Hereditary amyloidoses associated with transthyretin mutations

Abstract

Hereditary amyloidoses form a clinically and genetically heterogeneous group of autosomal-dominantly inherited diseases characterized by the ubiquitous extracellular deposit of fibrillary aggregated proteins. Main components of these unsolvable deposits are physiologic proteins that became amyloidogenic through genetically determined conformation changes resulting in an increase in beta-sheet structures. In the vast majority of cases, the offending protein is variant transthyretin (TTR), of which over 80 mutations are known. Among these, substitution of valine by methionine in position 30 (TTR-Met30) is the most commonly encountered. In typical cases, TTR amyloidoses present with polyneuropathy, carpal tunnel syndrome, autonomic insufficiency, cardiomyopathy, and gastrointestinal features, occasionally accompanied by vitreous opacities and renal insufficiency. Rarely, involvement of the leptomeningeal or meningovascular structures dominates the clinical picture. The clinical expression is highly variable, with many atypical manifestations. Asymptomatic mutations have recently been identified. The age of onset varies greatly between early adulthood and old age. Late-onset atypical manifestations and occurrence of asymptomatic carriers render identification of affected family members difficult despite autosomal-dominant inheritance. Orthotopic liver transplantation (OLT) is the only effective therapy available today. This OLT stops progression of the disease, which is otherwise invariably fatal, by removal of the main production site of the amyloidogenic protein. However, cardiac involvement may progress after OLT for unknown reasons. The indication for OLT and its success depend on the grade of cardiovascular and autonomic dysfunction at the time of surgery, age, comorbidity, and type of mutation. Alternative treatment modalities with drugs stabilizing the native tetrameric conformation of TTR, inhibiting fibril formation or breaking beta-sheet structures, are currently being intensively studied.