Mutations Affecting C3 Protein Activity Linked to aHUS in Case Report

Mutations Affecting C3 Protein Activity Linked to aHUS in Case Report
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Mutations leading to the overactivation of the complement regulator protein C3 should be recognized as a cause of atypical hemolytic uremic syndrome (aHUS), a case report highlights.

The report, “Complement C3 mutation causing atypical hemolytic uremic syndrome successfully treated with eculizumab,” was published in the journal Hematology, Transfusion and Cell Therapy.

aHUS is caused by the progressive destruction of red blood cells due to the abnormal activation of the complement system — a set of more than 20 blood proteins that form part of the body’s immune defenses.

Statistics indicate that in up to 50% of people with aHUS, abnormalities in the complement system are caused by mutations in genes coding for complement regulator proteins, such as C3.

Investigators at the University of South Dakota reported on two people with aHUS triggered by a mutation that led to the overactivation of C3, who were successfully treated with the complement inhibitor Soliris (eculizumab).

The first patient was a 33-year-old man who arrived at the hospital’s emergency department complaining of fever, muscle aches, sore throat, cough, and bloody urine (hematuria). He did not have a recent medical history of abdominal pain or diarrhea.

Clinical evaluation found acute kidney injury, low platelet counts (thrombocytopenia), and anemia. He was started on plasmapheresis due to the concern that he could possibly have thrombotic thrombocytopenic purpura (TTP), a condition in which small blood vessels become leaky, causing bleeding and extensive bruising.

Plasmapheresis, also known as plasma exchange, is a form of treatment in which a patient receives plasma (the liquid portion of blood obtained after removing all blood cells) from a healthy donor.

A kidney biopsy performed due to increasingly poor kidney function revealed the patient had thrombotic microangiopathy (TMA), a condition in which the small blood vessels inside the kidneys become clogged, ultimately leading to kidney failure.

After finding the activity of the von Willebrand factor-cleaving protein, also known as ADAMTS13, to be normal, physicians discarded the possibility of TTP and stopped plasmapheresis.

The man was then started on Soliris for presumed aHUS. Treatment led to a rapid improvement in both kidney function and  hemolysis (red blood cell destruction). Subsequent genetic tests confirmed the man carried a mutation (c.481C > T) in the C3 gene.

The second patient was a 34-year-old woman who arrived at the hospital with unusual vaginal bleeding. She had started experiencing nausea, vomiting, and diarrhea six days prior, and was treated symptomatically. Although her diarrhea started to subside soon after, mid-cycle vaginal bleeding began.

Apart from high blood pressure (hypertension), initial examinations found nothing unusual. She received emergency treatment for high blood pressure and was admitted to the intensive care unit for further testing.

These tests found anemia, low platelet counts, and high levels of the inflammatory marker lactate dehydrogenase (LDH), raising the possibility of TTP. However, further analyses also showed normal levels of ADAMTS13.

As with the first patient, a kidney biopsy found signs of TMA, and the woman was started on Soliris for possible aHUS, in combination with hemodialysis and medications to lower her blood pressure.

Genetic tests revealed she carried the same mutation (c.481C > T) in the C3 gene. She continued treatment with Soliris, and her kidney function gradually improved to the point where hemodialysis was no longer required.

“These cases and the existing literature support the importance of recognizing this pathological variant as a cause for aHUS,” the investigators wrote.

“Both patients responded well to the eculizumab therapy and have been in remission, with a gradual decrease in the frequency of eculizumab administration. Further studies on such patients might characterize disease behavior and prognosis specifically related to this mutation,” they added.

Joana holds a BSc in Biology, a MSc in Evolutionary and Developmental Biology and a PhD in Biomedical Sciences from Universidade de Lisboa, Portugal. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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Inês holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she specialized in blood vessel biology, blood stem cells, and cancer. Before that, she studied Cell and Molecular Biology at Universidade Nova de Lisboa and worked as a research fellow at Faculdade de Ciências e Tecnologias and Instituto Gulbenkian de Ciência.

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Joana holds a BSc in Biology, a MSc in Evolutionary and Developmental Biology and a PhD in Biomedical Sciences from Universidade de Lisboa, Portugal. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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