Twenty Years of a Pre-Symptomatic Testing Protocol for Late-Onset Neurological Diseases in Portugal Vinte Anos de um Protocolo de Teste Pré-Sintomático para Doenças Neurológicas de Início Tardio em Portugal

Abstract

Introduction:
The national protocol of genetic counselling and pre-symptomatic testing for late-onset neurological diseases began in Portugal in 1995. Initially, it was accessible only to adults at-risk for Machado-Joseph disease, but was later extended to other hereditary ataxias, to Huntington's disease and to familial amyloid polyneuropathy caused by Val30Met mutation at the transthyretin gene. The aim of this study was to describe the profile of the population seeking pre-symptomatic testing, while also reflecting on the experience of conducting the protocol of multidisciplinary sessions since 1996.

Material and methods:
We conducted a retrospective study and collected data from clinical records of consultands who requested pre-symptomatic testing at our centre in Porto (Portugal) during the first twenty years of practice (1996 - 2015).

Results:
A total of 1446 records were reviewed. The most common reason for testing was to reduce uncertainty (41.7%). The rate of withdrawals before results disclosure was lower (16%) than reported in other international experiences with pre-symptomatic testing, while 45% of the consultands dropped out the protocol after learning the test results (73.5% of them were non-carriers). As far as the mutation carriers were concerned, 29.6% adhered to the protocol a year after test disclosure. Consultands that had learned about presymptomatic testing through healthcare professionals tended to adhere more to pre-symptomatic testing consultations.

Discussion:
The profile of Portuguese consultands at risk for late-onset neurological diseases is similar to those reported in other international programs. The largest group in this data set was the one comprising the subjects at risk for familial amyloid polyneuropathy caused by Val30Met mutation at the transthyretin gene, and it is likely that therapeutic options for this condition may have influenced this result. Adherence to pre-symptomatic testing may change in the future since effective therapies are available (or given the fact that people think effective treatments are imminent).

Conclusion:
This study reflects the first comprehensive description of a Portuguese experience with pre-symptomatic testing for late onset neurological diseases. The development of innovative approaches to improve the consultands' experience with pre-symptomatic testing and their engagement in genetic departments is still a challenge in Portuguese genetics healthcare departments. A better coordination among primary care and genetics healthcare services is needed.

Full text

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RESUMO
Introdução: Em 1995 foi iniciado em Portugal um protocolo nacional para o aconselhamento genético e teste pré-sintomático de doen-
ças neurológicas de início tardio. Inicialmente, foi disponibilizado para indivíduos adultos em risco para a doença de Machado-Joseph
e posteriormente estendido a outras ataxias hereditárias, doença de Huntington e polineuropatia amiloidótica familiar ATTR Val30Met.
O objetivo deste estudo é descrever o perl dos consultandos envolvidos no teste pré-sintomático desde 1996, e reetir no protocolo
de sessões multidisciplinares.
Material e Métodos: Realizámos um estudo retrospetivo com recolha de dados dos processos clínicos dos utentes que solicitaram
teste pré-sintomático ao longo dos primeiros 20 anos do Centro de Genética Preditiva e Preventiva (1996 - 2015), localizado no Porto,
Portugal.
Resultados: Analisámos um total de 1446 processos clínicos; a principal motivação para a realização do teste pré-sintomático foi
o alívio da incerteza (41,7%). A taxa de abandono do protocolo antes da comunicação dos resultados do pré-sintomático (16% dos
casos) foi mais baixa do que em outras experiências internacionais; 45% dos consultandos abandonaram o protocolo depois de sa-
berem o resultado do teste pré-sintomático (73,5% dos quais eram não-portadores). 29,6% de consultandos portadores continuaram
envolvidos no protocolo um ano após saberem o resultado do teste pré-sintomático. Os consultandos encaminhados para o protocolo
através de outros prossionais de saúde revelaram maior adesão ao protocolo.
Discussão: O perl sociodemográco dos consultandos no Centro de Genética Preditiva e Preventiva é similar ao reportado noutras
experiências internacionais. Os consultandos em risco para polineuropatia amiloidótica familiar ATTR Val30Met representaram o maior
grupo nos nossos dados, sendo provável que as opções terapêuticas disponíveis para esta doença tenham inuenciado este resulta-
do. A adesão ao teste pré-sintomático poderá alterar-se no futuro quando terapias ecazes estiverem disponíveis (ou as pessoas as
percepcionem como estando iminentes).
Conclusão: Este trabalho constitui a descrição mais completa até ao momento publicada acerca da realização de teste pré-sinto-
mático em Portugal. O desenvolvimento de abordagens com vista à melhoria da experiência dos consultandos com os testes pré-
-sintomáticos e ao seu envolvimento nos serviços de genética é um desao atual, assim como a melhor articulação dos mesmos com
os cuidados de saúde primários.
Twenty Years of a Pre-Symptomatic Testing Protocol for
Late-Onset Neurological Diseases in Portugal
Vinte Anos de um Protocolo de Teste Pré-Sintomático para
Doenças Neurológicas de Início Tardio em Portugal
* Co-primeiros autores.
1. Instituto de Investigação e Inovação em Saúde (i3S). Universidade do Porto. Porto. Portugal.
2. UnIGENe and Centre for Predictive and Preventive Genetics (CGPP). IBMC – Institute for Molecular and Cell Biology. Universidade do Porto. Porto. Portugal.
3. Instituto de Ciências Biomédicas Abel Salazar. Universidade do Porto. Porto. Portugal.
 Autor correspondente: Milena Paneque. milenaph@ibmc.up.pt
Recebido: 14 de março de 2018 - Aceite: 01 de agosto de 2018 | Copyright © Ordem dos Médicos 2019
Milena PANEQUE*,1,2,3, Joana FÉLIX*,1,2, Álvaro MENDES1,2, Carolina LEMOS1,2,3, Susana LÊDO1,2, João SILVA1,2,
Jorge SEQUEIROS1,2,3
Acta Med Port 2019 Apr;32(4):295-304 ▪ https://doi.org/10.20344/amp.10526
ABSTRACT
Introduction: The national protocol of genetic counselling and pre-symptomatic testing for late-onset neurological diseases began
in Portugal in 1995. Initially, it was accessible only to adults at-risk for Machado-Joseph disease, but was later extended to other
hereditary ataxias, to Huntington’s disease and to familial amyloid polyneuropathy caused by Val30Met mutation at the transthyretin
gene. The aim of this study was to describe the prole of the population seeking pre-symptomatic testing, while also reecting on the
experience of conducting the protocol of multidisciplinary sessions since 1996.
Material and Methods: We conducted a retrospective study and collected data from clinical records of consultands who requested
pre-symptomatic testing at our centre in Porto (Portugal) during the rst twenty years of practice (1996 - 2015).
Results: A total of 1446 records were reviewed. The most common reason for testing was to reduce uncertainty (41.7%). The rate of
withdrawals before results disclosure was lower (16%) than reported in other international experiences with pre-symptomatic testing,
while 45% of the consultands dropped out the protocol after learning the test results (73.5% of them were non-carriers). As far as the
mutation carriers were concerned, 29.6% adhered to the protocol a year after test disclosure. Consultands that had learned about pre-
symptomatic testing through healthcare professionals tended to adhere more to pre-symptomatic testing consultations.
Discussion: The prole of Portuguese consultands at risk for late-onset neurological diseases is similar to those reported in other
international programs. The largest group in this data set was the one comprising the subjects at risk for familial amyloid polyneuropathy
caused by Val30Met mutation at the transthyretin gene, and it is likely that therapeutic options for this condition may have inuenced
this result. Adherence to pre-symptomatic testing may change in the future since effective therapies are available (or given the fact that
people think effective treatments are imminent).
Conclusion: This study reects the rst comprehensive description of a Portuguese experience with pre-symptomatic testing for late-
onset neurological diseases. The development of innovative approaches to improve the consultands’ experience with pre-symptomatic
testing and their engagement in genetic departments is still a challenge in Portuguese genetics healthcare departments. A better
coordination among primary care and genetics healthcare services is needed.
Keywords: Genetic Counseling; Genetic Testing; Neurodegenerative Diseases; Portugal; Quality of Health Care

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Paneque M, et al. 20 years of pre-symptomatic testing in Portugal, Acta Med Port 2019 Apr;32(4):295-304
Palavras-chave: Aconselhamento Genético; Doenças Neurodegenerativas; Portugal; Qualidade de Cuidados de Saúde; Testes Ge-
néticos
INTRODUCTION
Predictive testing, also known as presymptomatic test-
ing (PST), is a type of genetic test used to determine the ge-
netic status of at 50%-risk subjects in order to predict their
possibilities of developing a given disease in the future. Pre-
dictive testing for late-onset neurological diseases (LONDs)
was rst offered in 1983 when linkage analysis made it pos-
sible to identify subjects at increased risk for Huntington’s
disease (HD).1,2 In 1993, PST by direct mutation analysis
was rst possible for HD, expanding to other dominantly
inherited neurological diseases a few years later. Then in
1997, the protocol of genetic counselling and psychosocial
support for PST proposed for HD became the model used
worldwide for those diseases.3
In Portugal, PST was rst available for transthyretin
(TTR)-related familial amyloid polyneuropathy (FAP) in
1986 through biochemical testing,4 and years later, by mo-
lecular analysis. Val30Met is by far the most common dis-
ease-related mutation.5 PST for Machado-Joseph disease
(MJD, also known as spinocerebellar ataxia type 3, SCA3)
was rst offered in 1995.6 A national protocol of multidis-
ciplinary sessions was then implemented at ve genetics
departments in Portugal and made accessible to all adults
at risk for LONDs. The implementation followed a compre-
hensive protocol of genetic counselling and psychosocial
evaluation and support, rst aimed at MJD/SCA3 and other
SCAs, and later extended to HD and FAP ATTR Val30Met,
among others.6 All of these diseases are dominantly inherit-
ed, progressive, highly incapacitating and have no effective
cure. Some therapeutic measures are available for FAP. For
example, liver transplantation has been possible for over 20
years now7 and more recently, Tafamidis,8 was released as
a new drug used to delay loss of peripheral nerve function.
In Portugal, some areas present the world’s high-
est frequency for MJD/SCA3 (national prevalence of 3.1 :
100 000, but 835.2 in Flores, 27.1 in the Azorean island of
São Miguel, and 14.4 in the central region of mainland Por-
tugal).9 Huntington disease has a more uniform prevalence,
estimated at 5 – 10: 100 000,11,12 similar to what is found
in most of other European countries. Particularly, FAP has
a prevalence of 163.1: 100 000 in the region of Póvoa de
Varzim/Vila do Conde, just north of Porto where FAP was
initially detected and one of the major clusters of patients
worldwide is found.10 Therefore, these disorders represent
a public health problem in these high prevalence clusters.
Due to the high incidence of these disorders in some
regions of Portugal, early detection is essential to improve
patients’ prognosis and management. Consequently, it is
extremely important to offer proper genetic counselling and
PST to at-risk relatives after the identication of the genetic
defect in a single family.13
The international guidelines established for PST high-
light the relevance of establishing a respectful relationship
between counsellor and consultand, the communication of
test-related information, and the availability of pre and post-
test counselling, including psychosocial support.14,15 Our ex-
perience in Portugal shows that genetic testing for LONDs
calls for special attention from genetic counsellors, clinical
psychologists and other health professionals.16-20 Longitudi-
nal studies of 10 years after PST demonstrated that, prior to
PST, participants had higher levels of psychopathology than
a year after receiving their test results, regardless of that re-
sult.19 Also, the time of contact with the disease in the family
and the gender of the affected parent had an impact on the
psychological outcome of PST.20 Evidence has also been
collected acknowledging the inuence of the counsellor’s
skills and the quality of the counsellor-consultand relation-
ship based on the perceived satisfaction of consultands.21,22
Similarly to recently published studies on national expe-
riences with related programs,23-28 we describe in this study
the experience gained at our centre in conducting PST in
Portugal. We aim to characterize the prole of the popula-
tion seeking PST at the Centre for Predictive and Preven-
tive Genetics (CGPP) outpatient clinic, while also reecting
on the experience of conducting a PST program since 1996.
MATERIAL AND METHODS
The Portuguese PST protocol
The PST protocol has been implemented for over 20
years at an outpatient clinic in Porto (Centre for Predictive
and Preventive Genetics CGPP-IBMC), mostly covering the
northern region of the country, but not restricted to it. The
protocol for genetic counselling in the context of PST (Fig.
1) has been published elsewhere.6,19 In general, this proce-
dure follows the guidelines produced by the International
Huntington Association and the World Federation of Neu-
rology (WFN) Research Group on Huntington’s Chorea;29
it includes (1) a pre-test neurological examination, a psy-
chosocial assessment, and at least two genetic counselling
sessions; (2) a session for disclosure of results; and (3) a
psychosocial follow-up at 3 weeks, at 6 months, and a year
after the results. In addition, it is possible to undergo further
genetic counselling sessions and/or psychological, social
service or psychiatric intervention, whenever appropriate.6
Subjects
From 1996 to 2015, 1498 persons sought PST at CGPP.
Of these, 1230 received their genetic test results (Fig. 2); 28
were excluded from the PST protocol after the rst visit (2
due to psychiatric problems, which was incompatible at the
time with PST); 20 were found not to be at risk for a LOND
(usually at 25% risk before a parent was tested and proved
to be non-carrier), and 6 were excluded because they were
still minors (younger than 18 years). Another 240 subjects
withdrew from the protocol in one of the pre-test sessions,
before the disclosure of results.

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Figure 1 – General protocol of pre-symptomatic testing in use at our centre
Pre-test sessions Post-test sessions
Registration
Results
disclosure
Information
Social
evaluation
Psychosocial assessment
• Duration of contact, kinship,
gender of transmiting parent
(Anamnesis)
• Anxiety (SAS)
• Depression (BDO)
1st Psychological
follow-up
• Anxiety (SAS)
• Depression (BDO)
2nd Psychological
follow-up
• Anxiety (SAS)
• Depression (BDO)
3rd Psychological
follow-up
• Anxiety (SAS)
• Depression (BDO)
1st Blood
sample
1st Genetic
Counselling
Session
2nd Genetic
Counselling
Session 2nd Blood
sample
3 weeks
3 weeks
3 weeks
6 months
6 months

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Procedure
We reviewed the registration forms and all written docu-
mentation of the genetic counselling sessions from 1498
clinical records. We carried out a retrospective descriptive
study of consultands’ prole, looking at social and demo-
graphic variables (gender, age, marital status, number of
offspring, education and family history).
The PST protocol includes two pre-test genetic counsel-
ling sessions. An essential point of these sessions is the
exploration of psychosocial and motivational issues related
to the test request, which are usually explored using open
questions. The technique is used to explore the motiva-
tions for testing, the anticipated impact of possible results,
and the sources of knowledge about the disease and PST.
Also, the information on the perceived satisfaction of the
consultands with the PST protocol, and if they would recom-
mend it to other persons as well as their general sugges-
tions, are questioned. All this information is expected to be
clearly registered in the consultands’ clinical le. However,
because the information is obtained via open questions, it
is common to nd that consultands referred more than one
answer for each explored theme.
According to the disease at risk, requests were clus-
tered in four groups: (1) FAP ATTR Val30Met; (2) HD; (3)
MJD; and (4) other LONDs, such as CADASIL (cerebral au-
tosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy), SCA2 and SCA7 (spinocerebellar
ataxia types 2 and 7) and DRPLA (dentatorubral-pallidoluy-
sian atrophy).
When consultands registered in the protocol, during their
rst visit to the centre, written consent for electronic registry
of their data is requested as required by national legisla-
tion, and for respective analysis. During the rst genetic
counselling session, all consultands were informed about
Figure 2 – Flowchart of the outcome of the pre-symptomatic testing and its results
1498 consultands
requested PST
1230 performed PST
680 non-carriers 550 carriers
240 withdrew 28 exclusions
Table 1 - Uptake of pre-symptomatic testing
Disease Nº records
Pre-test
withdrawals Exclusions
Results
of the genetic test
Follow-up withdrawals Protocol concluded –
after 3rd psychology
appointment
(12 months)
After
results communication
After 1st psychology
appointment
(3 weeks)
After 2nd psychology
appointment
(6 months)
Before the 1st
session
Before the 2nd
session
Before the results
session Carrier Non-carrier Carrier Non-carrier Carrier Non-carrier Carrier Non-carrier Carrier Non-carrier
FAP 1,174
(78.4%)
100
(8.5%)
38
(3.2%)
35
(3.0%)
19
(1.6%)
439
(44.7%)
543
(55.3%)
120
(27.3%)
348
(64.1%)
117
(26.7%)
121
(22.3%)
78
(17.8%)
53
(9.8%)
124
(28.2%)
21
(3.8%)
HD 230
(15.3%)
21
(9.1%)
19
(8.3%)
10
(4.3%)
6
(2.6%)
75
(43.1%)
99
(56.9%)
23
(30.7%)
49
(49.5%)
12
(16.0%)
19
(19.2%)
14
(18.7%)
7
(7.1%)
26
(34.6%)
24
(24.2%)
MJD 55
(3.7%)
4
(7.3%)
6
(10.9%)
0
(0%)
1
(1.8%)
20
(45.5%)
24
(54.6%)
4
(20.0%)
6
(25.0%)
6
(30.0%)
7
(29.1%)
0
(0%)
1
(4.2%)
10
(50.0%)
10
(41.7%)
Other LONDs* 39
(2.6%)
3
(3.5%)
2
(5.1%)
2
(5.1%)
2
(5.1%)
16
(53.3%)
14
(46.7%)
2
(12.5%)
10
(71.4%)
9
(56.3%)
2
(14.28%)
2
(12.5%)
0
(0%)
3
(18.7%)
2
(14.3%)
Sub-total 128
(8.5%)
65
(4.3%)
47
(3.1%)
550
(44.7%)
680
(55.3%)
149
(26.5%)
413
(73.5%)
144
(49.2%)
149
(50.8%)
94
(60.6%)
61
(39.4%)
163
(74.1%)
57
(25.9%)
Totals 1498
(100%)
240
(16.0%)
28
(1.9%)
1,230
(82.1%)
562
(45.7%)
293
(23.8%)
155
(12.6%)
220
(17.9%)
* Other late-onset neurological diseases: SCA2, SCA7, CADASIL & DRPLA

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the PST procedures. The PST protocol was also explained
in detail. The consultands had the opportunity to raise ques-
tions, doubts or concerns (this opportunity was reiterated in
the second session and special emphasis was placed on
any questions or doubts arising).
Data analysis
Descriptive statistics and categorical variables were
analysed using the chi-square test. The Kruskal-Wallis
non-parametric test was used to determine if there were
signicant differences between the disease groups regard-
ing quantitative variables. Signicance was set at α ≤ 0.05.
Statistical analyses were performed using the Statistical
Program for Social Sciences (SPSS), version 20.0 for Win-
dows. The Statistical procedures adopted are those ap-
proaches commonly used to evaluate these types of vari-
ables.
RESULTS
Socio-demographic prole and disease-related fea-
tures
Between 1996 and 2015, 1498 people requested PST
at CGPP clinical facilities. Of these, 28 (1.9%) were not eli-
gible for PST and 240 (16.0%) withdrew from the protocol
before the disclosure of test results (Table 1). The reasons
for withdrawal are unknown as they were not explored by
the clinical team for ethical reasons. However, according
to what has been recorded in the clinical les, professional
notes from genetic counselling and psychological pre-test
sessions, withdrawal might be related to consultands’ gains
of new perspectives, such as being at a higher risk than
their previous subjective perception. On the other hand, it
may be due to inaccurate understanding of the disease, in-
cluding myths and beliefs. All clarications along pre-test
sessions may have prompted a different awareness and
further reection on the implications of the test and some-
times fears of being unable to cope with an unfavourable
result. We found that written documentation of consultands-
reported experience was not uniformly registered by the
professionals. Therefore, registration of the information in
the clinical les is inconsistent.
The mean-age at the time of testing was 30.7 years
(range 14 - 95 years, SD 12.8 years) (Table 2). The number
of PST performed per year according to the at-risk disease
is illustrated in Fig. 3. Persons at-risk for FAP ATTR Val-
30Met (which has an earlier onset - mean of 33 years in the
Portuguese population) had a signicantly lower mean-age
(28.8 years; p < 0.001) than those for the other diseases.
Female consultands represented 56.0% of the sample, in
a male/female ratio of 1 : 1.27 (p < 0.001); females pre-
dominated for all disease groups (FAP: p = 0.005; HD: p <
0.001 and MJD: p = 0.001), except for the other LONDs (p
= 0.853); 47.8% were married or in a relationship; 60.9%
did not have offspring; those at risk for FAP ATTR Val30Met
(younger, on average) had fewer offspring than the others
(34.3%; p < 0.001).
The educational level was signicantly different among
consultands (p < 0.001). Those at risk for other LONDs had
higher education (39.4% had a university degree), while
55.9% of the consultands at risk for FAP ATTR Val30Met
had not completed more than secondary education). A ma-
ternal family history of the disease was predominant among
consultands at risk for FAP ATTR Val30Met (55.8%), MJD
(51.0%), and other LONDs (72.4%), while persons at risk
for HD presented only 45.4% of maternal family background
(Table 2).
Reasons for testing, anticipated changes after testing,
and source of knowledge of PST
The consultands-reported reasons for testing, antici-
pated changes, and source of knowledge of PST were not
recorded uniformly. The reasons for PST were recorded
for 1215 individuals (82%). The most common reasons for
undertaking PST were “to relieve uncertainty” (41.7%), “to
Table 1 - Uptake of pre-symptomatic testing
Disease Nº records
Pre-test
withdrawals Exclusions
Results
of the genetic test
Follow-up withdrawals Protocol concluded –
after 3rd psychology
appointment
(12 months)
After
results communication
After 1st psychology
appointment
(3 weeks)
After 2nd psychology
appointment
(6 months)
Before the 1st
session
Before the 2nd
session
Before the results
session Carrier Non-carrier Carrier Non-carrier Carrier Non-carrier Carrier Non-carrier Carrier Non-carrier
FAP 1,174
(78.4%)
100
(8.5%)
38
(3.2%)
35
(3.0%)
19
(1.6%)
439
(44.7%)
543
(55.3%)
120
(27.3%)
348
(64.1%)
117
(26.7%)
121
(22.3%)
78
(17.8%)
53
(9.8%)
124
(28.2%)
21
(3.8%)
HD 230
(15.3%)
21
(9.1%)
19
(8.3%)
10
(4.3%)
6
(2.6%)
75
(43.1%)
99
(56.9%)
23
(30.7%)
49
(49.5%)
12
(16.0%)
19
(19.2%)
14
(18.7%)
7
(7.1%)
26
(34.6%)
24
(24.2%)
MJD 55
(3.7%)
4
(7.3%)
6
(10.9%)
0
(0%)
1
(1.8%)
20
(45.5%)
24
(54.6%)
4
(20.0%)
6
(25.0%)
6
(30.0%)
7
(29.1%)
0
(0%)
1
(4.2%)
10
(50.0%)
10
(41.7%)
Other LONDs* 39
(2.6%)
3
(3.5%)
2
(5.1%)
2
(5.1%)
2
(5.1%)
16
(53.3%)
14
(46.7%)
2
(12.5%)
10
(71.4%)
9
(56.3%)
2
(14.28%)
2
(12.5%)
0
(0%)
3
(18.7%)
2
(14.3%)
Sub-total 128
(8.5%)
65
(4.3%)
47
(3.1%)
550
(44.7%)
680
(55.3%)
149
(26.5%)
413
(73.5%)
144
(49.2%)
149
(50.8%)
94
(60.6%)
61
(39.4%)
163
(74.1%)
57
(25.9%)
Totals 1498
(100%)
240
(16.0%)
28
(1.9%)
1,230
(82.1%)
562
(45.7%)
293
(23.8%)
155
(12.6%)
220
(17.9%)
* Other late-onset neurological diseases: SCA2, SCA7, CADASIL & DRPLA

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prepare for disease onset” (23.2%), “family planning”
(23.2%) and “to inform the offspring” (18.0%).
The anticipated changes after testing results were re-
corded for 902 individuals (63%). As changes anticipated
in response to a potential carrier result, 32.4% of con-
sultands referred emotional instability, among which ve
people (1.7%) expressed suicidal ideation; four of them (2
females, 2 males) were at risk for FAP ATTR Val30Met and
one (female) for HD. Additionally, 21.6% of the consultands
anticipated changes in family planning, while 23.5% said
they would look for therapeutic options (even if these did
not exist) and seek medical care; and 22.5% expressed that
nothing would change in their lives. On the other hand, un-
der a scenario of a non-carrier result, 41.6% denied any fu-
ture potential changes; while 37.4% mentioned they would
be happy and relieved, 16.9% anticipated some positive
change in their lives, and 4.1% expressed their desire of
having more children.
The source of knowledge about the availability of PST
was recorded from 922 individuals (64.6%). Consultands
Figure 3 – Number of PST performed per year according to the at-risk disease
0
10
20
30
40
50
60
70
80
90
100
110
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2007 2008 2009 2010 2011 2012 2013 2014
FAP
HD
MJD
CADASIL + Ataxias
20152006
Table 2 - Social and demographic data of subjects who underwent pre-symptomatic testing (PST), 1996 - 2015 (showing valid percentage)
Disease
Gender
Age
Marital status
Consultands who
had offspring
Education Family history
Female Male Single Married Divorced Widow/er Illiterate-4th
year
5th - 9th
year
10th - 12th
year
Higher
education Maternal Paternal
FAP
(n = 1174)
635
(53.4%)
539
(46.6%) 28.8 577
(51.6%)
469
(45.2%)
21
(1.8%)
15
(1.4%)
362
(34.3%)
88
(9.2%)
430
(44.7%)
328
(34.1%)
115
(12.0%)
603
(55.8%)
477
(44.2%)
HD
(n = 230)
146
(64.3%)
84
(35.7%) 37.0 63
(29.7%)
131
(63.2%)
10
(5.4%)
4
(1.7%)
107
(53.8%)
25
(14.4%)
49
(28.1%)
64
(36.8%)
36
(20.7%)
89
(45.4%)
107
(54.6%)
MJD
(n = 55)
37
(72.9%)
18
(27.1%) 40.7 9
(15.0%)
30
(72.5%)
4
(2.5%)
4
(10.0%)
34
(72.3%)
11
(26.2%)
11
(26.2%)
11
(26.2%)
9
(21.4%)
25
(50.0%)
25
(50.0%)
Other LONDs*
(n = 39)
21
(51.7%)
18
(48.3%) 37.7 10
(20.7%)
28
(75.9%)
1
(3.4%)
0
(0%)
21
(53.8%)
4
(12.1%)
10
(30.3%)
6
(18.2%)
13
(39.4%)
21
(72.4%)
8
(27.6%)
Total 839
(56.0%)
659
(44.0%) 30.7 659
(47.9%)
658
(47.8%)
36
(2.6%)
23
(1.7%)
524
(39.1%)
128
(10.6%)
500
(41.3%)
409
(33.8%)
173
(14.3%)
738
(54.5%)
616
(45.5%)
* Other late-onset neurological diseases: SCA2, SCA7, CADASIL & DRPLA

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learned about PST through health professionals (59.7%);
through relatives, friends, or colleagues (30.1%); or via the
Internet (10.2%). In FAP ATTR Val30Met, the predominant
source of knowledge about PST was the family or individual
search (p < 0.001), which was higher than for the other dis-
eases.
Test outcomes, follow-up adherence, evaluation of the
PST protocol, and potential endorsement
Of the 1230 subjects who received the test results
(81.1%), 55.3% were reported as non-carriers (n = 680)
and 44.7% were reported as carriers (n = 550) (p < 0.001)
(Table 1). On the other hand, almost half (45.7%) of the
subjects dropped out of the psychosocial follow-up offered
regardless of test result (n = 562), of which 73.5% were
non-carriers. One year after the communication of results,
220 subjects (17.9%) were still involved in the long-term
psychological follow-up session of the protocol. The higher
percentage of those who completed one-year of follow-up
were pre-symptomatic carriers (74.1%) (p < 0.001). Never-
theless, they represent 29.6% of subjects informed as carri-
ers at test disclosure.
We found that 23% of the 551 consultands that had
learned about PST through healthcare professionals tended
more to complete the PST protocol (p < 0.001), when com-
pared to 12.4% of the 371 subjects that reported no previ-
ous medical advice.
The evaluation of the PST protocol sessions was re-
corded for 293 individuals. The PST protocol followed was
evaluated positively by 87.7% of consultands. The reasons
included its structure of pre- and post-test sessions and the
multidisciplinary approach (35.8%), the personalized atten-
tion provided by the professional team (20.1%), the exist-
ence of psychosocial support (14.7%), the support offered
while preparing for potential results (10.0%), and the fact
that the information provided resulted in feelings of relief
(7.0%). The remaining 12.3% of the individuals reported
negative aspects, namely the time lapse between blood
collection and the results disclosure (28.8%), the dura-
tion of the whole PST protocol (23.3%), the difculties to
access the centre premises (13.7%) and the perception of
the psychology consultations as uncomfortable - due to the
length of the psychometric evaluation (11.0%), or the nega-
tive feelings prompted in the consultation (12.3%) -, and the
information provided perceived as complex (10.9%).
The potential endorsement of the PST protocol was
recorded for 339 consultands, of which 96.8% would rec-
ommend it to relatives and other at-risk persons. The rea-
sons for recommendation were mainly the access to health
information provided by the protocol (46.7%), the profes-
sional follow-up (12.2%), the relief of uncertainty (11.6%),
the implicit benets of the information (9.3%), the ability to
prepare for the future (7.7%), the consideration of repro-
ductive options (6.5%), and the benets from psychosocial
support and counselling prior to results (6.0%). The other
3.2% considered that undertaking PST is a personal deci-
sion that depends on the psychological readiness and the
experience of each subject.
DISCUSSION
The data presented here reects the rst comprehen-
sive description of the Portuguese experience with a pro-
tocol for PST in LONDs, covering 20 years of experience
(1996 - 2015). This study adds to a previous body of re-
search conducted by researchers of the CGPP multidiscipli-
nary team.12,16-22 The results allowed the characterization of
the consultands who requested PST at the CGPP facilities
as well as some insights on how we could improve our prac-
tice.
The prole of the Portuguese consultands at risk for
LONDs is similar to that accounted in other international
reports.23-28 For example, motivations for taking a PST and
the higher rate of the test uptake in women (56%) are con-
sistent with the ndings from Cuba, the United Kingdom
and Brazil.23-28 This may be explained by the role typically
ascribed to women as gatekeepers in the management
of health-related issues in general and of genetic risks
in particular,30 and also by the fact that women are more
Table 2 - Social and demographic data of subjects who underwent pre-symptomatic testing (PST), 1996 - 2015 (showing valid percentage)
Disease
Gender
Age
Marital status
Consultands who
had offspring
Education Family history
Female Male Single Married Divorced Widow/er Illiterate-4th
year
5th - 9th
year
10th - 12th
year
Higher
education Maternal Paternal
FAP
(n = 1174)
635
(53.4%)
539
(46.6%) 28.8 577
(51.6%)
469
(45.2%)
21
(1.8%)
15
(1.4%)
362
(34.3%)
88
(9.2%)
430
(44.7%)
328
(34.1%)
115
(12.0%)
603
(55.8%)
477
(44.2%)
HD
(n = 230)
146
(64.3%)
84
(35.7%) 37.0 63
(29.7%)
131
(63.2%)
10
(5.4%)
4
(1.7%)
107
(53.8%)
25
(14.4%)
49
(28.1%)
64
(36.8%)
36
(20.7%)
89
(45.4%)
107
(54.6%)
MJD
(n = 55)
37
(72.9%)
18
(27.1%) 40.7 9
(15.0%)
30
(72.5%)
4
(2.5%)
4
(10.0%)
34
(72.3%)
11
(26.2%)
11
(26.2%)
11
(26.2%)
9
(21.4%)
25
(50.0%)
25
(50.0%)
Other LONDs*
(n = 39)
21
(51.7%)
18
(48.3%) 37.7 10
(20.7%)
28
(75.9%)
1
(3.4%)
0
(0%)
21
(53.8%)
4
(12.1%)
10
(30.3%)
6
(18.2%)
13
(39.4%)
21
(72.4%)
8
(27.6%)
Total 839
(56.0%)
659
(44.0%) 30.7 659
(47.9%)
658
(47.8%)
36
(2.6%)
23
(1.7%)
524
(39.1%)
128
(10.6%)
500
(41.3%)
409
(33.8%)
173
(14.3%)
738
(54.5%)
616
(45.5%)
* Other late-onset neurological diseases: SCA2, SCA7, CADASIL & DRPLA

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frequently driven by the concern of transmission to off-
spring.31 Reasons for uptake are also similar to those given
when PST rst became available.2,3,16
Particularly, individuals at-risk for FAP ATTR Val30Met
are the youngest and the largest group requesting PST at
our centre. This is largely explained by the earlier age-of-
onset of this disease, but also by the more recent therapeu-
tic alternatives available. Although, FAP ATTR Val30Met is
globally considered to be a rare disease, it has its historical
cluster along the northern coast of Portugal10,11 with a long-
standing national patients association that plays an impor-
tant role in the advocacy and information provision among
affected families.32 Furthermore, it may be expected that the
same higher adherence to PST will occur for other LONDs
after the introduction of new therapeutic options such as
the use of antisense oligonucleotides-based strategies that
might have a dramatic effect on the treatment of many neu-
rological conditions in the near future.33
Additionally, the predominance of non-carriers in the
studied sample is in accordance to what has been previ-
ously described in other PST programs.23-28 In fact, several
persons at risk wait until they are older to come forward for
PST, when their actual genetic risk is lower than the a priori
risk of 50%. Also, some consultands come at a 25% risk,
when their potentially transmitting parent died from other
causes.
This retrospective look at the protocol we have conduct-
ed for PST showed a lower rate of withdrawal before the
disclosure of results compared to other reports.23-28,34 On
the other hand, about 45% of the consultands have dropped
the protocol right after knowing the test results. At that time,
the proportion of drop-out cases was one carrier per three
non-carriers, while at one-year follow-up those who con-
cluded the protocol were mainly presymptomatic carriers,
perhaps due to the medical consultation for neurological
assessment/check-up that is appointed at the term of the
protocol. This suggests that the consultands value know-
ing their genetics status but after that, they may not need
any further clinical contacts. Several reasons might explain
this, such as: the lack of support from employers, fear of
breach of privacy and discrimination at work, stigmatisa-
tion issues,35 or transportation costs and geographical dis-
tance from the centre, the time lapse between consultations
and loss of work hours. Another important fact is that after
nishing the protocol many presymptomatic carriers often
begin to be followed at neurology departments outside the
CGPP clinical facilities.
It is an interesting fact that after the communication of
results withdrawals were considerably lower among carri-
ers (26.5%) since they may experience a greater need for
psychosocial support and have the greatest potential ben-
ets. Other reports have indicated this drop-out rate to be
as low as 5% over two years of follow-up, but up to 69%
over 10 years;34 and contrarily to our results, those with-
drawals were higher among carriers, described as having
higher scores for hopelessness, intrusion and avoidance.36
Again, this difference may be explained in our sample by
the fact that the majority of the consultands came from FAP
ATTR Val30Met families, where there are therapeutic inter-
ventions available, as opposed to most other LONDs.
We would like to comment particularly on the relevant
role played by family physicians in Primary Care Genet-
ics. The results of this study showed how consultands that
had learned about PST through healthcare professionals
tended to adhere more to PST consultations. This indicates
that providing information in advance to perform genetic
tests seems to inuence the decision-making process. The
tendency may also be justied by the fact that these are
well-established referral procedures followed by family phy-
sicians, which has contributed to a better management of
the disease and to health education within affected commu-
nities. The latter aspect is even more relevant considering
the prevalence of limited health literacy in the Portuguese
population.37
The potential for collaboration between primary health-
care professionals and specialists from Genetics depart-
ments has already been described.38 The current model
does not meet the needs of the current situation. Both
specialties should develop better coordination to face the
Genetics challenges and the possibilities of preventing and
managing many of the conditions in which genetics play a
key role.
Limitations of the study and implications for practice
Because our PST protocol was carried out by differ-
ent professionals along the years, models of practice and
procedures of documentation of consultands-reported ex-
perience were neither standardised nor uniformly recorded.
Therefore, perhaps the major limitation of this report lies in
the discrepancies found in the registration of the informa-
tion in the clinical les. This is a reminder of the relevance
of keeping digital records consistent and updated along
the protocol. The current data does not allow us to assess
a reliable uptake of our PST protocol. As there are more
centres conducting PST now, even in our region, it is not
possible to estimate the number of the at-risk population for
those genetic conditions in our country. Additionally, there
are regional differences in terms of prevalence of the con-
ditions, while the area covered by our centre is not clearly
dened and there are referrals frequently coming from other
regions.
Moreover, the specic clinical features of the different
LONDs inuenced the results, particularly in view of the
high predominance of consultands for FAP ATTR Val30Met.
Thus, the statistical data must be interpreted cautiously.
CONCLUSION
We believe the relevance of this retrospective study
lies in being the rst comprehensive view of PST in Portu-
gal. No other studies have been reported so far. We also
consider that two major contributions were made: the call
for the national harmonization of practice and discussion
of the genetic counselling guidelines for PST that are fol-
lowed in other Portuguese centres; and the demonstration

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Paneque M, et al. 20 years of pre-symptomatic testing in Portugal, Acta Med Port 2019 Apr;32(4):295-304
of the major role that family physicians can have in genetics
healthcare.
In particular, national genetic services would benet
from evidence based research on the practice of genetic
counselling. Namely, 1) how professional skills inuence
the process and potential outcomes of genetic counselling;
2) the efcacy of different genetic counselling interventions
and models; and 3) how recently developed tools for quality
assessment can be further used at a national level for the
improvement of practice.
ACKNOWLEDGEMENTS
The authors would like to thank all the consultands who
participated in the presymptomatic testing protocol at our
genetics centre. The authors are also indebted to all the
professionals involved in our multidisciplinary team since
the establishment of the national protocol, namely Marga-
rida Branco, Teresa Brito, Teresa Coelho, Paula Coutinho,
Manuela Fleming, Ângela Leite, Isabel Lereno, Alice Lopes,
Leal Loureiro, Mónica Marta, Jorge Pinto Basto, José Car-
los Rocha, Luísa Rolim, and Paula Valente.
The authors thank Milaydis Sosa for proofreading this
manuscript.
PROTECTION OF HUMAN AND ANIMAL SUBJECTS
The authors declare that the research procedures were
performed according to the regulations of the institution’s
ethics committee and the Code of Ethics of the World Medi-
cal Association (Declaration of Helsinki).
CONFIDENTIALITY OF DATA
The authors declare that they have followed the proto-
cols of their work centre regarding the publication of data
from patients.
CONFLICT OF INTEREST
The authors declare no conict of interests.
FUNDING
No nancial support was received by any author.
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