title: Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Mario Negri Institute for Pharmacological Research, Clinical Research Center for Rare Diseases, Aldo e Cele Daccò, Via Camozzi, 3-24020 Ranica (BG), Italy. marina.noris@marionegri.it.
authors.forename: Marina
authors.initials: M
authors.lastname: Noris
authors.forename: Jessica
authors.initials: J
authors.lastname: Caprioli
authors.forename: Elena
authors.initials: E
authors.lastname: Bresin
authors.forename: Chiara
authors.initials: C
authors.lastname: Mossali
authors.forename: Gaia
authors.initials: G
authors.lastname: Pianetti
authors.forename: Sara
authors.initials: S
authors.lastname: Gamba
authors.forename: Erica
authors.initials: E
authors.lastname: Daina
authors.forename: Chiara
authors.initials: C
authors.lastname: Fenili
authors.forename: Federica
authors.initials: F
authors.lastname: Castelletti
authors.forename: Annalisa
authors.initials: A
authors.lastname: Sorosina
authors.forename: Rossella
authors.initials: R
authors.lastname: Piras
authors.forename: Roberta
authors.initials: R
authors.lastname: Donadelli
authors.forename: Ramona
authors.initials: R
authors.lastname: Maranta
authors.forename: Irene
authors.initials: I
authors.lastname: van der Meer
authors.forename: Edward M
authors.initials: EM
authors.lastname: Conway
authors.forename: Peter F
authors.initials: PF
authors.lastname: Zipfel
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Goodship
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
mesh_terms: D000293:Adolescent; D000328:Adult; D000369:Aged, 80 and over; D001323:Autoantibodies / Q000097:blood; D016009:Chi-Square Distribution; D003176:Complement C3 / Q000235:genetics; D017242:Complement Factor H / Q000235:genetics; D003165:Complement System Proteins / Q000235:genetics* / Q000276:immunology; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics* / Q000276:immunology / Q000401:mortality / Q000628:therapy; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053208:Kaplan-Meier Estimate; D016030:Kidney Transplantation; D008297:Male; D051916:Membrane Cofactor Protein / Q000235:genetics; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011110:Polymorphism, Genetic; D016016:Proportional Hazards Models; D012008:Recurrence; D012042:Registries; D018570:Risk Assessment; D012307:Risk Factors; D018180:Thrombomodulin / Q000235:genetics; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D001323:Autoantibodies; C038245:C3 protein, human; C497857:CD46 protein, human; C493495:CFH protein, human; D003176:Complement C3; D051916:Membrane Cofactor Protein; C546931:THBD protein, human; D018180:Thrombomodulin; D017242:Complement Factor H; D003165:Complement System Proteins