Hereditary ATTR Amyloidosis in Austria: Prevalence and Epidemiological Hot Spots

Abstract

Background: Hereditary transthyretin amyloidosis (hATTR) is an autosomal dominantly inherited disorder caused by an accumulation of amyloid fibrils in tissues due to mutations in the transthyretin (TTR) gene. The prevalence of hATTR is still unclear and likely underestimated in many countries. In order to apply new therapies in a targeted manner, early diagnosis and knowledge of phenotype-genotype correlations are mandatory. This study aimed to assess the prevalence and phenotypic spectrum of hATTR in Austria. Methods: Within the period of 2014–2019, patients with ATTR-associated cardiomyopathy and/or unexplained progressive polyneuropathies were screened for mutations in the TTR gene. Results: We identified 43 cases from 22 families carrying 10 different TTR missense mutations and confirmed two mutational hot spots at c.323A>G (p.His108Arg) and c.337G>C (p.Val113Leu). Two further patients with late onset ATTR carried TTR variants of unknown significance. The majority of patients initially presented with heart failure symptoms that were subsequently accompanied by progressive polyneuropathy in most cases. A total of 55% had a history of carpal tunnel syndrome before the onset of other organ manifestations. Conclusions: Our study underlined the relevance of hATTR in the pathogenesis of amyloid-driven cardiomyopathy and axonal polyneuropathy and indicated considerable genetic heterogeneity of this disease in the Austrian population. The estimated prevalence of hATTR in Austria based on this study is 1:200,000 but a potentially higher number of unknown cases must be taken into account. With respect to new therapeutic approaches, we strongly propose genetic testing of the TTR gene in an extended cohort of patients with unexplained heart failure and progressive polyneuropathy.

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

“…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]. This similarity in the frequency of ATTRHis88Arg in Austria and in Hungary may be explained by the common historic background of the Austro-Hungarian Empire.…”

“…This is the first report of the prevalence, epidemiology, and geno-and phenotypes of Hungarian ATTRv patients. Apart from Bulgaria, where the ATTRGlu89Gln mutation is endemic, these data in the Eastern and Central European region were available only for Austria, from a recently published study [8]. To the best of our knowledge, all known families and patients with ATTRv in Hungary were captured in this retrospective analysis.…”

“…The THAOS registry of ATTRv provides epidemiological information from the US, South America, some Asian countries, and Western Europe, but information about ATTRv in Eastern and Central Europe, apart from the endemic region in Bulgaria, was scarce until the recent publication of Austrian data [8].…”

Diagnosis and treatment of cardiac amyloidosis: an interdisciplinary consensus statement

“…These can be significant for patient prognosis, as they can give rise to cardioembolic events based on atrial fibrillation, collapse/syncope, or sudden cardiac death due to higher grade atrioventricular block or ventricular tachycardia. In particular, the Austrian hot spot mutation His108Arg is associated with increased incidence of ventricular tachycardia [ 38 ].…”

“…The Val50Met TTR mutation primarily affects the neurological system (HAP), while Val142Ile is frequently related to cardiac amyloidosis [ 16 ]. In recent years, several Austrian families carrying TTR mutations have been identified [ 38 ]. The most commonly found mutation in Austria, His108Arg, is related to a mixed cardiac and neurological phenotype.…”