Clinical Practice and Diagnostic Trends in Hereditary Transthyretin Amyloidosis: A 25-Year Observational Study

Background and Objectives: Hereditary transthyretin amyloidosis (ATTRv), a multisystemic disorder caused by transthyretin (TTR) gene mutations, exhibits phenotypic heterogeneity that can hamper recognition in non-endemic areas. Here, we investigated the clinical practice of ATTRv amyloidosis over an extended period and examined the challenges currently faced in non-endemic regions. Materials and Methods: We conducted an observational study of 18 patients with ATTRv amyloidosis diagnosed at Oita University and its affiliated hospitals between 2000 and 2025, using both retrospective and prospective data collection, to evaluate clinical features, treatments, and outcomes. Results: The median age at disease onset was 64 years, and 27.8% of patients had a family history of the disease. Val30Met (V30M) was the most common (55.6%) mutation; Tyr114Ser was the most common non-V30M variant. Sensory disturbances (50%) were the most common initial symptoms, followed by cardiac symptoms (38.9%). The cardiology department most frequently diagnosed ATTRv amyloidosis, followed by the neurology department. Two patients were relatives of previously diagnosed probands and were therefore identified during their first visit to the initial department. New diagnoses increased over time (1 in 2000-2009, 7 in 2010-2019, and 10 in 2020-2025), although diagnostic delays persisted. After the therapeutic agents shifted from patisiran to vutrisiran, the serum TTR value decreased (p = 0.0078) without significant deterioration in cardiac parameters. In the current treatment era, longer-term survivors have been observed, but multiple organ dysfunction has become more apparent, and ocular manifestations have emerged as a clinically important problem, particularly in patients with longer disease duration (p = 0.0169). Conclusions: Physicians in various departments must remain vigilant for the presence of ATTRv amyloidosis. Addressing challenges faced by long-term survivors, including ocular manifestations and central nervous system complications, has become crucial, even in non-endemic areas.