Atypical adult-onset methylmalonic acidemia and homocystinuria presenting as hemolytic uremic syndrome.
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ABSTRACT:
SUBMITTER: Navarro D
PROVIDER: S-EPMC5886929 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Hemolytic uremic syndrome (HUS) is a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. The atypical form of HUS is a disease characterized by complement overactivation. Inherited defects in complement genes and acquired autoantibodies against complement regulatory proteins have been described. Incomplete penetrance of mutations in all predisposing genes is reported, suggesting that a precipitating event or trigger is required to unmask the complement regulatory deficiency. The underlying genetic defect predicts the prognosis both in native kidneys and after renal transplantation. The successful trials of the complement inhibitor eculizumab in the treatment of atypical HUS will revolutionize disease management.
| S-EPMC3863953 | biostudies-literature
Project description:The WT1 variant is confirmed to be pathogenic for Denys–Drash syndrome (DDS), a rare disorder characterized by early-onset nephrotic syndrome and renal failure, pseudo-hermaphroditism, and a high risk of Wilms' tumor. Several cases of DDS presenting with atypical hemolytic uremic syndrome (aHUS) have been reported. Here we report the case of a 2-year-old child who was diagnosed with WT1 missense variant, associated with DDS and initial presentation of aHUS. Complement factor H autoantibodies were negative. Complement regulatory system-related gene variants were not found, but a de novo heterozygous c.754G>A missense variant in exon 9 of WT1 gene was detected, resulting in a p. Asp252Asn substitution, by next-generation sequencing. The patient was a female morphologically but proved to be a genetic male because of karyotype 46, XY with normally developed female external genitalia. Bilateral nephrectomy and renal transplantation were performed 1 year later, and there was no recurrence of aHUS at 10 months after transplantation.
| S-EPMC7775732 | biostudies-literature
Project description:Atypical hemolytic uremic syndrome (aHUS) is a disease characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia and acute kidney injury. The histopathologic lesions of aHUS include thrombotic microangiopathy involving the glomerular capillaries and thrombosis involving arterioles or interlobar arteries. Extra-renal manifestations occur in up to 20% of patients. The majority of aHUS is caused by complement system defects impairing ordinary regulatory mechanisms. Activating events therefore lead to unbridled, ongoing complement activity producing widespread endothelial injury. Pathologic mutations include those resulting in loss-of-function in a complement regulatory gene (CFH, CFI, CD46 or THBD) or gain-of-function in an effector gene (CFB or C3). Treatment with the late complement inhibitor, eculizumab - a monoclonal antibody directed against C5 - is effective.
| S-EPMC5472348 | biostudies-other
Project description:Atypical hemolytic uremic syndrome (aHUS) is a disorder characterized by thrombocytopenia and microangiopathic hemolytic anemia due to endothelial injury. aHUS is felt to be caused by defective complement regulation due to underlying genetic mutations in complement regulators or activators, most often of the alternative pathway. Mutations causing aHUS can be subdivided into two groups, loss of function mutations (affecting factor H, factor H-related proteins, membrane co-factor protein, and factor I), and gain of function mutations (affecting factor B and C3). As more information becomes available on the relationship between specific mutations and clinical outcome, complete genetic workup of aHUS patients becomes more and more important. In this review, we will discuss the genetic background of aHUS, the role of complement for aHUS pathogenesis, and the different groups of specific mutations known to be involved in the pathogenesis of aHUS.
| S-EPMC6404389 | biostudies-literature
Project description:The hemolytic-uremic syndrome consists of the triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. The common form of the syndrome is triggered by infection with Shiga toxin-producing bacteria and has a favorable outcome. The less common form of the syndrome, called atypical hemolytic-uremic syndrome, accounts for about 10% of cases, and patients with this form of the syndrome have a poor prognosis. Approximately half of the patients with atypical hemolytic-uremic syndrome have mutations in genes that regulate the complement system. Genetic factors in the remaining cases are unknown. We studied the role of thrombomodulin, an endothelial glycoprotein with anticoagulant, antiinflammatory, and cytoprotective properties, in atypical hemolytic-uremic syndrome.We sequenced the entire thrombomodulin gene (THBD) in 152 patients with atypical hemolytic-uremic syndrome and in 380 controls. Using purified proteins and cell-expression systems, we investigated whether thrombomodulin regulates the complement system, and we characterized the mechanisms. We evaluated the effects of thrombomodulin missense mutations associated with atypical hemolytic-uremic syndrome on complement activation by expressing thrombomodulin variants in cultured cells.Of 152 patients with atypical hemolytic-uremic syndrome, 7 unrelated patients had six different heterozygous missense THBD mutations. In vitro, thrombomodulin binds to C3b and factor H (CFH) and negatively regulates complement by accelerating factor I-mediated inactivation of C3b in the presence of cofactors, CFH or C4b binding protein. By promoting activation of the plasma procarboxypeptidase B, thrombomodulin also accelerates the inactivation of anaphylatoxins C3a and C5a. Cultured cells expressing thrombomodulin variants associated with atypical hemolytic-uremic syndrome had diminished capacity to inactivate C3b and to activate procarboxypeptidase B and were thus less protected from activated complement.Mutations that impair the function of thrombomodulin occur in about 5% of patients with atypical hemolytic-uremic syndrome.
| S-EPMC3530919 | biostudies-literature
Project description: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.
| S-EPMC3750341 | biostudies-other
Project description:BackgroundPregnancy outcomes in patients with atypical hemolytic uremic syndrome (aHUS) are not well-documented. Here, we present characteristics of and outcomes for patients with aHUS who became pregnant while enrolled in the Global aHUS Registry.MethodsThe observational Global aHUS Registry (NCT01522183), initiated in April 2012, collects demographics, disease history, treatment, and outcomes data for patients with aHUS, regardless of treatment approach. This descriptive analysis includes patients from the Registry with evaluable pregnancy data supplemented with pharmacovigilance information; the number of pregnancies, outcomes, and exposure to eculizumab were evaluated.ResultsAs of April 1, 2019, 44 pregnancies were recorded in 41 patients, with 24 pregnancies exposed to eculizumab. Pathogenic variants were identified in 48.8% of patients. Three patients were on dialysis and 6 patients had a kidney graft at the time of pregnancy. Excluding elective terminations, 85.3% of pregnancies resulted in live births. Elective terminations were recorded in 22.7% of pregnancies, miscarriages occurred in 9.1% of pregnancies, and late fetal death in 2.3% of pregnancies. No malformations or anomalies were reported.ConclusionsOur results show that in women with aHUS, even on dialysis or with a kidney graft, pregnancy is possible with careful monitoring for aHUS flares and prematurity. Prophylactic or therapeutic eculizumab offers disease control with low-risk of fetal abnormalities.
| S-EPMC8820436 | biostudies-literature
Project description:Atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) have been linked to mutations in many of the proteins that are involved in alternative complement pathway activation. Age and etiology confounded, the prevalence of such mutations has been reported to be over 30 to 50% in these diseases. However, the cohorts studied included many children or individuals with a familial history of complement-related disorders and genetic tests were usually limited to exome sequencing of known causative or risk-associated genes. In this study, a retrospective adult cohort of 35 patients with biopsy-proven thrombotic microangiopathy (the largest in Canada) and 10 patients with C3 glomerulopathy was tested through an extended exome panel to identify causative defects in associated or candidate genes including those of the alternative and terminal complement pathways. A variant of unknown significance was also analyzed for pathogenicity through in vitro studies. To our surprise, the prevalence of known causative or risk-associated variants in either of these cohorts was found to be less than ~ 15% overall. However, the panel used and analyses carried out allowed to identify novel variants of potential clinical significance and a number of candidate genes. The prevalence of known genetic defects in adult-onset aHUS and C3G is thus probably much lower than 30 to 50%. Our results also point towards the importance of investigating diseases of the alternative complement pathway through extended exome panels and in vitro analyses. KEY MESSAGES: The alternative complement pathway plays a major role in the pathogenesis of hemolytic uremic syndrome and C3 glomerulopathy. Based on previous studies, both disorders have been commonly linked to variants in the various intermediates that sustain or regulate this pathway. The prevalence of such mutations in the adult-onset and sporadic forms of these diseases is probably much lower than expected based on larger series. The sporadic forms of complementopathies are likely to involve additional genes that are yet to be uncovered.
| S-EPMC8770394 | biostudies-literature
Project description:Combined methylmalonic aciduria and homocystinuria, cblC type (MMACHC), is the most common inborn error of cellular vitamin B12 metabolism and is caused by mutations in the MMACHC gene. This metabolic disease results in impaired intracellular synthesis of adenosylcobalamin and methylcobalamin, coenzymes for the methylmalonyl-CoA mutase and methionine synthase enzymes, respectively. The inability to produce normal levels of these two coenzymes leads to increased concentrations of methylmalonic acid and homocysteine in plasma and urine, together with normal or decreased concentration of methionine in plasma. Here, we report a novel homozygous deletion mutation (NM_015506.2:c.392_394del) resulting in an in-frame deletion of amino acid Gln131 and late-onset disease in a 23-year-old male. The patient presented with sensory and motoric disabilities, urine and fecal incontinence, and light cognitive impairment. There was an excessive urinary excretion of methylmalonic acid and greatly elevated plasma homocysteine. The clinical symptoms and the laboratory abnormalities responded partly to treatment with hydroxycobalamin, folinic acid, methionine, and betaine. Studies on patient fibroblasts together with spectroscopic activity assays on recombinant MMACHC protein reveal that Gln131 is crucial in order to maintain enzyme activity. Furthermore, structural analyses show that Gln131 is one of only two residues making hydrogen bonds to the tail of cobalamin. Circular dichroism spectroscopy indicates that the 3D structure of the deletion mutant is folded but perturbed compared to the wild-type protein.
| S-EPMC3755550 | biostudies-literature
Project description:Pathologic thrombosis is a major cause of mortality. Hemolytic-uremic syndrome (HUS) features episodes of small-vessel thrombosis resulting in microangiopathic hemolytic anemia, thrombocytopenia and renal failure. Atypical HUS (aHUS) can result from genetic or autoimmune factors that lead to pathologic complement cascade activation. Using exome sequencing, we identified recessive mutations in DGKE (encoding diacylglycerol kinase ?) that co-segregated with aHUS in nine unrelated kindreds, defining a distinctive Mendelian disease. Affected individuals present with aHUS before age 1 year, have persistent hypertension, hematuria and proteinuria (sometimes in the nephrotic range), and develop chronic kidney disease with age. DGKE is found in endothelium, platelets and podocytes. Arachidonic acid-containing diacylglycerols (DAG) activate protein kinase C (PKC), which promotes thrombosis, and DGKE normally inactivates DAG signaling. We infer that loss of DGKE function results in a prothrombotic state. These findings identify a new mechanism of pathologic thrombosis and kidney failure and have immediate implications for treating individuals with aHUS.
| S-EPMC3719402 | biostudies-literature