Novel C3 Mutation Causing Atypical Hemolytic Uremic Syndrome Successfully Treated with Eculizumab

Introduction: Hemolytic Uremic Syndrome (HUS) is a rare thrombotic microangiopathic disease characterized by hemolytic anemia, thrombocytopenia, and acute renal failure occurring after infection with a Shiga-like toxin producing bacteria. Patients without evidence of infection with such kind of bacteria are described as having atypical HUS (aHUS). aHUS can be classified as sporadic or familial, and both conditions are associated with complement abnormalities, more specifically with dysregulation of the alternative complement pathway. Familial aHUS is caused, most of the times, by either gain of function mutations in activators of complement or loss of function mutations in complement regulators. Among others, the genes commonly mutated in a HUS are CFH, C3, CFB, MCP and etc. Here we describe a novel mutation in C3 present in a patient with familial aHUS, and the successful treatment of this patient with the complement inhibitor Eculizumab.

Report: A 40-year-old female presented at the emergency room with headache and anasarca. Physical exam was consistent with hypertension, pale skin and mucous membranes. Blood tests revealed renal insufficiency, anemia and low platelet counts. She had no history of infections. The first diagnostic hypothesis was thrombotic thrombocytopenic purpura and she was started on plasmapheresis and hemodialysis. She was discharged 40 days later with clinical improvement. One week after discharge she was admitted at our hospital with recurrence of the clinical picture. Blood tests at admission showed hemoglobin = 7,8 g/dL, platelet counts = 70.000 / uL, LDH = 1024 U/L, Creatinine = 4, 19 mg/dl, ADAMTS13 activity = 79%, C3 = 29,5 mg/dL, C4 = 16.2 mg/dL and factor H = 212 µg/mL. The patient informed that her mother and five aunts, died around 40 to 50 years of age due to renal insufficiency. Plasmapheresis and hemodialysis were resumed and she was started on Rituximab 375 mg/m² weekly. After an initial clinical response, but soon anemia, low platelets and high LDH recurred. At that point we made a hypothesis of aHUS, ordered a C3 sequencing and started a therapeutic trial with Eculizumab. She received 900 mg of eculizumab during four weeks, and maintenance of 1200 mg every two weeks. She showed a continuous improvement after the first dose and was discharged after the third dose, without the need for hemodialysis, with a serum creatinine = 2.1 mg/dl, hemoglobin = 711 g/dL, platelet counts = 262.000 / uL and LDH = 1024 U/L. Now, 6 months after discharge she remains in remission of her disease, with normal blood counts and serum creatinine of is 1.6 mg/dL with Eculizumab maintenance at dose of 1200 mg twice a month. The C3 sequencing revealed the following heterozygous mutations in the 6^thexon, c.640C>T (p.Pro214Ser). Since this variant has not been previously described in the medical literature, we performed an in silico analysis using Polyphen2 software and the result was probably pathogenic.

Discussion: We have presented a patient with aHUS harboring a novel heterozygous mutation in C3. At least 47 C3 mutations have been described at the FH aHUS database (http://www.fh-hus.org/) spanning almost the entire sequence of the gene (from Lys65 to Val1658). The mutation described here is novel and functional studies to characterize its consequences are needed. But the very strong family history, coupled with the clinical evolution of the patient, the in silico protein analysis and the complete response to eculizumab strongly suggests that this variant is pathogenic and may be used in the future as a predictor of response to Eculizumab.