Unique Phenotypes With Corresponding Pathology in Late-Onset Hereditary Transthyretin Amyloidosis of A97S vs. V30M

Abstract

ObjectiveHereditary transthyretin amyloidosis (ATTRv) encompasses different phenotypes among various genotypes. The analysis of the natural history and risk factors of faster progression in different genotypes would refine the treatment strategy.MethodsThe clinical manifestations of ATTRv from A97S (p.A117S) of Taiwanese and late-onset V30M (p.V50M) of Japanese were compared. An autopsy study of A97S was performed.ResultsThere existed three unique features in the A97S cohort compared to the V30M cohort: (1) dysphagia, (2) carpal tunnel syndrome (CTS), and (3) onset age. First, dysphagia was common in A97S (53.4%) but not in V30M and served as a contributor to fast disease progression. All phases of swallowing were affected. In the autopsy pathology, there were extensive amyloid deposits in the viscera and nerves of the tongue, larynx, and esophagus. In A97S, 45 patients (43.3%) had a history of CTS before the onset of length-dependent symptoms by 3 years. The amyloid deposition was more prominent in the median nerve than that in the transverse carpal ligament. The onset age at different stages was younger in the A97S cohort than the V30M cohort by 4–5 years.ConclusionThese phenotypic characteristics together with autopsy pathology in A97S are distinct from V30M. Early dysphagia in A97S correlated with fast progression. In A97S, median neuropathy leading to CTS might be in a continuous spectrum of ATTRv course rather than an independent disease entity. Such observations may serve as a foundation to explore and analyze unique phenotypes among various genotypes.

Cardiomyopathy correlates to nerve damage in p.A117Slate‐onset transthyretin amyloid polyneuropathy

“…In contrast to the most common TTR p. V50M mutation in western countries and Japan, 13 p. A117S mutation constitutes the majority of late‐onset ATTRv‐PN with cardiomyopathy in Taiwan and has also been reported in China and Southeast Asia 14–17 . Our recent report comparing the manifestations in patients with p. A117S and late‐onset p. V50M showed comparable clinical phenotypes and disease progression, and heart failure or sudden death due to cardiac amyloidosis was the predominant cause of death in both groups of patients 18 . In the present study, we combined echocardiography, CMR, and 99m Tc PYP scans to explore cardiac involvement in late‐onset ATTRv‐PN with predominant p. A117S genotype, which is invariantly associated with cardiomyopathy during the disease course 18,19 .…”

“…The present study investigated the cardiomyopathic changes and their clinical and neuropathic associations in late‐onset ATTRv‐PN patients, the majority of whom were p. A117S mutant, which shared a similar phenotype to p. V50M mutant. 18 The important findings included (1) all the enrolled late‐onset ATTRv‐PN patients with various stages of severity consistently manifested cardiomyopathy as shown by significant radiotracer uptake on 99m Tc‐PYP SPECT imaging, (2) the cardiomyopathy was associated with compromised cardiac functional capacity (NYHA class I–III), significantly thicker IVSd on echocardiography; higher ECV, longer myocardial native T1, increased LVMi, and higher MVR on CMR, and elevated pro‐BNP in the blood, (3) the abnormal CMR parameters and elevated pro‐BNP level were associated with higher clinical stage, lower quality of life, more severe disability, and more autonomic dysfunction, and (4) there were significant correlations between the CMR biomarkers of cardiomyopathy and pathophysiological parameters of polyneuropathy. These findings suggested that cardiomyopathy is highly prevalent, related to neuropathic changes in both small‐ and larger‐fiber nerves and can reflect the overall severity and functional deficits in late late‐onset ATTRv‐PN patients.…”

“…There are over 130 pathogenic mutations of the TTR gene, and there is an association between the specific mutation and the predominant phenotype, although there is considerable overlap. 1 , 3 Although the heart is also commonly involved in ATTRv‐PN, 35 especially in the late‐onset form, 4 , 18 the cardiac manifestations, and their clinical associations with polyneuropathy in ATTRv‐PN, are not clear. In the present study, all the enrolled patients with late‐onset ATTRv‐PN with different severities from the early to late PND stage consistently showed remarkable 99m Tc‐PYP uptake, and all visual scores were equal to or larger than grade 2.…”

“… 14 , 15 , 16 , 17 Our recent report comparing the manifestations in patients with p. A117S and late‐onset p. V50M showed comparable clinical phenotypes and disease progression, and heart failure or sudden death due to cardiac amyloidosis was the predominant cause of death in both groups of patients. 18 In the present study, we combined echocardiography, CMR, and 99m Tc PYP scans to explore cardiac involvement in late‐onset ATTRv‐PN with predominant p. A117S genotype, which is invariantly associated with cardiomyopathy during the disease course. 18 , 19 We aimed to explore the phenotypes of cardiac amyloidosis and their correlates with the clinical manifestation of polyneuropathy in late‐onset ATTRv‐PN.…”

“… 18 In the present study, we combined echocardiography, CMR, and 99m Tc PYP scans to explore cardiac involvement in late‐onset ATTRv‐PN with predominant p. A117S genotype, which is invariantly associated with cardiomyopathy during the disease course. 18 , 19 We aimed to explore the phenotypes of cardiac amyloidosis and their correlates with the clinical manifestation of polyneuropathy in late‐onset ATTRv‐PN.…”