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NIH Undiagnosed Diseases Program: Interviews with William Gahl, M.D., Ph.D.

February 1, 2011
William Gahl, M.D., Ph.D.


Clinical researchers at the National Institutes of Health's (NIH) Undiagnosed Diseases Program (UDP) have identified the genetic cause of a rare and debilitating vascular disorder not previously explained in the medical literature. The adult-onset condition is associated with progressive and painful arterial calcification affecting the lower extremities, yet spares patients' coronary arteries. The new disease finding was published Feb. 3, 2011 in the New England Journal of Medicine.

Provided here are video sound bites of an interview with co-author William A. Gahl, M.D., Ph.D., NHGRI clinical director and director of the NIH Undiagnosed Diseases Program.

Video Sound Bites

Sound Bites by William Gahl, M.D., Ph.D.
Clinical Director, National Human Genome Research Institute
Bethesda, Maryland
Clip # Running Time Quotes (Text) MPG File* MP4 File**
1 17 seconds

So my name William A Gahl and I'm an M.D., Ph.D. and a Pediatrician and a clinical and biochemical geneticist. I see patients with in born metabolism and do clinical research and some basic research to the particular disorders that our patients have.

(56.2 MB)
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2 20 seconds

The NIH Undiagnosed Diseases Program is an initiative to help us to diagnose patients who long sought a diagnosis but haven't been able to get one. It also helps us find new things about biochemistry cell biology and even new diseases and new pathways for the medical profession.

(67.6 MB)
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3 11 seconds

There are really two main goals for the UDP. One is to make diagnosis for people but the other is find out more about medicine and find new diseases.

(35.5 MB)
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4 27 seconds

Well the patients who come to us in the Undiagnosed Diseases Program are unique. That is to say they have been through many medical investigations and no diagnosis has been found. That makes them good candidates for possibly having a new disease that nobody has ever seen before.

(60.8 MB)
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5 42 seconds

NIH has a strong contingent of consultants from many different medical specialties and we're able to bring their expertise to bear upon individual case and also to bring people in the same room to discuss that case. We're also able to bring patients in here over the course of the week to get enough clinical studies done that would've taken perhaps a year or two years on an outpatient basis because insurance is required for those individuals where as it isn't required for us. In addition, we have the capacity to do state of the art genetic screening and genetic studies to try to determine the molecular basis for some of these disorders.

(60.8 MB)
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6 60 seconds

The paper coming out in the new England journal of medicine on February 3rd is really the pinnacle of our success at a research level. In other words we do things clinically that is extremely beneficial. But this is a case in which we actually found a new disease and the new disease has new implications we think, for other disorders. That new disease involves individuals and we identify nine of them around the world, nine in three different families, who have calcifications of the large vessels of their bodies. Largely the vessels below their waist, but also in one case involving the vessels that go up into the head, the external carotid. In addition, there is calcification of some of the joints, especially the hands and the feet. So why does this calcification occur? Well, we found the genetic defect and then put that together with the biochemical defect and now we know why that occurs and this has not been described before.

(136 MB)
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7 53 seconds

This is a defect in a gene called NT5E. And that gene makes a protein called CD73. CD73 is an enzyme so it converts one molecule to another. What it converts is AMP which is Adenosine monophosphate. And it converts it to inorganic phosphate and adenosine. And it turns out, and we only know this because of those families, turn out that adenosine is necessary for the cells of the vessels of our bodies, large vessels, to not be calcified. So, the adenosine inhibits that calcification and it does so in a particular way that we're still working out the details of. But it's clear that adenosine is important for that, and that's a new finding for the field of vascular biology.

(169 MB)
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8 56 seconds

The significance of a finding like this is really not determined immediately.  In other words, we won't really know how significant this is until perhaps a year from now, five years, ten years from now.  Because this has the potential to have applications to all sorts of calcification processes in our body.  Including the normal calcification processes of bone, and possibly abnormal calcification processes in other places including calcification in the vessels.  So it has the potential to be enormously important and have great implications but it also possible that it could have implications largely only for these individual families that are affected.  But I do think that the science part of this, that is to knowledge that adenosine has these functions and is critically important for fields of investigations that are both basic and clinical.

(178 MB)
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9 40 seconds

Well I think it's likely to have applications at least conceptually, if not practically, to other disorders. For example, there's calcification of the vessels of what we use to call hardening of the arteries, atherosclerosis. That is probably a different mechanism but the role of adenosine in even that should now be investigated. And then there are calcifications of organs and vessels when there is damage. And that calcification process may involve adenosine as well. We don't know that yet but I think there is a real possibility that they'll be broad applications.

(129 MB)
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10 1 minute,
42 seconds

Yes, a family came to us. Actually, there was only one individual and then her sister from Ohio, and there complaint was that when they walked, it hurts them to walk. So we would call this claudication, and it really has to with insufficient supply of blood to the legs in fact they could walk between one to six blocks or so without having pain. But they also had unique x-rays so the x-rays of their lower extremities starting at their Femoral Arteries and their popliteal arteries. Which involves just below the waist and at the knee. Those arteries were outlined by calcium on a plain film. So there was no contrast there. So we knew that there was calcium in those vessels and they were huge too they were larger than they should be. So, blood flow through them would be impaired and in fact we know they must have other vessels around smaller vessels that have grown to supply their legs. But that was such a unique finding that we immediately accepted the patient into the Undiagnosed Disease Program, brought them here, and then found out that these two sisters that had two other brothers and another sister all of whom had the same thing. And then we found out that their parents were third cousins, and that helped us find the gene because now we knew that this must be what we call autosomal recessive disorder in other words, both copies of the gene being affected, and that helped us in our genetic analysis to find the approximate location of the gene and then to focus on the exact location of the gene.

(322 MB)
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11 1 minute,
39 seconds

Well the NHGRI our institute has been enormously beneficial for us in finding genes and especially finding the particular gene.  What we did was what we call a million SNP or single nucleotide polymorphism Array.  In other words, we were able to analyze a million different particular basis across the entire three billion basis of our genome and those were scattered across the entire genome.  And there specific basis in fact, they either have one base or another base that the polymorphism part of it.  So, we're able to look at that array to see if these five individuals were affected had what we call homozygosity, meaning the same particular base at this spot, this one, this one, this one, this one, and it turned out that there was one area in the entire three billion bases that had different nucleotides that were the same.  And that area was several million bases long, and it had ninety-two genes and really that work was done by the genomics core here at NHGRI and are people were able to analyze that and find that region and that really what allowed to focus on that particular gene within that region.  So NHGRI made an enormous contribution to that.

(313 MB)
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12 1 minute,
28 seconds

Well the fact that we were able to find that CD73 is really the defective protein in these individuals allows us to address therapy. And in this case, since we know Adenosine is not being produced appropriately in those vascular or vessel cells, means that we can provide that Adenosine or else we could work what we would call downstream of adenosine. In other words, whatever adenosine affects which in this case is the inhibition of adenosine monophosphate. That means if adenosine doesn't do it in these individuals, we can give them something that will inhibit Acal and phosphate and we hope prevent further calcification.
I don't think that our treatment for these individuals will reverse the existing calcification. There might be a little bit of what we call plasticity or ability to heal, but largely we want to prevent further calcification because really the possible consequence of this is to require an amputation. In fact, one the individuals who we saw here has already had a Femoral arterial bypass, meaning they took out that and they sort of went around it with a graft. So it's pretty serious stuff for these individuals.

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13 51 seconds

Well the next step for our study of the calcification patients is to try to determine a therapy and that involves two things. One is a bench investigation and that is to determine what molecules would be most efficient at preventing the calcification in cells in culture because turns out these individual cells form increase adenosine monophosphate and they calcify in a dish. So we put drugs in there to determine which one's will work. And then we'll take those drugs and write an IRB protocol in other words our institutes review board has to review that and make a proposal to treat those individuals with those drugs and that will be the therapy portion of this.

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14 28 seconds

I would point out too that we actually have another patient who has a different disorder of calcification in the vessels of his brain whom we've gotten a skin biopsy from and turns out that his cells in culture also have increased adenosine monophosphate which means that there will be other diseases that we're about to discover that may have this particular pathway impaired as well.

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15 1 minute,
8 seconds

The NIH Undiagnosed Disease Program was announced on May 19, 2008. So it's been going on about 2 1/2 years. Since that time we have had about 4700 inquiries. Not all those inquiries result in actual applications. But we've had medical records sent to us about 1700 individuals and we accepted about 370 or so, and seen probably about 340 of those seen and discharged them for a week here at the NIH Clinical Center. And 2/3 of the individuals we reject but the ones that we see are very pleased and we've made some diagnoses, we found a new disease, the diagnoses we're roughly speaking most proud of are ultra rare disorders that are very difficult to diagnose and require some sort of thinking about and getting together and sophisticated testing.

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16 18 seconds

That's true, the Undiagnosed Diseases Program has at its fingertips a lot of resources both in terms of intellectual content and the availability of consultants and also in term of advanced technology

(59 MB)
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17 2 minutes,
36 seconds

Yes, most of the patients who are enrolled in the UDP and excepted in our program find the UDP as there last hope and often their greatest hope because they have been to major medical centers and these are really chronic disorders that have been going on for 1-20 years or so. So they sort come to live with this and many of them are in sort of a plateau stage with respect to their hope they don't have to much and then they find the UDP and they well another fresh pair of eyes, new approaches etc. So then are very excited about this and they have huge amounts of hope. Against a background of really desperation but, that immediate hope is what they come to and what I greet them with when I first see them at the beginning of the week. But I try to sort of mute that a little bit because we really do fail most of the time in finding a diagnosis but pretty much what I said goes over their heads they really don't except. They will verbalize oh yes we know we don't have that expectation but we find that even though people will say that in the beginning of the week when Friday comes and we have a rap up session with them, they will have visible disappointment when we haven't found something major. But then will tell them that we continue to work on this and you have a bunch of bright minds and a lot of technology behind this investigation so we'll get back you and we do. But really this is all against this backdrop of how difficult it is for us as human beings to deal with uncertainty and uncertainty is the major issue in the undiagnosed diseases program. It has effects on family because patients can't tell their relatives what they've got and sometimes the family thinks they are making it up on doctors because when they go to a doctor the physician feels inadequate not having made a diagnosis, not knowing how to give prognosis or treatment. And really self esteem, because probably patients themselves have self doubt too. So you never want to take away that hope that you're going to find something but you also don't want to create unreasonable expectations.

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18 1 minutes,
33 seconds

You know I can give you an example that perhaps most acute but telling. It was a patient from the Midwest, about a 49 year old guy or so, police officer and he came to us with neurological symptoms and never had testing for Amyotrophic lateral sclerosis, ALS and we sent off the testing and found a diagnosis based on that. And we told the family what we thought it was and this man was there with his wife who is now taking care of him mainly because he can't do everything. Even though I had little to do with this family during that week at the end we sat down and talked with them and after we talked to them for a little bit the wife just hugged me. So this was really a death sentence that we have given this man. And yet, she was incredibly appreciative of knowing the diagnosis and what the future might be. So I think that sort of illustrates how badly we as human beings seek knowledge and expectations for the future. Many patients would rather have the knowledge that they have a bad terrible or even fatal disease than to go on with that uncertainty.

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Last updated: May 30, 2014