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Introduction: C3 glomerulopathy (C3G) is an ultrarare renal disease characterized by deposition of complement component C3 in the glomerular basement membrane (GBM). Rare and novel genetic variation in complement genes and autoantibodies to complement proteins are commonly identified in the C3G population and thought to drive the underlying complement dysregulation that results in renal damage. However, disease heterogeneity and rarity make accurately defining characteristics of the C3G population difficult. Methods: Here, we present a retrospective analysis of the Molecular Otolaryngology and Renal Research Laboratories C3G cohort. This study integrated complement biomarker testing and in vitro tests of autoantibody function to achieve the following 3 primary goals: (i) define disease profiles of C3G based on disease drivers, complement biomarkers, and age; (ii) determine the relationship between in vitro autoantibody tests and in vivo complement dysregulation; and (iii) evaluate the association between autoantibody function and disease progression. Results: The largest disease profiles of C3G included patients with autoantibodies to complement proteins (48%) and patients for whom no genetic and/or acquired drivers of disease could be identified (43%). The correlation between the stabilization of convertases by complement autoantibodies as measured by in vitro modified hemolytic assays and systemic biomarkers that reflect in vivo complement dysregulation was remarkably strong. In patients positive for autoantibodies, the degree of stabilization capacity predicted worse renal function. Conclusion: This study implicates complement autoantibodies as robust drivers of systemic complement dysregulation in approximately 50% of C3G but also highlights the need for continued discovery-based research to identify novel drivers of disease.
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C3 glomerulopathy (C3G) and atypical hemolytic uremic syndrome (aHUS) are two rare diseases caused by dysregulated activity of the alternative pathway of complement secondary to the presence of genetic and/or acquired factors. Complement factor I (FI) is a serine protease that downregulates complement activity in the fluid phase and/or on cell surfaces in conjunction with one of its cofactors, factor H (FH), complement receptor 1 (CR1/CD35), C4 binding protein (C4BP) or membrane cofactor protein (MCP/CD46). Because altered FI activity is causally related to the pathogenesis of C3G and aHUS, we sought to test functional activity of select CFI missense variants in these two patient cohorts. We identified 65 patients (16, C3G; 48, aHUS; 1 with both) with at least one rare variant in CFI (defined as a MAF < 0.1%). Eight C3G and eleven aHUS patients also carried rare variants in either another complement gene, ADAMTS13 or THBD. We performed comprehensive complement analyses including biomarker profiling, pathway activity and autoantibody testing, and developed a novel FI functional assay, which we completed on 40 patients. Seventy-eight percent of rare CFI variants (31/40) were associated with FI protein levels below the 25th percentile; in 22 cases, FI levels were below the lower limit of normal (type 1 variants). Of the remaining nine variants, which associated with normal FI levels, two variants reduced FI activity (type 2 variants). No patients carried currently known autoantibodies (including FH autoantibodies and nephritic factors). We noted that while rare variants in CFI predispose to complement-mediated diseases, phenotypes are strongly contingent on the associated genetic background. As a general rule, in isolation, a rare CFI variant most frequently leads to aHUS, with the co-inheritance of a CD46 loss-of-function variant driving the onset of aHUS to the younger age group. In comparison, co-inheritance of a gain-of-function variant in C3 alters the phenotype to C3G. Defects in CFH (variants or fusion genes) are seen with both C3G and aHUS. This variability underscores the complexity and multifactorial nature of these two complement-mediated renal diseases.
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Síndrome Hemolítico-Urêmica Atípica , Fator I do Complemento , Síndrome Hemolítico-Urêmica Atípica/genética , Autoanticorpos/genética , Fator I do Complemento/genética , Proteínas do Sistema Complemento/genética , Proteínas do Sistema Complemento/metabolismo , Humanos , FenótipoRESUMO
Atypical hemolytic uremic syndrome is an ultra-rare disease characterized by microangiopathic hemolytic anemia, thrombocytopenia and acute kidney injury. Its pathogenesis is driven most frequently by dysregulated cell-surface control of the alternative pathway of complement secondary to inherited and/or acquired factors. Here we evaluated two unrelated patients with atypical hemolytic uremic syndrome. The first, a five-year-old Caucasian female, presented at 10 months with schistocytes, thrombocytopenia and kidney injury. The second, a 55-year-old Caucasian female, presented at age 31 following caesarean section for preeclampsia. Complement biomarker testing was remarkable for undetectable levels of C3 in both. Circulating levels of C5 and properdin were also low consistent with over-activity of the alternative and terminal pathways of complement. Genetic testing identified a heterozygous novel variant in CFB (c.1101 C>A, p.Ser367Arg) in both patients. Functional studies found strong fluid-phase C3 cleavage when normal and proband sera were mixed. Cell-surface C3b deposition was strongly positive when patient serum was supplemented with C3. In vitro control of C3 convertase activity could be restored with increased concentrations of factor H. Thus, CFB p.Ser367Arg is a gain-of-function pathogenic variant that leads to dysregulation of the alternative pathway in the fluid-phase and increased C3b deposition on cell surfaces. Our study highlights the complexities of complement-mediated diseases like atypical hemolytic uremic syndrome and illustrates the importance of functional studies at the variant level to gain insight into the disease phenotype.
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Síndrome Hemolítico-Urêmica Atípica , Adulto , Síndrome Hemolítico-Urêmica Atípica/diagnóstico , Síndrome Hemolítico-Urêmica Atípica/genética , Cesárea , Pré-Escolar , Fator B do Complemento/genética , Fator H do Complemento/genética , Via Alternativa do Complemento/genética , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , GravidezRESUMO
Factor H (FH), a member of the regulators-of-complement-activation (RCA) family of proteins, circulates in human plasma at concentrations of 180-420 mg/L where it controls the alternative pathway (AP) of complement in the fluid phase and on cell surfaces. When the regulatory function of FH is impaired, complement-mediated tissue injury and inflammation occur, leading to diseases such as atypical hemolytic uremic syndrome (a thrombotic microangiopathy or TMA), C3 glomerulopathy (C3G) and monoclonal gammopathy of renal significance (MGRS). A pathophysiological cause of compromised FH function is the development of autoantibodies to various domains of the FH protein. FH autoantibodies (FHAAs) are identified in 10.9% of patients with aHUS, 3.2% of patients with C3G, and rarely in patients with MGRS. The phenotypic variability of FHAA-mediated disease reflects both the complexity of FH and the epitope specificity of FHAA for select regions of the native protein. In this paper, we have characterized FHAA epitopes in a large cohort of patients diagnosed with TMA, C3G or MGRS. We explore the epitopes recognized by FHAAs in these diseases and the association of FHAAs with the genetic deletion of both copies of the CFHR1 gene to show how these disease phenotypes are associated with this diverse spectrum of autoantibodies.
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Síndrome Hemolítico-Urêmica Atípica/imunologia , Autoanticorpos/sangue , Glomerulonefrite/imunologia , Paraproteinemias/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Síndrome Hemolítico-Urêmica Atípica/sangue , Síndrome Hemolítico-Urêmica Atípica/epidemiologia , Síndrome Hemolítico-Urêmica Atípica/genética , Biomarcadores/sangue , Criança , Pré-Escolar , Proteínas Inativadoras do Complemento C3b/genética , Fator H do Complemento/imunologia , Epitopos , Feminino , Deleção de Genes , Predisposição Genética para Doença , Glomerulonefrite/sangue , Glomerulonefrite/epidemiologia , Glomerulonefrite/genética , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Paraproteinemias/sangue , Paraproteinemias/epidemiologia , Paraproteinemias/genética , Fenótipo , Prevalência , Estudos Retrospectivos , Estados Unidos/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Genetic variation in complement genes is a predisposing factor for atypical hemolytic uremic syndrome (aHUS), a life-threatening thrombotic microangiopathy, however interpreting the effects of genetic variants is challenging and often ambiguous. METHODS: We analyzed 93 complement and coagulation genes in 400 patients with aHUS, using as controls 600 healthy individuals from Iowa and 63,345 non-Finnish European individuals from the Genome Aggregation Database. After adjusting for population stratification, we then applied the Fisher exact, modified Poisson exact, and optimal unified sequence kernel association tests to assess gene-based variant burden. We also applied a sliding-window analysis to define the frequency range over which variant burden was significant. RESULTS: We found that patients with aHUS are enriched for ultrarare coding variants in the CFH, C3, CD46, CFI, DGKE, and VTN genes. The majority of the significance is contributed by variants with a minor allele frequency of <0.1%. Disease-related variants tend to occur in specific complement protein domains of FH, CD46, and C3. We observed no enrichment for multiple rare coding variants in gene-gene combinations. CONCLUSIONS: In known aHUS-associated genes, variants with a minor allele frequency >0.1% should not be considered pathogenic unless valid enrichment and/or functional evidence are available. VTN, which encodes vitronectin, an inhibitor of the terminal complement pathway, is implicated as a novel aHUS-associated gene. Patients with aHUS are not enriched for multiple rare variants in complement genes. In aggregate, these data may help in directing clinical management of aHUS.
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Síndrome Hemolítico-Urêmica Atípica/genética , Adolescente , Adulto , Idoso , Síndrome Hemolítico-Urêmica Atípica/sangue , Fatores de Coagulação Sanguínea/genética , Criança , Pré-Escolar , Proteínas do Sistema Complemento/genética , Bases de Dados Genéticas , Feminino , Frequência do Gene , Predisposição Genética para Doença , Testes Genéticos , Variação Genética , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Mutação , Vitronectina/genética , Adulto JovemRESUMO
Atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) are associated with dysregulation and overactivation of the complement alternative pathway. Typically, gene analysis for aHUS and C3G is undertaken in small patient numbers, yet it is unclear which genes most frequently predispose to aHUS or C3G. Accordingly, we performed a six-center analysis of 610 rare genetic variants in 13 mostly complement genes (CFH, CFI, CD46, C3, CFB, CFHR1, CFHR3, CFHR4, CFHR5, CFP, PLG, DGKE, and THBD) from >3500 patients with aHUS and C3G. We report 371 novel rare variants (RVs) for aHUS and 82 for C3G. Our new interactive Database of Complement Gene Variants was used to extract allele frequency data for these 13 genes using the Exome Aggregation Consortium server as the reference genome. For aHUS, significantly more protein-altering rare variation was found in five genes CFH, CFI, CD46, C3, and DGKE than in the Exome Aggregation Consortium (allele frequency < 0.01%), thus correlating these with aHUS. For C3G, an association was only found for RVs in C3 and the N-terminal C3b-binding or C-terminal nonsurface-associated regions of CFH In conclusion, the RV analyses showed nonrandom distributions over the affected proteins, and different distributions were observed between aHUS and C3G that clarify their phenotypes.
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Síndrome Hemolítico-Urêmica Atípica/genética , Complemento C3/genética , Fator H do Complemento/genética , Via Alternativa do Complemento/genética , Glomerulonefrite Membranoproliferativa/genética , Síndrome Hemolítico-Urêmica Atípica/patologia , Complemento C3/metabolismo , Via Alternativa do Complemento/fisiologia , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Glomerulonefrite Membranoproliferativa/patologia , Humanos , Masculino , Mutação de Sentido Incorreto/genéticaRESUMO
Background: C3 glomerulonephritis (C3GN) is caused by alternate complement pathway over-activation. It frequently progresses to end-stage renal disease, recurs in two-thirds of transplants and in half of these cases progresses to allograft loss. There is currently no proven treatment for C3GN. Case Presentation: We describe a family segregating pathogenic alleles of complement factor H and I (CFH and CFI). The only member carrying both mutations developed C3GN. Prolonged delayed graft function after deceased donor transplantation, heavy proteinuria and isolated C3 hypocomplementemia prompted an allograft biopsy confirming diagnosis of recurrent C3GN. Discussion: This is the first report of early recurrence of C3GN in an allograft in a patient with known mutations in complement regulatory genes and no preexisting para-proteinemia. Complement activation resulting from ischemia-reperfusion injury from prolonged cold ischemia time unabated in the setting of deficiency of two major complement regulators likely led to the early and severe recurrence. In atypical hemolytic uremic syndrome, the terminal complement cascade activation in the sentinel event initiating endothelial injury; blockade at the level of C5 convertase with eculizumab is uniformly highly effective in management. C3 glomerulopathies (C3GN and dense deposit disease) are a more complex and heterogeneous group. The relative degree of dysregulation at the levels of C3 and C5 convertases and therefore response to eculizumab varies among patients. In our patient, the clinical response to eculizumab was dramatic with recovery of allograft function and complete resolution of proteinuria. We review all cases of recurrent C3 glomerulopathy treated with eculizumab and discuss how complement biomarkers may aid in predicting response to therapy.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Fator H do Complemento/genética , Fibrinogênio/genética , Glomerulonefrite/genética , Transplante de Rim/efeitos adversos , Mutação , Doadores de Tecidos , Aloenxertos , Biomarcadores/metabolismo , Biópsia , Ativação do Complemento , Fator H do Complemento/metabolismo , Via Alternativa do Complemento , DNA/genética , Análise Mutacional de DNA , Fibrinogênio/metabolismo , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/metabolismo , Humanos , Falência Renal Crônica/cirurgia , Glomérulos Renais/patologia , Masculino , Pessoa de Meia-Idade , Linhagem , RecidivaRESUMO
C3 glomerulopathy (C3G) is an ultra-rare complement-mediated renal disease characterized histologically by the predominance of C3 deposition within in the glomerulus. Familial cases of C3G are extremely uncommon and offer unique insight into the genetic drivers of complement dysregulation. In this report, we describe a patient who presented with C3G. Because a relative carried the same diagnosis, we sought an underlying genetic commonality to explain the phenotype. As part of a comprehension genetic screen, we completed multiplex ligation-dependent probe amplification across the complement factor H related region and identified amplification alterations consistent with a genomic rearrangement. Using comparative genomic hybridization, we narrowed and then cloned the rearrangement breakpoints thereby defining a novel fusion gene that is translated into a serum protein comprised of factor H related-5 (short consensus repeats 1 and 2) and factor H-related-2 (short consensus repeats 1-4). These data highlight the role of factor H related proteins in the control of complement activity and illustrate how perturbation of that control leads to C3G.
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Proteínas Inativadoras do Complemento C3b/genética , Proteínas do Sistema Complemento/genética , Glomerulonefrite Membranoproliferativa/genética , Adulto , Western Blotting , Hibridização Genômica Comparativa , Feminino , Humanos , Masculino , Reação em Cadeia da Polimerase Multiplex , LinhagemRESUMO
The thrombotic microangiopathies (TMAs) and C3 glomerulopathies (C3Gs) include a spectrum of rare diseases such as atypical hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, C3GN, and dense deposit disease, which share phenotypic similarities and underlying genetic commonalities. Variants in several genes contribute to the pathogenesis of these diseases, and identification of these variants may inform the diagnosis and treatment of affected patients. We have developed and validated a comprehensive genetic panel that screens all exons of all genes implicated in TMA and C3G. The closely integrated pipeline implemented includes targeted genomic enrichment, massively parallel sequencing, bioinformatic analysis, and a multidisciplinary conference to analyze identified variants in the context of each patient's specific phenotype. Herein, we present our 1-year experience with this panel, during which time we studied 193 patients. We identified 17 novel and 74 rare variants, which we classified as pathogenic (11), likely pathogenic (12), and of uncertain significance (68). Compared with controls, patients with C3G had a higher frequency of rare and novel variants in C3 convertase (C3 and CFB) and complement regulator (CFH, CFI, CFHR5, and CD46) genes (P<0.05). In contrast, patients with TMA had an increase in rare and novel variants only in complement regulator genes (P<0.01), a distinction consistent with differing sites of complement dysregulation in these two diseases. In summary, we were able to provide a positive genetic diagnosis in 43% and 41% of patients carrying the clinical diagnosis of C3G and TMA, respectively.
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Nefropatias/diagnóstico , Nefropatias/genética , Glomérulos Renais , Microangiopatias Trombóticas/diagnóstico , Microangiopatias Trombóticas/genética , Adolescente , Criança , Pré-Escolar , Complemento C3 , Feminino , Testes Genéticos/métodos , Humanos , Nefropatias/imunologia , MasculinoAssuntos
Síndrome Hemolítico-Urêmica Atípica/metabolismo , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Adolescente , Biomarcadores/metabolismo , Estudos de Casos e Controles , Estudos de Coortes , Ativação do Complemento , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Valor Preditivo dos Testes , Trombocitopenia/metabolismo , Adulto JovemAssuntos
Proteínas ADAM/genética , Síndrome Hemolítico-Urêmica Atípica/diagnóstico , Proteína Cofatora de Membrana/genética , Proteínas ADAM/imunologia , Proteína ADAMTS13 , Adulto , Síndrome Hemolítico-Urêmica Atípica/genética , Síndrome Hemolítico-Urêmica Atípica/imunologia , Sequência de Bases , Criança , Via Alternativa do Complemento/genética , Via Clássica do Complemento/genética , Diagnóstico Diferencial , Feminino , Expressão Gênica , Heterozigoto , Humanos , Masculino , Proteína Cofatora de Membrana/imunologia , Dados de Sequência Molecular , Mutação , Linhagem , Púrpura Trombocitopênica Trombótica/diagnóstico , Púrpura Trombocitopênica Trombótica/genética , Púrpura Trombocitopênica Trombótica/imunologia , Fator de von Willebrand/genética , Fator de von Willebrand/imunologiaRESUMO
BACKGROUND AND OBJECTIVES: C3 glomerulopathy (C3G) applies to a group of renal diseases defined by a specific renal biopsy finding: a dominant pattern of C3 fragment deposition on immunofluorescence. The primary pathogenic mechanism involves abnormal control of the alternative complement pathway, although a full description of the disease spectrum remains to be determined. This study sought to validate and define the association of complement dysregulation with C3G and to determine whether specific complement pathway abnormalities could inform disease definition. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study included 34 patients with C3G (17 with C3 glomerulonephritis [C3GN] and 17 with dense deposit disease [DDD]) diagnosed between 2008 and 2013 selected from the C3G Registry. Control samples (n=100) were recruited from regional blood drives. Nineteen complement biomarkers were assayed on all samples. Results were compared between C3G disease categories and with normal controls. RESULTS: Assessment of the alternative complement pathway showed that compared with controls, patients with C3G had lower levels of serum C3 (P<0.001 for both DDD and C3GN) and factor B (P<0.001 for both DDD and C3GN) as well as higher levels of complement breakdown products including C3d (P<0.001 for both DDD and C3GN) and Bb (P<0.001 for both DDD and C3GN). A comparison of terminal complement pathway proteins showed that although C5 levels were significantly suppressed (P<0.001 for both DDD and C3GN) its breakdown product C5a was significantly higher only in patients with C3GN (P<0.05). Of the other terminal pathway components (C6-C9), the only significant difference was in C7 levels between patients with C3GN and controls (P<0.01). Soluble C5b-9 was elevated in both diseases but only the difference between patients with C3GN and controls reached statistical significance (P<0.001). Levels of C3 nephritic factor activity were qualitatively higher in patients with DDD compared with patients with C3GN. CONCLUSIONS: Complement biomarkers are significantly abnormal in patients with C3G compared with controls. These data substantiate the link between complement dysregulation and C3G and identify C3G interdisease differences.
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Fator Nefrítico do Complemento 3/metabolismo , Complemento C3/metabolismo , Complemento C5/metabolismo , Complemento C7/metabolismo , Fator B do Complemento/metabolismo , Glomerulonefrite Membranoproliferativa/sangue , Adolescente , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Criança , Complemento C3d/metabolismo , Complemento C5a/metabolismo , Feminino , Glomerulonefrite Membranoproliferativa/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Postinfectious glomerulonephritis is a common disorder that develops following an infection. In the majority of cases, there is complete recovery of renal function within a few days to weeks following resolution of the infection. In a small percentage of patients, however, the glomerulonephritis takes longer to resolve, resulting in persistent hematuria and proteinuria, or even progression to end-stage kidney disease. In some cases of persistent hematuria and proteinuria, kidney biopsies show findings of a postinfectious glomerulonephritis even in the absence of any evidence of a preceding infection. The cause of such 'atypical' postinfectious glomerulonephritis, with or without evidence of preceding infection, is unknown. Here we show that most patients diagnosed with this 'atypical' postinfectious glomerulonephritis have an underlying defect in the regulation of the alternative pathway of complement. These defects include mutations in complement-regulating proteins and antibodies to the C3 convertase known as C3 nephritic factors. As a result, the activated alternative pathway is not brought under control even after resolution of the infection. Hence, the sequela is continual glomerular deposition of complement factors with resultant inflammation and development of an 'atypical' postinfectious glomerulonephritis.
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Via Alternativa do Complemento , Glomerulonefrite/imunologia , Infecções/complicações , Adolescente , Adulto , Idoso , Biópsia , Convertases de Complemento C3-C5/fisiologia , Feminino , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/etiologia , Glomerulonefrite/patologia , Humanos , Rim/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
Atypical hemolytic uremic syndrome (aHUS) is a rare renal disease (two per one million in the USA) characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Both sporadic (80% of cases) and familial (20% of cases) forms are recognized. The study of familial aHUS has implicated genetic variation in multiple genes in the complement system in disease pathogenesis, helping to define the mechanism whereby complement dysregulation at the cell surface level leads to both sporadic and familial disease. This understanding has culminated in the use of Eculizumab as first-line therapy in disease treatment, significantly changing the care and prognosis of affected patients. However, even with this bright outlook, major challenges remain to understand the complexity of aHUS at the genetic level. It is possible that a more detailed picture of aHUS can be translated to an improved understanding of disease penetrance, which is highly variable, and response to therapy, both in the short and long terms.
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Síndrome Hemolítico-Urêmica/genética , Síndrome Hemolítico-Urêmica/imunologia , Síndrome Hemolítico-Urêmica Atípica , Proteínas do Sistema Complemento/genética , Proteínas do Sistema Complemento/imunologia , Variação Genética , HumanosRESUMO
OBJECTIVE: Recent preliminary evidence suggests that gene mutations in the alternative pathway of complement may play a crucial role in the pathogenesis of HELLP syndrome. To verify this hypothesis, a consecutive series of women who developed the syndrome was screened for variants in alternative pathway genes. METHODS: The coding sequences and intron-exon boundaries of the complement factor H (CFH), complement factor I (CFI), Membrane Cofactor Protein (MCP), complement factor B (CFB) and C3 were sequenced in 33 women with a diagnosis of HELLP syndrome. RESULTS: Three patients carried heterozygotic variants - two in CFI and one in MCP. One of the two CFI mutations, was previously described as an unremarkable polymorphism. Conversely, computational analyses for the remaining two cases suggest that they may have a functional impact. CONCLUSIONS: The present study confirms that the alternative pathway of complement may play a role in the pathogenesis of HELLP syndrome. However, its overall contribution to the determinism of the syndrome is less relevant than initially reported.
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Via Alternativa do Complemento/genética , Síndrome HELLP/genética , Síndrome HELLP/imunologia , Adulto , Idade de Início , Fator I do Complemento/genética , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Idade Gestacional , Síndrome HELLP/epidemiologia , Síndrome HELLP/etiologia , Humanos , Recém-Nascido , Proteína Cofatora de Membrana/genética , Polimorfismo Genético , Gravidez , Segundo Trimestre da Gravidez/imunologia , Terceiro Trimestre da Gravidez/imunologia , Estudos RetrospectivosRESUMO
There are several syndromes in which both hearing and renal function are impaired. The two best known are branchio-oto-renal (BOR) syndrome and Alport syndrome. These are reviewed along with several other rarer syndromes. BOR is especially important since it is likely to be first recognized by the otolaryngologist because of the hearing and branchial anomalies. It is important for the practicing otolaryngologist to recognize these disorders and to ensure that renal problems are being treated. In addition, the syndromes discussed here are all hereditary and referral to a clinical geneticist may be helpful to the individual and family.
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Síndrome Brânquio-Otorrenal/genética , Nefrite Hereditária/genética , Síndrome Brânquio-Otorrenal/diagnóstico , Síndrome Brânquio-Otorrenal/terapia , Colágeno Tipo IV/genética , Diagnóstico Diferencial , Aconselhamento Genético , Hereditariedade , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação , Nefrite Hereditária/diagnóstico , Nefrite Hereditária/terapia , Proteínas Nucleares/genética , Proteínas Tirosina Fosfatases/genética , Encaminhamento e ConsultaRESUMO
BACKGROUND: Little information is available on a long-term follow-up in Bartter syndrome type I and II. METHODS: Clinical presentation, treatment and long-term follow-up (5.0-21, median 11 years) were evaluated in 15 Italian patients with homozygous (n = 7) or compound heterozygous (n = 8) mutations in the SLC12A1 (n = 10) or KCNJ1 (n = 5) genes. RESULTS: Thirteen new mutations were identified. The 15 children were born pre-term with a normal for gestational age body weight. Medical treatment at the last follow-up control included supplementation with potassium in 13, non-steroidal anti-inflammatory agents in 12 and gastroprotective drugs in five patients. At last follow-up, body weight and height were within normal ranges in the patients. Glomerular filtration rate was <90 mL/min/1.73 m(2) in four patients (one of them with a pathologically increased urinary protein excretion). In three patients, abdominal ultrasound detected gallstones. The group of patients with antenatal Bartter syndrome had a lower renin ratio (P < 0.05) and a higher standard deviation score (SDS) for height (P < 0.05) than a previously studied group of patients with classical Bartter syndrome. CONCLUSIONS: Patients with Bartter syndrome type I and II tend to present a satisfactory prognosis after a median follow-up of more than 10 years. Gallstones might represent a new complication of antenatal Bartter syndrome.
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Síndrome de Bartter/genética , Mutação/genética , Canais de Potássio Corretores do Fluxo de Internalização/genética , Simportadores de Cloreto de Sódio-Potássio/genética , Síndrome de Bartter/classificação , Síndrome de Bartter/tratamento farmacológico , Estatura , Peso Corporal , Pré-Escolar , Feminino , Seguimentos , Taxa de Filtração Glomerular , Heterozigoto , Homozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Prognóstico , Membro 1 da Família 12 de Carreador de Soluto , Fatores de TempoRESUMO
Although the diagnosis of Gitelman syndrome (GS) and Bartter syndrome (BS) is now feasible by genetic analysis, implementation of genetic testing for these disorders is still hampered by several difficulties, including large gene dimensions, lack of hot-spot mutations, heavy workup time, and costs. This study evaluated in a cohort of patients with genetically proven GS or BS diagnostic sensibility and specificity of a diuretic test with oral hydrochlorothiazide (HCT test). Forty-one patients with GS (22 adults, aged 25 to 57; 19 children-adolescents, aged 7 to 17) and seven patients with BS (five type I, two type III) were studied; three patients with "pseudo-BS" from surreptitious diuretic intake (two patients) or vomiting (one patient) were also included. HCT test consisted of the administration of 50 mg of HCT orally (1 mg/kg in children-adolescents) and measurement of the maximal diuretic-induced increase over basal in the subsequent 3 h of chloride fractional clearance. All but three patients with GS but no patients with BS and pseudo-BS showed blunted (<2.3%) response to HCT; patients with BS and the two patients with pseudo-BS from diuretic intake had increased response to HCT. No overlap existed between patients with GS and both patients with BS and pseudo-BS. The response to HCT test is blunted in patients with GS but not in patients with BS or nongenetic hypokalemia. In patients with the highly selected phenotype of normotensive hypokalemic alkalosis, abnormal HCT test allows prediction with a very high sensitivity and specificity of the Gitelman genotype and may avoid genotyping.
Assuntos
Síndrome de Bartter/diagnóstico , Diuréticos , Síndrome de Gitelman/diagnóstico , Hidroclorotiazida , Adolescente , Adulto , Síndrome de Bartter/genética , Criança , Doença Crônica , Estudos de Coortes , Diagnóstico Diferencial , Feminino , Síndrome de Gitelman/genética , Humanos , Hipopotassemia/diagnóstico , Masculino , Pessoa de Meia-Idade , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Little information on the management and long-term follow-up of patients with biallelic mutations in the chloride channel gene CLCNKB is available. METHODS: Long-term follow-up was evaluated from 5.0 to 24 years (median, 14 years) after diagnosis in 13 patients with homozygous (n = 10) or compound heterozygous (n = 3) mutations. RESULTS: Medical treatment at last follow-up control included supplementation with potassium in 12 patients and sodium in 2 patients and medical treatment with indomethacin in 9 patients. At the end of follow-up, body height was 2.0 standard deviation score or less in 6 patients; 2 of these patients had growth hormone deficiency. Body weight (Assuntos
Síndrome de Bartter/genética
, Canais de Cloreto/genética
, Mutação
, Adolescente
, Adulto
, Alelos
, Síndrome de Bartter/tratamento farmacológico
, Criança
, Pré-Escolar
, Feminino
, Seguimentos
, Humanos
, Masculino
, Fatores de Tempo
RESUMO
Two siblings (brother and sister) with renal tubular hypokalemic alkalosis underwent clinical, biochemical and molecular investigations. Although the biochemical findings were similar (including hypokalemia, metabolic alkalosis, hyperreninemia, hyperaldosteronism and normal blood pressure), the clinical findings were different: the boy, who also presented syndromic signs, developed glomerular proteinuria and renal biopsy revealed focal segmental glomerular sclerosis; the girl showed the typical signs of classic Bartter syndrome. As described in a previous paper, a heterozygous mutation (frameshift 2534delT) was demonstrated in the gene encoding the thiazide-sensitive NaCl co-transporter (SLC12A3) of the distal convoluted tubule; the second molecular analysis revealed a compound heterozygous mutation (A61D/V149E) in the CLCNKB chloride channel gene in both subjects, inherited in trans from the parents. The children were finally diagnosed as having classic Bartter syndrome. These cases represent the first report of the simultaneous presence of heterozygous and compound heterozygous mutations in the SLC12A3 and CLCNKB genes, both of which are involved in renal salt losing tubulopathies, and confirm previous observations regarding classic Bartter syndrome phenotype variability in the same kindred.