Undiagnosed Diseases Network works patients’ mysteries
Cause of illnesses not always found.
By Gina Kolata
They are patients with diseases that mystify doctors, people whose symptoms are dismissed as psychosomatic, who have been given misdiagnosis upon misdiagnosis.
They have confounded experts and have exhausted every hope save one: the Undiagnosed Diseases Network, a federally funded project that includes 12 clinical centers, including one at the National Institutes of Health in Bethesda, Maryland.
Researchers in the network pursue every possible clue — gleaned from genetics, imaging, biochemistry, clinical exams — to discover what is wrong with these patients.
In a recent study, 1,519 patients were referred to the network, but less than half were accepted for intensive evaluation at no charge. The network evaluated 382 participants and found a diagnosis for 132 of them. Since the study ended, the investigators have diagnosed another 128 patients.
For some, there was a treatment, often a drug on the market for another condition.
Those who come away without a diagnosis or treatment are told that if the science improves and an answer for them emerges, the network will contact them.
“We never give up,” said Dr. Euan Ashley, a geneticist at Stanford University and co-director of the network.
Here are three patients who have been through a diagnostic marathon few can imagine.
Sara Silva, 44; Pacifica, California
The symptoms: Sixteen years ago, Silva was a healthy marathon runner. Her life changed abruptly, though, after a holiday party for her husband’s law firm.
At the event, she suddenly felt a burning, searing pain in her hands and feet. Her legs started swelling. She was frightened, but the next day she seemed fine — so she ignored the episode.
But the symptoms recurred and worsened, until they were with her all the time.
“I haven’t worn shoes for four years because the pain is so bad,” she said. She cannot bear heat: “My house is at 62 degrees, even in winter. I can’t cook or use the oven. I can’t have warm food or warm showers.”
“This life is challenging,” Silva said. “Pain is something you learn to respect.”
Intensive testing: She saw scores of doctors and went to the Mayo Clinic twice for an exhaustive work-up, to no avail.
She ended up at the Stanford pain clinic, where doctors said her primary disease is erythromelalgia, a rare condition in which blood vessels become blocked and inflamed. But no one knew how she got it.
In early 2018, Silva was accepted into the Stanford site of the Undiagnosed Diseases Network. She had further genetic testing, but they all led to a dead end.
The diagnosis: None as yet. And doctors cannot give her a prognosis. Silva has not given up and said she is “still hoping to one day get that phone call from them with a solid answer as to what my little monster actually is and how to stomp it out like a hairy spider.”
Dee Reynolds, 60; Northern Virginia
The symptoms: They began in 2005 and slowly got worse. Her speech slurred, she began weaving when she walked. Her sense of balance was precarious.
Year after year, Reynolds sought an answer, visiting doctor after doctor, getting test after test, including gene sequencing. But no one could figure out what was wrong.
In 2018, she was accepted into
the Undiagnosed Diseases Network.
“I had a year’s worth of testing in four days,” she recalled. “The first day was 25 vials of blood.” She had a skin biopsy, an MRI, psychological exams and eye exams. Doctors sequenced not just her genes, but the nearby regions of DNA that control them.
The diagnosis: Reynolds has an inherited disease that usually occurs in childhood: Niemann-Pick Type C. The typical patient is a child who develops difficulties with walking and coordination because of a steady accumulation of lipids inside the body’s cells, which damages the central nervous system. The disease progresses relentlessly to include seizures and dementia. Typically young patients die of aspiration pneumonia within a decade.
The prognosis: It’s hard to know. Reynolds’ disease has progressed, but extremely slowly.
The treatment: There is no approved therapy for the disease. But there are clinical trials of experimental therapies underway. If approved, Toro hopes Reynolds can benefit from these
treatments.
Zarko Stanacev, 67; Atlanta
The symptoms: In 2007, Stanacev began having repeated episodes of hearing loss.
In 2010, Stanacev was hospitalized with meningitis. He had a high fever and a headache. It was clear that his brain was inflamed, but there was no bacterial or viral infection.
After a few days, he recovered, only to get meningitis again. And again, and again. Between 2010 and 2017, he had 30 episodes for no apparent reason.
The episodes would start with chills and a fever, which would progress hour by hour. “By the next morning he was almost unresponsive,” said his wife, Dejana Stanacev, 55. “Each time he went to the hospital, I didn’t know if he would get out.”
The disease, whatever it was, kept getting worse. Soon he could not walk and was in constant pain, all over his body. His mind was cloudy; he was unable to concentrate.
Intensive testing: There was no doubt that Zarko Stanacev had meningitis — his brain was inflamed. But why? Antibiotics did not help, and neither did steroids, which should tamp down an inflammation.
No matter how many times he was tested, doctors found no sign of a bacterial or viral infection. Late last year, Stanacev was referred to the Undiagnosed Diseases site at the NIH.
He received the full gamut of testing: imaging, blood draws, genetic analyses and, possibly most important, a lumbar puncture to obtain cerebrospinal fluid, which bathes the brain. That fluid showed clear signs of extensive inflammation.
The diagnosis: The Stanavecs got a phone call in April from the clinic. Researchers had figured it out.
Stanavec had an extremely rare mutation in a gene, NLRP3, which helps direct cells to activate a protein, interleukin 1 beta, that is part of the immune response to infections. The mutation made him produce an NLRP3 protein that was always active — even when there was no infection. The treatment: The good news for him was that there is a drug on the market — anakinra, used to treat rheumatoid arthritis — that blocks interleukin 1. Stanacev for an injection of anakinra. His pain melted away. He got up from his wheelchair. He could think clearly again. “It was like a fog lifted from my brain,” he said.