Résumé
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
(
) 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.
This article evaluates the influence of
sequence variations on both clinical/biological phenotype and ADAMTS13 conformation in USS.
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.
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
sequence variations (
= 43), spread all over
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
sequence variations (
= 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
sequence variations) whose ADAMTS13 antigen levels were detectable: 14 of 16 patients (87.5%) exhibited abnormalities of ADAMTS13 conformation.
In USS, age-onset defines two entities and
sequence variations modify ADAMTS13 conformation.