The Doctor for the Undiagnosed

A leader of the Undiagnosed Diseases Network on solving medical mysteries

It usually takes up to eight years for a person with a rare disorder to reach a diagnosis. And yet having one is often critical to unlock treatment options and insurance coverage.

Since 2008, the National Institutes of Health (NIH) has funded a relatively unknown network of physicians focused on providing diagnoses and treatment for people with mysterious disorders that have flummoxed their doctors. Sometimes referred to as “the clinic of last resort,” the Undiagnosed Diseases Network (UDN) includes 12 clinics across the nation where teams of medical experts use imagining, physical exams, and advanced genetic sequencing to crack some of the toughest medical cases. So far, doctors and scientists at the UDN have evaluated 1,029 people and diagnosed 283.

The leader of the network is Dr. William Gahl, the clinical director of the National Human Genome Research Institute at the NIH. He spoke to Medium about the challenges of diagnosing tough cases.

This interview has been edited and condensed for clarity.

Medium: Why is a diagnosis important?

William Gahl: There are many benefits to having a diagnosis. People think it might lead to therapy, but it doesn’t always, at least not for all the diagnoses that we make at the Undiagnosed Diseases Network. Of course, diagnoses for common diseases most often leads to therapy. Getting a diagnosis makes people members of a community. It also eliminates a lot of the doubt about their condition; because when you can’t name a disease, people are suspicious around you. When you go to a doctor who can’t give a diagnosis then that can be frustrating for them, and they may not want to see you.

Even if we don’t make a diagnosis, we keep their file, and we keep their cases in our memories.

What do you look for when selecting patients to enroll in the UDN?

Something unique and something that might help us find new pathways. It might be a unique bone abnormality or an incredible inflammation that’s apparent in the skin. For us, because a significant portion of what we are studying is genetic, it’s extremely helpful if there are other family members with similar conditions.

How long can it take for someone to reach a diagnosis at the UDN?

There are two stages in the process. There’s the time before they come to us, where people have their disorder for anywhere from half a year to up to four decades without a diagnosis. We seldom make the diagnosis in the one week period where we see them for initial testing, but we continue to work on these diagnoses for years. Infinity is the time that we take. Even if we don’t make a diagnosis, we keep their file, and we keep their cases in our memories. Sometimes a new disease will be discovered and we look into it further and we’ve made some diagnoses based on that. If we’ve done the genetic testing for an individual, we can review it again at a future stage. There may be more genes now associated and identified for their condition.

What is one of the most unusual cases your team has worked on that’s stuck with you?

Well, the issue of sticking with me is a temporal issue. We have some recent cases we solved that stick with me, and there are ones we haven’t solved that I think about. We had one man come in who had what appeared to be meningitis. His brain was inflamed and he had a fever, but there were no signs of a bacterial infection. What we found was that he had a mutation that activates a protein, called interleukin 1 beta, that causes the initiation of the immune system’s inflammatory process. This protein was being produced in huge amounts. It was causing headaches and hurting his ability to think well. He was in a wheelchair. There was an available drug on the market that blocks interleukin 1. He came into the clinic and we gave him the drug. Within hours he got better. He stood up and walked out. We were stunned by that.

Why is it important to study rare diseases, generally?

When we discover a new disease, it can tells us about a pathway that could impact other, more common diseases. There may be a milder form of that disease, and there may, in fact, be common therapies available that could help. And the pathway that is revealed by the new genetic disease not only informs science and medicine, but captures the interest of the pharmaceutical industry, because it can reveal druggable targets.

Have there been changes in genomics or genomic testing technology that have made your job easier?

Yes, actually, the common use of exome sequencing and next generation sequencing started shortly after we started the program in 2008. The cost of an exome sequencing has fallen so much and and has really evolved rare disease discovery. Methods of analyzing DNA sequences are also improving, so we know with more certainty what could be a disease-causing change (i.e. a mutation) and what changes are benign.

The UDN is currently funded by NIH — how do you envision it evolving in the future?

I don’t control the budget. But I think it would be valuable if, in the future, undiagnosed diseases programs were maintained at medical clinics throughout the world. It’s valuable for patients. A second aspect is that we can continue to feed our database. There’s a UDN database that has all the phenotypes and genotypes of the people we see, and that’s incredibly valuable. We can invite more individuals to put their data into it. If you think about the cost of this program, it’s basically the wing of an airplane. And patients who come to us have undergone previous medical testing that cost tens of thousands to millions of dollars.

There are a lot of people living with undiagnosed conditions who may not end up at the UDN. What advice do you have for people going through a diagnostic odyssey?

I think that if local physicians can’t make a diagnosis, then people should definitely see several different specialists, if they can. This is perhaps best done at university-based medical centers.

Health and science journalist. Former editor of Medium’s Covid-19 Blog and deputy editor at Elemental. TIME Magazine writer before that

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