Doctors are a lot like detectives. They gather clues from physical exams, family history, blood tests, imaging scans, and other sources to solve the mystery of patients' symptoms. Physicians involved in the Undiagnosed Diseases Program (UDP), established by the National Institutes of Health (NIH) in Bethesda, MD, are the ultimate detectives, trying to unravel some of the most baffling cases.

The diseases they discover are mostly rare—often affecting fewer than 50 people in the world—with an array of symptoms that have stumped other physicians. Many of these patients and their families have already been to dozens of doctors and taken hundreds of tests, only to get no diagnosis or lead to more dead ends. Through the UDP, they benefit from the expertise of a panel of physicians and receive unrestricted access to the latest medical technology.

Since it was established in 2008, the UDP has accepted 750 patients for weeklong diagnostic odysseys that usually include the latest genetic screening methods, state-of-the-art imaging, and other tests and panels. Doctors in the program have diagnosed 25 to 50 percent of their patients.

More Site, More Cases

Last September, the NIH launched the Undiagnosed Diseases Network (UDN) at seven medical centers across the country, including Baylor College of Medicine in Houston, Duke Medical Center in Durham, NC, Stanford Medical Center in Stanford, CA, Vanderbilt University Medical Center in Nashville, Harvard Teaching Hospitals in Boston, the University of California at Los Angeles Medical Center, and the NIH.

The expansion of a single program into a seven-center network dramatically increases the number of patients that can be accepted. It also means patients and their families may not have to travel as far in their quest for a diagnosis.

All-Access Pass

"When patients come to one of our centers, they are seen by a dream team," says Paul Fisher, MD, PhD, a pediatric neurologist who leads the Stanford center along with geneticist Euan Ashley, MD, PhD, and cardiologist Jonathan Bernstein, MD, PhD. "They also have access to an enormous array of diagnostic resources at some of the nation's top medical institutions."

All UDN data—imaging, genetic testing, blood tests, and other information—are stored in a highly secured cloud-based data-hosting service, which doctors at any of the sites can access instantly to help them make a diagnosis.

A Family Affair 

Because the UDN is an NIH-supported research program, patients do not pay for any of the research-related testing or examinations, but they must consent to have their information securely shared as part of that research, says Camilo Toro, MD, a clinical neurologist at the original UDP site at the NIH. Family members should also be willing to share medical information. "Contributions from families allow us to sort information and come up with significant findings," says Dr. Toro.

The program isn't a panacea, says Dr. Fisher. "We're not going to diagnose everyone, and even if you get a diagnosis, there may be no treatment. But specialists try to find answers."

A Real Odyssey

Lynnie Morgan has been looking for answers for more than 35 years. Her daughter, Amy, now 38, appeared to develop normally until she was 3 months old. Then she started having seizures—infantile spasms at first, then, just before her first birthday, major generalized tonic-clonic seizures, in which she lost consciousness and had violent muscle contractions. She also had vision problems, developmental delays, a strange wide-legged gait, and, in junior high, the sudden onset of hallucinations and dementia.

Countless diagnoses—mitochondrial disease, Segawa syndrome (an inherited disorder that can cause rigidity and developmental delays), genetic epilepsies—were considered and rejected before the Morgans heard about the UDP. After getting a referral from their primary care physician, they applied, were accepted, and spent a week in Bethesda in early 2014, while Amy underwent gene sequencing, magnetic resonance imaging and computed tomography scans, and many neurologic tests.

Before the UDP could diagnose Amy, another program the Morgans had applied to—the Phoenix-based Translational Genomics Research Institute (TGen)—found the answer. Amy has two mutations on a gene called TBC1D24, but her disorder is not associated with any of the five conditions known to be caused by mutations on that gene. "Amy has a disorder they didn't know existed," says Lynnie.

The diagnosis has brought some closure and the hope that the discovery of the mutations will lead to new potential treatments, either during Amy's lifetime or in the future.

Even though the UDP didn't find the diagnosis first, Lynnie says going through the program was an oasis in a difficult medical journey. "The whole time we were at the UDP everyone treated us, and Amy, with such dignity. It was a slice of heaven, being told we weren't crazy."

HOW TO APPLY:: To apply to the Undiagnosed Diseases Network, ask your doctor to write a referral letter including:

• A summary of your medical problems
• A history of evaluations, tests, treatments, and medications (past and current)
• Previous diagnoses
• The doctor's own thoughts about a possible diagnosis
• Prenatal and birth history, if the patient is a child

Submit the referral letter, along with an electronic application, through the UDN's website: undiagnosed.hms.harvard.edu. The whole process should take less than 20 minutes.