Bobbi Pritt, M.D. (00:34):

Hello, I'm Dr. Bobbi Pritt, a clinical microbiologist and laboratory leader at Mayo Clinic, and your host for today's episode. Dr. Bill Morice is back to discuss trending topics. Then I'll welcome Dr. Matthew Schultz for an inside look at a novel urine test that's helping identify a common inherited nerve disorder. Bill, welcome back.

William Morice II, M.D., Ph.D. (00:55):

Yeah, so always great to be with you, Bobbi.

Bobbi Pritt, M.D. (00:57):

Always great to have you. And we have a few things to talk about today. There's some hot topics in the news, and there was an article that caught my eye on cultivating a comprehensive test menu for organ transplant patients, that I thought would have some good things for us to discuss.

William Morice II, M.D., Ph.D. (01:14):

Yeah. You always seem to find good things to discuss. But I do like that article in particular for a lot of different reasons. On the one hand, as someone that's grown up through Mayo Clinic as a student, and then on staff, it represents how we think about diagnostics, and there's a quote in there, in that article, kind of like, “We were doing panels before panels were cool” kind of thing. Basically, the way we practice laboratory medicine is very much a reflection of our integrated practice in that we try and think about all the things that someone needs for the answer, right? As opposed to just an array of tests. And that's what's really neat about this article. It describes how in the complex setting of organ transplantation, how we organize the testing around that to really provide answers that the patients and the providers need.

Because there's a lot of different things going on. There's immunosuppression. Therefore, there's risk of infection on the one hand, particularly if you're over immunosuppressed, but if you're under immunosuppressed, there's risk of organ damage. And so, it's complex and there's drug levels and there's all a lot of the things that go into the management of these patients, and they're all interrelated. So, what's really cool is that in DLMP, we've really designed the testing experience for the patient. So it takes into account that complexity and kind of deconvolutes it, if you will.

Bobbi Pritt, M.D. (02:25):

I agree. These are complex patients to take care of and, and we'll include a link to the article in our news line. But I wanted to comment on just a couple things. One thing that really stood out to me was how Mayo Clinic Laboratories’ connection with Mayo Clinic allows us to really offer industry-leading panels for transplant care. Do you want to comment on that connection?

William Morice II, M.D., Ph.D. (02:46):

Of course I do. Yes. It's really gratifying because just a week ago, I was actually in Arizona. Every year we bring together all of our sales and many of our field operational staff from Mayo Clinic Laboratories to kind of come together just the time to connect, not just with each other, but also we have leaders from across DLMP. So we had the leadership of DLMP Florida, Rochester, and Arizona all present. And then we have other DLMP consultants that come and interact. And we do have a sales team that's out there servicing the patients with transplantation and their doctors and providers. That's what's great is they get to learn directly, not just what the tests are, which someone can look up online, but kind of why they're designed the way they are and how someone can really benefit from testing in that way.

And that that testing is actually available for patients not at Mayo through Mayo Clinic Labs, right? So it's a way to extend our model of care beyond your walls. That's what makes it really gratifying for us, for me personally, I feel like almost proselytized the world with the great things that people like you and others are doing within our department. And of course, we grow from that too, because transplant in different settings and different parts of the world has different challenges. And so, as you know from your role in DLMP and infectious disease, that means we have to think more broadly and holistically around patient needs in the department itself. So, it's really a great kind of symbiosis, if you will.

Bobbi Pritt, M.D. (04:04):

Yeah, absolutely. It's one of the most gratifying things for me, too, in my job. And I get to help look at those panels and put together testing algorithms. As you said, our transplant population are often immunocompromised. They're at risk for a lot of infectious diseases. So, we do a lot of testing in this area, and no one transplant patient is the same. Really being able to look at, say, lung transplant recipients versus renal transplant recipients and then consider the types of tests that they'll need is really important.

William Morice II, M.D., Ph.D. (04:37):

Exactly. Yeah. And being able then to deliver on that too, and deliver on that, that's not just one test. But here's a test that you need that really takes into consideration all those specific things that the patient just mentioned, and also where that care needs to be provided. So, I have to say, it's funny that I am in what would be considered a business role now, but it really feels just an extension of the work I've done at Mayo Clinic for almost 40 years now. Just thinking about how the best way to serve patients and keep their needs front and center. You know, the needs of the patients come first.

Bobbi Pritt, M.D. (05:05):

Absolutely. And you know, I will mention that at Mayo Clinic we do nearly twice as many solid organ transplants as any other center in the U.S. So, our experience really helps us with our knowledge and our experience to drive the appropriate testing.

William Morice II, M.D., Ph.D. (05:21):

Yeah. The way that we think about testing is a reflection of our integrated practice. So, we not only do so many, but the lab is an integral part, excuse me, of that care delivery process, right. We're not seen as just a service. We're seen as a key member and key members of the team that are really designing that experience. So, it's great. And of course, in our department too, it goes over to not just even just testing, but also into our transfusion medicine division, which is in the department, and thinking about products and blood products and other things. So, it's great. You go on and on, but it's nice that that article really captures that really great relationship we have with our institution, with our patients, and then with patients not in our walls through Mayo Clinic Laboratories.

Bobbi Pritt, M.D. (06:06):

Yeah. Well, you know, that was one article. The other article we could just touch on briefly is an article that first appeared in Mayo Clinic's “Tomorrow's Cure” podcast about early-stage research and emerging technologies that are reshaping what's possible in rheumatoid arthritis care. And, one of the things that jumped out to me as a laboratorian was a discussion about using AI, something we've talked about a lot, and multi-source data, also something we've talked about a lot, including wearables, to use and to help identify individuals that are more likely to develop rheumatoid arthritis. So, I thought that was something where it's a nice real-world example of using the technologies we've mentioned multiple times.

William Morice II, M.D., Ph.D. (06:49):

Yeah. And, I think we're just going hear more and more of this. I think it's very important that you and I and others in laboratory medicine continue to talk about it, because it'll be an area where we have to kind of parse out what's really validated and trustable, if you will, in terms of these things versus what is not because that's when we cross over to the consumer side, it becomes really important. But the flip side is, I do think over time it's going to really change the paradigm about how people even think about getting testing and how it's maybe it’s not going to a doctor and telling them your symptoms. It might be data coming off your watch and your phone and other things, and they're saying, "Hey." Continuous glucose monitoring, which is getting more and more popular. There'll be all these other data feeds that will drive the patient's need for testing. So, it'll be interesting to watch it develop, no doubt.

Bobbi Pritt, M.D. (07:34):

Yeah. Especially where there are areas where there are gaps. So, one of the things that was a key point from the article is that our traditional blood tests will only predict future rheumatoid arthritis about 30% of the time. So, there is a gap to be filled, and I think that's why researchers are turning to AI and these multisource data.

William Morice II, M.D., Ph.D. (07:52):

Yeah. No, it has great promise. We'll just have to keep our ear to the ground and help guide that.

Bobbi Pritt, M.D. (07:58):

Perfect. Yeah. Well, we'll put again, the links to these articles in the show notes if anyone wants to read them in their entirety or listen to the podcast. But it was great to hit on the highlights with you, Bill.

William Morice II, M.D., Ph.D. (08:09):

Always is.

Bobbi Pritt, M.D. (08:10):

All right, until next time.

William Morice II, M.D., Ph.D. (08:11):

Until next time. Thanks, Bobbi.

Bobbi Pritt, M.D. (08:18):

Welcome to today's deep dive. We're going to go beyond the headlines with Dr. Matthew Schultz, a clinical biochemical geneticist in Mayo Clinic's Biochemical Genetics Laboratory. He was integral in developing a novel test for a recently identified peripheral neuropathy, something we'll be exploring in more detail today. Dr. Schultz, thank you so much for joining us.

Matthew Schultz, Ph.D. (08:40):

Thank you so much for having me on, Dr. Pritt.

Bobbi Pritt, M.D. (08:43):

So, can we start, maybe have you explain how this assay works and what information it provides?

Matthew Schultz, Ph.D. (08:50):

Of course. So, this assay is a targeted biochemical assay that supports the diagnosis of a genetic condition called sorbitol dehydrogenase deficiency, or SORD deficiency. So, this causes an inherited peripheral neuropathy that can present in patients with distal weakness, especially in the legs and feet, and can result in balance and gait issues presenting in childhood, even up through early adulthood. And so, it's caused by biallelic variants in the SORD gene and the condition is described only in 2020, yet we understand it today to be a relatively common cause of this sort of genetic neuropathy. And so we were interested in the biochemical genetics lab to have a way to screen and diagnose these patients on a biochemical level. And so, our laboratory specializes in biochemical profiles to diagnose inherited metabolic conditions. And this gene is an enzyme, it is sorbitol dehydrogenase. And so, this is responsible for the conversion of sorbitol to fructose in your body.

And so, our assay measures sorbitol and as a reporter for if this enzyme is functioning well or not. And the assay itself measures two components, sorbitol and xylitol, which is a related sugar compound. And in patients with elevations of both of these compounds, it demonstrates that they have sorbitol dehydrogenase deficiency. Why this is a reliable test is important for this condition, as it enables screening of these conditions or of this specific condition in patients. Because we have a relatively accessible specimen, a random urine collection that can just be frozen and sent to the lab, and then it gives a relatively binary answer of yes or no, your patient has this condition. And then it works very well with molecular genetic testing, where it's a separate layer of information at the biochemical level where you can determine whether or not variants are impacting a patient's function at the biochemical level. And so, this is especially important, as this is a newer condition and there are trials underway. And so we must wait for, of course, the outcome to know for sure. But my hope is that we would have some treatment options for patients affected with these conditions in the future.

Bobbi Pritt, M.D. (11:12):

Yeah, that would be wonderful, Dr. Schultz. Now, I know last year there was a unique use case of the test to screen members of an Amish community in Pennsylvania. Can you tell us more about that?

Matthew Schultz, Ph.D. (11:23):

I would love to. So, this is part of our validation studies to determine that this was approach that worked well for this condition, and it was a unique collaboration between the Clinic for Special Children in Pennsylvania, which works closely with the Amish population there. They have worked together for years to support those individuals with care, but also are active in promoting different treatments and describing conditions that are prominent in the Amish community. So, we had gotten through the initial use of this test and had demonstrated this profile was useful for this condition and had the word out looking for more patients where we might be able to test to gain confidence and learn more. And this group contacted us and said, "We have an Amish family, multigeneration, you know, with lots of individuals who may have this diagnosis." They had detected one proband, which is a single individual in a family with this condition and were interested in screening the entire family.

So, we were very excited to one, help them learn if they, you know, individuals in the family had this condition. And it also will help us learn about our test performance. And so we, for anyone who consented and wanted to, ran this assay for this family, and we gave them our results, which were yes or no basically, from this quantitative assay and our interpretation of it. And, we were happy to see that we were 100% concordant at the end of the day with molecular testing and our assay and the clinical presentation in these patients. So we were able to give them an answer of whether or not they were affected with this condition, but also demonstrated to us that this test was performing very well in this sort of prospective cohort. And, I should say this was part of a broader cohort of patients and international collaboration. I really want to give credit to a genetic counselor, Amy White, in our lab, who was instrumental in keeping this together and to expand it between individuals in Pennsylvania, New York, Iowa, Montreal, and even in the Middle East. So truly a broad effort that helped bring this test validation forward and demonstrate that this profile is useful for patients with this condition.

Bobbi Pritt, M.D. (13:38):

Wow. What a great study. Well, looking in a broader sense, can you share some situations where physicians today in any clinical setting might consider using this test in their practice?

Matthew Schultz, Ph.D. (13:51):

Yes. One of which I had already mentioned. I think screening a patient. Peripheral neuropathy is such a common condition and there's so many causes, only a subset of which are genetic. But if you do have a suspicion of a genetic axonal-type peripheral neuropathy, this test is a relatively inexpensive, accessible specimen that can give you a pretty quick binary yes or no answer. Does this person have this condition or not? I think that can be very useful if you consider this use case. And the second is along genetic testing. And so, genetic testing is also a common approach to evaluate these conditions. And I should say the SORD enzyme has pseudogene, a closely related stretch of DNA which makes genetic testing sometimes problematic and difficult. And we know that there are instances of our testing at the biochemical level where an individual has had a single variant detected and a gene, but we'd run the biochemical test and we can show unambiguously at the biochemical level that they're affected, and then those individuals go back and do more research-based molecular testing and find a second variant. So, we have great uses and great cases to illustrate that the biochemical level of information does provide additional assurance for confirming results as well as flagging cases that really need a second look in terms of the workup and you know, likelihood that this could be the answer for this patient.

Bobbi Pritt, M.D. (15:23):

Wow, that's really interesting. Well, thank you, Dr. Schultz, for spending time with us today and for taking the time to explain this interesting new test that will hopefully help a lot of patients.

Matthew Schultz, Ph.D. (15:34):

Thank you so much, Dr. Pritt, for having me today.

Bobbi Pritt, M.D. (15:42):

Let's wrap up with the top takeaways and how to learn even more of the topics we discussed. So in our news summary, Dr. Morice joined me, where we discussed two recent stories that highlight the importance of diagnostics in advancing care. And the stories we discussed specifically talked about transplant medicine and rheumatology. They are both linked in the show notes if you'd like more information. And then in our deep dive, Dr. Matthew Schultz joined us for a deep dive into the SORD test, S-O-R-D, that he helped develop, and he shared really some compelling insight into how the assay is advancing research on a recently identified peripheral neuropathy and how physicians can use it to support care. So, for more information on the SORD test, you can find a link in the show notes, and this will bring you to another podcast that Dr. Schultz did with a genetic counselor, Amy White, on how the test was developed. Thank you for joining us today. If you haven't already, make sure you subscribe so you never miss an episode. In our next episode, I'll sit down with a physician from Mayo Clinic's OB/GYN practice to discuss how preeclampsia testing is changing how she cares for pregnant patients. I hope you'll join us.