A multicentric study of the disease risks and first manifestations in hereditary transthyretin amyloidosis (ATTRv): insights for an earlier diagnosis

Abstract

Background

In hereditary transthyretin amyloidosis (ATTRv), early manifestation and age at onset (AO) may vary strikingly. We assessed the disease’risk (penetrance), AO and initial features in ATTRv families to gain insights on the early disease presentation.

Methods

Genealogical information, AO and first disease manifestations were collected in ATTRv families, from Sweden, Italy (Sicily), Spain (Mallorca), France, Turkey, Brazil. Penetrance was computed using a non-parametric survival method.

Results

We analysed 258 TTRV30M kindreds and 84 carrying six other variants (TTRT49A, F64L, S77Y, S77F, E89Q, I107V). In ATTRV30M families, the earliest disease risk was found at age 20 years in the Portuguese and Mallorcan families and at age 30-35 years, in the French and Swedish groups. The risks were higher in men and in carriers of maternal descent. In families carrying TTR-nonV30M variants, the earliest disease risk ranged from 30 y-o in TTRT49A to 55 y-o in TTRI107V families. Peripheral neuropathy symptoms were the most frequent initial manifestations. Among patients carrying TTRnonV30M variants, about 25% had an initial cardiac phenotype, one third a mixed phenotype.

Conclusion

Our work provided solid data on the risks and early features of ATTRv in a spectrum of families to enhance an early diagnosis and treatment.

Keywords:

• Genetics
• peripheral neuropathy
• amyloid polyneuropathy
• transthyretin
• penetrance

Author contributions

VPB study design, study supervision, acquisition of data, statistical analysis, interpretation of data, drafting and revising the manuscript.

FG acquisition of data, statistical analysis, interpretation of data, drafting and revising the manuscript.

MO, IA, AM, LG, ECB, JGM, IL, MWC, LFP, YP, PF: acquisition and interpretation of data, drafting and revising the manuscript.

FA and GN statistical models and analysis, interpretation of data, drafting and revising the manuscript.

Ethics approval

The study was approved by the local ethics committees at each site: IRB00011558: no. 2019-028 (France), Dnr 2013-247-31 M (Sweden), IB 3858/19 PI (Mallorca-Spain), nr. 3/2016 (Sicily-Italy), no. 2017/929 (Turkey), CONEP no. 12294 (Brazil).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability

Anonymized data will be shared by request from any qualified investigator.

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.