Disease Detectives

In search of solutions for mystery illnesses
By Tara Hulen • Illustration by Laura Hannah
Illustration of doctor shining flashlight on DNA
In search of solutions for mystery illnesses
By Tara Hulen • Illustration by Laura Hannah
“When you hear hoofbeats, think horses, not zebras” is sound advice for medical students eager to treat an exotic disease when a patient likely has a more common illness. But what happens when those metaphorical zebras do come along? Sometimes a patient arrives with something so unusual that physicians have never seen anything like it. Even the best specialists can be stumped, leaving the patient with no answers, no diagnosis, and no solutions.

UAB’s new Undiagnosed Diseases Program, modeled after a groundbreaking initiative at the National Institutes of Health (NIH), aims to help patients solve baffling medical mysteries. These illnesses may be so rare that only a handful of people in the world have them; sometimes no other cases have been discovered.

Bruce Korf, M.D., chair of the Department of Genetics, began developing the UAB program after serving as chair of the advisory board for the NIH initiative and attending patient care conferences. UAB is piloting the undiagnosed diseases concept in the academic environment, he says. “We can do the hard things that aren’t always feasible in the course of day-to-day medical care,” he says. “That’s part of our mission as an academic medical center.”

Listening to the Story

Gustavo Heudebert, M.D., program co-director and an internal medicine professor, has convened a panel of UAB specialists to serve as medical Sherlocks. [Editor's note: Martin Rodriguez, M.D., an associate professor specializing in infectious diseases,stepped into Heudebert's role as program co-director in fall 2014.] Each week, the group examines a few carefully prescreened and condensed case files. In its first year, the program has seen nearly 30 patients; referrals have come from as far away as New York.

“First, we take time to hear the patient’s story,” Korf says. “These usually are patients who have gone from doctor to doctor for a long time. Then we review records—often pretty large piles of information. We try to find something about the story where our expertise and clinical tools can potentially make a contribution.”

Sequencing the patient’s genome to identify genetic markers can be part of the examination process, with a level of expert analysis not typically available to physicians in other settings, Korf explains. In fact, he calls it the program’s “ultimate weapon.” Heudebert adds that UAB scientists zero in on the exome—the part of the genome with richer information about diseases, including proteins the patient might lack—in an effort to explain symptoms.

Co-director and clinical geneticist Maria Descartes, M.D., says that in cases where a potentially inherited genetic disorder is discovered, family members can undergo genetic testing. Genetic counseling also can help patients and families better understand what the results mean for them and their children.

The number of cases the team sees is small and selective, Heudebert explains, because the program wants to focus its resources on cases most likely to lead to new medical discoveries that could provide patients with answers. In the NIH program, some of the mystery illnesses turned out to be diseases “known to medicine, but they were presenting in extraordinarily unusual ways,” Heudebert says. Neurological disorders, such as a variant of multiple sclerosis, and metabolic disorders were most common.

Many of the UAB patients have had some form of progressive neurological conditions, often manifesting as movement disorders or loss of cognitive function. “We have a few examples where we have discovered genetic mutations that may potentially be involved in some conditions,” Korf says. “It’s premature to say that we have described new entities, but they are significant leads.”

Delta Force for Disease

For internal medicine physicians on the front lines of initial diagnoses, the program “is a dream come true,” Heudebert says. “I can have a four-hour visit with a patient. I have basically every diagnostic and imaging test at my disposal. Then I have the undivided attention of my handpicked, preferred doctors—more than 1,300 in the system. It’s like having access to Delta Force or Navy SEALs.”

The process can take months, as opposed to quick solutions popularized on the TV show House, M.D. “Difficult questions are seldom easily—or quickly—answered,” says Carol Dahl, C.R.N.P., the program’s clinical coordinator.

“At the initial visit, we try to determine what patients are seeking from the evaluation,” Dahl says. “Parents of an infant or child might want to know the name of the condition in order to have a prognosis, which would allow them to prepare, emotionally and logistically, to continue to provide care. In contrast, adult patients are more likely seeking diagnoses leading to effective treatment.”

At UAB, as at the NIH, not every patient is guaranteed to receive a diagnosis or treatment plan, but the intensive review process provides “a tremendous amount of reassurance that everything that could be done has been done,” Heudebert says. In those cases, patients can be referred to specialists at UAB or elsewhere so that they don’t go home without guidance. In a recent survey, patients in the UAB program expressed their “gratitude for the opportunity to be heard, even if the evaluation is inconclusive,” Dahl says. “Many see the program as a last hope.”

To the Limit

UAB’s quest to unlock the secrets of mystery diseases bears similarities to space exploration. Korf, Descartes, and Heudebert talk about finding previously unknown diseases with the enthusiasm of an astronomer searching for a new star or planet. “Ultimately, this is what we train for—to tell people what is wrong and try to help if we can,” Descartes says. “Hopefully we can touch some people who have gone through a lot.”

Also like the space program, discoveries and advances from the new initiative could have a far-reaching impact. “There is already spinoff from the NIH research,” Heudebert notes. The understanding they gained from identifying new diseases “has already been applicable to other, known diseases.

“This is frontier medicine,” Heudebert says. “The team members are pushing their knowledge and expertise to the limit.”

Best of Both Worlds

Patients and physicians alike have shared a “great frustration that specialists are in a position to do things that our predecessors were unable to do—to sort out these hard problems—but it didn’t always translate immediately to something that could help a particular patient,” Korf says. “There wasn’t really any organized effort to solve the problem.

“Now UAB is offering cutting-edge genome sequencing along with the ability to take time, sit down, listen to the patient, and read through a mound of records,” Korf says. “It’s the best of modern and traditional medicine wrapped together, which offers powerful possibilities.”

Published October 2014