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.

So they wind up in the Undiagnosed Diseases Network, a federally funded project that includes 12 clinical centers, including one at the National Institutes of Health.

Researchers in the network pursue every possible clue — from genetics, imaging, biochemistry, exams — to discover what is wrong with these patients.

In a study, 1,519 patients were referred to the network, but less than half were accepted for intensive evaluation at no charge. The network completed evaluations of 382 participants and found a diagnosis for 132 of them. (Since the study ended, the investigators have diagnosed diseases in another 128 patients.)

For some — after years of struggling with enigmatic symptoms — there was good news: a treatment, often a drug on the market for another condition.

Yet even patients who come away with a diagnosis but without a treatment, say the experience can be rewarding. “Patients find it really valuable even just to give a name to the enemy,” said Dr. Euan Ashley, a geneticist at Stanford University and co-director of the network.

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,” Ashley said.

Here are stories that look at the lives of three patients who have been through a diagnostic marathon few can imagine.

She seemed drunk

Dee Reynolds’ symptoms began in 2005 and slowly got worse. Her speech slurred, her balance was precarious. She visited doctor after doctor, had test after test. In 2018, doctors in the Undiagnosed Diseases Network sequenced not just her genes, but the regions of DNA that control them.

It turned out that Reynolds, 60, has an inherited disease that almost invariably occurs in childhood: Niemann-Pick Type C. The problem is an accumulation of cholesterol and other lipids inside the body’s cells, which damages organs and the central nervous system. Typically young patients die within a decade. Reynolds got by for more than four decades before the disease started taking a toll.

“It is not unheard of to develop Niemann-Pick disease as an adult, but it is very, very rare,” said Dr. Camilo Toro, her neurologist at the NIH. “I’d read about it but never seen an adult patient.”

There is no approved therapy. But Reynolds said the diagnosis “helped me deal with the uncertainty.”

Runner couldn’t wear shoes

Sara Silva, 44, of Pacifica, Calif., was a marathon runner 16 years ago. But at a holiday party, she felt a burning, searing pain in her hands and feet.

The symptoms dissipated, then recurred — until they were with her all the time. The pain got worse.

“I haven’t worn shoes for four years,” she said. She cannot bear heat: “I can’t cook or use the oven. I can’t have warm food or warm showers.”

She usually has ice packs on her torso, and she takes heavy doses of pain medications. “This life is challenging,” Silva said. “Pain is something you learn to respect.”

She ended up at the Stanford pain clinic, where doctors said her primary disease is erythromelalgia, a condition in which blood vessels become blocked and inflamed. But no one knew how she got it. The Stanford team is continuing to search.

Meningitis, but no infection

Zarko Stanacev, 67, began having episodes of hearing loss in 2007. His doctor could not figure out what was going on.

Then in 2010, Stanacev was hospitalized with meningitis. He had a 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. Between 2010 and 2017, he had 30 episodes for no apparent reason. The disease kept getting worse.

There was no doubt that he had meningitis — his brain was inflamed. But why? Antibiotics did not help, and neither did steroids, which should tamp down an inflammation.

Finally, researchers at the NIH’s Undiagnosed Diseases Network figured out what was wrong. 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.

There are just two or three reported cases of this mutation in the medical literature, said Dr. William Gahl.

The good news for him was that there is a drug on the market — anakinra, used to treat rheumatoid arthritis — that blocks interleukin 1. After he got 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 to his wife.

“It was like a miracle,” Gahl said.