Hereditary Transthyretin Amyloidosis- Clinical and Genetic Characteristics of a Multiracial South-East Asian Cohort in Singapore

Abstract

Background and aims: Studies of hereditary transthyretin amyloidosis (ATTRv amyloidosis) in South-East Asia are underrepresented in the literature. We report the unique phenotypic and genetic characteristics of this disorder in a multiracial South-East Asian cohort. Methods: Patients with genetically proven ATTRv amyloidosis were identified over a 13-year period (2007–2020) at the National Neuroscience Institute, Singapore. Clinical, laboratory, genotypic and electrophysiological features were retrospectively reviewed. Results: 29 patients comprising Chinese, Malay, Burmese, Vietnamese and Indonesians with ATTRv amyloidosis were identified. Somatic neuropathy was the most common initial presentation, followed by carpal tunnel syndrome, autonomic dysfunction and cardiac dysfunction. ATTR-A97S (p.Ala117Ser) was the most common variant found in 14 patients, constituting 66.7%of ethnic Chinese patients and 48.3%of the entire cohort. Five patients had early-onset disease (age < 50 years) with the following variants: ATTR-V30M (p.Val50Met), ATTR-G47A (p.Gly67Ala), ATTR-S50I (p.Ser70Ile) and ATTR-A97S (p.Ala117Ser); one patient with ATTR-A97S (p.Ala117Ser) had isolated unilateral carpal tunnel syndrome with amyloid deposits identified on histological examination of the transverse carpal ligament. All early-onset patients had a positive parental history; two patients, with ATTR-S50I (p.Ser70Ile) and ATTR-Ala97Ser (p.Ala117Ser) respectively, demonstrated anticipation with mother-to-daughter inheritance. Amongst the 24 patients with late-onset disease (age≥50 years), two patients had novel variants, ATTR-G66D (p.Glu86Asp) and ATTR-A81V (p.Ala101Val) that were confirmed to be pathogenic based on the histological identification of transthyretin amyloid. Other identified variants included ATTR-V30M (p.Val50Met), ATTR-R34T (p.Arg54Thr), ATTR-S50I (p.Ser70Ile), ATTR-H88R (p.His108Arg) and ATTR-A97S (p.Ala117Ser). Conclusion: Our study further expands the genotypic and phenotypic knowledge regarding ATTRv amyloidosis.

Variant Transthyretin Amyloidosis (ATTRv) in Hungary: First Data on Epidemiology and Clinical Features

“…Among those seven patients who died during the follow-up, the cause of death was cardiac in five cases. This mutation was also found in one family recently in Asia [35]. ATTRHis88Arg mutation was reported also as the most common variant in a recent Austrian publication affecting six families [8].…”

Cardiac Amyloidosis: A Rare TTR Mutation Found in an Asian Female

“…Literature on TTR-related cardiac amyloidosis in Asian populations is limited and is exclusively case series. One such study [ 21 ] demonstrated the genotypic and phenotypic characteristics of familial TTR amyloidosis in a Southeast Asian cohort, where out of 29 patients from China, Malaysia, Myanmar, Vietnam, and Indonesia, 5 patients were found to have early-onset disease (age <50 years) with multiple variants which included Gly47Ala mutation. They have found somatic neuropathy to be the most common initial symptom, followed by carpal tunnel syndrome, as well as autonomic and cardiac dysfunction.…”

Clinical recommendations to diagnose and monitor patients with transthyretin amyloid cardiomyopathy in Asia

“…Available literature suggests that the main presenting pathologies of wild-type ATTR are cardiomyopathy, carpal tunnel syndrome, and spinal canal stenosis, while patients with hereditary ATTR present with a higher incidence of gait instability, gastrointestinal symptoms, urinary incontinence, and neuropathic pain 14,20,21 ; clinical experience suggests that these differences in presenting pathologies are also found in different populations of Asian patients. [22][23][24][25] Concomitant ATTR amyloidosis and severe aortic stenosis has been reported to be a relatively common finding in the elderly Indian population. 26 For hereditary ATTR in the Asian population, Ala97Ser (p.A97S) appears to be the most commonly identified mutation 23,24 | 899 (p.His108Arg), and ATTR-A97S (p.Ala117Ser).…”

“…[22][23][24][25] Concomitant ATTR amyloidosis and severe aortic stenosis has been reported to be a relatively common finding in the elderly Indian population. 26 For hereditary ATTR in the Asian population, Ala97Ser (p.A97S) appears to be the most commonly identified mutation 23,24 | 899 (p.His108Arg), and ATTR-A97S (p.Ala117Ser). 23 Of note, ATTR p.A97S has been described as cardiomyopathy as well as a polyneuropathic syndrome.…”

“…26 For hereditary ATTR in the Asian population, Ala97Ser (p.A97S) appears to be the most commonly identified mutation 23,24 | 899 (p.His108Arg), and ATTR-A97S (p.Ala117Ser). 23 Of note, ATTR p.A97S has been described as cardiomyopathy as well as a polyneuropathic syndrome. 22 A subsequent cardiac workup enables the identification of cardiac red flags, such as specific electrocardiography (ECG) features (low/relative low voltage vs. wall thickness) and echocardiography findings (aortic stenosis, HF with preserved ejection fraction [HFpEF], and relative apical sparing of longitudinal strain).…”