Dori Amir, Chorin Odelia, Ruhrman-Shahar Noa, Fellner Avi, Alon Tayir, Reznik-Wolf Haike, Barel Ortal, Fourey Dana, Zadok Osnat Itzhaki Ben, Aviv Yaron, Nikitin Vera, Ben-David Merav, Shavit-Stein Efrat, Goldis Rivka, Kaplan Batia, Shapiro Daniela, Pras Elon, Pollak Arthur, Meiner Vardiella, Arad Michael, Greenbaum Lior
Department of Neurology, Sheba Medical Center, Ramat Gan, Israel.
Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel.
Eur J Neurol. 2025 Feb;32(2):e70057. doi: 10.1111/ene.70057.
Hereditary transthyretin (ATTRv) amyloidosis is a rare, adult-onset autosomal-dominant disorder caused by pathogenic variants in the transthyretin (TTR) gene. Data about relevant variants in specific populations and typical initial manifestations may facilitate early diagnosis and treatment. We here describe the genetic landscape of ATTRv amyloidosis in Israel.
Genetic and clinical data of TTR variant carriers and ATTRv amyloidosis patients were collected from a national referral clinic and other subspecialty clinics in Israel. Genotype-phenotype correlations of the detected variants were detailed. In addition, two large Israeli exome sequence (ES) databases were screened for TTR variants.
Seven heterozygous disease-causing variants in TTR were identified among 95 adults (52 males, 50.7%). The Ser77Tyr variant was found in 68 (71.6%) subjects of Jewish Yemenite ancestry. Val122Ile was found in 9 (9.4%) subjects and was the only variant detected in individuals of Arab ethnicity. Other variants were Thr60Ala, Val30Met, Val32Ala, Ala81Val, and Glu89Val. Thirty-five individuals were ATTRv amyloidosis patients (25 males, 71.4%), diagnosed at a mean age of 62.5 ± 6.7 years, and 23 (63.7%) were due to Ser77Tyr. Initial symptoms were mostly related to carpal tunnel syndrome, and the sensitivity of scintigraphy was low for Ser77Tyr but high for Thr60Ala and Val32Ala variants. TTR pathogenic variants were detected in 14 of approximately 36,600 subjects who underwent ES, including Val122Ile in 9 subjects of Arab ethnicity.
Most ATTRv amyloidosis cases in Israel are attributable to the Ser77Tyr variant. However, other variants also contribute to disease occurrence, and testing is warranted in clinically suspected patients.
遗传性转甲状腺素蛋白（ATTRv）淀粉样变性是一种罕见的成人发病的常染色体显性疾病，由转甲状腺素蛋白（TTR）基因的致病变异引起。有关特定人群中相关变异和典型初始表现的数据可能有助于早期诊断和治疗。我们在此描述以色列ATTRv淀粉样变性的遗传情况。
从以色列的一家国家转诊诊所和其他专科诊所收集TTR变异携带者和ATTRv淀粉样变性患者的遗传和临床数据。详细分析检测到的变异的基因型-表型相关性。此外，对两个大型以色列外显子序列（ES）数据库进行TTR变异筛查。
在95名成年人（52名男性，占50.7%）中鉴定出7种TTR杂合致病变异。Ser77Tyr变异在68名（71.6%）犹太也门人后裔受试者中被发现。Val122Ile在9名（9.4%）受试者中被发现，是在阿拉伯族裔个体中检测到的唯一变异。其他变异为Thr60Ala、Val30Met、Val32Ala、Ala81Val和Glu89Val。35名个体为ATTRv淀粉样变性患者（25名男性，占71.4%），诊断时的平均年龄为62.5±6.7岁，其中23名（63.7%）由Ser77Tyr引起。初始症状大多与腕管综合征有关，闪烁扫描对Ser77Tyr的敏感性较低，但对Thr60Ala和Val32Ala变异的敏感性较高。在接受ES的约36,600名受试者中，有14名检测到TTR致病变异，其中包括9名阿拉伯族裔受试者中的Val122Ile。
以色列的大多数ATTRv淀粉样变性病例归因于Ser77Tyr变异。然而，其他变异也导致疾病发生，对于临床疑似患者有必要进行检测。
