Auer-Grumbach Michaela, Rettl Rene, Ablasser Klemens, Agis Hermine, Beetz Christian, Duca Franz, Gattermeier Martin, Glaser Franz, Hacker Markus, Kain Renate, Kaufmann Birgit, Kovacs Gabor G, Lampl Christian, Ljevakovic Neira, Nagele Jutta, Pölzl Gerhard, Quasthoff Stefan, Raimann Bernadette, Rauschka Helmut, Reiter Christian, Skrahina Volha, Schuhfried Othmar, Sunder-Plassmann Raute, Verheyen Nicolas D, Wanschitz Julia, Weber Thomas, Windhager Reinhard, Wurm Raphael, Zimprich Friedrich, Löscher Wolfgang N, Bonderman Diana
Department of Orthopaedics and Trauma Surgery, Medical University of Vienna, 1090 Vienna, Austria.
Department of Cardiology, Medical University of Vienna, 1090 Vienna, Austria.
J Clin Med. 2020 Jul 14;9(7):2234. doi: 10.3390/jcm9072234.
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 () 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.
Within the period of 2014-2019, patients with ATTR-associated cardiomyopathy and/or unexplained progressive polyneuropathies were screened for mutations in the gene.
We identified 43 cases from 22 families carrying 10 different 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 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.
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 gene in an extended cohort of patients with unexplained heart failure and progressive polyneuropathy.
遗传性转甲状腺素蛋白淀粉样变性（hATTR）是一种常染色体显性遗传性疾病，由转甲状腺素蛋白（TTR）基因突变导致组织中淀粉样原纤维蓄积引起。hATTR的患病率仍不明确，在许多国家可能被低估。为了有针对性地应用新疗法，早期诊断以及对表型 - 基因型相关性的了解必不可少。本研究旨在评估奥地利hATTR的患病率和表型谱。
在2014年至2019年期间，对患有ATTR相关性心肌病和/或不明原因进行性多发性神经病的患者进行TTR基因突变筛查。
我们从22个家族中鉴定出43例携带10种不同TTR错义突变的病例，并确认了c.323A>G（p.His108Arg）和c.337G>C（p.Val113Leu）这两个突变热点。另外两名迟发性ATTR患者携带意义未明的变异。大多数患者最初表现为心力衰竭症状，随后在大多数情况下伴有进行性多发性神经病。共有55%的患者在其他器官表现出现之前有腕管综合征病史。
我们的研究强调了hATTR在淀粉样蛋白驱动的心肌病和轴索性多发性神经病发病机制中的相关性，并表明该疾病在奥地利人群中存在相当大的遗传异质性。基于本研究，奥地利hATTR的估计患病率为1:200,000，但必须考虑到可能存在更多未知病例。关于新的治疗方法，我们强烈建议在不明原因心力衰竭和进行性多发性神经病的扩大患者队列中对TTR基因进行基因检测。
