Clinical and molecular insights into A97S variants in hereditary transthyretin amyloid polyneuropathy in South China

Abstract

Objective

This study aims to delineate the clinical profiles of the hereditary transthyretin amyloid polyneuropathy (ATTRv-PN) patients with A97S variant from southern China and the molecular characteristics of this mutant protein.

Methods

Fifteen ATTRv-PN patients with heterozygous A97S and one patient with homozygous A97S were included in the study. Serum TTR tetramer concentration was quantified through ultra-performance liquid chromatography. Stabilities of A97S-TTR were assessed through in vitro urea-mediated tryptophan fluorescence experiments, and nephelometry was employed in drug response assessment.

Results

All patients were late-onset (≥50 years) with a mean age of onset at 59.26 ± 5.06 years old. Patients displayed a mixed phenotype featuring sensory-motor neuropathy with autonomic dysfunction and cardiac involvement, such as palpitations and chest pain. Electrophysiological studies showed generally axonal impairment of sensory and motor nerves. Tafamidis-treated patients showed significantly higher TTR tetramer concentrations, approaching healthy controls’ levels. In vitro assessment showed that A97S-TTR was more kinetically stable than the V122I-TTR, and tetramer stabilisers inhibited A97S-TTR amyloid formation by more than 70%.

Conclusion

This study provides valuable insights into the clinical and molecular characteristics of ATTRv-PN patients with A97S from South China, particularly regarding the differences in disease progression and stability features.

Keywords:

• A97S-TTR
• A97S variant
• hereditary transthyretin amyloid polyneuropathy
• in vitro stability
• therapeutic efficacy

Acknowledgments

We appreciated the cooperation of the patients and their families.

Ethical approval

This study was undertaken in accordance with the guidelines of the Declaration of Helsinki and was approved by the ethics committee of the Third Xiangya Hospital of Central South University (NO. quick 22472).

Disclosure statement

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

Additional information

Funding

The work was funded by the National Natural Science Foundation of China (82171172, 81771366, 22222410, and 22374148), the China International Medical Foundation (CIMF-Z-2016-20-1801), the Hunan Provincial Natural Science Foundation (2022JJ30910), Dalian Science Foundation for Distinguished Young Scholars (2022RJ04), and Dalian Science and Technology Innovation Foundation (2023JJ12WZ037).