Distinct Patterns of Amyloid Pathology in Autopsies of Transthyretin S77Y and A97S Amyloidosis: Significance of Symptomatology and Cell Biology

Abstract

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.

Nerve pathology of microangiopathy and thromboinflammation in hereditary transthyretin amyloidosis

“…Previous pathology studies have implied additional mechanisms underlying nerve degeneration in ATTRv beyond amyloid deposition; for example, the pattern of nerve degeneration in ATTRv is generalized, 37 in contrast to (1) focal amyloid deposition only adjacent to some vessels of sural nerves and (2) low frequency of amyloid deposition in sural nerves compared to other nerves. 11 , 12 The absence of correlation between neurofilament(+) nerve fiber area and TTR(+) amyloid area in this study prompted us to test the vascular hypothesis, that is, microangiopathy might serve as an add‐on mechanism contributing to nerve degeneration in ATTRv. Previously, ATTRv vascular studies mainly focused on the deposition of amyloid fibrils and the relationship with the basement membrane of microvasculaures.…”

“…2,10 Furthermore, the relatively low number and uneven distribution of amyloid deposits in peripheral nerves could not fully explain the diffuse and generalized nerve degeneration in ATTRv. 11,12 The above clinical observation and discrepancy in neurodegeneration pattern raise the possibility of additional mechanisms contributing to nerve degeneration in ATTRv beyond the amyloid pathology. Frequently, ATTRv patients have cold extremities with pallor skin, 13,14 implying vasculopathy, which was previously attributed to autonomic neuropathy with deranged vasomotor control of microcirculation.…”

“…Despite the availability of silencing and stabilizing treatments for ATTRv, some patients continued experiencing the decline of neurological functions, that is, an increase in Neuropathy Impairment Score, the primary end‐point of these clinical trials 2,10 . Furthermore, the relatively low number and uneven distribution of amyloid deposits in peripheral nerves could not fully explain the diffuse and generalized nerve degeneration in ATTRv 11,12 . The above clinical observation and discrepancy in neurodegeneration pattern raise the possibility of additional mechanisms contributing to nerve degeneration in ATTRv beyond the amyloid pathology.…”