Hereditary transthyretin (ATTRv) amyloidosis is a systemic disease with amyloid deposition in the peripheral and autonomic nervous systems caused by mutation of transthyretin (TTR) gene. The mutant TTR S77Y is the second prevalent mutation in many countries. In Taiwan, A97S mutant accounts for more than 90% of cases. Although distinct clinical manifestations such as dysphagia, carpal tunnel syndrome, and sudden cardiac death occur, the underlying pathology has not been elucidated. Here, we report the first autopsy cases of ATTRv S77Y and A97S and comprehensively compare the pathology underlying the unique clinical manifestations. This study demonstrated the following: (1) distinct spatial patterns of amyloid deposits in peripheral nerves, with a tendency toward more amyloid deposition in the large peripheral nerves, particularly the median nerves, and scarcely in the sural nerves, and different amyloid distribution in different genotypes; (2) amyloid deposits in the conduction system of the heart in addition to surrounding cardiomyocytes; (3) extensive amyloid deposits in the larynx and gastrointestinal tract, contributing to the unique clinical symptom of dysphagia; and (4) characteristic TTR intracytoplasmic inclusions in the hepatocytes of A97S. The pathology of the first autopsied cases of ATTRv S77Y and A97S provides pathology and mechanisms underlying unique clinical manifestations.
Keywords: A97S; Cardiac conduction system; Dysphagia; Hepatocyte; Hereditary transthyretin amyloidosis; Peripheral neuropathy; S77Y.
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