Description of the First Cases with ADAMTS13 Mutations in Hungary
Authors: Réti Marienn , Sinkovits György , Cseprekál Orsolya , Csuka Dorottya , Szilágyi Ágnes , Farkas Zita , Klucsik Zsolt , Szederjesi Attila , Wágner László , Reusz György , Kremer Hovinga Johanna A. , Rigó János , Masszi Tamas , Prohászka Zoltan 
Published: October 2019

Abstract
INTRODUCTION:
Low ADAMTS13 activity is associated with an increased risk of thrombotic thrombocytopenic purpura (TTP). This may be caused by the presence of inhibitory autoantibody (immune-mediated TTP) or genetic deficiency of the enzyme. The latter condition is also known as Upshaw-Schulman syndrome (USS), the extremely rare congenital form of TTP. The clinical picture typically presents during infancy or early childhood but an increasing number of late-onset cases are detected.
OBJECTIVE:
Clinical and laboratory characterization of the first 5 Hungarian cases with ADAMTS13 mutations.
PATIENTS:
During the last 4 years, 5 cases with ADAMTS13 gene mutations were recognized in Hungary. All were adults, 4 females and 1 male. Two patients (Pts) showed an immune-mediated TTP like clinical picture, while 3 Pts were examined in conjunction with their pregnancies. The first Pt was an 18 years old girl, initially presenting with stroke and isolated cerebral vasculitis. She responded promptly to plasma exchange (PE) combined with immunosuppressive treatment (ISU) and acetylsalicylate (AS). However, severe headache with progressively decreasing platelet (PLT) count into the low normal range and repeatedly deficient ADAMTS13 activity returned after one week of PE cessation necessitating further treatment. ISU was stopped when cerebral vasculitis was excluded. There were several, plasma (PE/infusion) responsive severe headache+bradycardia episodes without hematologic manifestation in the follow-up period. The first TTP episode of the only male Pt occurred at age of 25 and the later clinical course highly resembled autoimmune relapsing (intermittent type) TTP. The Pt received several series of PEs, ISU, even splenectomy, before having the correct diagnosis. Interestingly, this Pt had unclassified HUS in the childhood. The 3rd case was a 40 years old woman with HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count) needing an immediate cesarean section (CS) in the 25th week of gestation. She achieved a spontaneous remission and remained symptom-free. The fourth Pt a 29 years old female had typical HUS at 3 years of age. Her kidney function slowly declined without HUS flares to end-stage kidney failure necessitating kidney transplantation. She had deep venous thrombosis (DVT) and intrauterine fetal death at 20 weeks of gestation. The workup showed decreased but not severely deficient ADAMTS13 activity. She received AS + low molecular weight heparin (LMWH) and increasing dose of plasma treatment starting at the 10th week of gestation of her next pregnancy. CS was done due to progressive hypertension and worsening placental circulation at the 30th week of gestation. The last Pt was a 41-year-old pregnant woman with recurrent abortions in her history. She received AS and LMWH only. The pregnancy was terminated by CS due to severe vaginal bleeding at the 30th week of gestation.
RESULTS:
Pts 1 and 2 with TTP clinical phenotype and Pt 3 with HELLP syndrome had deficient ADAMTS13 activity (0-0-8%, respectively). The activity was decreased but not deficient in Pts 4 and 5 (13-35%). All deficient Pts were compound heterozygous for ADAMTS13 mutations: c.3178C>T and c.4143-4144dupA (Pt1), c.1016_1017delCA and c.3199T>A (Pt2), c.1261C>T and c.3283C>T (Pt3). Three of these mutations were described in patients with USS, 1 in Pts with DVT, whereas 2 mutations are novel. By family study, we could demonstrate the association of c.1261C>T mutation described in DVT and one USS Pts with reduced ADAMTS13 activity. The two non-deficient cases were heterozygous for one of the following mutations: c.3178C>T and c.2839C>T. The previous was identified in late-onset USS, the latter has not yet been described, its association with reduced ADAMTS13 activity was also proven by family study.
CONCLUSIONS:
Clinical and molecular characterization of the first 5 Hungarian cases with ADAMTS13 mutations was presented. Compound heterozygous, damaging ADAMTS13 mutations with deficient plasma ADAMTS13 activity were associated with serious clinical consequences. In case of thrombotic microangiopathy in young patients with stroke, or HELLP syndrome, complete workup for ADAMTS13 activity and inhibitors is necessary, and genetic analysis should be considered. Three new ADAMTS13 mutations (c.1016_1017delCA, c.3199T>A , c.2839C>T) were identified and shown to be associated with decreased plasma ADAMTS13 activity.

Disclosures
Kremer Hovinga: Ablynx: Other: Member of Advisory Board; Shire: Other: Member of Advisory Board, Research Funding. Masszi:AbbVie: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Janssen-Cilag: Consultancy; BMS: Consultancy; Pfizer: Consultancy.