Revisiting Predicted Age of Disease Onset in a Korean Kindred with the Transthyretin Asp38Val Variant

Variant transthyretin amyloidosis (ATTRv) is a progressive, fatal disease with wide phenotypic and genetic heterogeneity. The emergence of disease-modifying therapies and ongoing preventive trials, such as Acoramidis Transthyretin Amyloidosis Prevention Trial in the Young, has made precise estimation of the predicted age of disease onset (PADO) critical for optimizing surveillance timing and determining trial eligibility in asymptomatic carriers. However, most existing PADO estimates are derived from Western populations, with limited data for Asian variants. We report a Korean kindred carrying the Asp38Val (p.Asp58Val) transthyretin variant, which presented with a mixed phenotype involving cardiomyopathy, neuropathy, and severe autonomic dysfunction, often with gastrointestinal manifestations. All affected men were diagnosed in their 40s to early 50s and died within five years, while female carriers showed a later and milder course. In contrast to prior single-case reports suggesting a PADO of approximately 55 years for this variant, pedigree-based family evaluation in this kindred suggested substantially earlier clinically apparent disease and a more aggressive course, particularly among male carriers. This discrepancy underscores the need to integrate variant type, family history, and population-specific modifiers when estimating PADO. As ATTRv management transitions toward preventive therapy, reliance on uniform Western reference values may delay timely surveillance and treatment planning or inadvertently exclude at-risk Asian carriers from pivotal trials. Family- and population-specific calibration of PADO will be essential to ensure equitable and timely application of emerging preventive strategies in hereditary amyloidosis.