Work

The phenotypic landscape of p.Ala117Ser transthyretin amyloidosis: distinct clinical profiles and outcomes versus wild-type ATTR

Year: 2025

Type: article

Abstract: BACKGROUND: This study aimed to (1) compare the clinical phenotype and outcomes of patients with transthyretin amyloidosis (ATTR) harboring the p.Ala117Ser variant versus those with wild-type ATTR (wtATTR), and (2) delineate the clinical spectrum of ATTR at our institution. METHODS: We conducted a single-center observational study of 43 consecutive symptomatic ATTR patients and 7 asymptomatic carriers of pathogenic ATTR variants. All underwent structured evaluation in the cardiomyopathy (CM) clinic. The primary endpoint was a composite of all-cause mortality or heart/heart-liver transplantation. RESULTS: Among the 50 patients enrolled with ATTR, hereditary ATTR (hATTR) accounted for 53%. Within the hATTR group, the p.Ala117Ser variant was the most frequently identified pathogenic variant, representing 40% of cases. Of the 43 symptomatic patients, 41 (95%) were diagnosed with ATTR-CM. Symptomatic p.Ala117Ser patients were younger, had universal neuropathy, and exhibited less advanced cardiac involvement compared with wtATTR. Three-year event-free survival was higher in p.Ala117Ser patients, remaining significant after excluding asymptomatic carriers (log-rank p = 0.006). Univariate predictors of adverse outcomes included wtATTR, prior heart failure hospitalization, elevated NT-proBNP, older age, increased wall thickness, and higher NYHA class. Multivariate analysis identified p.Ala117Ser variant as independently associated with improved outcomes (HR 0.23, 95% CI 0.06-0.95). CONCLUSIONS: The p.Ala117Ser variant emerged as the most common hATTR in our cohort. Symptomatic carriers were younger, had universal neuropathy (100%), had less advanced cardiac disease, and demonstrated superior survival and transplant-free outcomes compared with wtATTR. These findings highlight the value of genotype-guided evaluation and the potential for precision therapies tailored to regional TTR variants. TRIAL REGISTRATION: Clinical Trial Number: Not Applicable.

Source: BMC Cardiovascular Disorders

DOI: 10.1186/s12872-025-05313-3