Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, Bern, Switzerland.
Department for BioMedical Research, University of Bern, Bern, Switzerland.
Haematologica. 2019 Oct;104(10):2107-2115. doi: 10.3324/haematol.2019.216796. Epub 2019 Feb 21.
Congenital thrombotic thrombocytopenic purpura is an autosomal recessive inherited disease with a clinically heterogeneous course and an incompletely understood genotype-phenotype correlation. In 2006, the Hereditary TTP Registry started recruitment for a study which aimed to improve the understanding of this ultra-rare disease. The objective of this study is to present characteristics of the cohort until the end of 2017 and to explore the relationship between overt disease onset and ADAMTS13 activity with emphasis on the recurring c.4143_4144dupA mutation. Diagnosis of congenital thrombotic thrombocytopenic purpura was confirmed by severely deficient ADAMTS13 activity (≤10% of normal) in the absence of a functional inhibitor and the presence of mutations on both alleles. By the end of 2017, 123 confirmed patients had been enrolled from Europe (n=55), Asia (n=52, 90% from Japan), the Americas (n=14), and Africa (n=2). First recognized disease manifestation occurred from around birth up to the age of 70 years. Of the 98 different mutations detected, c.4143_4144dupA (exon 29; p.Glu1382Argfs*6) was the most frequent mutation, present on 60 of 246 alleles. We found a larger proportion of compound heterozygous than homozygous carriers of c.4143_4144dupA with overt disease onset at < 3 months of age (50% 37%), despite the fact that ADAMTS13 activity was <1% in 18 of 20 homozygous, but in only 8 of 14 compound heterozygous carriers. An evaluation of overt disease onset in all patients with an available sensitive ADAMTS13 activity assay (n=97) shows that residual ADAMTS13 activity is not the only determinant of age at first disease manifestation. Registered at .
先天性血栓性血小板减少性紫癜是一种常染色体隐性遗传性疾病，临床表现具有高度异质性，基因型与表型相关性尚不完全明确。2006 年，遗传性 TTP 登记处开始招募患者，旨在深入了解这种罕见疾病。本研究的目的是描述 2017 年底前该队列的特点，并探讨显性疾病发作与 ADAMTS13 活性之间的关系，重点关注反复出现的 c.4143_4144dupA 突变。先天性血栓性血小板减少性紫癜的诊断依据为 ADAMTS13 活性严重缺乏（正常活性的≤10%），无功能性抑制剂，且两个等位基因均存在突变。截止到 2017 年底，已从欧洲（n=55）、亚洲（n=52，90%来自日本）、美洲（n=14）和非洲（n=2）共招募 123 例确诊患者。首次发病时间从出生到 70 岁不等。在检测到的 98 种不同突变中，c.4143_4144dupA（外显子 29；p.Glu1382Argfs*6）是最常见的突变，246 个等位基因中有 60 个携带该突变。我们发现，与 3 月龄内显性疾病发作的杂合子相比，纯合子携带者携带 c.4143_4144dupA 的比例更高（50%比 37%），尽管 20 例纯合子中有 18 例 ADAMTS13 活性＜1%，而 14 例杂合子中只有 8 例。对所有可获得敏感 ADAMTS13 活性检测结果的患者（n=97）显性疾病发作情况进行评估，结果表明 ADAMTS13 活性的残留水平并不是疾病首次发作时年龄的唯一决定因素。登记于.
