Diagnostic & therapeutic challenges of presymptomatic hereditary transthyretin amyloidosis

Hereditary transthyretin amyloidosis (ATTRv) is a rare, lethal, autosomal dominant adult-onset genetic disorder provoked by mutations in the TTR gene. Until recently, therapeutic options were limited to liver transplantation and TTR stabilizers. Antisense oligonucleotides (ASO) and small interfering RNA (siRNA) treatments, now commercially available, have dramatically improved ATTRv neurological outcome, and affected patients' relatives are increasingly being identified at the presymptomatic stage. Guidelines for monitoring presymptomatic patients have been established by different groups. ATTRv disease onset is defined by a combination of pathologically proven amyloid TTR deposits, symptoms attributed to ATTRv, and clinical changes in comparison with initial assessment. However, several studies have shown that many presymptomatic patients present with subclinical abnormalities before amyloid deposits are observed, blurring the boundary between presymptomatic and symptomatic statuses. Future challenges include identifying biomarkers for better delineating the transition between presymptomatic and symptomatic, e.g., neurofilament light chain (NfL), and considering prophylactic treatment to prevent the onset of the disease.