Characterization and natural history of phenotypes in hereditary transthyretin amyloidosis
Authors: Saturi G , Sguazzotti M , Caponetti A G , Ponziani A , Accietto A , Giovannetti A , Ruotolo I , Massa P , Laurenzano F , Cecchieri F , Gagliardi C , Biagini E , Guaraldi P , Galie N , Longhi S 
Published: November 2023

Abstract

Background
Hereditary systemic amyloidosis (ATTRv), caused by mutations in the transthyretin (TTR) gene, is a rare systemic disease with autosomal dominant transmission, incomplete penetrance, and variable expressivity.

Purpose
The purpose of this study was to describe the population of individuals with pathogenic mutations for TTR, comparing the genotype and clinical-instrumental characteristics of patients based on phenotype. Subsequently, the disease course was investigated in terms of the onset of new clinical manifestations, survival, and hospitalizations for heart failure.

Methods
Clinical and instrumental data from 325 consecutive patients carrying a pathogenic mutation of the TTR gene (asymptomatic carriers, n=106; cardiac phenotype, n=49; neurological phenotype, n=49; mixed phenotype, n=121) were analyzed at Our Center between 1979 and August 2022.

Results
A total of 23 different mutations were found, with Ile68Leu (41.8%), Val30Met (19%), and Glu89Gln (10%) being the most represented. Dominant mutations were found in patients with cardiac and neurological phenotypes, respectively Ile68Leu and Val30Met, while patients with mixed phenotype had marked genotypic variability. Patients with cardiac amyloidosis (CA) were predominantly male and had a more advanced NYHA functional class at presentation, while subjects with neurological involvement showed greater motor disabilities. There was also a significant difference in the age of disease diagnosis between the three groups: cardiac phenotype 73.2 years (IQR 66.5 – 78.1), mixed phenotype 58.4 years (IQR 47- 66.3), neurological phenotype 44 years (IQR 33.5 – 62.9).
At the end of a median follow-up of 51 months (IQR 24 – 90 months), data from 290 subjects were analyzed, of whom 111 (38.3%) died and 123 (42.4%) had a major clinical event, including death or hospitalization for heart failure. Subjects without signs of disease had a prognosis similar to that of the healthy population, while patients with CA, with or without neurological manifestations, had a worse overall and event-free survival compared to those with isolated neurological phenotype.
On multivariate analysis, age at diagnosis, NYHA functional class, and an mPND score ³ 2 were independently associated with adverse clinical events.

Conclusions
This study confirms the important clinical heterogeneity of patients with ATTRv, where three main phenotypes can be identified, characterized by specific clinical, demographic, and instrumental features. Although in some cases it is possible to identify a genotype-phenotype correlation, the extreme variability of clinical presentation is evident even among patients sharing the same mutation. In the study cohort, patients with CA had a worse prognosis. However, this finding should be interpreted with caution because it is influenced by disease-modifying therapy, which was performed unevenly among the three phenotypes.Univariate and multivariateKaplan-Meier curves