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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.

SUBMITTER: Auer-Grumbach M

PROVIDER: S-EPMC7408866 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Hereditary ATTR Amyloidosis in Austria: Prevalence and Epidemiological Hot Spots.

Auer-Grumbach Michaela M Rettl Rene R Ablasser Klemens K Agis Hermine H Beetz Christian C Duca Franz F Gattermeier Martin M Glaser Franz F Hacker Markus M Kain Renate R Kaufmann Birgit B Kovacs Gabor G GG Lampl Christian C Ljevakovic Neira N Nagele Jutta J Pölzl Gerhard G Quasthoff Stefan S Raimann Bernadette B Rauschka Helmut H Reiter Christian C Skrahina Volha V Schuhfried Othmar O Sunder-Plassmann Raute R Verheyen Nicolas D ND Wanschitz Julia J Weber Thomas T Windhager Reinhard R Wurm Raphael R Zimprich Friedrich F Löscher Wolfgang N WN Bonderman Diana D

Journal of clinical medicine 20200714 7

<h4>Background</h4>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 (<i>TTR</i>) 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 ...[more]

PMID: 32674397

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Project description:IntroductionTransthyretin amyloidosis (ATTR amyloidosis) is a clinically heterogeneous disease caused by mutations in the transthyretin (TTR) gene or aggregation of wild-type transthyretin (ATTRwt). In Spain, there are two large endemic foci of ATTR amyloidosis caused by the Val30Met variant, with additional cases across the country; however, these data may be incomplete, as there is no centralized patient registry. The Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing, global, longitudinal, observational survey of patients with ATTR amyloidosis, including both inherited and wild-type disease, and asymptomatic patients with TTR mutations. This analysis aimed to gain a deeper understanding of the clinical profile of patients with ATTR amyloidosis in Spain.MethodsThis was a descriptive analysis of the demographic and clinical characteristics of symptomatic patients enrolled at six sites geographically dispersed throughout Spain (data cutoff: January 6, 2020). Patient data at enrollment, including genotype, demographics, and clinical presentation for symptomatic patients, were recorded. Patients were grouped by predominant phenotype based on clinical measures at enrollment: predominantly cardiac, predominantly neurologic, or mixed (cardiac and neurologic).ResultsThere were 379 patients (58.0% male; 63.3% symptomatic) enrolled in the six THAOS sites in Spain. Predominant genotypes were the Val30Met mutation (69.1%) or ATTRwt (15.6%). Predominant phenotype distribution was neurologic (50.4%), mixed (35.8%), and cardiac (13.8%) for all symptomatic patients (n = 240); neurologic (67.8%), mixed (21.2%), and cardiac (11.0%) for symptomatic Val30Met (n = 146); and mixed (64.9%), cardiac (22.8%), and neurologic (12.3%) for symptomatic ATTRwt (n = 57). Symptomatic patients reported a range of ATTR amyloidosis signs and symptoms at enrollment, with autonomic neuropathy and sensory neuropathy common in all phenotypes.ConclusionsThese results from THAOS highlight the phenotypic heterogeneity associated with ATTR amyloidosis in Spain and the importance of comprehensive neurologic and cardiac evaluations in all patients with ATTR amyloidosis.Trial registrationClinicalTrials.gov: NCT00628745.

Dataset Information

Hereditary ATTR Amyloidosis in Austria: Prevalence and Epidemiological Hot Spots.

Publications

Hereditary ATTR Amyloidosis in Austria: Prevalence and Epidemiological Hot Spots.

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