Not so rare after all: Rethinking hereditary transthyretin amyloidosis

Abstract

Introduction: Hereditary transthyretin amyloidosis (ATTRv) is a progressive multi-systemic disorder caused by extracellular deposits of misfolded transthyretin (TTR) protein. Presenting as cardiomyopathy, polyneuropathy, or mixed phenotypes, ATTRv exhibits high clinical heterogeneity, often causing diagnostic delays. Objective: This narrative review provides an updated overview of emerging epidemiological and registry insights, genotype–phenotype correlations, current diagnostic modalities, and evolving individualized therapies for ATTRv, emphasizing the clinical relevance of early identification. Methods: A literature search was conducted across medical databases to identify recent studies evaluating the clinical characteristics, diagnostic approaches, and therapeutic outcomes of ATTRv. Data from multinational registries, including the Transthyretin Amyloidosis Outcomes Survey, were examined to assess phenotypic variability across geographical regions and genotypes. Results: ATTRv presents with early- or late-onset phenotypes, the latter often showing advanced neurological and cardiac involvement at diagnosis, with Val30Met remaining the most prevalent global variant. Early recognition of clinical “red flags” and the use of bone scintigraphy facilitate prompt diagnosis, which is crucial for the timely initiation of disease-modifying therapies—including TTR stabilizers (e.g., tafamidis) and second-generation gene silencers—to suppress disease progression, improve survival, and reduce adverse cardiovascular events. Conclusion: Therapeutic strategies for ATTRv have advanced remarkably, rendering a historically fatal condition increasingly manageable. Emerging studies demonstrate that this condition is not as rare as commonly believed. Given its systemic nature, a coordinated, multidisciplinary approach remains crucial for screening and long-term patient care.