Pattern of inheritance of hereditary amyloidosis
Study of many types of hereditary amyloidosis has shown them to be attributable to single amino acid variants of TTR (ATTR). What is their pattern of inheritance? How is it treated?
Familial amyloid polyneuropathy is an autosomal dominant disease with peak onset between 20 and 60 years. The clinical features are similar to AL amyloidosis. A family history of amyloidosis should be sought and may or may not be present because spontaneous ATTR mutations can occur sporadically. Patients typically have a progressive peripheral and autonomic neuropathy. The heart and conduction system can also be involved. Treatment is liver transplantation, which removes the source of the variant TTR production and replaces it with normal TTR. Death occurs within 5 to 15 years without liver transplantation. A medical treatment, tafamidis meglumine, has been shown to bind to and stabilizes TTR tetramers preventing fibril formation and amyloid deposition. Randomized trials have shown slowing of neuropathy progression. Interestingly, diflunisal, a nonsteroidal antiinflammatory drug, also stabilizes TTR tetramers and has shown beneficial results in trials. Other therapies in trials for familial amyloid polyneuropathy include patisiran, a sRNAi, and inotersen, an antisense oliogonucleotide, which are RNA-targeted therapies that interfere with hepatic TTR synthesis.