Genetic counselling for at-risk family members with hereditary transthyretin amyloidosis: data from a single-centre study

Abstract

Background

Hereditary transthyretin-related amyloidosis is an autosomal dominant disorder. Recently, disease-modifying therapies (DMTs) have been developed. For at-risk individuals, genetic analysis aids in the early administration of medical care; however, few studies have evaluated the current status of genetic counselling and management of presymptomatic carriers of amyloidogenic variants.

Methods

We retrospectively evaluated the medical records of 202 consecutive participants.

Results

A total of 103 clients who received genetic counselling for predictive testing were at-risk, and 83 underwent predictive testing. Genetic testing results were positive in 33 patients, 11 of whom had confirmed amyloid deposition and were administered DMTs. For presymptomatic V30M (p.V50M) carriers, 32.0 ± 2.4 years (median ± standard error) was the age when amyloid deposition was first identified (95% confidence interval 27.4–36.6). Serum transthyretin (TTR) levels decreased serially with an estimated slope of −1.2 mg/dL/year.

Conclusions

Our study suggests the clinical utility of management using a combination of predictive testing and monitoring methods. Psychosocial support should be considered with collaboration between geneticists/genetic counsellors and psychologists. For a more optimised protocol for monitoring and designing future interventional trials in presymptomatic carriers, prospective cohort studies are necessary to clarify the natural history, particularly in the early stages of the disease.

Keywords:

• ATTRv amyloidosis
• disease-modifying therapies
• genetic counselling
• predictive testing
• TTR

Acknowledgments

The authors thank Dr. H. Hanafusa, Dr. T. Sakashita, Dr. S. Nagai, and Dr. N. Ohnishi for useful discussions.

Disclosure statement

Katsuya Nakamura received speaker honoraria from Alnylam Pharmaceuticals and Pfizer. Yoshiki Sekijima received speaker honoraria from Alnylam Pharmaceuticals and Pfizer. Other authors declare no competing interests.

Additional information

Funding

This study was supported in part by the Program for Grants-in-Aid from the Research Committee on Ataxia, and a Health Labour Sciences Research Grant from the Ministry of Health, Labour and Welfare, Japan (grant number JPMH23FC1010), a Grant-in-Aid from the Takeda Japan Medical Office Funded Research Grant, and a Grant-in-Aid from Pfizer Independent Medical Education.