Not So Rare After All: Rethinking Hereditary Transthyretin Amyloidosis

Background: Transthyretin amyloidosis (ATTR) is a rare, often underdiagnosed and undertreated, autosomal dominantly inherited, progressive disease that affects multiple systems of the body. It results from the extracellular accumulation of misfolded transthyretin (TTR) protein as insoluble amyloid fibrils, predominantly causing cardiomyopathy, polyneuropathy or mixed phenotypes. It can occur in a hereditary form (ATTRv) and in a wild-type form (ATTRwt), with over 150 different pathogenic mutations having been identified worldwide. The clinical presentation is highly variable, leading to a diagnostic delay of 2–5 years. Transthyretin (TTR) amyloidosis is an inherited disease for which recent advances in pathogenesis, diagnosis and treatment have revolutionized its management. Objectives: The aims of this review are to provide an update on the epidemiology and genotype-phenotype correlation, on current diagnostic techniques and on emerging and individualized treatments for this rare hereditary disease. Particular attention will be given to the early diagnosis Methods: A systematic literature search was conducted across major databases to identify studies addressing clinical characteristics, diagnostic modalities, and treatment outcomes in hereditary and wild-type ATTR amyloidosis. Registry data from THAOS and other multinational cohorts were analyzed to evaluate phenotypic variability across genotypes and geographic regions. Results: Clinical presentation of TTR related amyloidosis (h-Amyloid) can range from early onset to late onset with late onset having worse neurological and cardiac involvement at time of diagnosis. The Val30Met mutation is the most common TTR mutation worldwide, however patients with non-V30M mutations can have very different presentations of h-amyloidosis. Identifying “red flag” symptoms in a patient with suspicious clinical presentation can initiate correct diagnostic pathway. Non-invasive imaging, especially bone scintigraphy, has greatly facilitated the diagnosis of patients with Transthyretin related cardiac amyloidosis (ATTR-CM). First generation h-amyloid treatments or TTR stabilizers such as tafamidis have been shown to significantly improve survival in patients with h-amyloidosis. The second generation treatments such as RNA silencers (patisiran, vutrisiran, inotersen, eplontersen) have been shown to halt the disease progression. Present data from small to moderate-sized patient cohorts demonstrate that TTR-targeting therapy is associated with reduction of cardiovascular events and improvement in survival compared with current standard of care. Early recognition of key clinical features and application of a diverse diagnostic strategy, in conjunction with timely initiation of disease-modifying therapy, are critical to optimal management of patients with hereditary transthyretin (ATTR) amyloidosis. Conclusions: The therapeutic options have evolved and improved in recent years, and with current diagnostic tools, the opportunity to alter the natural history of a disease that was once invariably fatal is better than ever. Because the disease is systemic, a thorough, multidisciplinary approach to patient management is ideal.