Genetic and Clinical Spectrum of Hereditary Transthyretin Amyloidosis in Brazil

Transthyretin hereditary amyloidosis (ATTRv) clinical variability has been widely reported, not only across countries and variants but also among families and distinct regions within a single nation. One of the principal challenges in disease management is the accurate determination of age of onset (AOO), which is heterogeneous and has therapeutic implications given the availability of disease-modifying treatments.

This study characterizes the genetic landscape and clinical onset spectrum of ATTRv in an admixed Brazilian cohort of 175 patients.

Seven TTR pathogenic variants (p.Val50Met, p.Val142Ile, p.Ile127Val, p.Ile88Leu, p.Ala39Asp, p.Phe84Leu, p.Tyr98Phe) were identified. The most common was p.Val50Met (58.8%), followed by p.Val142Ile (29.7%) and p.Ile127Val (7.4%). Notably, 44% of V122I had a neurological onset. Close clinical monitoring of presymptomatic carriers reduced age at diagnosis by 10.5 years. The median AOO was 50 years, with V30M patients presenting earlier (38.5 years) than V122I (p.Val142Ile) (60y) and I107V (p.Ile127Val) (60 years). Familial cases showed a 20.5-year earlier AOO than sporadic cases. In Brazil, late-onset (> 50 years) V30M is more common than previously reported (37.5%); ethnicity can influence AOO within the same variant, and for the first time, we show a distinct geographic pattern: early-onset V30M is more frequent in São Paulo/South, whereas late-onset V30M predominates in the central region.

This study emphasizes the heterogeneity of ATTRv presentation in admixed populations and underscores the need for expanded screening and multicenter studies to refine genotype-phenotypic correlations.