Factors determining penetrance in familial atypical haemolytic uraemic syndrome

Sansbury, Francis H.; Cordell, Heather J.; Bingham, Coralie; Bromilow, Gilly; Nicholls, Anthony; Powell, Roy; Shields, B M; Smyth, Lucy; Warwicker, Paul; Strain, Lisa; Wilson, Valerie; Goodship, Judith A.; Goodship, Timothy H.J.; Turnpenny, Peter D.

doi:10.1136/jmedgenet-2014-102498

Cited by 26 publications

(27 citation statements)

References 40 publications

(41 reference statements)

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“…However, the majority of aHUS cases are sporadic, occurring in the absence of any prior family history. Furthermore, even in familial forms of aHUS, penetrance is incomplete [52–54]. Taken together, these findings support the model of aHUS as a two-hit disease, in which genetic alterations confer susceptibility, but additional genetic or environmental risk factors influence the risk for development of disease in carriers.…”

Section: Atypical Hemolytic Uremic Syndrome (Ahus)supporting

confidence: 57%

Complementopathies

Baines

Brodsky

2017

Blood Reviews

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The complement system is an essential part of the innate immune system that requires careful regulation to ensure responses are appropriately directed against harmful pathogens, while preventing collateral damage to normal host cells and tissues. While deficiency in some components of the complement pathway is associated with increased susceptibility to certain infections, it has also become clear that inappropriate activation of complement is an important contributor to human disease. A number of hematologic disorders are driven by complement, and these disorders may be termed “complementopathies”. This includes paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), cold agglutinin disease (CAD) and other related disorders, which will be the focus of this review. A better understanding of the central role of the complement system in the pathophysiology of these disorders may allow for application of therapies directed at blocking the complement cascade.

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Section: Atypical Hemolytic Uremic Syndrome (Ahus)supporting

confidence: 57%

Complementopathies

Baines

Brodsky

2017

Blood Reviews

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“…However, these were all reported in a (very) low frequency in the general population, and prediction software was not conclusive about their pathogenicity, which makes it more likely that these variants are disease modifying and not disease causing. This is not remarkable, as an incomplete penetrance is seen in HUS: healthy family members can carry disease-causing mutations [46]. This indicates that additional triggers, genetic and/or environmental, are probably needed for the disease to develop.…”

Section: Discussionmentioning

confidence: 99%

Serological and genetic complement alterations in infection-induced and complement-mediated hemolytic uremic syndrome

et al. 2016

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BackgroundThe role of complement in the atypical form of hemolytic uremic syndrome (aHUS) has been investigated extensively in recent years. As the HUS-associated bacteria Shiga-toxin-producing Escherichia coli (STEC) can evade the complement system, we hypothesized that complement dysregulation is also important in infection-induced HUS.MethodsSerological profiles (C3, FH, FI, AP activity, C3d, C3bBbP, C3b/c, TCC, αFH) and genetic profiles (CFH, CFI, CD46, CFB, C3) of the alternative complement pathway were prospectively determined in the acute and convalescent phase of disease in children newly diagnosed with STEC-HUS or aHUS. Serological profiles were compared with those of 90 age-matched controls.ResultsThirty-seven patients were studied (26 STEC-HUS, 11 aHUS). In 39 % of them, including 28 % of STEC-HUS patients, we identified a genetic and/or acquired complement abnormality. In all patient groups, the levels of investigated alternative pathway (AP) activation markers were elevated in the acute phase and normalized in remission. The levels were significantly higher in aHUS than in STEC-HUS patients.ConclusionsIn both infection-induced HUS and aHUS patients, complement is activated in the acute phase of the disease but not during remission. The C3d/C3 ratio displayed the best discrepancy between acute and convalescent phase and between STEC-HUS and aHUS and might therefore be used as a biomarker in disease diagnosis and monitoring. The presence of aberrations in the alternative complement pathway in STEC-HUS patients was remarkable, as well.Electronic supplementary materialThe online version of this article (doi:10.1007/s00467-016-3496-0) contains supplementary material, which is available to authorized users.

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“…Two common CFH and MCP polymorphisms, the CFH-H3 and MCP-ggaac haplotypes, respectively, are also specifically associated with increased aHUS risk. It is thought that carriers of these haplotypes present reduced levels of FH and MCP compared to non-carriers (Caprioli et al, 2003;Esparza-Gordillo et al, 2005;Sansbury et al, 2014), which increases susceptibility to aHUS in carriers of associated complement mutations (Caprioli et al, 2003;Esparza-Gordillo et al, 2005).…”

Section: Cfh Mutationsmentioning

confidence: 98%

Complement genetics and susceptibility to inflammatory disease. Lessons from genotype–phenotype correlations

Córdoba

2016

Immunobiology

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Factors determining penetrance in familial atypical haemolytic uraemic syndrome

Cited by 26 publications

References 40 publications

Complementopathies

Complementopathies

Serological and genetic complement alterations in infection-induced and complement-mediated hemolytic uremic syndrome

Complement genetics and susceptibility to inflammatory disease. Lessons from genotype–phenotype correlations

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