A novel mutation in the Complement Factor B gene (CFB) and atypical hemolytic uremic syndrome

Tawadrous, Hanan; Maga, Tara; Sharma, Josefina; Kupferman, Juan C.; Smith, Richard J.H.; Schoeneman, Morris J.

doi:10.1007/s00467-009-1415-3

Cited by 44 publications

(33 citation statements)

References 25 publications

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“…Fivety seven per cent of C3-mutated patients and 88% of THBD-mutated patients who received plasmatherapy in the Italian Registry had a response (either complete or partial remission (hematological remission with renal sequel), and 43% and 13% respectively progressed to death or ESRF [18]. Remission with PE or PI has been reported in 2 patients with C3 mutation [84,121] and 3 with CFB mutation [80][81][82].…”

Section: Plasmatherapy In Patients With C3 Cfb or Thbd Mutationmentioning

confidence: 99%

Atypical Hemolytic Uremic Syndrome

Loirat¹,

Frémeaux‐Bacchi²

2016

Pediatric Kidney Disease

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Hemolytic uremic syndrome (HUS) is defined by the triad of mechanical hemolytic anemia, thrombocytopenia and renal impairment. Atypical HUS (aHUS) defines non Shiga-toxin-HUS and even if some authors include secondary aHUS due to Streptococcus pneumoniae or other causes, aHUS designates a primary disease due to a disorder in complement alternative pathway regulation. Atypical HUS represents 5 -10% of HUS in children, but the majority of HUS in adults. The incidence of complement-aHUS is not known precisely. However, more than 1000 aHUS patients investigated for complement abnormalities have been reported. Onset is from the neonatal period to the adult age. Most patients present with hemolytic anemia, thrombocytopenia and renal failure and 20% have extra renal manifestations. Two to 10% die and one third progress to end-stage renal failure at first episode. Half of patients have relapses. Mutations in the genes encoding complement regulatory proteins factor H, membrane cofactor protein (MCP), factor I or thrombomodulin have been demonstrated in 20-30%, 5-15%, 4-10% and 3-5% of patients respectively, and mutations in the genes of C3 convertase proteins, C3 and factor B, in 2-10% and 1-4%. In addition, 6-10% of patients have anti-factor H antibodies. Diagnosis of aHUS relies on 1) No associated disease 2) No criteria for Shigatoxin-HUS (stool culture and PCR for Shiga-toxins; serology for anti-lipopolysaccharides antibodies) 3) No criteria for thrombotic thrombocytopenic purpura (serum ADAMTS 13 activity > 10%). Investigation of the complement system is required (C3, C4, factor H and factor I plasma concentration, MCP expression on leukocytes and anti-factor H antibodies; genetic screening to identify risk factors). The disease is familial in approximately 20% of pedigrees, with an autosomal recessive or dominant mode of transmission. As penetrance of the disease is 50%, genetic counseling is difficult. Plasmatherapy has been first line treatment until presently, without unquestionable demonstration of efficiency. There is a high risk of post-transplant recurrence, except in MCP-HUS. Case reports and two phase II trials show an impressive efficacy of the complement C5 blocker eculizumab, suggesting it will be the next standard of care. Except for patients treated by intensive plasmatherapy or eculizumab, the worst prognosis is in factor H-HUS, as mortality can reach 20% and 50% of survivors do not recover renal function. Half of factor I-HUS progress to end-stage renal failure. Conversely, most patients with MCP-HUS have preserved renal function. Anti-factor H antibodies-HUS has favourable outcome if treated early.

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Section: Plasmatherapy In Patients With C3 Cfb or Thbd Mutationmentioning

confidence: 99%

Atypical Hemolytic Uremic Syndrome

Loirat¹,

Frémeaux‐Bacchi²

2016

Pediatric Kidney Disease

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“…These patients have a continuously activated alternative pathway, with very low C3 levels. These mutations are rare, accounting for 1%-4% of patients with aHUS [79] . In 25% of patients a functional consequences of the mutation has been identified.…”

Section: Complement Factor B Mutations and C3 Mutationsmentioning

confidence: 99%

Update on hemolytic uremic syndrome: Diagnostic and therapeutic recommendations

Salvadori

Bertoni²

2013

WJN

116

111

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Hemolytic uremic syndrome (HUS) is a rare disease. In this work the authors review the recent findings on HUS, considering the different etiologic and pathogenetic classifications. New findings in genetics and, in particular, mutations of genes that encode the complement-regulatory proteins have improved our understanding of atypical HUS. Similarly, the complement proteins are clearly involved in all types of thrombotic microangiopathy: typical HUS, atypical HUS and thrombotic thrombocytopenic purpura (TTP). Furthermore, several secondary HUS appear to be related to abnormalities in complement genes in predisposed patients. The authors highlight the therapeutic aspects of this rare disease, examining both "traditional therapy" (including plasma therapy, kidney and kidneyliver transplantation) and "new therapies". The latter include anti-Shiga-toxin antibodies and anti-C5 monoclonal antibody "eculizumab". Eculizumab has been recently launched for the treatment of the atypical HUS, but it appears to be effective in the treatment of typical HUS and in TTP. Future therapies are in phases Ⅰ and Ⅱ. They include anti-C5 antibodies, which are more purified, less immunogenic and absorbed orally and, anti-C3 antibodies, which are more powerful, but potentially less safe. Additionally, infusions of recombinant complement-regulatory proteins are a potential future therapy.

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“…In aHUS, dysregulation occurs at the cell surface, and multiple mutations in complement genes and their functional impact have been characterized in affected patients. [25][26][27][28][29][30][31][32] DDD is rarer than aHUS and has not been studied as thoroughly. 13,14,21,33 It is caused by fluid-phase dysregulation of the C3 and C5 convertases that leads to accumulation of complement debris-C3b breakdown products and sMAC-in renal glomeruli.…”

Section: Discussionmentioning

confidence: 99%

Allelic Variants of Complement Genes Associated with Dense Deposit Disease

Abrera-Abeleda¹,

Nishimura²,

Frees³

et al. 2011

Journal of the American Society of Nephrology

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The alternative pathway of the complement cascade plays a role in the pathogenesis of dense deposit disease (DDD). Deficiency of complement factor H and mutations in CFH associate with the development of DDD, but it is unknown whether allelic variants in other complement genes also associate with this disease. We studied patients with DDD and identified previously unreported sequence alterations in several genes in addition to allelic variants and haplotypes common to patients with DDD. We found that the likelihood of developing DDD increases with the presence of two or more risk alleles in CFH and C3. To determine the functional consequence of this finding, we measured the activity of the alternative pathway in serum samples from phenotypically normal controls genotyped for variants in CFH and C3. Alternative pathway activity was higher in the presence of variants associated with DDD. Taken together, these data confirm that DDD is a complex genetic disease and may provide targets for the development of disease-specific therapies.

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A novel mutation in the Complement Factor B gene (CFB) and atypical hemolytic uremic syndrome

Cited by 44 publications

References 25 publications

Atypical Hemolytic Uremic Syndrome

Atypical Hemolytic Uremic Syndrome

Update on hemolytic uremic syndrome: Diagnostic and therapeutic recommendations

Allelic Variants of Complement Genes Associated with Dense Deposit Disease

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