[[email protected]] - Università degli studi di Siena sito... · University ofGenova Siena, 28 Settembre2009 OspedaliGalliera 19-10:25 Cui prodest? Genetic counselling is a

University of Genova Ospedali Galliera

1 - 10:25

Malattia di Alzheimer e demenze familiari

LA CONSULENZA GENETICA E I TEST GENETICI NELLA PRATICA CLINICAINDICAZIONI, PERCORSI E INTERPRETAZIONI

Siena, 28 settembre 2009

Emilio Di Maria

Dipartimento di Neuroscienze, Oftalmologia e Genetica

Università di Genova

e

SSD di Genetica Medica

EO Ospedali Galliera di Genova

[[email protected]]

EmilioLA CONSULENZA GENETICA E I TEST GENETICI NELLA PRATICA CLINICA - INDICAZIONI, PERCORSI E INTERPRETAZIONI

Siena, 28 Settembre 2009University of Genova Ospedali Galliera

2 - 10:25



3 - 10:25

After Auguste D.

� Alzheimer, A.: Ueber eine eigenartige Erkrankung der Himrinde. AllgZ Psychiat Med 64: 146-148, 1907.

� Alzheimer, A.: Ueber eigenartige Krankheitsfalle des spateren Alters. Z Ges Neurol Psychiat 4: 356-385, 1911.

� Schottky, J.: Ueber praesenile Verbloedungen.

Z Ges Neurol Psychiat 140: 333-397, 1932.

� familial form of presenile dementia in 4 generations

� Sjogren, T.; Sjogren, H.; Lindgren, A. G. H.: Morbus Alzheimer and morbus Pick: a genetic, clinical and patho-anatomical study.

Acta Psychiat Neurol Scand 82: 1-152, 1952.

� multifactorial inheritance



4 - 10:25

after Auguste D…

AD PD

MNDFTD

ataxiasessential tremor

common

rare

sporadic

environm.

early-onset

familial, Mendelian

genetic

FTD-U

FTDP-17FALS

PARKsEOAD

SCAs, FRDA

MSA

DEMENTIA MOVEMENT DISORDER

PSP

CBD

IBMPFD

FXTAS



5 - 10:25

AD PD

MNDFTD


common

rare

sporadic

environm.

early-onset

familial, Mendelian

genetic

FTD-U

FTDP-17FALS

PARKsEOAD

SCAs, FRDA

MSA


PSP

CBD

IBMPFD

FXTAS



6 - 10:25



7 - 10:25

APP mutations



8 - 10:25

APP mutations



9 - 10:25

APP mutations



10 - 10:25

Autosomal dominant AD mutations

Alzheimer Disease & Frontotemporal Dementia Mutation Database

http://www.molgen.ua.ac.be/ADMutations/[last accession: 14.03.08]

455203

3.96%184.93%10PSEN2

79.34%36181.28%165PSEN1

16.70%7613.79%28APP

# Families# MutationsGene



11 - 10:25

Autosomal dominant AD: summary



12 - 10:25

take-home messages

�Esistono forme genetiche, mendeliane di demenza�geni, mutazioni, effetto biologico noti

� rare

�geneticamente eterogenee

�È possibile effettuare un test genetico per demenza



13 - 10:25

G

G

G

AD family?



14 - 10:25

AD families



15 - 10:25

SporadicAD

[prevalence:~1/10 >65yrs.]

EOADAD

[prevalence: ~ 5/105]

<5%



16 - 10:25

SporadicAD

Familial ADEOADAD



17 - 10:25

AD families



18 - 10:25

take-home messages


� rare


�È possibile effettuare un test genetico per demenza,

�se clinicamente utile�al paziente

�alla famiglia

�È indicato effettuare una consulenza genetica



19 - 10:25

Cui prodest?

Genetic counselling is a communication process which deals with the

human problems associated with the occurrence, or risk of occurrence, of a

genetic disorder in a family. This process involves an attempt by one or more

appropriately trained persons to help the individual or the family to

� comprehend the medical facts, including the diagnosis, the probable course of

the disorder and the available management;

� appreciate the way heredity contributes to the disorder and the risk of

recurrence in specified relatives;

� understand the options for dealing with the risk of recurrence;

� choose the course of action which seems appropriate to them in view of their

risk and their family goals and act in accordance with the decision;

� make the best possible adjustment to the disorder in an affected family

member and/or to the risk of recurrence of that disorder.

Ad hoc committee on genetic counselling. Report to the American Society of Human Genetics, Am. J. Hum. Genet., 1975



20 - 10:25

First Law of Socio-Genetics: Celibacy is not hereditary.

Anonymous



21 - 10:25

Un test genetico è un test



22 - 10:25

Predictive values are function of:

PrevalenceSensitivity = true pos. / (true pos. + false neg.)Specificity = true neg / (true neg. + false pos.)

Positive predictive value = true pos. / (true pos. + false pos.)Negative predictive value = true neg. / (true neg. + false neg.)

Affecteds Non-affecteds

Total

Test + true pos. false pos. true pos.+ false pos.

Test - false neg. true neg. false neg.+ true neg.

Total true pos.+ false neg.

false pos.+ true neg.



23 - 10:25

…for a given late-onset genetic disease:

Prevalence: lowGenetic heterogeneity ~ 0Penetrance ~ 1


Total

Test + ∼1 ∼0 1

Test - ∼0 ∼1 1

Total 1 1

Positive predictive value = true pos. / (true pos. + false pos.) ~ 1Negative predictive value = true neg. / (true neg. + false neg.) ~ 1



24 - 10:25

… or for this late-onset genetic disease:

Prevalence: lowGenetic heterogeneity > 0Penetrance < 1


Total

Test + 8 2 10

Test - 92 898 990

Total 100 900 1000

Positive predictive value = true pos. / (true pos. + false pos.) = 8/10 = 80%Negative predictive value = true neg. / (true neg. + false neg.) = 92/990 ~ 9%



25 - 10:25

… or for any other late-onset genetic disease:

Prevalence: lowGenetic heterogeneity > 0Penetrance < 1


Total

Test + <1 >0 1

Test - >0 <1 1

Total 1 1

Positive predictive value = true pos. / (true pos. + false pos.) << 1Negative predictive value = true neg. / (true neg. + false neg.) << 1



26 - 10:25

… and for any late-onset genetic disease:

Penetrance < 1

Negative predictive value << 1

Genetic heterogeneity > 0

Positive predictive value << 1



27 - 10:25

take-home messages


� rare



�se clinicamente utile

� tenendo presente i valori predittivi [bassi]




28 - 10:25

Online Mendelian Inheritance in Man



29 - 10:25

Apolipoprotein E

� 3 isoforms; E2, E3, E4

� coded by 3 alleles: ε2, ε3, ε4

� allele frequency ~ 0.08 0.75 0.17

� genotype frequency: ε3/ ε4 ~ 0.50

ε4/ ε4 ~ 0.15



30 - 10:25

ApoE & AD

� Pericak-Vance, M. A.; Yamaoka, L. H.; Haynes, C. S.; et al.: Genetic linkage

studies in Alzheimer's disease families. Exp. Neurol. 102: 271-279, 1988

� Corder, E. H.; Saunders, A. M.; Strittmatter, W. J.; Schmechel, D. E.; Gaskell, P.

C.; Small, G. W.; Roses, A. D.; Haines, J. L.; Pericak-Vance, M. A.: Gene dose

of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late

onset families. Science 261: 921-923, 1993

� 2007:



31 - 10:25

Apolipoprotein E

� 3 isoforms; E2, E3, E4

� coded by 3 alleles: ε2, ε3, ε4

� allele frequency ~ 0.08 0.75 0.17

� genotype frequency: ε3/ ε4 ~ 0.50

ε4/ ε4 ~ 0.15

� OR (95% CI) ε3/ ε4 = 3.2 (2.8–3.8)

[Bertram et al 2007] ε4/ ε4 = 14.9 (10.8–20.6)



32 - 10:25

ApoE testing



33 - 10:25

Genetic testing for AD: recommendations



34 - 10:25

Genetic testing for dementia: recommendations



35 - 10:25



36 - 10:25

A brief summary



37 - 10:25

take-home messages

�Esistono forme genetiche, mendeliane di demenza� geni, mutazioni, effetto biologico noti

� rare



� se clinicamente utile

� tenendo presente i valori predittivi [bassi]

�È frequente l’aggregazione familiare

�La componente genetica costituisce un fattore di rischio� variabile all’interno della popolazione

�La genotipizzazione di ApoE non è clinicamente utile�non va effettuata in ambito clinico




38 - 10:25

È sempre difficile fare previsioni, ma èimpossibile quando riguardano il futuro.

G.B. Shaw


39 - 10:25




Emilio Di Maria



e



[[email protected]]



40 - 10:25

Unicuique suum

AD PD

MNDFTD


common

rare

sporadic

environm.

early-onset

familial, Mendelian

genetic

FTD-U

FTDP-17FALS

PARKsEOAD

SCAs, FRDA

MSA


PSP

CBD

IBMPFD

FXTAS



41 - 10:25

FTDP-17

University of Genova

Gene MAPT (17q21): mutazioni

� Identificazione del locus associato a FTDP

� Identificazione di mutazioni del gene MAPT� esoni 9, 10, 11, 12, 13:

• ∆K280, 248L, L266V, G272V, N279K, N296N, N296H, delN296, P301L, P301S, S305N, S320F, V337M, R406W

� introne 10: • +3, +13, +14, +16

� esone 1: • R5H

131211109



42 - 10:25

Autosomal dominant FTDP-17 mutations

Alzheimer Disease & Frontotemporal Dementia Mutation Databasehttp://www.molgen.ua.ac.be/ADMutations/[last accession: 30.05.08]

41%12541%42MAPT




43 - 10:25

FTD linked to chr. 17 - tau negative, MAPT negative



44 - 10:25

FTD-U



45 - 10:25

FTD linked to chr. 17 – FTD-U



46 - 10:25

FTD-U pathology

Baker et al., Nature 2006



47 - 10:25

FTD-U clinics

Cruts & Van Broeckoven, TIGS 2008



48 - 10:25

GRN mutations




49 - 10:25

Autosomal dominant FTD mutations

47%15549%56GRN

38%12540%42MAPT



Cruts & Van Broeckoven, TIGS 2008



50 - 10:25

Unicuique suum

AD PD

MNDFTD


common

rare

sporadic

environm.

early-onset

familial, Mendelian

genetic

FTD-U

FTDP-17FALS

PARKsEOAD

SCAs, FRDA

MSA


PSP

CBD

IBMPFD

FXTAS



51 - 10:25

VCP exon 5 c.464G>A

R155H

II:2II:1

III:2 III:4 III:5III:3

IV:3

III:1

IV:1 IV:2

I:2I:1

II:3 II:6 II:8 II:10 II:12II:4

III:7 III:8

2

IV:4

II:5

III:10 III:12 III:13 III:14III:9

IV:5

III:11

IV:7 IV:8IV:6

V:1

III:15

IV:9

II:7

III:17 III:18III:16

IV:10

III:19

IV:11

II:9

III:20

II:11

III:21

2 3 2 2 2

6 2

III:6

FTD + myopathy



52 - 10:25


53 - 10:25




Emilio Di Maria



e



[[email protected]]


54 - 10:25

Progetto pilota per la sperimentazione di un

protocollo di consulenza genetica integrata

per le demenze familiari.



55 - 10:25Progetto pilota per la sperimentazione di un protocollo di consulenza genetica integrata per le demenze familiari - EVIDENCE

Genetic testing for familial dementiaReference literature

�Recommendations and guidelines:�McConnell LM, Koenig BA, Greely HT, RaffinTA. Genetic testing and Alzheimer disease: recommendations of the Stanford Programs in Genomics, Ethics, and Society. Genet Test 3:3-12, 1999.

�Williamson J, LaRusse S. Genetics and Genetic Counseling: Recommendations for Alzheimer's Disease, Frontotemporal Dementia, and Creutzfeldt-Jakob Disease. Curr Neurol NeurosciRep 4:351-357, 2004.

�Waldemar G, Dubois B, Emre M, et al. Recommendations for the diagnosis and management of Alzheimer's disease and other disorders associated with dementia: EFNS guideline. Eur J Neurol 14:21-26, 2007.

� Other selected literature relevant to the problem:� Tibben A, Stevens M, de-Wert GM et al. Preparing forpresymptomatic DNA testing for early onset Alzheimer's disease/cerebral haemorrhage and hereditary Pickdisease. J Med Genet 34:63-72, 1997.

� Liddell MB, Lovestone S, Owen MJ. Genetic risk of Alzheimer's disease: advising relatives. Br J Psychiatry178:7-11, 2001.

� Amadori S, Gigola L, Di Maria E, et al. Relevant issues in genetic counseling for familial dementia: a study on attitudes towards testing in at-risk relatives. Eur J HumGenet 10(S1):313, 2002.

Lessons from Huntington’s disease

�Specific guidelines were published soon after the availability of direct testing [International Huntington Association (IHA) and the World Federation of Neurology (WFN) Research Group on Huntington's Chorea. Guidelines for the molecular genetics predictive test in Huntington's disease 1994].

�Very low incidence (<1%) of catastrophic events [Almqvist 1999].

�Pre-test psychological measures are the best predictors of post-test distress [Decrunayenaere1999].

�Mean anxiety and depression levels decrease one year after a good test result, do not significantly change in the case of a bad test result [Decrunayenaere 1996].

Lacking evidence:

� No specific criteria were recommended for clinical diagnostic testing on affected individuals.

� The real impact of the predictive test over a long-term period may have been underestimated [Timman 2004].



56 - 10:25

Caso indice

Valutazione clinicae anamnestica

eligibileallo studio

Consulenza GeneticaInformativa

Consensoallo studio

Sì

NOstop

PedigreeCartella clinica

eligibileper il test

Consulenza GeneticaFollow-up

Consensoal test

Sì

no CRFs, test psicologici

Consulenza GeneticaPre-test (2 sessioni)

NO test CRFs, test psicologici, dati qualitativi

Sì TEST

Testdiagnostico

CRFs, test psicologici, dati qualitativi

Clinico, Neuropsichiatra, Genetista



Genetista, Psicologo

Clinico, Neuropsichiatra, Genetista, Psicologo

Genetista

Equipe Documentazione

Genetista, Biologo

Processo:consulenza geneticaintegrata

Esito [atteso]: informazione e adattamento rispetto al rischio genetico di ricorrenza.

Prodotti attesi:

stima relativa della domanda e del bisogno degli utenti;

valutazione di appropriatezza del processo.

Utenti:

Famiglie con ricorrenza di disturbi cognitivi gravi.



57 - 10:25

Caso indice




Consensoallo studio

Sì

NOstop

PedigreeCartella clinica



Consensoal test

Sì

no CRFs, test psicologici


NO testCRFs, test psicologici, dati qualitativi

Sì TEST

Testdiagnostico

CRFs, test psicologici, dati qualitativi






Genetista

Equipe Documentazione

Genetista, Biologo



58 - 10:25

Caso indice




Consensoallo studio

Sì



Consensoal test

Sì


Sì TEST

Testdiagnostico

Familiare sano a rischio

eligibileal

protocollo

Consensoallo studio

Sì

TEST


Consensoal test

NO

Consulenza GeneticaPre-test (n sessioni)

Sì TEST

Testpresintomatico




Genetista, Biologo

NO

NONO


Equipe



59 - 10:25

Stage 1

� collection of family history and assessment of genetic risk;� information on the genetics of the disease, on test procedures, on the protocol;

� collection of applicant’s data on motivations, autonomy in decision-making, expectations;

� discussion of pros and cons of the possible test outcome.

Stage 2

� Neurological/neuropsychological examination of the applicant.

� assessment and discussion of coping strategies;� assessment of comprehension of the information received;

� Team evaluation of fulfilment of inclusion criteria. � informed consent signature; blood sample collection.

Stage 3

� disclosure of test results;� counselling regarding coping with test results.Early follow-up phone call (one week interval):

� informal assessment of emotional state.Long-term follow-up:

� exploration of long-term psychological impact.

Presymptomatic testing protocol

Pre-test counselling

proceed with the test?

Test disclosure

YES

NOMAYBE

Follow-up

Genetic Test



60 - 10:25

Documents

[[email protected]] - Università degli studi di Siena sito... · University ofGenova Siena, 28 Settembre2009 OspedaliGalliera 19-10:25 Cui prodest? Genetic counselling is a