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Scirpa et al. Vessel Plus 2022;6:52 https://dx.doi.org/10.20517/2574-1209.2021.74 Page 5 of 11

In some Italian regions, mainly Emilia-Romagna and Tuscany, the Ile68Leu TTR mutation is endemic,
being responsible for the majority of cases with predominant cardiac involvement in this area, and it shares
with Val122Ile advanced age at presentation, high prevalence of carpal tunnel syndrome (about 40% of
patients affected), and a homogeneous echocardiographic profile with symmetric hypertrophy and a normal
or near-normal left ventricle ejection fraction [19,20] , resembling ATTRwt. Therefore, it is essential to perform
genetic testing in all patients presenting with a phenotype consistent with ATTR cardiac amyloidosis, as
outlined below.

Fibril composition can deeply influence the clinical presentation; indeed, in Val30Met ATTR, full-length
TTR (Type B fibrils) is associated with earlier-onset disease with minor cardiac involvement, while
fragmented TTR (Type A fibrils) is associated with later-onset disease with preeminent cardiac
[4]
[30]
involvement . Among Val30Met patients , it was noted that fibril composition was quite consistent
between families suggesting that genetic, epigenetic, and environmental factors, all still unknown, may have
a role in amyloid fibril composition. The fibril composition-clinical presentation correlation is still under
evaluation; what has been described thus far is that patients with Type A fibrils after liver transplantation
[31]
present heart failure worsening in contrast to patients with Type B fibrils and that the majority of patients
with Type A and no patient with Type B fibrils have myocardial uptake at bone scintigraphy . The
[32]
importance of amyloid fibril composition needs to be further largely evaluated to determine if it has
prognostic and diagnostic implications.

Sex seems to have a protective role in ATTRv; data from the THAOS registry show that women who carry a
pathogenic mutation, compared to men, less commonly have cardiac involvement (28% vs. 72%) with less
severe manifestation . Furthermore, the male prevalence was notably lower overall in asymptomatic
[33]
carriers, suggesting a lower genetic penetrance in women compared with men . In the Val122Ile mutation,
[33]
there is also a sex-related genotype-phenotype expression correlation. Indeed, female Val122Ile patients
present predominantly with polyneuropathy phenotype, while males have predominantly cardiovascular or
mixed phenotype , and, among Val122Ile patients with cardiac involvement, females are significantly older
[16]
at diagnosis compared to males (76 years vs. 69 years) even if they have similar cardiac chamber function
[34]
and rate of mortality, suggesting a slower progression of disease in women . All these differences are likely
related to the interaction of epigenetic mechanisms and sex-related protective hormones, given that those
women with higher degrees of myocardial involvement are more likely to be post-menopausal .
[35]
In addition, it has been reported that the age of onset in male offspring is earlier when the disease is
inherited from the mother, leading to a higher penetrance [16,17] . This anticipation of disease onset may be
caused by parental imprinting phenomenon, or it has been hypothesized to be a consequence of the
interaction of the mitochondrial genome with the expression of the TTR gene .
[36]

Genetic variants located in the non-coding regions of the TTR gene can modulate the clinical phenotype
[37]
influencing gene expression. Iorio et al. demonstrated that specific expression patterns are related to
particular phenotypic presentations, thus suggesting a key role of the differential TTR gene expression
profiles across different tissues in determining the phenotype. In the same way, variants in the regulatory
regions of the TTR gene may account for the large variability of the age of onset, as described for Val30Met
patients [38,39] .

When to perform the genetic test?
Genetic testing typically should be reserved for patients with a confirmed or suspected diagnosis of
inherited disease and for asymptomatic at-risk family members . Molecular confirmation of a diagnosis
[40]