Ala97Ser transthyretin amyloidosis-associated polyneuropathy, clinical and neurophysiological profiles in a Thai cohort

Abstract

Background Ala97Ser transthyretin amyloidosis-associated polyneuropathy (ATTRA97S-PN) is a rare form of inherited polyneuropathy, usually manifesting with late-onset (> 50) progressive polyneuropathy. This mutation is mostly prevalent in Taiwanese and Han-Chinese individuals. The aim of this study was to describe the clinical and comprehensive neurophysiological profiles of ATTRA97S-PN in Thai patients. Methods The clinical profiles and serial neurophysiologic studies (nerve conduction study (NCS), quantitative sensory test (QST), and comprehensive autonomic function test (AFT)) of symptomatic ATTRA97S-PN patients who had been followed-up at King Chulalongkorn Memorial Hospital during 2010–2020 were retrospectively reviewed. Results Nine symptomatic patients (55.6 % were male) from four unrelated families were included. All were Thais of mixed Thai Chinese descent. The mean age of onset was 48.3 (32–60) years. The mean age at diagnosis was 54.8 (33–66) years. Three patients developed early-onset (< 40y) polyneuropathy. The mean Neuropathy Impairment Score was 41.33 (10–92) at diagnosis. Sensory (9/9) and autonomic (9/9) neuropathies were more frequent than motor neuropathy (5/9), which appeared in the late stage of disease. Hypoesthesia in the feet, and gastrointestinal autonomic symptoms were frequently reported as the initial symptoms. The course of neuropathy progressed over years to decades. The worsening of neuropathy tended to progress faster once motor nerves were affected in both clinical and neurophysiological aspects. Concurrent cardiac amyloidosis was found in 6/9 patients. NCS showed length-dependent sensorimotor axonal polyneuropathy in 5/9 patients, and median neuropathy at the wrist (mostly bilateral) in 7/9 patients. QST showed abnormalities in the vibratory detection threshold, the cold detection threshold and the heat pain sensation in 8/9, 8/9 and 7/7 tested patients, respectively. AFT results were abnormal in all. The mean composite autonomic severity score was 5 (3–9). Conclusions This clinical study is the first of ATTRA97S-PN in Thai patients. The mixed polyneuropathy-cardiopathy phenotype was the most common manifestation. In this cohort, the age of onset was lower, and the course of neuropathy was relatively longer, than that in previous studies. Some patients may develop early-onset polyneuropathy. This mutation has not yet been documented in any population other than Han Chinese-related populations, probably suggesting a founder effect. Further studies are warranted.

Characteristics of Patients with Hereditary Transthyretin Amyloidosis-Polyneuropathy (ATTRv-PN) in NEURO-TTRansform, an Open-label Phase 3 Study of Eplontersen

“…In our cohort, all 23 patients from Taiwan had the A97S TTR sequence variant, and this variant was not reported in any other region. This corroborates published data noting a high prevalence of the A97S variant among and generally limited to patients from Taiwan or China and patients of Chinese descent [19,[28][29][30][31].…”

TTR Gly83Arg Mutation: Beyond Familial Vitreous Amyloidosis

“…However, neuropathy might strike a patient after many years of blurred vision. It was worthy of note that bilateral CTS was likely to occur and could be a vital red flag sign, which seemed like that of Ala97Ser mutation (17,18). Based on our cohort, heterogeneity of patients with Gly83Arg mutation-related ATTR also existed.…”

Cardiomyopathy correlates to nerve damage in p.A117S late‐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 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 , 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.…”