Partial ADAMTS13 deficiency in atypical hemolytic uremic syndrome.

Complement dysregulation leads to atypical hemolytic uremic syndrome (aHUS), while ADAMTS13 deficiency causes thrombotic thrombocytopenic purpura. We investigated whether genetic variations in the ADAMTS13 gene partially explain the reduced activity known to occur in some patients with aHUS. We measured complement activity and ADAMTS13 function, and completed mutation screening of multiple complement genes and ADAMTS13 in a large cohort of aHUS patients. In over 50% of patients we identified complement gene mutations. Surprisingly, 80% of patients also carried at least 1 nonsynonymous change in ADAMTS13, and in 38% of patients, multiple ADAMTS13 variations were found. Six of the 9 amino acid substitutions in ADAMTS13 were common single nucleotide polymorphisms; however, 3 variants-A747V, V832M, and R1096H- were rare, with minor allele frequencies of 0.0094%, 0.5%, and 0.32%, respectively. Reduced complement and ADAMTS13 activity (<60% of normal activity) were found in over 60% and 50% of patients, respectively. We concluded that partial ADAMTS13 deficiency is a common finding in aHUS patients and that genetic screening and functional tests of ADAMTS13 should be considered in these patients.

A novel hybrid CFHR1/CFH gene causes atypical hemolytic uremic syndrome.

BACKGROUND: Mutations in complement factor H (CFH) are associated with complement dysregulation and the development of an aggressive form of atypical hemolytic uremic syndrome (aHUS) that progresses to end-stage renal disease (ESRD) and in most patients has a high rate of recurrence following transplantation. Sequence analysis of CFH and its downstream complement factor H-related genes (CFHR1-5) reveals several macrohomologous blocks caused by large genomic duplications. This high degree of sequence identity renders this area susceptible to nonallelic homologous recombination (NAHR) events, resulting in large-scale deletions, duplications, and the generation of hybrid CFH genes. CASE-DIAGNOSIS: Here, we report the finding of a novel CFHR1/CFH hybrid gene created by a de novo NAHR event in a 14-year-old girl with aHUS. The resulting fusion protein contains the first three short consensus repeats (SCRs) of CFHR1 and the terminal two SCRs of CFH. CONCLUSIONS: This finding demonstrates a novel pathogenic mechanism for the development of aHUS. Additionally, since standard Sanger sequencing is unable to detect such rearrangements, all aHUS patients should receive comprehensive genetic screening that includes analysis of copy number variation in order to identify patients with poor clinical prognoses.

Rare case of bilateral blindness caused by Streptococcus dysgalactiae spp equisimilis endophthalmitis in the setting of meningitis.

Endogenous endophthalmitis (EE) is a rare infectious disease of the intraocular tissues with a major risk of significant visual loss. We describe a case of a female patient who presented with altered mental status and vision loss. The patient was found to have bacteraemia, meningitis and bilateral EE caused by Streptococcus dysgalactiae spp equisimilis The patient was clinically stabilised but continued to demonstrate profound visual loss at 5-month follow-up. To our knowledge, this is the first case report of this organism causing meningitis complicated by EE. Furthermore, this infection may have heralded a diagnosis of cancer.