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

• Published in: Amyloid p. 1
• Main Authors: Wang, Qingping, Wang, Mengdie, Zhu, Xiying, Liu, Lei, Wang, Mengli, Sun, Jialu, Li, Xiaobo, Huang, Shunxiang, Cao, Wanqian, Liu, Yu, Zhang, Ruxu
• Format: Journal Article
• Language: English
• Published: England 31.07.2024
• Subjects: A97S-TTR; A97S variant; hereditary transthyretin amyloid polyneuropathy; therapeutic efficacy; in vitro stability
• ISSN: 1744-2818
• DOI: 10.1080/13506129.2024.2383467

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. 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 urea-mediated tryptophan fluorescence experiments, and nephelometry was employed in drug response assessment. 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. 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%. 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.