Atypical hemolytic uremic syndrome with MCP/CD46 anomaly
General Information (adopted from Orphanet):
Synonyms, Signs:
AHUS, SUSCEPTIBILITY TO, 2
AHUS2
Atypical HUS with MCP/CD46 anomaly
Hemolytic-uremic syndrome without diarrhea with MCP/CD46 anomaly
aHUS with MCP/CD46 anomaly
D-HUS with MCP/CD46 anomaly
Pirson et al. (1987) described 3 Belgian brothers who developed atypical HUS at ages 27, 31, and 35 years. C3 levels at presentation were normal and there was no recovery of renal function. All 3 brothers had a ... Pirson et al. (1987) described 3 Belgian brothers who developed atypical HUS at ages 27, 31, and 35 years. C3 levels at presentation were normal and there was no recovery of renal function. All 3 brothers had a cadaver kidney transplant, and all had a functioning graft with no recurrence of HUS 21 to 94 months later. Two sisters, aged 36 and 39 years old, did not develop HUS despite pregnancy and prolonged oral contraception. These brothers were subsequently studied by Warwicker et al. (1998) and Richards et al. (2003). Since the original report, 1 of the brothers died from hepatic failure with portal hypertension of unknown etiology and another developed Waldenstrom macroglobulinemia. In a comparison of 14 aHUS patients with MCP mutations and 42 with CFH mutations, Caprioli et al. (2006) found that patients with MCP mutations had an overall better prognosis. Complete remission was observed in 85.7% of patients with MCP mutations compared to 17.5% of patients with CFH mutations. Only 1 patient with an MCP mutation developed end-stage renal failure and none died during the acute episode, whereas end-stage renal failure and death occurred in 22% and 30%, respectively, of patients with CFH mutations. Most (85%) of the patients with MCP mutations retained normal renal function compared to 22.5% of patients with CFH mutations. The onset of the disease was associated with an infectious event in all patients with MCP mutations, compared to 70% with CFH mutations. Treatment with plasma infusion did not result in better disease resolution in patients with MCP mutations, perhaps because MCP is a membrane-bound protein and plasma infusion or exchange would not correct the defect theoretically. Kidney transplantation in patients with MCP mutations resulted in better long-term graft survival and better clinical benefit compared to those with CFH mutations. C3 (120700) levels were decreased in 33.3% of patients with MCP mutations.
In 2 related patients with a family history of aHUS, Noris et al. (2003) identified a heterozygous mutation in the MCP gene (120920.0001).
In 3 Belgian brothers with aHUS (Pirson et al., 1987), Richards et al. ... In 2 related patients with a family history of aHUS, Noris et al. (2003) identified a heterozygous mutation in the MCP gene (120920.0001). In 3 Belgian brothers with aHUS (Pirson et al., 1987), Richards et al. (2003) identified a heterozygous mutation in the MCP gene (120920.0002). Esparza-Gordillo et al. (2005) identified a specific SNP haplotype in the MCP gene that was overrepresented in aHUS patients and strongly associated with the severity of the disease. Linkage disequilibrium analysis suggested that the haplotype included the CR1 (120620), DAF (CD55; 125240), and C4BPA (120830) genes. Two SNPs in the haplotype influenced the transcription activity of the MCP promoter in transient transfection experiments. The SNP haplotype block was particularly frequent among patients who carried mutations in CFH (134370), MCP, or CFI (217030). Esparza-Gordillo et al. (2005) suggested that complement regulatory molecules may act as a protein network, and that multiple mutations involving plasma- and membrane-associated complement regulatory proteins are necessary to impair protection of host tissues and to confer significant predisposition to aHUS. In affected members of 2 aHUS families, Richards et al. (2003) identified 2 different heterozygous mutations in the MCP gene: a 6-bp deletion (120920.0002) and a ser206-to-pro substitution (S206P; 120920.0003). Affected members of a third family were homozygous for the S206P mutation. Caprioli et al. (2006) identified 14 mutations in the MCP gene (see, e.g., 120920.0004-120920.0006) in 20 (12.8%) of 156 patients with atypical HUS. Three patients from 1 family were compound heterozygotes, 2 patients from 1 family carried a homozygous mutation, and the others were heterozygotes. Affected individuals from 2 families had mutations in both the MCP and CFH genes. Most (93%) MCP mutations clustered in the 4 SCRs at the N-terminal region of MCP, indicating the importance of this region for complement regulation. The mutations resulted in either reduced protein expression or impaired C3b binding capability. Analyses of available relatives revealed a decreased penetrance of 54%. Esparza-Gordillo et al. (2006) reported a large Spanish pedigree with aHUS in which 2 affected members had 3 molecular risk factors: a mutation in the MCP gene that decreased MCP expression on the cell surface, a mutation in the CFI gene that resulted in premature termination, and a SNP haplotype of MCP that had been shown to decrease transcriptional activity. Family members with only 1 or 2 of these molecular defects did not develop the disease. The findings indicated an additive effect for mutations in the MCP and CFI genes and supported the notion that aHUS results from defective protection of cellular surfaces from complement activation. Esparza-Gordillo et al. (2006) also commented that the concurrence of multiple hits in complement regulatory proteins may be necessary to confer susceptibility to the disease. This would also explain the observed decreased penetrance of most mutations.