Atypical HUS: Don't stop the research

Project location: ITALY
Project start date: February 2003 - Project end date: February 2004
Project number: 2002-10
Beneficiary: MARIO NEGRI



2003 Report

HUS is a disease of microangiopathic hemolytic anemia and thrombocytopenia with signs of renal involvement. A genetic underlying defect is unlikely to have a main role in typical D+ HUS that should be considered a distinct syndrome and kept separated from all the other forms of atypical HUS that are believed to have an hereditary predisposition to microvascular thrombosis. Only 30% of HUS patients do have Factor H mutations indicating that other genes may be involved. ADAMTS13 (a vWF-cleaving protease) activity has been found deficient in thrombotic thrombocytopenic purpura (TTP, a disease related to HUS), and linkage analysis and mutation screening provided evidence that mutations in ADAMTS13 gene lead to an inactive enzyme and to TTP. Recently, a complete deficiency of the ADAMTS13 activity in patients with HUS has been reported. In our series of patients two families presented each with one patient with HUS and one with TTP, who lacked ADAMTS13 activity, further confirming that the protease defect cannot be narrowed to specific subtypes of thrombotic microangiopathies. These data support the concept that deficiency of ADAMTS13 activity may result in either the HUS or the TTP phenotype.

The general aim of this application is to study ADAMTS13 abnormalities in atypical HUS.


So far ADAMTS13 activity was measured in 76 patients with different forms of atypical HUS (30 patients with the sporadic form, 17 patients with the recurrent form, and 29 patients with the familial form). Until now we have identified 6 patients (one patient with the sporadic form, 3 patients with recurrent HUS and 2 patients with the familial form) who have complete absence of ADAMTS13 activity. No autoantibodies were found in these patients. We measured ADAMTS13 activity in the available relatives of these patients. The deficiency has been probably inherited as an autosomal recessive trait as documented by half normal levels of ADAMTS13 activity in their asymptomatic parents and in obligate carriers.

Linkage analysis was performed. A recessive mode of inheritance can fit the haplotype data and ADAMTS13 activity levels in HUS. Search for mutation by direct sequencing is undergoing. Until now we have identified 3 new mutations in ADAMTS13 gene in two patients with the familial form of HUS.

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