The high frequency of complement factor H related CFHR1 gene deletion is restricted to specific subgroups of patients with atypical haemolytic uraemic syndrome

Dragon-Durey, M.A.; Blanc, Caroline; Marliot, Florence; Loirat, Chantal; Blouin, Jacques; Sautès-Fridman, Catheriné; Fridman, Wolf Herman; Frémeaux‐Bacchi, Véronique

doi:10.1136/jmg.2008.064766

Cited by 143 publications

(118 citation statements)

References 19 publications

Supporting

Mentioning

113

Contrasting

Order By: Relevance

“…Here we showed that genetic abnormalities or anti-CFH autoantibodies are present in a substantial proportion of patients with sporadic idiopathic aHUS. In most patients, anti-CFH autoantibodies were associated with CFHR1-3 deletion, confirming published data (12,25). Interestingly, we found genetic abnormalities-mainly in CFH-also in patients with pregnancyassociated aHUS, post-transplant aHUS, and other systemic or renal diseases, whereas no patients with secondary aHUS had anti-CFH autoantibodies.…”

Section: Discussionsupporting

confidence: 77%

Relative Role of Genetic Complement Abnormalities in Sporadic and Familial aHUS and Their Impact on Clinical Phenotype

Noris¹,

Caprioli²,

Bresin³

et al. 2010

Clinical Journal of the American Society of Nephrology

891

1,194

View full text Add to dashboard Cite

Background and objectives: Hemolytic uremic syndrome (HUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Most childhood cases are caused by Shiga toxin-producing bacteria. The other form, atypical HUS (aHUS), accounts for 10% of cases and has a poor prognosis. Genetic complement abnormalities have been found in aHUS.Design, setting, participants, and measurements: We screened 273 consecutive patients with aHUS for complement abnormalities and studied their role in predicting clinical phenotype and response to treatment. We compared mutation frequencies and localization and clinical outcome in familial (82) and sporadic (191) cases.Results: In >70% of sporadic and familial cases, gene mutations, disease-associated factor H (CFH) polymorphisms, or anti-CFH autoantibodies were found. Either mutations or CFH polymorphisms were also found in the majority of patients with secondary aHUS, suggesting a genetic predisposition. Familial cases showed a higher prevalence of mutations in SCR20 of CFH and more severe disease than sporadic cases. Patients with CFH or THBD (thrombomodulin) mutations had the earliest onset and highest mortality. Membrane-cofactor protein (MCP) mutations were associated with the best prognosis. Plasma therapy induced remission in 55 to 80% of episodes in patients with CFH, C3, or THBD mutations or autoantibodies, whereas patients with CFI (factor I) mutations were poor responders. aHUS recurred frequently after kidney transplantation except for patients with MCP mutations.Conclusions: Results underline the need of genetic screening for all susceptibility factors as part of clinical management of aHUS and for identification of patients who could safely benefit from kidney transplant.

show abstract

Section: Discussionsupporting

confidence: 77%

Relative Role of Genetic Complement Abnormalities in Sporadic and Familial aHUS and Their Impact on Clinical Phenotype

Noris¹,

Caprioli²,

Bresin³

et al. 2010

Clinical Journal of the American Society of Nephrology

891

1,194

View full text Add to dashboard Cite

show abstract

“…CFHR1 deletion was screened using multiplex ligation-dependent probe amplification as previously reported. 40 …”

Section: Methodsmentioning

confidence: 99%

Pregnancy-Associated Hemolytic Uremic Syndrome Revisited in the Era of Complement Gene Mutations

Fakhouri¹,

Roumenina²,

François³

et al. 2010

Journal of the American Society of Nephrology

396

395

View full text Add to dashboard Cite

In contrast to pregnancy-associated thrombotic thrombocytopenic purpura, the pathogenesis and presentation of pregnancy-associated atypical hemolytic uremic syndrome (P-aHUS) remain ill-defined. We conducted a retrospective study to assess the presentation and outcomes of patients presenting with P-aHUS and the prevalence of alternative C3 convertase dysregulation. P-aHUS occurred in 21 of the 100 adult female patients with atypical HUS, with 79% presenting postpartum. We detected complement abnormalities in 18 of the 21 patients. The outcomes were poor: 62% reached ESRD by 1 month and 76% by last follow-up. The risk for P-aHUS was highest during a second pregnancy. Thirty-five women, 26 (74%) of whom had complement abnormalities, had at least one pregnancy before the onset of a non-pregnancy-related aHUS. Outcomes did not differ between patients with pregnancy-related and non-pregnancy-related aHUS. Mutations in the SCR19-20 domains of factor H were less frequent in P-aHUS patients compared with non-pregnancy-related aHUS. Pregnancies in female patients with complement abnormalities (n ϭ 44) were complicated by fetal loss and preeclampsia in 4.8% and 7.7%, respectively. Better understanding of complement dysregulation in pregnancy complications is essential, especially to guide development of pharmacologic agents to modulate this system.

show abstract

“…Titers of anti-FH IgG were significantly higher at the acute phase than in remission. Indeed, in the 26 patients tested, the mean of titers at disease onset was significantly higher than that in remission (11,564 versus 1104 AU/ml, respectively, P Ͻ 0.0001) (Figure 3). For seven patients, prospective follow-up revealed a correlation between anti-FH titer increase (Ͼ2000 UA/ml) and the occurrence of relapse (nine relapses).…”

Section: Long-term Evolution and Treatmentmentioning

confidence: 99%

“…11 Sequences of probes were designed to determine dosage for exon 23 of CFH, exon 5 of CFHR1, and exon 3 of CFHR3 along with the control probe C1INH exon 8. Reagents of MLPA reaction were purchased from MRC Holland (Amsterdam, The Netherlands), and the reaction was carried out according to the manufacturer's recommended protocol.…”

Section: Multiplex Ligation-dependent Probe Amplificationmentioning

confidence: 99%

“…9,10 Most patients lack the circulating complement Factor H-related proteins (CFHR) 1 and 3 because of a homozygous deletion of CFHR1 and CFHR3. 7,11,12 Currently, only a few descriptive reports concerning the clinical and biologic data, and the treatment modalities are available. [5][6][7][8]10,[12][13][14][15][16] We report here the clinical, biologic, and genetic features of 45 aHUS patients who presented anti-FH autoantibodies.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Clinical Features of Anti-Factor H Autoantibody–Associated Hemolytic Uremic Syndrome

Dragon-Durey

Sethi²,

Bagga³

et al. 2010

Journal of the American Society of Nephrology

252

283

View full text Add to dashboard Cite

Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy that associates, in 70% of cases, with genetic or acquired disorders leading to dysregulation of the alternative pathway of complement. Autoantibody directed against Factor H causes at least 6% to 10% of aHUS cases, but only a few clinical reports are available. Here, we describe the clinical, biologic, genetic features, treatment, and outcome of 45 patients who presented with aHUS associated with anti-FH autoantibody. We found that this form of aHUS primarily affects children between 9 and 13 years old but it also affects adults. It presents with a high frequency of gastrointestinal symptoms and with extrarenal complications and has a relapsing course. Activation of the alternative pathway of complement at the onset of disease portends a poor prognosis. Early specific treatment may lead to favorable outcomes. These data should improve the recognition and diagnosis of this form of aHUS and help identify patients at high risk of a poor outcome.

show abstract

The high frequency of complement factor H related CFHR1 gene deletion is restricted to specific subgroups of patients with atypical haemolytic uraemic syndrome

Abstract: The high frequency of CFHR1 deletion in aHUS patients is restricted to the subgroups of patients presenting with anti-FH autoantibodies or, to a lesser degree, CFI mutation. These results suggest that the CFHR1 deletion plays a secondary role in susceptibility to aHUS.

Cited by 143 publications

References 19 publications

Relative Role of Genetic Complement Abnormalities in Sporadic and Familial aHUS and Their Impact on Clinical Phenotype

Relative Role of Genetic Complement Abnormalities in Sporadic and Familial aHUS and Their Impact on Clinical Phenotype

Pregnancy-Associated Hemolytic Uremic Syndrome Revisited in the Era of Complement Gene Mutations

Clinical Features of Anti-Factor H Autoantibody–Associated Hemolytic Uremic Syndrome

Contact Info

Product

Resources

About