Severe deficiency of the specific von Willebrand factor-cleaving protease (ADAMTS 13) activity in a subgroup of children with atypical hemolytic uremic syndrome

Veyradier, Agnès; Obert, Bernadette; Haddad, Élie; Cloarec, Sylvie; Nivet, Hubert; Foulard, M; Lesure, Francois; Delattre, P.; Lakhdari, Mustapha; Meyer, Dominique; Girma, Jean‐Pierre; Loriat, Chantal

doi:10.1067/mpd.2003.79

Cited by 91 publications

(79 citation statements)

References 36 publications

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“…1,8 Remuzzi et al and Veyradier et al also noted that it can be very difficult to clinically differentiate congenital TTP (Upshaw-Schulman syndrome due to deficiency of ADAMTS13) from infantile-onset aHUS. 1,8 Partial deficiency of ADAMTS13 also has been reported in sepsis 9,10 and pregnancyassociated HELLP syndrome (hemolysis, elevated liver enzyme, and low platelet), 11 both diseases associated with TMA.…”

Section: Discussionmentioning

confidence: 99%

Partial ADAMTS13 deficiency in atypical hemolytic uremic syndrome

Feng

Eyler

Zhang

et al. 2013

Blood

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• Reduction in ADAMTS13 function and complement dysregulation coexist in a significant number of patients with aHUS.• Variations in the ADAMTS13 gene (polymorphisms and rare variants) are partly responsible for the reduced ADAMTS13 function in aHUS.Complement dysregulation leads to atypical hemolytic uremic syndrome (aHUS), while ADAMTS13 deficiency causes thrombotic thrombocytopenic purpura. We investigated whether genetic variations in the ADAMTS13 gene partially explain the reduced activity known to occur in some patients with aHUS. We measured complement activity and ADAMTS13 function, and completed mutation screening of multiple complement genes and ADAMTS13 in a large cohort of aHUS patients. In over 50% of patients we identified complement gene mutations. Surprisingly, 80% of patients also carried at least 1 nonsynonymous change in ADAMTS13, and in 38% of patients, multiple ADAMTS13 variations were found. Six of the 9 amino acid substitutions in ADAMTS13 were common single nucleotide polymorphisms; however, 3 variants-A747V, V832M, and R1096H-were rare, with minor allele frequencies of 0.0094%, 0.5%, and 0.32%, respectively. Reduced complement and ADAMTS13 activity (<60% of normal activity) were found in over 60% and 50% of patients, respectively. We concluded that partial ADAMTS13 deficiency is a common finding in aHUS patients and that genetic screening and functional tests of ADAMTS13 should be considered in these patients. (Blood.

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Section: Discussionmentioning

confidence: 99%

Partial ADAMTS13 deficiency in atypical hemolytic uremic syndrome

Feng

Eyler

Zhang

et al. 2013

Blood

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“…Numbers indicate the position of the last represented amino acid in splitting (double contour or "tram track" appearance) of the glomerular basement membrane, thereby causing injury of podocytes, glomerular capillaries, and mesangial cells. 2 Familial occurrence has been described for both primary/idiopathic forms of MPGN [3][4][5][6] and for rare forms of thrombotic microangiopathy, [7][8][9][10] but little is known about the underlying genetic etiology. We performed homozygosity mapping and whole exome sequencing in a large index family from Turkey with four siblings affected with autosomal recessive disease with histologic signs of MPGN accompanied by prominent endothelial distress to identify genetic variants causative of this admixed phenotype.…”

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confidence: 99%

DGKE Variants Cause a Glomerular Microangiopathy That Mimics Membranoproliferative GN

Özaltın

Li²,

Rauhauser³

et al. 2013

Journal of the American Society of Nephrology

132

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Renal microangiopathies and membranoproliferative GN (MPGN) can manifest similar clinical presentations and histology, suggesting the possibility of a common underlying mechanism in some cases. Here, we performed homozygosity mapping and whole exome sequencing in a Turkish consanguineous family and identified DGKE gene variants as the cause of a membranoproliferative-like glomerular microangiopathy. Furthermore, we identified two additional DGKE variants in a cohort of 142 unrelated patients diagnosed with membranoproliferative GN. This gene encodes the diacylglycerol kinase DGK«, which is an intracellular lipid kinase that phosphorylates diacylglycerol to phosphatidic acid. Immunofluorescence confocal microscopy demonstrated that mouse and rat Dgk« colocalizes with the podocyte marker WT1 but not with the endothelial marker CD31. Patch-clamp experiments in human embryonic kidney (HEK293) cells showed that DGK« variants affect the intracellular concentration of diacylglycerol. Taken together, these results not only identify a genetic cause of a glomerular microangiopathy but also suggest that the phosphatidylinositol cycle, which requires DGKE, is critical to the normal function of podocytes.

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“…In rare cases, renal involvement is severe enough to cause endstage renal failure (1,(21)(22)(23)(24)(25). Those patients' clinical manifestations are difficult to distinguish from those of hemolytic uremic syndrome (HUS), a form of thrombotic microangiopathy characterized by predominant renal involvement, often with renal failure (1,20,26).…”

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confidence: 99%

Complement Factor H Mutation in Familial Thrombotic Thrombocytopenic Purpura with ADAMTS13 Deficiency and Renal Involvement

Noris¹,

Bucchioni²,

Galbusera³

et al. 2005

Journal of the American Society of Nephrology

129

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Thrombotic thrombocytopenic purpura is a rare disorder of small vessels that is associated with deficiency of the von Willebrand factor-cleaving protease ADAMTS13, which favors platelet adhesion and aggregation in the microcirculation. The disease manifests mainly with central nervous system symptoms, but cases of renal insufficiency have been reported. Presented are findings of the genetic basis of phenotype heterogeneity in thrombotic thrombocytopenic purpura in two sisters within one family. The patients had ADAMTS13 deficiency as a result of two heterozygous mutations (causing V88M and G1239V changes). In addition, a heterozygous mutation (causing an S890I change) in factor H of complement was found in the patient who developed chronic renal failure but not in her sister, who presented with exclusive neurologic symptoms. 16: 117716: -118316: , 200516: . doi: 10.1681 T hrombotic thrombocytopenic purpura (TTP) is a disease of small vessels characterized by anemia that is caused by erythrocyte fragmentation in the microcirculation and thrombocytopenia that is caused by intravascular thrombi of aggregated platelets (1). Recent studies provided substantial evidence that 70 to 80% of cases of TTP are triggered by a deficiency of ADAMTS13 (2-4), a plasma metalloprotease that cleaves von Willebrand factor multimers soon after their secretion by endothelial cells (1,5-7). ADAMTS13 deficiency can be constitutive, as a result of homozygous or double heterozygous mutations in the corresponding gene (8 -13), or acquired, as a result of the presence of circulating inhibitory antibodies (1,3,4,14 -20). J Am Soc NephrolTTP manifests mainly with central nervous system symptoms, but cases of renal insufficiency have been reported (1). In rare cases, renal involvement is severe enough to cause endstage renal failure (1,21-25). Those patients' clinical manifestations are difficult to distinguish from those of hemolytic uremic syndrome (HUS), a form of thrombotic microangiopathy characterized by predominant renal involvement, often with renal failure (1,20,26). This difficulty has given rise to a heated debate on whether a severe deficiency of ADAMTS13 activity is enough to distinguish TTP from HUS (27,28).Here we present findings of the genetic basis of phenotype heterogeneity in patients with congenital ADAMTS13 deficiency. We studied a family with two affected sisters, one who presented with exclusive neurologic symptoms and the other one with severe renal involvement that required chronic dialysis. These diverse clinical manifestations suggested to us that the genetic background could be different. Materials and Methods PatientsA woman, now 60 yr old (F48), and her younger sister (F45, died in 2002 at the age of 55 yr) were referred to our International Registry of Recurrent and Familial HUS/TTP in 1996 because of history of recurrent and familial thrombotic microangiopathy. The youngest brother died at the age of 15 yr of leukemia. The other four siblings (three male and one female) all seem to be healthy and have no sig...

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Severe deficiency of the specific von Willebrand factor-cleaving protease (ADAMTS 13) activity in a subgroup of children with atypical hemolytic uremic syndrome

Cited by 91 publications

References 36 publications

Partial ADAMTS13 deficiency in atypical hemolytic uremic syndrome

Partial ADAMTS13 deficiency in atypical hemolytic uremic syndrome

DGKE Variants Cause a Glomerular Microangiopathy That Mimics Membranoproliferative GN

Complement Factor H Mutation in Familial Thrombotic Thrombocytopenic Purpura with ADAMTS13 Deficiency and Renal Involvement

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