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INTERNATIONAL REGISTRY of RECURRENT and FAMILIAL HEMOLYTIC UREMIC SYNDROME (HUS) and THROMBOTIC THROMBOCYTOPENIC PURPURA INTERNATIONAL REGISTRY of RECURRENT and FAMILIAL HEMOLYTIC UREMIC SYNDROME (HUS) and THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP) HYSTORY: The Registry was established in 1996. AIM OF THE REGISTRY: - understanding the pathogenesis of HUS/TTP - studying the genetic and biochemical abnormalities of HUS/TTP - finding the best therapeutic approach for patients - collecting clinical and genetic data of patients and their families - giving up-to-date information to physicians and families

THE THROMBOTIC MICROANGIOPATHY (TMA) The term “thrombotic microangiopathy” (TMA) defines a lesion of vessel THE THROMBOTIC MICROANGIOPATHY (TMA) The term “thrombotic microangiopathy” (TMA) defines a lesion of vessel wall thickening (mainly arterioles and capillaries), intraluminal platelet thrombosis and partial or complete obstruction of the vessel lumina 1. HUS microangiopathic haemolysis, thrombocytopenia and renal failure TTP microangiopathic haemolysis, thrombocytopenia and cerebral lesions HUS and TTP are entities pathologically indistinguishable 1 Caprioli J. et al. Human Molecular Genetics, 2003, Vol. 12, No. 24: 3385 -3395

FORMS OF HUS/TTP: The most common form of HUS in children, with predominant renal FORMS OF HUS/TTP: The most common form of HUS in children, with predominant renal failure, is associated with a particular gastro-intestinal infection. This form usually has an excellent prognosis. There also rare forms of HUS/TTP without gastro-intestinal infection, that have a much poorer prognosis: - relapsing form (when the patient has severaò relapses of the disease) - familial form (when there at least 2 subjects with HUS/TTP in the same family) TTP is the most common form of TMA in adults and manifests with prevailing neurological symptoms.

THERAPY OF HUS/TTP: Early plasma-exchange or plasma infusion of an health donor are the THERAPY OF HUS/TTP: Early plasma-exchange or plasma infusion of an health donor are the current therapies for acute phases of the disease. Dialysis is necessary if there is an acute renal failure

HOW FAR IS RESEARCH? There a lot of research studies ongoing about HUS/TTP to HOW FAR IS RESEARCH? There a lot of research studies ongoing about HUS/TTP to understand the pathogenesis and to find the specific therapies of the disease. Researchers involving are studying the role of substances of the blood coagulation and particularly some proteins of the complement system, and are studying the genetic aspects of HUS/TTP. As for therapy: research is working on the optimisation of plasma treatment for patients.

WHAT OUR RESEARCH LABORATORY OF THE REGISTRY IS DOING TO BETTER UNDERSTAND HUS/TTP? GENETIC WHAT OUR RESEARCH LABORATORY OF THE REGISTRY IS DOING TO BETTER UNDERSTAND HUS/TTP? GENETIC AND BIOCHEMICAL STUDIES ON: Factor H – CFH - a plasmatic circulating protein produced by the liver and involved in the regulation of the complement system, that is often spoiled in patients with HUS. Membrane Cofactor Protein – MCP - a complement regulatory protein. Recently our researchers have found a mutation of MCP gene in a family with HUS. ADAMTS 13 – the Von Willebrand Factor cleaving protease – an enzyme which degrades the VWF multimers, preventing platelet adhesion and aggregation in the microcirculation. The plasma levels of ADAMTS 13 protease in some patients (particularly with TTP) are absent or very low, due to a constitutive or acquired defective activity. 2 Noris M. et al. Lancet, 2003, Vol. 362: 1542 -1547

WHAT THE REGISTRY RESEARCHERS ARE DOING? Recently* our researchers found 17 different mutations in WHAT THE REGISTRY RESEARCHERS ARE DOING? Recently* our researchers found 17 different mutations in the factor H gene of 33 patients with HUS referred to the Registry. 3 Caprioli et al. Human Molecular Genetics, 2003, Vol. 12, No. 24: 3385 -3395

MUTATIONS FOUND IN FACTOR H GENE FROM PATIENTS REFERRED TO THE REGISTRY R L MUTATIONS FOUND IN FACTOR H GENE FROM PATIENTS REFERRED TO THE REGISTRY R L Trp 1183 Arg H G Arg 60 Gly STOP H Tyr 951 His W Cys 1163 Trp Gln 950 His del A 1494 -1496 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 NH 2 COOH WT A K R Q L K A L I Y N S Y STOP R N D Gly 1194 Asp T Glu 1172 Stop E G M STOP E I A S Val 1197 Ala E A V R E K LE Y S G I F P D A Glu 1198 Ala V T V W C C C NH 2 H P C T K A K T R R COOH R G L Y Q Q T R STOP Arg 1215 Gln H L SR S S 24 bp deletion C C C Arg 1210 Cys

PARTICIPATING CENTERS OF THE INTERNATIONAL REGISTRY OF HEMOLYTIC UREMIC SYNDROME AND THROMBOTIC THROMBOCYTOPENIC PURPURA: PARTICIPATING CENTERS OF THE INTERNATIONAL REGISTRY OF HEMOLYTIC UREMIC SYNDROME AND THROMBOTIC THROMBOCYTOPENIC PURPURA: n n Italian Centers: 72 Abroad Centers: 39 Bergamo DENMARK U. S. A UK CANADA BELGIUM ARGENTINA RSA SAUDI ARABIA ISRAEL GERMANY SWITZERLAND PORTUGAL SPAIN

THE INTERNATIONAL REGISTRY OF HUS/TTP: PATIENTS DATA Atypical forms HUS TTP Familial forms 54 THE INTERNATIONAL REGISTRY OF HUS/TTP: PATIENTS DATA Atypical forms HUS TTP Familial forms 54 (within 29 families) 8 (within 6 families) Recurrent forms 51 36 Sporadic forms 106 22 Tot. 211 Tot. 66

CONTACTS We perform biochemical and genetic analyses for patients with atypical form of HUS/TTP. CONTACTS We perform biochemical and genetic analyses for patients with atypical form of HUS/TTP. For information and for other questions and for any other questions, please contact: Clinical Research Center for Rare Diseases Aldo e Cele Daccò Mario Negri Institute for Pharmacological Research Via G. B. Camozzi, 3 -24020 - Ranica (BG) Italy Phone: +39 -035 -4535304 Fax: +39 -035 -4535373 E-mail: [email protected] it Contact persons: Elena Bresin, MD Erica Daina, MD Sara Gamba, RN