Hereditary Transthyretin-Related Amyloidosis Ongoing Observational Study: A Baseline Report of the First 3167 Participants

Sabine Rösner; Luba M Pardo; Aida M Bertoli-Avella; Volha Skrahina; Pierre Engel; Sabine Schröder; Susan Zielske; Valerie Bonke; Janett Kreth; Gina Westphal; Felix Reder; Snezana Skobalj; Susanne Zielke; Xenia Bogdanovic; Paula Grieger; Jörg Rennecke; Thomas Skripuletz; Monica Patten; Birgit Aßmus; Katrin Hahn; Arndt Rolfs; Peter Bauer; TRAM study

doi:10.3390/jcm13206197

Hereditary Transthyretin-Related Amyloidosis Ongoing Observational Study: A Baseline Report of the First 3167 Participants

J Clin Med. 2024 Oct 17;13(20):6197. doi: 10.3390/jcm13206197.

Authors

Sabine Rösner¹, Luba M Pardo¹, Aida M Bertoli-Avella¹, Volha Skrahina¹, Pierre Engel¹, Sabine Schröder¹, Susan Zielske¹, Valerie Bonke¹, Janett Kreth¹, Gina Westphal¹, Felix Reder¹, Snezana Skobalj¹, Susanne Zielke¹, Xenia Bogdanovic¹, Paula Grieger¹, Jörg Rennecke¹, Thomas Skripuletz^{2

3}, Monica Patten⁴, Birgit Aßmus⁵, Katrin Hahn^{6

7}, Arndt Rolfs^{1

8}, Peter Bauer^{1

9}; TRAM study

Affiliations

¹ CENTOGENE GmbH, 18055 Rostock, Germany.
² Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.
³ Amyloidosis Center of Lower Saxony, Hannover Medical School, 30625 Hannover, Germany.
⁴ Department of Cardiology, University Heart and Vascular Center, 20148 Hamburg, Germany.
⁵ Department of Cardiology and Angiology, University Hospital Giessen and Marburg, 35043 Marburg, Germany.
⁶ Department of Neurology, Charitè-Universitätsmedizin, Amyloidosis Center Charité, 10117 Berlin, Germany.
⁷ Amyloidosis Center Charité Berlin (ACCB), Charité Universitätsmedizin, 10117 Berlin, Germany.
⁸ RCV GmbH, Institute for Rare Disease Diagnostics, 10629 Berlin, Germany.
⁹ Medical Faculty, University Rostock, 18057 Rostock, Germany.

Abstract

Background: Hereditary transthyretin-related amyloidosis is a clinically heterogeneous autosomal dominant disease caused by pathogenic variants in the TTR gene (hATTR amyloidosis). Objective: The current study describes the demographic, clinical, and genetic characteristics of patients with suspected hATTR amyloidosis. Methods: This study is part of the "Hereditary transthyretin-related amyloidosis and longitudinal monitoring of TTR-positive patients" (TRAMmoniTTR) study. This study included 3167 participants, along with their clinical details. Principal component (PC) analysis was used to analyze their clinical symptomatology. Next-generation sequencing of the TTR gene was performed and genotype-phenotype relationships were investigated. We compared the demographic and clinical characteristics using the principal components (PCs) and also compared participants with and without the TTR pathogenic variants. Results: We identified five main clinical phenotypes out of 22 single symptoms that explained 49% of the variation. The first two PCs referred to polyneuropathy and cardiomyopathy. We found significant differences between gender and PC-polyneuropathy and PC-cardiomyopathy, with male over-representation in the higher quantiles of PC-polyneuropathy and male under-representation in the lowest quantiles of PC-cardiomyopathy. We identified 92 participants with hATTR (3%), exhibiting 17 unique heterozygous TTR variants. The p.Val50Met variant was the most frequent. Furthermore, 503 participants (20%) were identified with ATTR and no relevant TTR variants (ATTRwt). We detected significant differences between the ATTRwt and hATTR groups, with male gender predominance in only the ATTRwt group and a positive family history of polyneuropathy and/or cardiomyopathy among the hATTR participants. Conclusions: The current clinical and genetic characterization of this cohort serves as a foundation for further longitudinal monitoring and assessment.

Keywords: Hereditary Transthyretin-Related Amyloidosis; TTR; hATTR amyloidosis.

Grants and funding

The study was funded by Alnylam Pharmaceuticals Inc., Cambridge, MA, USA. The funders of this study had no role in the study design, data analysis, data interpretation, or writing of the manuscript.