ADAMTS13 Gene Mutations Influence ADAMTS13 Conformation and Disease Age-Onset in the French Cohort of Upshaw–Schulman Syndrome

Abstract

Background Congenital thrombotic thrombocytopaenic purpura (TTP) or Upshaw–Schulman syndrome (USS) is a rare, life-threatening, inherited thrombotic microangiopathy (TMA). USS is mostly due to bi-allelic recessive sequence variations of the a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13 (ADAMTS13) gene inducing a severe ADAMTS13 deficiency (activity < 10 IU/dL). In healthy individuals, ADAMTS13 circulates in a folded conformation where CUB domains interact with the spacer domain. The spacer–CUB interaction is abrogated when ADAMTS13 is conformationally activated. Objective This article evaluates the influence of ADAMTS13 sequence variations on both clinical/biological phenotype and ADAMTS13 conformation in USS. Patients and Methods All USS patients from the French registry for TMAs (1 January 2000 to 1 June 2017) were investigated for ADAMTS13 genotype, phenotype (activity, antigen and autoantibodies) and conformation. Clinical records were analysed (inaugural acute TTP and follow-up). Child-onset USS was compared with adult-onset USS. Results Fifty-six USS patients from 51 families (34 child-onset and 22 adult-onset cases) were enrolled. Child-onset USS was characterized by a large panel of ADAMTS13 sequence variations (n = 43), spread all over ADAMTS13 gene and not correlated with either clinical features or plasmatic ADAMTS13 parameters. In contrast, adult-onset USS, consisting exclusively in pregnancy-induced TTP, included a smaller and distinct panel of ADAMTS13 sequence variations (n = 20) because of one mutation (p.Arg1060Trp) present in 82% of patients. ADAMTS13 conformation was studied in 16 USS patients (5 child-onset and 11 adult-onset USS, encompassing 16 distinct ADAMTS13 sequence variations) whose ADAMTS13 antigen levels were detectable: 14 of 16 patients (87.5%) exhibited abnormalities of ADAMTS13 conformation. Conclusion In USS, age-onset defines two entities and ADAMTS13 sequence variations modify ADAMTS13 conformation.

Insights from the Hereditary Thrombotic Thrombocytopenic Purpura Registry: Discussion of Key Findings Based on Individual Cases from Switzerland

“…The clinical presentation of hTTP is variable, even within families 6,10,12 resulting in diagnostic delay and not seldom misdiagnoses, such as neonatal jaundice because of blood group incompatibility, immune-mediated thrombocytopenia (ITP), hemolytic uremic syndrome (HUS), and premature stroke without recognizing the true underlying cause. [13][14][15] Clinical presentation of TTP episodes is often less distinct than in immune-mediated TTP with autoantibody-mediated ADAMTS13 deficiency. 3, [16][17][18][19] Signs and symptoms of endorgan ischemia that respond to plasma treatment may be present even without (severe) thrombocytopenia and microangiopathic hemolytic anemia.…”

“…3, [16][17][18][19] Signs and symptoms of endorgan ischemia that respond to plasma treatment may be present even without (severe) thrombocytopenia and microangiopathic hemolytic anemia. Historically, a dichotomous distribution of age at disease onset had been suggested, 13,20,21 with patients presenting before the age of 5 years, and a second peak after puberty in early adulthood, often during pregnancy. 13,[22][23][24] As many of these latter patients underwent exchange transfusions soon after birth, 6,10 a genuine adult onset can be questioned.…”

Anti‐ADAMTS13 autoantibodies in immune‐mediated thrombotic thrombocytopenic purpura do not hamper ELISA‐based quantification of ADAMTS13 antigen

“…This ADAMTS13 antigen ELISA was validated in‐house, but the validation was not published at that time . Different clinical laboratories used our ADAMTS13 antigen ELISA in the meantime and validated the assay in their laboratories . In the current paper we report the in‐house validation of this ADAMTS13 antigen ELISA to document the reliability of our assay.…”

Congenital thrombotic thrombocytopenic purpura in a large cohort of patients carrying a novel mutation in ADAMTS13 gene

“…In contrast, our results may support an assumption, that phenotype severity cannot be attributed to ADAMTS13 deficiency alone and that other environmental and hereditary modifiers may influence disease course. It is also plausible that some, yet unknown, modulatory genes [2] or conformational changes [9] may affect ADAMTS13 activity. Identification of the genotype-phenotype associations in cTTP is challenging partly because most of the patients with established mutations in previous series were not homozygous for the same mutations but rather compound heterozygotes [5,6].…”