Transthyretin-associated neuropathic amyloidosis - Pathogenesis and treatment

Hereditary amyloidoses form a clinically and genetically heterogeneous grou p of autosomal dominantly inherited diseases characterized by the deposit o f unsoluble protein fibrils in the extracellular matrix. They typically pre sent with polyneuropathy, carpal tunnel syndrome, autonomic insufficiency, and cardiomyopathy and gastrointestinal features, occasionally accompanied by vitreous opacities and renal insufficiency. Other phenotypes are charact erized by nephropathy, gastric ulcers, cranial nerve dysfunction, and corne al lattice dystrophy. Rarely, involvement of the leptomeningeal or cerebral structures dominates the clinical picture. The age at onset is as early as 17 and as late as 78 years. The basic constituents of amyloid fibrils are physiologic proteins that have become amyloidogenic through genetically det ermined conformation changes. Mutated transthyretin (TTR), formerly termed prealbumin, is the most frequent offender in hereditary amyloidosis. Orthot opic Liver transplantation (OLT) stops the progression of the disease, whic h is otherwise invariably fatal, by removing the main production site of th e amyloidogenic protein. The indications for OLT and its success depend on the grade of cardiovascular and autonomic dysfunction at the time of surger y, age, comorbidity, and type of mutation. Alternative treatment modalities with drugs stabilizing the native tetrameric conformation of TTR and inhib iting fibril formation are currently being intensively studied.