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Genetic sleuths solve a medical mystery in breakthrough study

SALT LAKE CITY — For much of her adult life, Roma Jean Ockler was never far away from the next infection.

Every six weeks or so, she'd land in the doctor’s office. Usually she had a sinus infection or pneumonia.

"It kind of became a way of life," said Ockler, now 70. "You just go to the doctor and go to the doctor and go to the doctor."

It wasn't until Ockler mentioned that her sister and two nephews have the same problems — that they are also constantly sick — that her immunologist, Dr. Harry Hill, realized there was a way to catch the culprit.

Hill, an immunologist with the University of Utah, teamed up with two colleagues. They didn't know it at the time, but their quest to find the gene causing the Ocklers' problems would take six years — and use the power of precision medicine to point the way to new therapies for immune deficiency disorders.

This kind of genetic detective work would have been impossible 10 years ago when the cost of sequencing a whole human genome was roughly $10 million, according to one of the researchers, Dr. Attila Kumanovics.

But now, companies are offering whole genome sequencing for as little as $1,000.

"The development is amazing in that sense," said Kumanovics, a molecular genetic pathologist.

But genetic sleuthing can be slow and grueling work. Kumanovics and his colleague, Dr. Karl Voelkerding, knew they had to find enough unrelated families to prove that the disease has a common cause. With a relatively uncommon disease like common variable immunodeficiency, they might have to scour the world.

So they sequenced Ockler, her sister and their children. Then they put out a call to researchers around the world to look for families with similar symptoms.

Then, for six years, they waited.

Common variable immunodeficiency is a tough disease affecting about 1 in 20,000 people, according to Hill. The illnesses that fall under its umbrella are characterized by low levels of antibodies and constant infections.

Researchers have identified genetic causes for about 15 percent of common variable immunodeficiency cases. For the rest, the cause is unknown.

People with the disease often get infections in their lungs, sinuses, ears and gastrointestinal tract over and over again.

“Two or three serious pneumonias a year is not at all unusual,” Hill said. “And I’m not talking about walking pneumonia; I’m talking really serious.”

Ockler and her family learned to deal with it most of the time. But the Highland woman said she was shaken in 2014 when she contracted pneumonia so bad that she landed in the hospital and had to undergo surgery to "scrape it off my lungs."

"I was pretty close to cashing it in," Ockler said. "It was very, very scary for my family — and scary for Dr. Hill."

Ockler’s sister, Peggy Foster, battles recurrent bronchitis and sinusitis. She also contracted the H1N1 virus in 2009 — better known as swine flu — and was hospitalized for pneumonia in January.

Two of Foster's sons who have the disease also fight recurrent pneumonia and bronchitis.

They all need 14 to 21 days of antibiotics compared with the usual 10-day course because their immune systems are so weak.

"I don't handle doors, doorknobs, anything out in public," Ockler said. "Around my home, except for my bath towel, there's paper towels everywhere, hand sanitizer everywhere. You try to be really careful and it helps, but it doesn't guarantee anything."

It doesn't help that many doctors don’t know much about common variable immunodeficiency.

Because some of these infections are so common, it usually takes years for doctors to realize something is seriously wrong.

“I think a lot of them tend to look on you as maybe a hypochondriac,” Ockler said.

The problem is so bad that Hill designed cards for patients to give to doctors if they end up in the hospital for an infection.

The card tells doctors that they can’t tell Ockler “to take a lot of aspirin and drink a lot of fluids,” Hill said. “They probably need IV antibiotics, and they probably need to be treated with another dose of intravenous immunoglobulin.”

That’s the only reliable treatment for common variable immunodeficiency — an IV or syringe full of antibodies that Ockler and her relatives usually take once a month, priced at up to $10,000 a pop.

Hill jokes that he has one assistant who spends all day “fighting insurance companies” to get them to cover the treatment.

"We have to prove how low the (immunoglobulin levels) are; we have to prove they need antibodies. They have to prove they have serious recurring infections, and then it's usually the same thing every year," Hill said.

All this was likely on Kumanovics’ mind when he received a message last February from a researcher at Rockefeller University in New York.

He described what the University of Utah researchers had hoped for — another family with mutations of the same gene as the Ocklers and Fosters.

After that, the messages started streaming in. All in all, five more families from across the U.S. and Europe were identified.

All had mutations in a gene known as IKZF1 that is responsible for the proper development of blood cells, including white blood cells and plasma cells.

It was a eureka moment for Kumanovics.

“You often work months and years to achieve something,” he said. “So when you get there, it’s really exciting.”

The results were published in the New England Journal of Medicine on Wednesday.

Researchers found that four of Ockler's and Foster's children and seven of their grandchildren have the genetic mutation. One of them survived leukemia, another illness that has been linked to mutations in the IKZF1 gene.

That "blew us away,” Foster said.

The discovery provides families like the Ocklers with critical information when it comes to being proactive about treating even minor infections, Kumanovics said.

It also legitimizes their condition to other doctors and insurance companies, according to Hill.

“If we can identify a mutation that causes this, then we have a lot better chance that we won’t have to fight quite as hard,” he said.

The study is likely to lead to better treatments that will be tailored for each patient, researchers said. Other genes that were recently discovered to be responsible for different types of common variable immunodeficiency have already pointed the way to new therapies, according to Kumanovics.

Ockler said she keeps imagining something like an insulin pump that can mete out medication on-demand at the correct dose.

“I’m hopeful,” she said. “Probably not in my lifetime, knowing how long things take — but for posterity.”

Kumanovics said researchers aren’t there yet but that the Ocklers brought researchers much closer.

“In order to really understand the disease and how to treat it, you have to know exactly what the problem is," he said.

"This is very important because it's very useful," he added. "But it's not the end of the story."


Twitter: DaphneChen_