Hereditary Transthyretin Amyloidosis

Hereditary transthyretin amyloidosis (ATTRv) is a severe, adult-onset, autosomal dominant systemic disease caused by mutations in the TTR gene. Mutations destabilize the native tetrameric structure of the transport protein transthyretin, promoting its proteolytic cleavage and dissociation into full-length and fragmented monomers. Monomeric species misfold and aggregate as amyloid fibrils, infiltrating the extracellular milieu of various tissues and organs, including the heart, the peripheral nerves, the kidneys, the gastrointestinal tract, and the eyes. ATTRv amyloidosis can manifest with a wide range of symptoms, with cardiomyopathy and polyneuropathy being the most frequent phenotypes (ATTRv-CM and ATTRv-PN, respectively). Gastrointestinal, ophthalmological, renal and central nervous system symptoms are also common. The onset and severity of the disease vary according to the different mutations, being also influenced by sex, ethnicity, and still putative geographical and environmental factors. ATTRv-PN typically presents with progressive length-dependent sensorimotor polyneuropathy, initially affecting lower limbs, and autonomic neuropathy. ATTRv-CM main manifestations are heart failure, conduction disorders, and valvular heart disease. If untreated, prognosis is generally poor and deeply determined by cardiac involvement, with a median survival of 5–15 years from symptoms onset. Early diagnosis and treatment are crucial to prevent or delay irreversible organ damage and improve patient’s quality of life.