Aged onset of amyloidosis caused by transthyretin gene mutations

Background: The authors have established that missense mutations of the transthyretin gene cause middle age onset of familial systemic amyloidosis. The purpose of the present study was to investigate molecular abnormalities of the serum protein, transthyretin in patients with aged onset of cardiac amyloidosis or amyloidotic polyneuropathy in whom there was no positive family history of amyloidosis. Methods: DNA and isolated amyloid fibril proteins were extracted from biopsy or postmortem tissue samples taken from five patients with cardiac amyloidosis and 15 patients with amyloidotic polyneuropathy, in whom histological diagnosis of amyloidosis had been established by immunostaining for transthyretin. Results: DNA analysis of the transthyretin gene and protein sequencing of the amyloid fibrils revealed that three of the five patients with cardiac amyloidosis were associated with transthyretin Met 30, and the remaining two patients were associated with transthyretin Ile 50. Of the 15 patients with amyloidotic polyneuropathy, 12 were associated with transthyretin Met 30, two with transthyretin Ile 50, and one with transthyretin Ser 109. Conclusion: The clinical findings, results of DNA sequencing and structural analysis of amyloid protein are presented here for six representative subjects. Molecular abnormalities of transthyretin are the cause of some patients with aged onset of amyloidosis without a positive family history. Even when transthyretin‐type amyloid was first diagnosed at autopsy, it was possible to identify transthyretin gene mutations by the use of small pieces of tissue samples.