Clinical and genetic profile of patients enrolled in the Transthyretin Amyloidosis Outcomes Survey (THAOS): 14-year update

Abstract

Background: Transthyretin amyloidosis (ATTR amyloidosis) is a rare, life-threatening disease caused by the accumulation of variant or wild-type (ATTRwt amyloidosis) transthyretin amyloid fibrils in the heart, peripheral nerves, and other tissues and organs.

Methods: Established in 2007, the Transthyretin Amyloidosis Outcomes Survey (THAOS) is the largest ongoing, global, longitudinal observational study of patients with ATTR amyloidosis, including both inherited and wild-type disease, and asymptomatic carriers of pathogenic TTR mutations. This descriptive analysis examines baseline characteristics of symptomatic patients and asymptomatic gene carriers enrolled in THAOS since its inception in 2007 (data cutoff: August 1, 2021).

Results: This analysis included 3779 symptomatic patients and 1830 asymptomatic gene carriers. Symptomatic patients were predominantly male (71.4%) and had a mean (standard deviation [SD]) age of symptom onset of 56.3 (17.8) years. Val30Met was the most common genotype in symptomatic patients in South America (80.9%), Europe (55.4%), and Asia (50.5%), and more patients had early- versus late-onset disease in these regions. The majority of symptomatic patients in North America (58.8%) had ATTRwt amyloidosis. The overall distribution of phenotypes in symptomatic patients was predominantly cardiac (40.7%), predominantly neurologic (40.1%), mixed (16.6%), and no phenotype (2.5%). In asymptomatic gene carriers, mean (SD) age at enrollment was 42.4 (15.7) years, 42.4% were male, and 73.2% carried the Val30Met mutation.

Conclusions: This 14-year global overview of THAOS in over 5000 patients represents the largest analysis of ATTR amyloidosis to date and highlights the genotypic and phenotypic heterogeneity of the disease.

Clinicaltrials: gov Identifier: NCT00628745.

Keywords: Amyloidosis; Cardiomyopathy; Polyneuropathy; Registry; Transthyretin.

Conflict of interest statement

AD reports research grants from Celgene, Millennium, Pfizer, Janssen, and Alnylam; and has received funding from Pfizer for meeting expenses (travel) and attended advisory boards for Akcea and Intellia. TC reports serving as a medical advisor for Pfizer and receiving funding for scientific meeting expenses (travel, accommodation, and registration) from Pfizer. IC reports consulting fees and funding for scientific meeting expenses (travel, accommodation, and registration) from Pfizer. MW-C reports research funding, consulting fees, and travel support for advisory boards and meetings from FoldRx Pharmaceuticals and Pfizer. JW reports consulting fees and travel support for lectures and advisory boards from Pfizer and Alnylam, and consulting fees from Akcea. AVK reports reimbursement for study visits from Pfizer during the conduct of the study. CR reports research grants from Pfizer and consultancy fees from Pfizer, Alnylam, and Prothena. VP-B reports serving as a medical advisor for Pfizer, Alnylam, Eidos, and Ionis. JG-M reports speaker fees from Pfizer, Alnylam, and Akcea. MSM reports grants from Pfizer during the conduct of the study; grants and personal fees from Pfizer, Eidos, Prothena, and Ionis; grants from Alnylam; and personal fees from GSK and Akcea outside the submitted work. MG reports grants and advisory board and consultancy fees paid to her institution from Alnylam, Eidos, Prothena, and Pfizer. DC and LA are full-time employees of Pfizer and hold stock and/or stock options with Pfizer.

© 2022. The Author(s).

Figures

Fig. 1

Geographic distribution of all patients enrolled in the Transthyretin Amyloidosis Outcomes Survey (THAOS)

Fig. 2

Regional distribution of genotype subgroups in symptomatic patients. The proportion of patients with each genotype shown by region in a the overall population of symptomatic patients and in patients with b predominantly cardiac, c predominantly neurologic, and d mixed phenotypes. The sum of values for each region in each figure equals one. Val30Met early onset and late onset n based on all patients with available data for disease diagnosis; 128 patients with the Val30Met mutation and no date of diagnosis were not included. Genotype categories of patients with no phenotype can be found in Additional file 2. Cardiac mutations include Val122Ile, Leu111Met, Thr60Ala, and Ile68Leu. ATTRwt amyloidosis = wild-type transthyretin amyloidosis

Fig. 3

Regional distribution of phenotype at enrollment in symptomatic patients. The proportion of patients with each phenotype shown by region in a the overall population of symptomatic patients and by genotype category, b ATTRwt amyloidosis, c Val30Met early onset, d Val30Met late onset, e cardiac mutations, and f non-Val30Met excluding cardiac mutations. The sum of values for each region in each figure equals one. Val30Met early onset and late onset n based on all patients with available data for disease diagnosis; 128 patients with the Val30Met mutation and no date of disease diagnosis were not included in the genotype category breakdown. Cardiac mutations include Val122Ile, Leu111Met, Thr60Ala, and Ile68Leu. ATTRwt amyloidosis = wild-type transthyretin amyloidosis

Fig. 4

Distribution of phenotype at enrollment in symptomatic patients according to genotype category. The proportions of patients with each phenotype are shown by genotype. The sum of values for each genotype equals one. Val30Met early onset and late onset n based on all patients with available data for disease diagnosis; 128 patients with the Val30Met mutation and no date of diagnosis were not included. Cardiac mutations include Val122Ile, Leu111Met, Thr60Ala, and Ile68Leu. ATTRwt amyloidosis = wild-type transthyretin amyloidosis

Fig. 5

Symptom categories at enrollment in symptomatic patients according to genotype category.Val30Met early onset and late onset n based on all patients with available data for disease diagnosis; 128 patients with Val30Met and no date of disease diagnosis were not included. ATTRwt amyloidosis = wild-type transthyretin amyloidosis