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Figure 1. Factors influencing phenotypic expression in ATTRv.

GENOTYPE-PHENOTYPE CORRELATION
Phenotypic expression is mostly influenced by the causative TTR gene mutation. However, even in the
presence of the same mutation, clinical manifestations may differ among individuals due to other
determinants, e.g., age, gender, fibril composition, geographical location, environmental factors, and
modulator genes [3,13] [Figure 1].

Taking into account the type of TTR gene mutation, ATTR can be divided into four main groups: Val30Met
early onset (neurological), Val30Met late onset (neurological/mixed), non-Val30Met mixed phenotype, and
non-Val30Met cardiac phenotype. Five main mutations are associated with an exclusive or predominant
[3]
cardiac phenotype: Val122Ile, Thr60Ala, Val30Met (late-onset), Ile68Leu, and Leu111Met .
Most TTR mutations are linked to a specific geographical location, and each mutation presents a distinct
phenotype, as described in [Table 1] [14-29] . In a unique manner, the Italian scenario is characterized by high
genotypic heterogeneity: 26 different mutations can be identified, and the most frequent are Val30Met,
followed by Glu89Gln, Ile68Leu, and Phe64Leu .
[10]
Val30Met is probably the most common TTR mutation worldwide, particularly in Portugal, where it has an
estimated prevalence of 0.09%, reaching 73.3% of detected mutations in the THAOS registry .It has
[15]
variable disease manifestations and penetrance depending on geographic location [3,14-17] . The prominent
features of Portuguese and Japanese endemic Val30Met ATTR are sensorimotor polyneuropathy and
autonomic neuropathy, with early onset (third to fourth decade of life); cardiomyopathy is rare, while
conduction disturbances are relatively frequent [15-18] . The clinical profile of Swedish endemic Val30Met
ATTR is characterized by a slower disease progression with higher age of onset of disease (fifth to sixth
decade of life) and lower penetrance [15-18] . Non-endemic Val30Met ATTR has a lower age-related penetrance
with more frequent cardiomyopathy and milder autonomic dysfunction than endemic ones [15-18] .