Recommendations for pre-symptomatic genetic testing for hereditary transthyretin amyloidosis in the era of effective therapy: a multicenter Italian consensus

Marina Grandis ,Luca Pradotto ,Silvia Fenu ,Stefano Tozza ,Cesare Danesino ,Francesco Cappelli ,Loredana Melchiorri ,Lucia Trevisan ,Paola Rimessi ,Chiara Gemelli ,Marco Luigetti ,Anna Mazzeo ,Davide Pareyson ,Giovanna Ferrandes ,Federico Perfetto ,Francesco Benedicenti ,Giulia Bisogni ,Marco Canepa ,Laura Obici ,Giacomo Tini ,Fiore Manganelli ,Gian Maria Fabrizi ,Chiara Briani ,Paola Mandich

doi:10.1186/s13023-020-01633-z

Abstract

Hereditary transthyretin amyloidosis (ATTRv, v for variant) is a late-onset, autosomal dominant disease caused by progressive extracellular deposition of transthyretin amyloid fibrils, leading to organ damage and death. For other late-onset fatal diseases, as Huntington’s disease, protocols for pre-symptomatic genetic testing (PST) are available since decades. For ATTRv, limited experience has been reported to date, mostly gathered before the availability of approved therapies. We aimed at developing recommendations for a safe and feasible PST protocol in ATTRv in the era of emerging treatments, taking also into account Italian patients’ characteristics and healthcare system rules. After an initial survey on ongoing approaches to PST for ATTRv in Italy, two roundtable meetings were attended by 24 experts from 16 Italian centers involved in the diagnosis and care of this disease. Minimal requirements for PST offer and potential critical issues were highlighted. By November 2019, 457 families affected by ATTRv with 209 molecularly confirmed pre-symptomatic carriers were counted. The median age at PST was 41.3 years of age, regardless of the specific mutation. Half of the Italian centers had a multidisciplinary team, including a neurologist, an internist, a cardiologist, a medical geneticist and a psychologist, although in most cases not all the specialists were available in the same center. A variable number of visits was performed at each site. Experts agreed that PST should be offered only in the context of genetic counselling to at risk individuals aged 18 or older. Advertised commercial options for DNA testing should be avoided. The protocol should consist of several steps, including a preliminary clinical examination, a pre-test information session, an interval time, the genetic test and a post-test session with the disclosure of the test results, in the context of an experienced multidisciplinary team. Recommendations for best timing were also defined. Protocols for PST in the context of ATTRv can be refined to offer at risk individuals the best chance for early diagnosis and timely treatment start, while respecting autonomous decisions and promoting safe psychological adjustment to the genetic result.

Highlights

Hereditary transthyretin amyloidosis (ATTRv) is an autosomal dominant, late-onset disease caused by the extracellular deposition of amyloid fibrils formed by misfolded transthyretin mutants [1, 2]
Since all therapies are maximally effective in the early stages, the need to preserve at risk individuals from the psychological consequences of a positive test should be balanced against the possibility to offer them a close monitoring [16], prompting treatment start as soon as minor, but clinically meaningful disease signs, are detected
We address the medical, psychological, ethical, and legal issues related to pre-symptomatic genetic testing (PST) for ATTRv and provide recommendations for optimal timing and setting to offer it

Summary

Introduction

Hereditary transthyretin amyloidosis (ATTRv) is an autosomal dominant, late-onset disease caused by the extracellular deposition of amyloid fibrils formed by misfolded transthyretin mutants [1, 2]. Based on this know-how and on their personal experience, a few years ago, experts of the European Network for TTR-FAP (familial amyloid polyneuropathy) proposed recommendations for pre-symptomatic genetic testing and managements of individuals at risk for ATTRv [15].

Results

Conclusion