Do Patients with Homozygosity and Compound Heterozygosity for Variants in the Transthyretin Amyloidosis TTR Gene Have More Severe and Earlier Clinical Conditions?

Silva, Tonnison de Oliveira; Nascimento, Samuel Ulisses Chaves Nogueira do

Arq Bras Cardiol: Imagem cardiovasc. 2025; 38(2): e20250027

Editorial

Do Patients with Homozygosity and Compound Heterozygosity for Variants in the Transthyretin Amyloidosis TTR Gene Have More Severe and Earlier Clinical Conditions?

Tonnison de Oliveira

Silva

, Samuel Ulisses Chaves Nogueira do

Nascimento

DOI: 10.36660/abcimg.20250027i

The prevalence of homozygotes for the Val142Ile genetic variant in the transthyretin (TTR) gene is extremely low in the general population (0.72%). This prevalence is slightly higher in endomyocardial biopsy studies (6% to 10%) and in cohorts involving reference centers for TTR cardiac amyloidosis (4% to 14%).^,

Homozygotes represent a distinct subpopulation within the spectrum of cardiac amyloidosis, with clinical characteristics that appear to differ substantially from those of heterozygotes. This genetic variation has been associated with an onset of clinical manifestations in younger patients compared with heterozygotes and also with a higher risk of serious cardiovascular events, such as heart failure and ventricular arrhythmias.³ Besides the earlier onset, observational studies indicate that the disease has a more aggressive phenotypic behavior in homozygous patients, characterized by greater ventricular thickening, worse diastolic function, and a higher load of amyloid fibrils in the heart.³ Thus, homozygotes usually have a higher risk of developing early and more severe heart failure than heterozygotes.^–