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Background <p>This study aimed to (1) compare the clinical phenotype and outcomes of patients with transthyretin amyloidosis (ATTR) harboring the <i>p.Ala117Ser</i> variant versus those with wild-type ATTR (wtATTR), and (2) delineate the clinical spectrum of ATTR at our institution.</p> Methods <p>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.</p> Results <p>Among the 50 patients enrolled with ATTR, hereditary ATTR (hATTR) accounted for 53%. Within the hATTR group, the <i>p.Ala117Ser</i> 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 <i>p.Ala117Ser</i> patients were younger, had universal neuropathy, and exhibited less advanced cardiac involvement compared with wtATTR. Three-year event-free survival was higher in <i>p.Ala117Ser</i> patients, remaining significant after excluding asymptomatic carriers (log-rank <i>p</i> = 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 <i>p.Ala117Ser</i> variant as independently associated with improved outcomes (HR 0.23, 95% CI 0.06–0.95).</p> Conclusions <p>The <i>p.Ala117Ser</i> 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.</p> Trial registration <p>Clinical Trial Number: Not Applicable.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月18日

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  • Phakin Tuntiwongkosee,
  • Patchara Kochaiyapatana,
  • Prasit Phowthongkum,
  • Jakkrit Amornvit,
  • Khanidta Saicharoen,
  • Pairoj Chattranukulchai,
  • Krailerk Chettakulanurak,
  • Sarinya Puwanant

摘要

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.