Black urine helps spot second rare disease in two brothers with ahUS
Unusual symptom leads to diagnosis of rare inherited metabolic disorder
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Two brothers with atypical hemolytic uremic syndrome (aHUS) were also diagnosed with a rare inherited metabolic disorder after doctors in Turkey investigated the unusual symptom of urine that repeatedly turned black, according to a case report.
The siblings, ages 24 and 19, had experienced several episodes of aHUS, a disease marked by the destruction of red blood cells (hemolysis) and problems with the kidneys. But their dark urine, along with long-standing joint pain and other symptoms, eventually led doctors to discover that both also had alkaptonuria, a condition in which certain substances build up in the body.
“To our knowledge, this is the first report of the coexistence of aHUS and [alkaptonuria],” researchers wrote. They added that the case highlights that “persistent or recurrent black discoloration of urine” in people with aHUS “should not be assumed to result solely from hemolysis.”
The study, “When two rare diseases meet: atypical hemolytic uremic syndrome and alkaptonuria in two siblings,” was published in CEN Case Reports.
Brothers’ kidney function recovered after repeated aHUS episodes
aHUS occurs when part of the immune system, called the complement system, becomes overly active. This causes tiny blood clots to form in small blood vessels, a process known as thrombotic microangiopathy (TMA), leading to hemolysis, low platelet counts, and kidney injury.
Certain genetic mutations can increase the risk of developing aHUS, but an additional trigger, such as an infection, is often necessary for symptoms to develop.
Alkaptonuria is a rare inherited disease wherein the body cannot properly break down certain protein building blocks. As a result, a substance called homogentisic acid builds up, causing urine to turn dark when exposed to air. Over time, it can also cause dark pigmentation in body tissues and painful joint problems.
In this report, researchers in Turkey described what they believe is the first documented case of aHUS and alkaptonuria occurring together in two brothers whose parents were close biological relatives. Both had experienced repeated episodes of aHUS, but their kidney function recovered each time.
Brothers carried mutations in two genes
The older brother first became ill at age 20, with nausea, vomiting, abdominal pain, anemia, low platelet counts, and acute kidney injury. He recovered after receiving corticosteroids, medications that suppress immune activity, and plasma exchange, a procedure that replaces the liquid portion of blood to help replenish missing or defective proteins that regulate complement activity.
Three years later, he experienced another episode following a respiratory infection. This time, doctors noticed something unusual: urine collected during his hospitalization had turned black.
His younger brother had a similar history, experiencing three episodes between ages 16 and 17. At age 19, a respiratory infection preceded a fourth episode, accompanied by kidney injury, low platelet counts, and unusually dark urine.
The similarities prompted doctors to investigate a possible inherited cause. Both brothers had long-standing back and knee pain, dark pigmentation in the whites of their eyes, and a history of urine turning black. Their family also recalled black stains appearing on their diapers during infancy.
Genetic testing revealed that both carried the same mutation in CD46, a gene linked to aHUS. But both also carried a mutation in another gene, called HGD, which is implicated in alkaptonuria. Together with their symptoms, these findings confirmed that the brothers had two separate inherited diseases.
These cases demonstrate that unusual clinical findings accompanying TMA should not automatically be attributed to aHUS alone.
The researchers noted that the dark urine could easily have been mistaken for a consequence of aHUS, which can cause blood or substances released from damaged red blood cells to appear in urine. In alkaptonuria, however, the discoloration results from the buildup of homogentisic acid, which turns dark when exposed to air.
Both brothers received the aHUS-approved medication Soliris (eculizumab). Their blood cell counts returned to normal, and both maintained normal kidney function during 12 months of follow-up.
However, protein continued to leak into their urine, suggesting lingering kidney damage. Doctors prescribed medications to protect the kidneys and reduce protein loss, which gradually declined but did not completely resolve.
The brothers also continued to experience chronic back and knee pain. Neither had started treatment specifically for alkaptonuria, and further assessments were needed to determine whether the disease had damaged their joints or other organs.
“These cases demonstrate that unusual clinical findings accompanying TMA should not automatically be attributed to aHUS alone,” the researchers wrote. “Careful assessment of atypical clinical features, supported by genetic testing when appropriate, may facilitate recognition of coexisting inherited disorders, particularly in consanguineous families, and improve diagnostic accuracy and long-term patient management.”
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