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1.
Blood Cells Mol Dis ; 103: 102780, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37516005

RESUMO

We report here an instructive case referred at 16 months-old for exploration of hemolysis without anemia (compensated anemia with reticulocytosis). The biology tests confirmed the hemolysis with increased total and indirect bilirubin. The usual hemolysis diagnosis tests were normal (DAT, G6PD, PK, Hb electrophoresis) except cytology and ektacytometry suggesting an association of multiple red blood cell (RBC) membrane disorders. This led us to propose a molecular screening analysis using targeted-Next Generation Sequencing (t-NGS) with a capture technique on 93 genes involved in RBC and erythropoiesis defects. We identified 4 missense heterozygous allelic variations, all of them were described without any significance (VUS) in the SLC4A1, RhAG, PIEZO1 and SPTB genes. The study of the familial cosegregation and research functional tests allowed to decipher the role of at least two by two genes in the phenotype and the hemolytic disease of this young patient. Specialized t-NGS panel (or virtual exome/genome sequencing) in a disease-referent laboratory and the motivated collaboration of clinicians, biologists and scientists should be the gold standard for improving the diagnosis of the patients affected with RBC diseases or rare inherited anemias.


Assuntos
Doenças Hematológicas , Esferocitose Hereditária , Humanos , Esferocitose Hereditária/diagnóstico , Esferocitose Hereditária/genética , Espectrina/genética , Sequenciamento de Nucleotídeos em Larga Escala , Hemólise , Mutação , Eritrócitos , Fenótipo , Proteína 1 de Troca de Ânion do Eritrócito/genética , Canais Iônicos/genética
2.
J Am Soc Nephrol ; 31(4): 829-840, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32034108

RESUMO

BACKGROUND: The pathophysiology of the leading cause of pediatric acute nephritis, acute postinfectious GN, including mechanisms of the pathognomonic transient complement activation, remains uncertain. It shares clinicopathologic features with C3 glomerulopathy, a complement-mediated glomerulopathy that, unlike acute postinfectious GN, has a poor prognosis. METHODS: This retrospective study investigated mechanisms of complement activation in 34 children with acute postinfectious GN and low C3 level at onset. We screened a panel of anticomplement protein autoantibodies, carried out related functional characterization, and compared results with those of 60 children from the National French Registry who had C3 glomerulopathy and persistent hypocomplementemia. RESULTS: All children with acute postinfectious GN had activation of the alternative pathway of the complement system. At onset, autoantibodies targeting factor B (a component of the alternative pathway C3 convertase) were found in a significantly higher proportion of children with the disorder versus children with hypocomplementemic C3 glomerulopathy (31 of 34 [91%] versus 4 of 28 [14%], respectively). In acute postinfectious GN, anti-factor B autoantibodies were transient and correlated with plasma C3 and soluble C5b-9 levels. We demonstrated that anti-factor B antibodies enhance alternative pathway convertase activity in vitro, confirming their pathogenic effect. We also identified crucial antibody binding sites on factor B, including one correlated to disease severity. CONCLUSIONS: These findings elucidate the pathophysiologic mechanisms underlying acute postinfectious GN by identifying anti-factor B autoantibodies as contributing factors in alternative complement pathway activation. At onset of a nephritic syndrome with low C3 level, screening for anti-factor B antibodies might help guide indications for kidney biopsy to avoid misdiagnosed chronic glomerulopathy, such as C3 glomerulopathy, and to help determine therapy.


Assuntos
Autoanticorpos/sangue , Ativação do Complemento/fisiologia , Complemento C3/metabolismo , Fator B do Complemento/imunologia , Glomerulonefrite/sangue , Glomerulonefrite/diagnóstico , Criança , Pré-Escolar , Fator Nefrítico do Complemento 3/metabolismo , Feminino , França , Humanos , Masculino , Estudos Retrospectivos
3.
Kidney Int ; 92(5): 1232-1241, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28712854

RESUMO

C3 Glomerulopathies, which include Dense Deposit Disease and C3 Glomerulonephritis, are associated with genetic and acquired dysregulation of the C3 convertase alternative pathway of complement. The potential role of the activation of the C5 convertase has not been studied extensively. Here we analyzed IgG samples from patients with C3 Glomerulopathies to identify circulating autoantibodies that stabilize the C3 alternative pathway (C3 Nephritic Factors) as well as C5 convertases (C5 Nephritic Factors), thus preventing decay of these enzyme complexes. Rare variants in alternative pathway genes were found in 28 of 120 tested patients. C3 and C5 Nephritic Factors were found in 76 of 101 (75%) and 29 of 59 (49%) of the patients, respectively. Therefore, we compared the results of the assays for the C3 and C5 nephritic factors functional activity: 29% were positive for C3 Nephritic Factors alone, 39% were positive for both C3 and C5 Nephritic Factors, and 10% were positive for C5 Nephritic Factors alone. We found that the addition of properdin-enhanced stabilization of C3 convertase in the presence of IgG doubly positive for both Nephritic Factors, while it did not modify the stabilization mediated by IgG solely positive for C3 Nephritic Factors. Both C3 and C5 Nephritic Factors correlated with C3 consumption, while only C5 Nephritic Factors correlated with sC5b9 levels. C5 Nephritic Factors-positive patients were more likely to have C3 Glomerulonephritis than Dense Deposit Disease. Thus, dysregulation of the C5 convertase contributes to C3 Glomerulopathies inter-disease differences and may have direct therapeutic implications.


Assuntos
C3 Convertase da Via Alternativa do Complemento/imunologia , Fator Nefrítico do Complemento 3/imunologia , Convertases de Complemento C3-C5/imunologia , Via Alternativa do Complemento/imunologia , Glomerulonefrite Membranoproliferativa/imunologia , Adolescente , Adulto , Criança , Fator Nefrítico do Complemento 3/análise , Fator Nefrítico do Complemento 3/genética , Convertases de Complemento C3-C5/metabolismo , Complexo de Ataque à Membrana do Sistema Complemento/análise , Feminino , Seguimentos , Glomerulonefrite Membranoproliferativa/sangue , Glomerulonefrite Membranoproliferativa/genética , Glomerulonefrite Membranoproliferativa/mortalidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Fenótipo , Properdina/metabolismo , Testes Sorológicos , Adulto Jovem
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