NHGRI logo

Expanding the limits of modern medicine

NIH Undiagnosed Diseases Network will address abundance of mystery cases 

Dunham, Michelle and three-year-old Lilly Aurelius. Photo, used with permission, by Anne Staveley.
Dunham, Michelle and three-year-old Lilly Aurelius.  Photo used with permission, by Anne Staveley

Although alarmed at the sight of a red stream instead of straw-colored urine, Dunham Aurelius didn't realize that he needed to see a doctor. An endurance runner and triathlete in his early 20s, he brushed off the physical discomfort and reasoned that he may have pushed too hard on a long Sunday run. When the bleeding persisted, Aurelius made an appointment with a urologist, a specialist in diseases of the urinary tract and reproductive organs. The doctor diagnosed a kidney stone, the first of many that Aurelius would endure throughout his 20s and 30s. He became an all-too-frequent patient of urologists, as well as of endocrinologists and nephrologists, who specialize, respectively, in diseases of endocrine glands and kidneys.

Aurelius' kidneys formed stones at a size and frequency that surprised his doctors. He has passed more than 15 stones; one calcium phosphate mass in his kidney measured three centimeters. His doctors detected high vitamin D levels in his blood but they weren't sure of its significance or why he developed these stones.

Aurelius is not alone in his medical odyssey. The National Institutes of Health (NIH) Office of Rare Diseases Research, part of the National Center for Advancing Translational Sciences, estimates that about six percent of patients seeking their assistance have an undiagnosed disease. Some 15 percent of patients remain undiagnosed with a disorder after more than five years.

Aurelius expelled many kidney stones without recourse to medical intervention. Once, he brought a bag of stones to his urologist, who hailed him as an ultimate fighter of the kidney stone world. Some stones, however, required painful and sometimes dangerous procedures. The problem worsened to the point that Aurelius was having multiple surgeries a year. He started to become desperate for a diagnosis at age 38, almost 20 years after his first stone.

In 2008, Aurelius' endocrinologist at the University of New Mexico Health Sciences Center learned about the Undiagnosed Diseases Program (UDP), a new NIH program. The UDP was recruiting patients whose conditions were unexplained despite doctors' best efforts to make a diagnosis. The new program would accept referrals if there were some clue for a multidisciplinary team of doctors at NIH to follow up. In Aurelius' case, the clue was his high vitamin D levels.

In 2009, he became the 37th of 75 patients evaluated in the first year of the UDP, during a week-long visit to the NIH Clinical Center. Through genomic analysis conducted in subsequent months, NIH doctors ultimately discovered that mutations in Aurelius' DNA caused loss in the function of an enzyme called CYP24A1, which results in high vitamin D levels. With his wife's help, Aurelius made dietary changes that have brought about vast improvements in his condition.

"I started to look for foods with low or no sodium and no vitamin D and, knock on wood, it's made all the difference." Aurelius just reached the two-year, stone-free mark. "This has been the longest running time that I have not had stones," he said. "I attribute that to diet and the NIH. I'm pretty happy."

UDP uses state-of-the-art DNA sequencing technologies

On Aurelius' team was William "Bill" Gahl, M.D., Ph.D., NHGRI clinical director and founding director of the UDP. Despite soaring credentials and numerous professional awards, the affable Dr. Gahl connects personally with UDP patients while puzzling over their difficult biological problems. He reads medical records that arrive on his desk in waves and he leads trainees from specialized clinics and labs on genetic rounds to school them about individuals in the UDP program. Dr. Gahl's staff extracts DNA from patients' blood and, through state-of-the-art DNA sequencing technologies, tries to detect genetic variations that cause their rare conditions.

"We expected to diagnose maybe 10 or 15 percent of the patients that we actually admitted, and we have achieved roughly that," said Dr. Gahl.  "To a certain extent, simply making a diagnosis is a help to patients. Some certitude in their lives, some expectation and some prognosis that's associated with a diagnosis is comforting."

Among the approximately 100 diagnoses made in the first five years of the program, UDP clinicians reported some of the rarest of conditions seen in the world. These included one of just five cases in the world of a form of epilepsy, a case in which a dermatological condition has so far been identified in just six families worldwide and a case of a neurodegenerative condition reported in just 20 families. In its first two years, the largest number of UDP applications came from neurology referrals. The UDP diagnosed a form of amyotrophic lateral sclerosis, or Lou Gehrig's disease, as well as an unusual form of developmental delay, both of which have only recently been reported as distinct diseases.  

"We are very genetics oriented because that is so integral to a diagnosis," said Dr. Gahl. In fact, the UDP has identified 15 genes that have not previously associated with human disease.

The UDP team also discovered new diseases. Their first was reported in February 2011, when the UDP team, with collaborators from the National Heart, Lung and Blood Institute, published a paper in the New England Journal of Medicine. The adult-onset condition is associated with progressive and painful arterial calcification affecting the lower extremities. Dr. Gahl and his colleagues diagnosed the rare arterial condition in nine individuals from three unrelated families-the only people known to have the disorder. The researchers called it arterial calcification due to CD73 deficiency, or ACDC.

Dr. Gahl keeps a running set of statistics on the UDP. From its launch through the first quarter of 2013, NIH received more than 7,500 inquiries from patients and physicians, more than 2,700 medical records and accepted 620 patients into the program. More than 550 patients have been evaluated at the NIH Clinical Center.  

Expansion on the Horizon

The UDP has been so successful at using state-of-the-art genomic tools to diagnose difficult cases, that NIH is expanding the program into a national initiative called the Undiagnosed Diseases Network (UDN). The NIH Common Fund, a program created to support programs of shared interest among many NIH institutes, will invest $145 million over seven years to establish the network. The UDN will address hundreds of prospective cases and apply novel approaches made possible by new molecular technologies.

"The launch of the Undiagnosed Diseases Network coincides with important advances in biomedical science, especially in the field of genomics, which are critical for diagnosing rare conditions," said Teri Manolio, M.D., Ph.D. As director of NHGRI's Division of Genomic Medicine, she oversees the nearly 15-member working group tasked with planning the UDN expansion.

The NIH Common Fund will expand the capacity of the UDP, initially supporting up to seven clinical sites at academic institutions across the United States. Since the July 2012 announcement, the working group, with representation from the Common Fund as many as 10 NIH's institutes and centers, has planned and announced funding opportunities to support the new clinical sites as well as a coordinating center. Funding is expected to begin in fiscal year 2014, with patient recruitment to begin shortly thereafter.

"This is the only Common Fund program focused on diagnoses," said Mary Perry, Ph.D., program leader in the NIH Office of Strategic Coordination, which oversees the Common Fund. "It's also the only one focused on rare disorders."

The UDN is unusual among Common Fund programs because it originated in the NIH intramural program based at NIH facilities. As such, it has the potential to become a prototype for transferring innovative approaches from the intramural program to extramural grant programs carried out at research organizations, including universities and other research facilities.

Core goals-diagnosis and discovery

In addition to continuing to run the UDP, Dr. Gahl will act as an advisor for the creation of core research facilities for the expanded program. The UDN will select cases for study based on criteria similar to that which brought so many novel cases to the UDP.

"The expansion allows for sharing of data among centers, meaning that groups of patients with the same disorder can be studied," Dr. Gahl said.  "We will be looking for patients who can give us insight into new disorders, with whom we have a chance of a diagnosis and who have had a medical work-up that eliminates the possibility of known disorders," Dr. Gahl said.

NIH will also select a UDN coordinating center. Through the coordinating center, information systems will allow all of the centers in the network to share, with appropriate consent and privacy protections, all of the clinical and genomic data generated on participating patients. The new network will include funds so that NIH researchers can work with a network of researchers to study genes that are newly associated with disorders.  Any expert within the network will be able to consult on a medical condition and contribute to a diagnosis. 

The network is proposed to start up, develop and test its operating procedures during a period from July 2014 to December 2015. When the clinical sites are fully operational, it is anticipated that each site will ultimately recruit at least 50 patients each year.

"This is a program that will create collaboration in the medical and scientific communities at NIH and around the country while making new discoveries, many that will improve the lives of patients living with undiagnosed diseases," Dr. Manolio said.

For more about the UDN, go to http://commonfund.nih.gov/diseases/index.aspx.

[Note: Patient recruitment for the network of clinical sites has not yet begun, but the original UDP continues its recruitment and diagnosis of patients. The website for the existing intramural program is http://rarediseases.info.nih.gov/undiagnosed.

Last updated: August 27, 2013