,NeystatM,FahnS,DarkF,TannenbergT,
DoddPR,HaywardN,KwokJB,SchofieldPR,AndreadisA,SnowdenJ,CraufurdD,NearyD,OwenF,
Oostra BA, Hardy J, Goate A, van Swieten J, Mann D, Lynch T, Heutink P. (1998) Association of
missenseand5'-splice-sitemutationsintauwiththeinheriteddementiaFTDP-17.Nature393:702-
705.
10. PoorkajP,BirdTD,WijsmanE,NemensE,GarrutoRM,AndersonL,AndreadisA,WiederholtWC,
RaskindM,SchellenbergGD. (1998)Tau isacandidategene forchromosome17 frontotemporal
dementia.AnnNeurol43:815-825.
11. SpillantiniMG,MurrellJR,GoedertM,FarlowMR,KlugA,GhettiB(1998)Mutationinthetaugene
infamilialmultiplesystemtauopathywithpreseniledementia.ProcNatlAcadSciUSA95:7737-
7741.
12. Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, Snowden J,
Adamson J, Sadovnick AD, Rollinson S, Cannon A, Dwosh E, Neary D,Melquist S, Richardson A,
DicksonD,BergerZ,EriksenJ,RobinsonT,ZehrC,DickeyCA,CrookR,McGowanE,MannD,Boeve
B, Feldman H, Hutton M. (2006) Mutations in progranulin cause tau-negative frontotemporal
dementialinkedtochromosome17.Nature442:916-919.
13. CrutsM,GijselinckI,vanderZeeJ,EngelborghsS,WilsH,PiriciD,RademakersR,VandenbergheR,
DermautB,MartinJJ,vanDuijnC,PeetersK,SciotR,SantensP,DePooterT,MattheijssensM,Van
denBroeckM,CuijtI,VennekensK,DeDeynPP,Kumar-SinghS,VanBroeckhovenC.(2006)Null
mutationsinprogranulincauseubiquitin-positivefrontotemporaldementialinkedtochromosome
17q21.Nature442:920-924.
14. DeJesus-HernandezM,MackenzieIR,BoeveBF,BoxerAL,BakerM,RutherfordNJ,NicholsonAM,
FinchNA, FlynnH, Adamson J, KouriN,WojtasA, SengdyP,HsiungGY, KarydasA, SeeleyWW,
JosephsKA,CoppolaG,GeschwindDH,WszolekZK,FeldmanH,KnopmanDS,PetersenRC,Miller
BL, Dickson DW, Boylan KB, Graff-Radford NR, Rademakers R. (2011) Expanded GGGGCC
hexanucleotiderepeatinnoncodingregionofC9ORF72causeschromosome9p-linkedFTDandALS.
Neuron72:245-256.
21
15. RentonAE,MajounieE,WaiteA,Simón-SánchezJ,RollinsonS,GibbsJR,SchymickJC,LaaksovirtaH,
vanSwietenJC,MyllykangasL,KalimoH,PaetauA,AbramzonY,RemesAM,KaganovichA,Scholz
SW, Duckworth J, Ding J, HarmerDW,Hernandez DG, Johnson JO,Mok K, RytenM, Trabzuni D,
GuerreiroRJ,OrrellRW,Neal J,MurrayA,Pearson J, Jansen IE,SondervanD,SeelaarH,BlakeD,
YoungK,HalliwellN,CallisterJB,ToulsonG,RichardsonA,GerhardA,SnowdenJ,MannD,NearyD,
NallsMA,PeuralinnaT,JanssonL,IsoviitaVM,KaivorinneAL,Hölttä-VuoriM,IkonenE,SulkavaR,
BenatarM,WuuJ,ChiòA,RestagnoG,BorgheroG,SabatelliM;ITALSGENConsortium,Heckerman
D,RogaevaE,ZinmanL,RothsteinJD,SendtnerM,DrepperC,EichlerEE,AlkanC,AbdullaevZ,Pack
SD,DutraA,PakE,Hardy J,SingletonA,WilliamsNM,HeutinkP,Pickering-BrownS,MorrisHR,
Tienari PJ, Traynor BJ. (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of
chromosome9p21-linkedALS-FTD.Neuron72:257-268.
16. GhidoniR,BenussiL,GlionnaM,FranzoniM,BinettiG.(2008)Lowplasmaprogranulinlevelspredict
progranulinmutationsinfrontotemporallobardegeneration.Neurology.71:1235-1239.
17. FinchN,BakerM,Crook,R,SwansonK,KuntzK,SurteesR,BisceglioG,Rovelet-LecruxA,BoeveB,
PetersenRC,DicksonDW,YounkinSG,DeramecourtV,CrookJ,Graff-RadfordNR,RademakersR.
(2009)Plasmaprogranulinlevelspredictprogranulinmutationstatusinfrontotemporaldementia
patientsandasymptomaticfamilymembers.Brain;132:583-591.
18. Sleegers K, Brouwers N, Van Damme P, Engelborghs S, Gijselinck I, van der Zee J, Peeters K,
MattheijssensM,CrutsM,VandenbergheR,DeDeynPP,RobberechtW,VanBroeckhovenC.(2009)
Serumbiomarkerforprogranulin-associatedfrontotemporallobardegeneration.AnnNeurol;65:
603-609.
19. GhidoniR,StoppaniE,RossiG,PiccoliE,AlbertiniV,PaterliniA,GlionnaM,PegoianiE,AgnatiLF,
FenoglioC,ScarpiniE,GalimbertiD,MorbinM,TagliaviniF,BinettiG,BenussiL. (2012)Optimal
plasmaprogranulin cutoff value for predicting null progranulinmutations in neurodegenerative
diseases:amulticenterItalianstudy.NeurodegenerDis.9(3):121-7.
20. BinettiG,BenussiL,RobertsS,VillaA,PasqualettiP,SheuCF,GigolaL,LussignoliG,DalFornoG,
BarbieroL,CorbelliniG,GreenRC,RossiniPM,GhidoniR.(2006)Areasofinterventionforgenetic
22
counsellingofdementia:cross-culturalcomparisonbetweenItaliansandAmericans.PatientEduc
Couns.64(1-3):285-93.
21. GoldmanJS,HahnSE,CataniaJW,LaRusse-EckertS,ButsonMB,RumbaughM,StreckerMN,Roberts
JS,BurkeW,MayeuxR,BirdT;AmericanCollegeofMedicalGeneticsandtheNationalSocietyof
Genetic Counselors (2011) Genetic counseling and testing for Alzheimer disease: joint practice
guidelines of the American College of Medical Genetics and the National Society of Genetic
Counselors.GenetMed.13(6):597-605.
22. GoldmanJS.(2012)NewapproachestogeneticcounselingandtestingforAlzheimer'sdiseaseand
frontotemporaldegeneration.CurrNeurolNeurosciRep.12(5):502-10.
23. Bruni AC, ConidiME, Bernardi L. (2014) Genetics in degenerative dementia: current status and
applicability.AlzheimerDisAssocDisord.28(3):199-205.
24. Gooding HC, Linnenbringer EL, Burack J, Roberts JS, Green RC, Biesecker BB. (2006). Genetic
susceptibility testing for Alzheimer disease: motivation to obtain information and control as
precursorstocopingwithincreasedrisk.PatientEducCouns.64(1-3):259-67.
25. Evers-KieboomsG,DecruyenaereM.(1998)PredictivetestingforHuntington'sdisease:achallenge
forpersonsatriskandforprofessionals.PatientEducCouns.35(1):15-26.
26. TibbenA,StevensM,deWertGM,NiermeijerMF,vanDuijnCM,vanSwietenJC.(1997)Preparing
for presymptomatic DNA testing for early onset Alzheimer's disease/cerebral haemorrhage and
hereditaryPickdisease.JMedGenet.34(1):63-72.
27. MacleodR,TibbenA,FrontaliM,Evers-KieboomsG,JonesA,Martinez-DescalesA,RoosRA,Editorial
CommitteeandWorkingGroup'GeneticTestingCounselling'oftheEuropeanHuntingtonDisease
Network'(2012)RecommendationsforthepredictivegenetictestinHuntington'sdisease.Clinical
Genetics83(3):221-231.
28. RobertsonM,BrownE,WhalleyL.(2014)Dementiaprevention:sharedquestionsforresearchand
clinicalmanagement.Maturitas.77(2):124-7.
29. TheHuntington’sDiseaseSocietyofAmerica.(1994)Guidelinesforgenetictesting.NewYork:The
Huntington’sDiseaseSocietyofAmerica.
23
30. InternationalHuntingtonAssociation(IHA)andtheWorldFederationofNeurology(WFN)Research
Group on Huntington's Chorea. (1994) Guidelines for the molecular genetics predictive test in
Huntington'sdisease.Neurology44(8):1533-1536.
31. MurphyM,BlackN, LampingD,McKeeC, SandersonC,Askham J,MarteauT. (1998)Consensus
development methods, and their use in clinical guideline development. Health Technology
Assessment.2:1-88.
32. McKhannGM,KnopmanDS,ChertkowH,HymanBT,JackCRJr,KawasCH,KlunkWE,KoroshetzWJ,
ManlyJJ,MayeuxR,MohsRC,MorrisJC,RossorMN,ScheltensP,CarrilloMC,ThiesB,WeintraubS,
PhelpsCH.(2011).ThediagnosisofdementiaduetoAlzheimer'sdisease:recommendationsfrom
theNational InstituteonAging-Alzheimer'sAssociationworkgroupsondiagnosticguidelines for
Alzheimer'sdisease.AlzheimersDement.7(3):263-9.
33. FolsteinMF,FolsteinSE,McHughPR.(1975)."Mini-mentalstate".Apracticalmethodforgrading
thecognitivestateofpatientsfortheclinician.JPsychiatrRes.12(3):189-98.
34. MorrisJC.(1993)TheClinicalDementiaRating(CDR):currentversionandscoringrules.Neurology.
43(11):2412-4.
35. ApoloneG,MosconiP,QuattrociocchiL,GianicoloEAL,GrothN,Ware JE Jr. (2005)Questionario
sullo statodi saluteSF-12 (Versione Italiana),Milano: IstitutodiRicercheFarmacologicheMario
Negri.
36. Centro Collaborativo Italianopartecipante al ProgettoWHOQOL (1997).Manuale per l’uso degli
strumentiWHOQOL(VersioneItaliana),Ginevra:DipartimentodiSaluteMentale,Organizzazione
MondialedellaSanità.
37. Spielberger CD. (1989) State-Trait Anxiety Inventory: Bibliography (2nd ed.), Palo Alto, CA:
ConsultingPsychologistsPress.
38. BeckAT,WardCH,MendelsonM,MockJ,ErbaughJ.(1961)Aninventoryformeasuringdepression.
ArchivesofGeneralPsychiatry,4:561–71.
39. Hamilton M. (1960) A rating Scale for Depression. Journal of Neurology, Neurosurgery and
Psychiatry.23:56-62.
24
40. CarverCS.(1997)Youwanttomeasurecopingbutyourprotocol’stoolong:ConsidertheBriefCOPE.
InternationalJournalofBehavioralMedicine.4(1):92-100.
41. FriborgO,BarlaugD,MartinussenM,Rosenvinge JH,HjemdalO. (2005)Resilience in relation to
personalityandintelligence.InternationalJournalofMethodsinPsychiatricResearch,14(1):29–
42.
42. WallstonKA,WallstonBS,DeVellisR.(1978)Developmentofthemultidimensionalhealthlocusof
control(MHLC)scales.HealthEducationMonographs,6:160-170.
43. GalaC,MusiccoF,DurbanoF,CesanaB.(1995)ItalianValidationofthemultidimensionalscaleof
‘‘HealthLocusofControl’’.NewTrendsinExperimentalandClinicalPsychiatry9:79–86.
44. BeckAT,WeissmanA.LesterD,TrexlerL.(1974).Themeasurementofpessimism:thehopelessness
scale.JournalofConsultingandClinicalPsychology,42(6),861–865.
45. PompiliM,IlicetoP,LesterD,Innamorati,.,Girardi,P,Tatarelli,R.(2009)BHSBeckHopelessness
Scale:Manuale,GiuntiO.S.OrganizzazioniSpeciali,Firenze,Italy.
46. CapraraGV,BarbaranelliC,BorgogniL.(1993).BigFiveQuestionnaire.O.S.OrganizzazioniSpeciali,
Firenze.
47. CapraraGV,BarbaranelliC,BorgogniL.(2000).BFQ:BigFiveQuestionnaire.Manuale(2nded.).O.S.
OrganizzazioniSpeciali,Firenze.
48. PorteriCandPetriniC. (2015)Research involvingsubjectswithAlzheimer’sdisease in Italy: the
possibleroleoffamilymembers.BMCMedicalEthics2015,16:12
49. LoyCT,SchofieldPR,TurnerAM,KwokJB.(2014).Geneticsofdementia.Lancet.383(9919):828-40.
50. WoodEM,FalconeD,SuhE,IrwinDJ,Chen-PlotkinAS,LeeEB,XieSX,VanDeerlinVM,GrossmanM
(2013). Development and validation of pedigree classification criteria for frontotemporal lobar
degeneration.JAMANeurol.70(11):1411-7.
51. DuitsFH,TeunissenCE,BouwmanFH,VisserPJ,MattssonN,ZetterbergH,BlennowK,HanssonO,
Minthon L, AndreasenN,Marcusson J,WallinA, RikkertMO, TsolakiM, Parnetti L,Herukka SK,
HampelH,DeLeonMJ,Schröder J,AarslandD,BlankensteinMA,ScheltensP,vanderFlierWM.
(2014)Thecerebrospinalfluid"Alzheimerprofile":easilysaid,butwhatdoesitmean?Alzheimers
Dement.10(6):713-723.
25
52. Benussi L, Ghidoni R, Pegoiani E, Moretti DV, Zanetti O, Binetti G. (2009) Progranulin
Leu271LeufsX10 is one of the most common FTLD and CBS associated mutations worldwide.
NeurobiolDis.;33(3):379-85.
53. Mitchell JA,DemirisG.(2005)Telegenetics:Thenextphaseintheprovisionofgeneticsservices?
GenetMed7(1):1-2.
54. ZilliacusEM,MeiserB, LobbEA,KellyPJ,Barlow-StewartK,Kirk JA, SpigelmanAD,WarwickLJ,
TuckerKM.(2011)Arevideoconferencedconsultationsaseffectiveasface-to-faceconsultationsfor
hereditarybreastandovariancancergeneticcounseling?GenetMed13(11):933-941.
55. Goldman JS, Rademakers R., Huey E.D., Boxer A.L.,Mayeux, R.,Miller B.L., BoeveB.F. (2011)An
algorithmforgenetictestingoffrontotemporallobardegeneration.Neurology.76(5):475–483.
56. BorroniB,PadovaniA.(2013)AnewalgorithmformoleculardiagnosticsinFTLD.Nat.Rev.Neurol.
9,241–242.
57. BernardiL,GeracitanoS,ColaoR,PuccioG,GalloM,AnfossiM,FrangipaneF,CurcioSA,MirabelliM,
TomainoC,VassoF,SmirneN,MalettaR,BruniAC.(2009)AbetaPPA713Tmutationinlateonset
Alzheimer'sdiseasewithcerebrovascularlesions.JAlzheimersDis.;17(2):383-9.
58. ConidiME,BernardiL,PuccioG,SmirneN,MuracaMG,CurcioSA,ColaoR,PiscopoP,GalloM,Anfossi
M,FrangipaneF,ClodomiroA,MirabelliM,VassoF,CupidiC,TorchiaG,DiLorenzoR,MandichP,
Confaloni A, Maletta RG, Bruni AC. (2015) Homozygous carriers of APP A713T mutation in an
autosomaldominantAlzheimerdiseasefamily.Neurology84(22):2266-73.
59. SignoriniS,GhidoniR,BarbieroL,BenussiL,BinettiG.(2004)Prevalenceofpathogenicmutations
inanItalianclinicalseriesofpatientswithfamilialdementia.CurrAlzheimerRes.1(3):215-8.
60. Benussi L, Ghidoni R, Binetti G. (2010) Progranulinmutations are a common cause of FTLD in
NorthernItaly.AlzheimerDisAssocDisord.24(3):308-9.
61. van der Zee J, Gijselinck I, Dillen L, Van Langenhove T, Theuns J, Engelborghs S, Philtjens S,
VandenbulckeM,SleegersK,SiebenA,BäumerV,MaesG,CorsmitE,BorroniB,PadovaniA,Archetti
S, Perneczky R, Diehl-Schmid J, de Mendonça A, Miltenberger-Miltenyi G, Pereira S, Pimentel J,
NacmiasB,BagnoliS,SorbiS,GraffC,ChiangHH,WesterlundM,Sanchez-ValleR,LladoA,GelpiE,
SantanaI,AlmeidaMR,SantiagoB,FrisoniG,ZanettiO,BonviciniC,SynofzikM,MaetzlerW,Vom
26
Hagen JM,SchölsL,HenekaMT, JessenF,MatejR,ParobkovaE,KovacsGG,StröbelT,SarafovS,
TournevI,JordanovaA,DanekA,ArzbergerT,FabriziGM,TestiS,SalmonE,SantensP,MartinJJ,
CrasP,VandenbergheR,DeDeynPP,CrutsM,VanBroeckhovenC;EuropeanEarly-OnsetDementia
Consortium.(2013)Apan-EuropeanstudyoftheC9orf72repeatassociatedwithFTLD:geographic
prevalence,genomicinstability,andintermediaterepeats.HumMutat.34(2):363-73.
62. BenussiL,RossiG,GlionnaM,TonoliE,PiccoliE,FostinelliS,PaterliniA,FloccoR,AlbaniD,Pantieri
R,CeredaC,ForloniG,TagliaviniF,BinettiG,GhidoniR.(2014)C9ORF72HexanucleotideRepeat
Number in Frontotemporal Lobar Degeneration: A Genotype-Phenotype Correlation Study. J
AlzheimersDis.38(4):799-808.
63. GalimbertiD,FenoglioC,SerpenteM,VillaC,BonsiR,ArighiA,FumagalliGG,DelBoR,BruniAC,
AnfossiM,ClodomiroA,CupidiC,NacmiasB,SorbiS,PiaceriI,BagnoliS,BessiV,MarconeA,Cerami
C,CappaSF,FilippiM,AgostaF,MagnaniG,ComiG,FranceschiM,RaineroI,GiordanaMT,RubinoE,
FerreroP,RogaevaE,XiZ,ConfaloniA,PiscopoP,BrunoG,TalaricoG,CagninA,ClericiF,Dell'Osso
B,ComiGP,AltamuraAC,MarianiC,ScarpiniE.(2013)Autosomaldominantfrontotemporallobar
degenerationdue to theC9ORF72hexanucleotide repeatexpansion: late-onsetpsychotic clinical
presentation.BiolPsychiatry.74(5):384-91.
64. Bagnoli S, Piaceri I, Tedde A, Piacentini S, Nannucci S, Bracco L, Sorbi S, Nacmias B. (2012)
ProgranulingeneticscreeninginfrontotemporallobardegenerationpatientsfromcentralItaly.Cell
MolNeurobiol.32(1):13-6.
65. BernardiL,FrangipaneF,SmirneN,ColaoR,PuccioG,CurcioSA,MirabelliM,MalettaR,AnfossiM,
GalloM,GeracitanoS,ConidiME,DiLorenzoR,ClodomiroA,CupidiC,MarzanoS,ComitoF,Valenti
V,ZirilliMA,GhaniM,XiZ,SatoC,MorenoD,BorelliA,LeoneRA,StGeorge-HyslopP,RogaevaE,
BruniAC.(2012)Epidemiologyandgeneticsoffrontotemporaldementia:adoor-to-doorsurveyin
southernItaly.NeurobiolAging.33(12):2948.e1-2948.e10.
66. BeckJ,PittmanA,AdamsonG,CampbellT,KennyJ,HouldenH,RohrerJD,deSilvaR,ShoaiM,Uphill
J,PoulterM,HardyJ,MummeryCJ,WarrenJD,Schott JM,FoxNC,RossorMN,Collinge J,MeadS.
(2014) Validation of next-generation sequencing technologies in genetic diagnosis of dementia.
NeurobiolAging.35(1):261-5.
27
67. GoldbergD.(1978)ManualoftheGeneralHealthQuestionnaire,NFERPublishingCo.:GreatBritain.
68. Miller SM. (1987) Monitoring and blunting: validation of a questionnaire to assess styles of
informationseekingunderthreat.JPersSocPsychol52:345–53.
69. Corney RH, Clare AW. (1985) The construction, development and testing of a self-report
questionnairetoidentifysocialproblems.PsychologicalMedicin,15(3):637-649.
70. BrughaT,BebbingtonP,TennantC,HurryJ.(1985)TheListofThreateningExperiences:asubsetof
12lifeeventcategorieswithconsiderablelong-termcontextualthreat.PsycholMed15:189–94.
71. TheWHOQOL Group. (1994) The development of theWorld Health Organization quality of life
assessment instrument (theWHOQOL). InQualityofLifeAssessment: InternationalPerspectives
(ed.J.OrleyandW.Kuyken),pp.41-57.SpringerVerlag:Heidelberg.
72. Roberts JS. (2000) Anticipating response to predictive genetic testing for Alzheimer’s disease.
Gerontologist40:43–52.
73. RobertsJS,ConnellCM.(2000)Illnessrepresentationsamongfirst-degreerelativesofpersonswith
Alzheimerdisease.AlzheimerDisAssocDisord14:129–36.
74. Hathaway SR, McKinley JC. (1997) MMPI-2 – Minnesota Multiphasic Personality Inventory-2;
Firenze:OrganizzazioniSpeciali.
75. SpielbergerCD,GorsuchRL,LusheneRE.(1970)ManualfortheState-TraitAnxietyInventory(Self-
evaluationquestionnaire).PaloAlto,CA:ConsultingPsychologistsPress.
76. Zung,WW.(1965)Aself-ratingdepressionscale,ArchivesofGeneralPsychiatry.12:63–70
77. ZungWW.(1971)Aratinginstrumentforanxietydisorders.Psychosomatics.12(6):371-9.
78. Hathaway SR,McKinley JC. (1943)Manual for theMinnesotaMultiphasic Personality Inventory,
NewYork:PsychologicalCorporation.
79. CarlesimoGA,CaltagironeC,GainottiG,FaddaL,GallassiR,LorussoS,MarfiaG,MarraC,Nocentini,
U,ParnettiL.(1996)TheMentalDeteriorationBattery:NormativeData,DiagnosticReliabilityand
QualitativeAnalysesofCognitiveImpairment,EuropeanNeurology.36:378–384.
28
Table1.Surveyofthegeneticcounselingprotocolsinuseatthelocalcentres.
IRCCSIstitutoCentroSan
GiovannidiDioFatebenefratelli
Brescia
IRCCSFondazioneIstituto
NeurologicoCarloBestaMilano
SpedaliCivili/UniversitàdiBrescia
UniversitàdiFirenze
CentroRegionaleNeurogeneticaLameziaTerme
FondazioneIRCCS
CàGrandaOspedaleMaggiorePoliclinicoMilano
Schedulingandphases
3Consultations(+followup)
3Consultations(+followup)
4Consultations(+followup)
4Consultations(+followup)
4Consultations(+followup)
3Consultations(+followup)
1-Informationalmeeting,Familyhealthhistorycollection,psychosocialassessment,neurologicalexamination,
1-Informationalmeeting,Familyhealthhistorycollection,psychologicalquestionnaires,neurologicalexamination
1-Informationalmeeting,Familyhealthhistorycollection
1-Familyhealthhistorycollection,neuropsychologicalassessment,neurologicalexaminationandinformationalmeetingonthedisease
1-Familyhealthhistorycollection,neuropsychologicalandpersonalityassessment,neurologicalexamination
1-Informationalmeeting,Familyhealthhistorycollection,psychologicalquestionnaires,neurologicalexamination
2-Psychologicalassessment,neuropsychologicalassessment,neurologicalexamination
2-Informationalmeetingonthegeneticriskandthegenetictest
2-Informationalmeeting
2-Bloodsamplecollection
2-Bloodsamplecollection
3-Bloodsamplecollection 3-Bloodsamplecollection
3-Bloodsamplecollection
2-Bloodsamplecollection
3-Disclosureofgenetictestresult
3-Disclosureofgenetictestresult
4-Disclosureofgenetictestresult
4-Disclosureofgenetictestresult
4-Disclosureofgenetictestresult
3-Disclosureofgenetictestresult
29
ProfessionalsintheTeam
Neurologist,Geneticist,Psychiatrist,Psychologist
Neurologist,Geneticist,Psychiatrist,Psychologist
Neurologist,Geneticist,Psychiatrist,Psychologist
Neurologist,Geneticist,Psychiatrist,Psychologist
Neurologist,Geneticist,Psychiatrist,Psychologist
Neurologist,Geneticist,Psychiatrist,Psychologist
Timetable60daysrequiredforthegenetic
testNotdefined Notdefined
About1monthbetween
firstandsecondconsultation;about1monthbetweenthirdandforthconsultation
Bloodsampleistakenwithin4weeksfromthe
secondconsultationNotdefined
FollowupAt12and24months
(irrespectiveoftestresult)
At6/12months(notmandatory)
At15and30days(incaseofpositivityatthe
test)
At1,3,6and12months(irrespective
oftestresult)
At1,3,6and12months
(irrespectiveoftestresult)
At6/12months(notmandatory)
Clinical/Psychological,CognitiveandPersonality
Test
BDI,STAI-Y,BFQ,GHQ,ISS,HLC,SPQ,SLEQ,WHOQOL-100,
SDABE
Psychologicalself-
administeredQuestionnaires
Semi-structuredinterview,MMPI-2,STAI,ZUNG,
Neuropsychologicaltests
Neuropsychologicalassessment
MMPI,MentalDeterioration
Battery
Psychologicalself-
administeredQuestionnaires
ProtocolsDiagnosticandPredictiveprotocol
Predictiveprotocol
DiagnosticandPredictiveprotocol
Predictiveprotocol Predictiveprotocol Predictiveprotocol
Abbreviations:BDI,BeckDepressionInventory[38];STAI-Y,StateTraitAnxietyInventory[37];BFQ,BigFiveQuestionnaire[46,47];GHQ,General
HealthQuestionnaire[67];ISS,InformationSeekingStyle[68];HLC,HealthLocusofControl[42];SPQ,SocialProblemQuestionnaire[69];SLEQ,
StressfulLifeEventsQuestionnaire[709];WHOQOL-100,TheWorldHealthOrganizationQualityofLifeassessment[71];SDABE,DementiaAttitudes
30
BeliefsandExperiences[20,72,73];MMPI-2,MinnesotaMultiphasicPersonalityInventory-2[74];STAI,StateTraitAnxietyInventory[75];ZUNG,Zung
self-ratingdepressionandanxietyscales[76,77];MinnesotaMultiphasicPersonalityInventory[78];MentalDeteriorationBattery[79].
31
Figure1.GeneticCounsellingprotocol.Flowchartforsymptomaticsubjects(A)andforat-riskrelatives
(B).
A)
32
B)
33
Figure2.GeneticTestingFlowchart.Step-by-stepalgorithmtoassistinthesearchofgeneticmutations,forcaseswithabnormalAβandtaulevelsin
thecerebrospinalfluid(CSF)(leftpanel)andwithnormalCSFvaluesordatanotavailable(rightpanel).
34