Rare Mutation Causing Adult-onset aHUS Provides Insights Into Disease

Rare Mutation Causing Adult-onset aHUS Provides Insights Into Disease
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The case of a man with atypical hemolytic uremic syndrome (aHUS) caused by a rare genetic mutation offers insights into the early diagnosis, disease mechanisms, and treatment of this uncommon disorder.

Published in the journal Medicine, the case study was titled “Atypical hemolytic uremic syndrome and acute tubular necrosis induced by complement factor B gene (CFB) mutation.”

Multiple mutations can underlie aHUS, a rare condition characterized by the formation of blood clots in the small vessels of the kidneys, as well as red blood cell destruction, low platelet counts, and kidney failure.

These mutations occur in genes related to a branch of the immune system, called the alternative complement pathway, that forms part of the body’s line of defense against disease-causing microbes.

Mutations in the complement factor B gene, CFB, are rare and adult-onset cases, such as the one presented here, are rarer still. That made an accurate diagnosis even more challenging.

The 56-year-old man had been unconscious for 10 hours when he was first treated at the hospital. He had become comatose after having spent four days experiencing nausea and fatigue and going two days without urinating.

Doctors eventually suspected the patient might have aHUS based on a series of observations that were consistent with the disease’s symptoms. These included lab tests showing signs of kidney function impairment, anemia associated with red blood cell destruction, and elevated lactate dehydrogenase (LDH) levels in the absence of infection. Of note, LDH is a marker of red blood cell destruction.

A negative Coomb test, which looks for the presence of self-reactive antibodies directed against a patient’s own blood cells, ruled out the possibility of an autoimmune disorder causing the man’s symptoms.

Continuous renal replacement therapy  — a special type of dialysis for critically ill patients — mechanical ventilation, and a blood transfusion were immediately started by the physicians.

The man regained consciousness after one day’s treatment and came off mechanical ventilation. However, his platelet counts and hemoglobin levels remained low. Of note, hemoglobin is the protein responsible for transporting oxygen in red blood cells.

He also had high blood pressure and remained unable to urinate.

Given the possible aHUS diagnosis, the doctors began plasmapheresis, a treatment that involves separating the plasma, or liquid portion of the blood, treating it, and then returning it to the patient. He additionally was given antibiotics and the blood pressure medication losartan, marketed as Cozaar.

The patient’s urine production increased to the point of excessive urination after two plasmapheresis sessions, after which it normalized. His platelet and hemoglobin counts recovered and remained normal at 15 months of follow-up, at which time the man was still clinically stable.

To try to identify the cause of the patient’s condition, the physicians then examined the man’s complement system. While most of the complement factor levels were normal, they discovered the patient had a disease-causing mutation in the CFB gene.

Despite having this mutation, the patient had never developed aHUS during childhood. The physicians who treated him suspected the disease was likely triggered by a serious bacterial lung infection. This infection, they wrote, “can activate the complement system, but a defect in [complement] factor B can induce a complement overactivation, and precipitate the episode of aHUS.”

“More reports of aHUS in patients with CFB gene mutation would likely provide further insights into the pathogenesis [mechanisms] of this rare disease, possibly uncovering the underlying mechanisms to aid in the early diagnosis and development of effective therapies,” they concluded.

Forest Ray received his PhD in systems biology from Columbia University, where he developed tools to match drug side effects to other diseases. He has since worked as a journalist and science writer, covering topics from rare diseases to the intersection between environmental science and social justice. He currently lives in Long Beach, California.
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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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Forest Ray received his PhD in systems biology from Columbia University, where he developed tools to match drug side effects to other diseases. He has since worked as a journalist and science writer, covering topics from rare diseases to the intersection between environmental science and social justice. He currently lives in Long Beach, California.
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