Tzagournissakis Minas, Foukarakis Emmanouil, Samonakis Dimitrios, Tsilimbaris Miltiadis, Michaelidou Kleita, Mathioudakis Lambros, Marinis Anastasios, Giannakoudakis Emmanouil, Spanaki Cleanthe, Skoula Irene, Erimaki Sofia, Amoiridis Georgios, Koutsis Georgios, Koukouraki Sofia, Stylianou Kostas, Plaitakis Andreas, Mitsias Panayiotis D, Zaganas Ioannis
Neurology Department (M. Tzagournissakis, C.S., S.E., P.D.M., I.Z.), University Hospital of Heraklion; Cardiology Department (E.F.), Venizelion General Hospital of Heraklion; Gastroenterology Department (D.S.), and Ophthalmology Department (M. Tsilimbaris), University Hospital of Heraklion; Neurogenetics Laboratory (K.M., L.M., A.M., I.S., G.A., A.P., I.Z.), Medical School, University of Crete, Heraklion; Neurology Department (E.G.), Venizelion General Hospital of Heraklion, Crete; Eginition Hospital (G.K.), Medical School, University of Athens; Nuclear Medicine Department (S.K.), University Hospital of Heraklion; and Renal Medicine Department (K.S.), University Hospital of Heraklion, Crete, Greece.
Neurol Genet. 2022 Sep 9;8(5):e200013. doi: 10.1212/NXG.0000000000200013. eCollection 2022 Oct.
Our goal was to study hereditary transthyretin-related amyloidosis (hATTR) in Crete, Greece.
We aimed at ascertaining all hATTR cases in Crete, an island of 0.62 million people. For this, we evaluated patients with polyneuropathy, autonomic involvement, cardiomyopathy, and/or ophthalmopathy suggestive of hATTR, who presented to the physicians of this study or were referred to them by other physicians. Genetic analyses were performed on all patients suspected of suffering from hATTR. We included in our observational longitudinal cohort study all individuals, residents of Crete, who, during the study period (1993-2019), were found to carry a pathogenic variant.
Over the past 27 years, 30 individuals (15 female patients, 15 male patients), from 12 apparently unrelated families, were diagnosed with hATTR, whereas evaluation of their offspring identified 5 asymptomatic pathogenic variant carriers. The most prevalent variant detected was p.Val50Met, affecting 19 patients (11 female patients, 8 male patients) and causing a rather consistent phenotype characterized by predominant polyneuropathy of early adult onset (median age of symptom onset: 30 years; range: 18-37 years). Specifically, patients affected by the p.Val50Met variant experienced progressive sensorimotor disturbances, involving mainly the lower extremities, associated with autonomic and/or gastrointestinal dysfunction. The second most frequent variant was p.Val114Ala, found in 10 patients (4 female patients, 6 male patients) who were affected at an older age (median age of symptom onset: 70 years; range: 54-78 years). This variant caused a predominantly cardiomyopathic phenotype, manifested by congestive heart failure and associated with peripheral neuropathy, carpal tunnel syndrome, and/or autonomic involvement. In these patients, cardiac amyloid deposition was detected on 99m-technetium pyrophosphate scintigraphy and/or heart biopsy. The third variant (p.Arg54Gly) was found in a 50-year-old male patient with ophthalmopathy due to vitreous opacities and positive family history for visual loss. As 22 patients were alive at the end of the study, we calculated the hATTR prevalence in Crete to be 35 cases per 1 million inhabitants.
Our study revealed that the prevalence of hATTR in Crete is one of the world's highest. Three different pathogenic variants causing distinct clinical phenotypes were identified in this relatively small population pool.
我们的目标是研究希腊克里特岛的遗传性转甲状腺素蛋白相关淀粉样变性（hATTR）。
我们旨在确定克里特岛（一个拥有62万人口的岛屿）上所有的hATTR病例。为此，我们评估了出现多神经病、自主神经受累、心肌病和/或提示hATTR的眼病的患者，这些患者前来参与本研究的医生处就诊或由其他医生转诊而来。对所有疑似患有hATTR的患者进行了基因分析。我们将在研究期间（1993 - 2019年）被发现携带致病性变异的所有克里特岛居民纳入了我们的观察性纵向队列研究。
在过去27年中，来自12个明显无亲缘关系家庭的30人（15名女性患者，15名男性患者）被诊断患有hATTR，而对其后代的评估发现了5名无症状的致病性变异携带者。检测到的最常见变异是p.Val50Met，影响了19名患者（11名女性患者，8名男性患者），并导致了一种相当一致的表型，其特征为成年早期以多神经病为主（症状发作的中位年龄：30岁；范围：18 - 37岁）。具体而言，受p.Val50Met变异影响的患者经历了进行性感觉运动障碍，主要累及下肢，并伴有自主神经和/或胃肠功能障碍。第二常见的变异是p.Val114Ala，在10名患者（4名女性患者，6名男性患者）中发现，这些患者发病年龄较大（症状发作的中位年龄：70岁；范围：54 - 78岁）。这种变异导致了以充血性心力衰竭为主要表现的心肌病表型，并伴有周围神经病、腕管综合征和/或自主神经受累。在这些患者中，通过99m锝焦磷酸盐闪烁扫描和/或心脏活检检测到心脏淀粉样沉积。第三个变异（p.Arg54Gly）在一名50岁男性患者中发现，该患者因玻璃体混浊出现眼病且有视力丧失的家族史阳性。由于在研究结束时22名患者存活，我们计算出克里特岛hATTR的患病率为每100万居民中有35例。
我们的研究表明，克里特岛hATTR患病率是世界上最高的之一。在这个相对较小的人群中鉴定出了三种导致不同临床表型的致病性变异。
