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.