Diagnosing the Undiagnosed

Imagine yourself the parent of a small child who is often sick or never quite well. You take her to one doctor after another, but she is still often sick and never quite well. You hear phrases such as “failure to thrive” and “not meeting milestones.” She has what one pediatrician refers to as an undiagnosed disease, which you find really scary. What is it like to have a child, or to be a patient, with a disease that modern medicine is unable to diagnose, and thus unable to cure, or to treat effectively, or to prevent?

“Somewhere in the range of 20 to 30% of such cases have been solved by genome sequencing so far,” says Euan Ashley, MD, PhD, Principal Investigator of Stanford’s Center for Undiagnosed Diseases (CUDS), part of the NIH-funded national Undiagnosed Diseases Network (UDN).

Ashley was speaking of some of the successes of the pilot program that was started at the NIH in 2008 to address the fact that “there were groups of patients out there who had gone from doctor to doctor to doctor trying to find help to get to the bottom of their mystery diseases. These were kids with neurological diseases and adults with heart problems, almost anything you could mention.”

When the leaders of the pilot UDP at the NIH went to get their program renewed and presented their successes, they were told that the Program not only would be renewed but also should be expanded, adding six more centers spread across the country. An RFA was published in 2012, Ashley applied and won, and in July 2014 Stanford became one of the six sites in the Undiagnosed Diseases Program-turned-Network.

So how does it work? Ashley responds, “A patient anywhere in the country with a disease that has resisted diagnosis can go to the website www.rarediseases.info.nih.gov and apply. If accepted, and upon receipt of a letter from their GP, the coordinating center at Harvard will assign the patient to the best site based on geography and expertise. Patients don’t get charged for it; the Network takes care of the cost.”

Ashley continues: “One undiagnosed disease that was described by the UDN in 2011 has a great name -- ACDC (arterial calcification due to deficiency of CD73). It’s a vascular calcification syndrome where blood vessels turn to bone at a very young age. The NIH scientists saw a number of people with the disease, worked out what was causing it, and published an important paper in the New England Journal of Medicine describing the new syndrome. That’s just one prominent example; overall the Network is helping a large number of patients that other centers cannot.”

One important reason why such progess has been made in recent years is the parallel progress made with genetic techniques, which vastly accelerated what could be accomplished. In 2008, you could sequence the genome for $3 million; today you can sequence the genome for $1 thousand. Ashley puts it succinctly: “Genomic technology has driven the success of the Network.” Indeed, this is the basis for the recent launch of a Clinical Genomics Service at Stanford.

For the undiagnosed diseases grant, Ashley states: “Three things defined our attempt to differentiate our site versus others during the application process: 1) genomic and other omic technology and interpretive tools that we’ve developed over the last few years; 2) the proximity of Silicon Valley; 3) telemedicine.

“One of the things that we talked about doing was making telemedicine an important part of what we would do as a site. First of all, we wanted to maximize what we can do with patients even before they come to Stanford as well as after they’ve made their first visit. But we also want to use telemedicine the other way around: we want to bring the experts -- from wherever they might be in the world -- into the room with the patient. If there’s one expert in the world who understands your condition, then we will get hold of that person using telemedicine. That’s a very exciting part of this grant.”

Ashley explains some of the characteristics of the Stanford site: “The Network at Stanford is joint between the two hospitals, for both kids and adults. We are also hoping that there will be a chance for residents to rotate onto our service, to come and be part of the workup of these patients. I think this is an important educational component.”

Ashley is co-chair of steering committee with Bill Gahl, MD, from the NIH, who started the pilot program in 2008. Stanford will host a meeting of the entire steering committee in January 2015, where all the site PIs will discuss their progress and, according to Ashley, “see what we will do next.”

Besides Ashley, other Stanford scientists involved in the leadership of the Network include two co-PIs: Jon Bernstein, MD (Pediatrics), and Paul Fisher, MD (Pediatric Neuro-oncology). Matthew Wheeler, MD (Cardiology), is Medical Director.