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Scirpa et al. Vessel Plus 2022;6:52 https://dx.doi.org/10.20517/2574-1209.2021.74 Page 7 of 11

genetic testing may be associated with the difficulty of accepting the results and their impact on professional
[50]
life, family, and relationships . Mutation carriers need to be aware of this, especially when the penetrance
[51]
of the familial TTR mutation is low, as in Val30Met late-onset or non-Val30Met cardiac phenotype .
A recent study highlighted the psychological consequences of the disease on both patients and at-risk
[52]
relatives, since they may often feel depressed (60%) or worry about the future (75%-80%), as well as guilty of
a possibility to pass the disease to offspring (40%-60%). Pre-symptomatic genetic testing can lead to anxiety,
depression, avoidance of the disease, and psychological distress, even in the case of a negative result
[53]
(“survivor guilt”), especially in women . Therefore, psychological support has to be offered to the index
patient and relatives, both to mutation carriers and those who did not undergo genetic testing or received a
negative result [46,53] .

Besides the strong psychological impact, being an asymptomatic gene carrier does not have consequences
on daily life since there are no specific restrictions or particular recommendations regarding leisure and
competitive sports or work activity. They should conduct themselves as other healthy people, except for
regular neurological and cardiological examinations, as outlined below.

MANAGEMENT OF GENOTYPE-POSITIVE, PHENOTYPE-NEGATIVE INDIVIDUALS
Since the new therapies are maximally effective in the early stages of the disease, there is a growing
agreement about the need for close monitoring of genotype-positive, phenotype-negative individuals to
assure a prompt treatment when minor disease signs are detected [44-46,48,54] . Recently, to determine when
this monitoring should start, it has been proposed to estimate the predicted age of disease onset (PADO),
which depends on the typical age of onset for the specific TTR gene mutation, the age of onset in other
[54]
members of the proband’s family, and the sex of the parent who carries the mutated gene . Expert
consensus has recommended starting monitoring pre-symptomatic individuals 10 years before PADO [54,55] .
Annual monitoring is the standard, but the frequency of screening visits can increase getting closer to the
PADO, especially for genotypes associated with more rapid disease progression. Abnormal findings or
symptoms could lead to a shorter follow-up to define their clinical significance [54,55] . Educating pre-
symptomatic carriers to recognize early disease-related symptoms is of paramount importance.

Screening visits consist of neurological and cardiological evaluations. The tests carried out during the
follow-up should be targeted at the expected phenotype for the specific mutation . As regards the
[55]
cardiological evaluation, 12-lead electrocardiogram (ECG), complete echocardiographic examination, and
cardiac biomarkers measurement (troponin and natriuretic peptides) should be performed every year . In
[7]
[7]
addition, 24 hECG monitoring may be useful to be completed every two years . CMR imaging and
scintigraphy with bone tracers should be carried out every three years or if any of the above complementary
[7]
tests is abnormal .
Bone scintigraphy is useful in the early identification of cardiac ATTR, even before wall thickness increases
or electrocardiographic voltages reduction is observed [56,57] . Biopsies, derived from non-specific sites or
clinically affected organs, are not routinely recommended due to their low sensitivity in the early stages so
that a negative result does not permit ruling out the disease.

The neurological evaluation consists of searching for autonomic dysfunction and peripheral neuropathy .
[57]
Autonomic dysfunction may be investigated, looking for symptoms such as orthostatic hypotension,
gastrointestinal disturbance, genitourinary signs, and erectile dysfunction, with the compound autonomic
dysfunction test. Peripheral neuropathy should be searched with clinical scales such as neuropathy