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Vol. LXII, No. 1
January 8, 2010

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Where Science, Hope and Sadness Intersect
New Undiagnosed Diseases Program Awash in Potential Patients

On the front page...

If the Clinical Center is the “House of Hope,” then one of NIH’s most recently established components, the Undiagnosed Diseases Program, must seem like a harried gatekeeper at the house’s new entryway. Similar to a bouncer at the most exclusive club in town, the UDP evaluates those waiting anxiously in a long queue to get in.

“This is a program that lets us see the juxtaposition of science and sadness in the world,” said Dr. William Gahl, head of the intramural program at NIH’s Office of Rare Diseases Research, which began the UDP nearly 2 years ago. “It lets us as investigators see the human condition in the person of all the patients who apply.”


  Dr. William Gahl of Undiagnosed Diseases Program  
  Dr. William Gahl of Undiagnosed Diseases Program  

Gahl, who also serves as NHGRI clinical director, is one third of what could be called NIH’s “3G network” for people suffering from unknown ailments. ORDR director Dr. Stephen Groft and CC director Dr. John Gallin form the remaining two-thirds. All three recently presented “Mystery Diagnosis—the Undiagnosed Diseases Program,” an hour-long update on the UDP’s progress since it began in May 2008 and accepted its first patients in July that year.

CC Tailor-Made for the UDP

Gallin said two major things are new about the UDP. “First,” he noted, “there is a call for all undiagnosed diseases with no phenotype restrictions.” Before now, only patients with a definite diagnosis and who met a clear set of study criteria were treated at the CC.

The Clinical Research Center is uniquely equipped to serve the UDP, he said. “Our nurses say, ‘There’s no other place like it.’” Since opening in 1953, the center has hosted more than 350,000 patients; about half of them have had rare diseases.

“We’re inviting anybody with an unexplained problem to make an inquiry,” Gallin pointed out. “Second, a multidisciplinary approach is given to every patient.”

From its vast cadre of credentialed physicians and highly educated nurses to its unique collection of specialized equipment for imaging and specimen testing and producing candidate drugs—all available free of charge to patients—the CRC offers medical care few hospitals can match.

“Our hope is that the facility will transform from being not only a national hospital for patients but also an institution that serves investigators both here and across the nation,” Gallin said.

‘Developing a Global Approach’

In some ways, NIH is long overdue in setting up the UDP.

According to Groft, when NIH first established the Rare Diseases Clinical Network in 2000, resources were funneled not toward diagnosis, but toward natural history studies of the disorders, training of the next generation of physicians that will treat such diseases and clinical trials.
Dr. Stephen Groft Dr. John Gallin
ORDR director Dr. Stephen Groft (l) and CC director Dr. John Gallin discuss NIH’s Undiagnosed Diseases Program.

The strategy now, he said, is to develop better characterization and diagnostic criteria for rare diseases, expand newborn screening programs (currently, states screen for up to 29 disorders), and increase focus on genetic diagnostic testing and counseling.

“We’re developing a global approach,” he said, “as more and more nations are coming on board with a focus on rare diseases. Most of the patients are being seen by a small number of investigators, but we’d like to see this program extended into more protocols and clinics here at the Clinical Center. At some point—if additional resources become available—we’d like to expand this into NIH’s Extramural Research Program, using the Clinical Center as a hub of activities. We have the Clinical Translational Science Awards program, the Rare Diseases Clinical Research Network and other existing research networks that are very fertile ground for introducing a program like this.”

Recreating the ‘Fascinoma Clinic’

The UDP is not a totally new concept, Gahl noted. In the 1960s and 1970s, NIH investigators routinely convened what they called a “fascinoma clinic.” Interesting, but baffling cases would come up for discussion and dissection by some of the hospital’s top physicians-turned-medical detectives.

The power of intellectual stimulation cannot be discounted, he said. “Our goals are, of course, to assist patients and come up with a diagnosis, but also to discover new diseases that will reveal something to us about biochemistry, about pathways, about cell biology.”

One common factor that complicates diagnosis (and frustrates patients)—particularly for most of the rare disease cases—is that symptoms show up not all at once, but sporadically over time—often over a number of years, Groft acknowledged. Some people write of having visited specialist after specialist, to no avail. NIH’s UDP often represents their last best chance to discover what’s wrong.

More Than One Year In, Going Strong

To get into the Clinical Center via the UDP, patients’ medical records and summary letters from physicians are submitted and triaged to NIH specialists in related medical fields. Those specialists recommend whether to accept the patient.
Groft, Gallin and Gahl form NIH’s 3G network for people with unknown ailments.
Groft, Gallin and Gahl form NIH’s 3G network for people with unknown ailments.

Since May 2008, the UDP has received more than 2,300 inquiries and 900-plus medical records; 190 patients have been accepted, including 80 children.

Gahl said the top three criteria for inviting the patient to the CC for in-person evaluation are whether the case offers a “good clue to pursue, unique presentation and whether the patient’s family is involved.

“The good news is that virtually every patient is pleased with the attention and the hope that we provide for them, and occasionally we solve a case,” he concluded, acknowledging that several new disease investigations have been initiated, and that the UDP seems to have brought scientists together in ways that are positive both for individual careers and for research in general.

The bad news includes dealing with the disappointment of the often desperate patients who are turned away. Still a relatively small unit, the UDP has been inundated with applicants as well as attention by the media and even Congress.

Disease Detective Wannabes, Beware

Finally, Gahl said that as fascinating as the work is (and as full as the work load), he does not recommend that researchers early in their careers concentrate exclusively on UDP cases.

“This is a program that doesn’t really fit into the current paradigm of professional advancement, because it’s so high-risk,” he said. “Someone could pursue a case for a couple of years and not find the cause. But more important, our advancement system values experts in a particular pathway; that takes years. The UDP has many different disorders to pursue and being a jack-of-all-trades does not get tenure.” NIHRecord Icon

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