A natural history analysis of asymptomatic gene carriers as they develop symptomatic transthyretin amyloidosis in the Transthyretin Amyloidosis Outcomes Survey (THAOS).

Background: Hereditary transthyretin amyloidosis (ATTRv amyloidosis) results from pathogenic mutations in the transthyretin () gene. This analysis aimed to better understand ATTRv amyloidosis development in asymptomatic gene carriers.

Methods: The Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing, global, longitudinal, observational survey of patients with transthyretin amyloidosis, including both inherited and wild-type disease, and asymptomatic gene carriers. Asymptomatic gene carriers were assessed longitudinally to identify those who developed ATTRv amyloidosis after enrolment in THAOS (data cut-off: 1 August 2021).

Results: Of 740 asymptomatic gene carriers, 268 (36.2%) (Val30Met, 212/613 [34.6%]; non-Val30Met, 48/111 [43.2%]) developed ATTRv amyloidosis within a median 2.2 years after enrolment. The most common first symptoms were sensory (49.5%) and autonomic (37.3%) neuropathy in Val30Met patients, and sensory neuropathy (45.8%) and cardiac disorder (22.9%) in non-Val30Met patients. Most patients first presented with a predominantly neurologic phenotype (Val30Met, 77.8%; non-Val30Met, 70.8%).

Conclusions: More than one-third of asymptomatic gene carriers in THAOS developed ATTRv amyloidosis within a median 2 years of enrolment. Val30Met versus non-Val30Met patients had a lower transition rate. Given the importance of early treatment, these findings underscore the need for identification and careful monitoring of at-risk gene carriers to enable prompt treatment.

Trial Registration: ClinicalTrials.gov: NCT00628745.