Helping People with Undiagnosed Rare Diseases Find Answers

Michele Herndon’s son Mitchell began developing symptoms of an ultra-rare neurological condition in 2012. He went for five years without answers and in 2017, enrolled in the Undiagnosed Diseases Network, an NIH-funded research study that seeks to diagnose people with the most puzzling conditions. He was diagnosed with the genetic disease Mitchell syndrome, which was named for him. He died from the disease in 2019. Herndon not only started the Mitchell & Friends Foundation but is today the program director of the Undiagnosed Diseases Network Foundation. There she has helped establish the UDNF’s new Patient Navigator Program, which is designed to answer general question undiagnosed patients may have, connect them to resources, and guide them through the UDN process. We spoke to Herndon and F. Sessions Cole, secretary of Undiagnosed Disease Network Foundation and professor of Pediatrics at Washington University School of Medicine, about the diagnostic odyssey, the work of the Undiagnosed Disease Network and the Undiagnosed Disease Network Foundation, and how the new Patient Navigator program works.

Daniel Levine: Michelle, Sesh, thanks for joining us.

F Sessions Cole: Thanks for having us. We’re very enthusiastic about both your podcast and our program. Yes, thanks so much for having us.

Daniel Levine: Well, we’re going to talk about the diagnostic odyssey many people with rare diseases face, the challenges of diagnosing a rare disease, and the Undiagnosed Disease Network Foundation’s new Patient Navigator program. Let’s start with the diagnostic odyssey. We see figures that get quoted often, but they’re usually based on small studies. Sesh, what’s known about the diagnostic odyssey for people with rare diseases? What does it take to get an accurate diagnosis?

F Sessions Cole: Well, it usually takes somewhere between seven and 10 years for people who have undiagnosed diseases to find a diagnosis, and finding a diagnosis frequently means visiting multiple different subspecialists, going through multiple different kinds of diagnostic testing from imaging to blood draws to specialized testing. And usually, this kind of diagnostic odyssey requires both persistence on the part of the undiagnosed person and eventually a quarterback of some kind who helps to integrate all of the prior knowledge that comes from all the testing, as well as from the attempts to improve the symptoms of the undiagnosed individual. And bringing all that information together is usually required in order to make a diagnosis.

Daniel Levine: The vast majority of rare diseases are genetic. I suspect people will assume that that would make it simple to get a diagnosis. Though there can be significant delays in getting to a point where genetic testing is done, it often fails to result in clear diagnosis. Where are we with regards to our ability to diagnose genetic diseases through genome testing and what can be done to improve diagnostic yields?

F Sessions Cole: We are definitely better off today than we were five years ago or 10 years ago, thanks to the fact that we are now much better able to look across an undiagnosed person’s entire DNA, all of the chromosomes, all of the patient’s or the individual’s genome, to try to identify specific differences in gene code that might be accounting for the symptoms and result in a diagnosis. The availability of what’s called whole genome sequencing or the ability to look across the entire 3 billion bits of gene code each of us has is an important step forward for us. However, there are many, many parts of the analysis of gene code that still require additional research and advancement. So we have a better understanding today of how to analyze gene code data, but we are still continuing to evolve rapidly to try to understand what parts of gene code are in fact causative for a diagnosis, and what parts of gene code are in fact not helpful for diagnosis.

Daniel Levine: Are there things you think need to be done to get patients to genetic testing more quickly, and will that just happen as cost for these tests fall?

F Sessions Cole: Well, I think the falling costs of tests is clearly an important part of improving access. However, there are other important considerations. First of all, providers, physicians, genetic counselors, trusted providers by individual patients need to become more aware of the importance and potential for making a diagnosis thanks to whole genome sequencing. In addition, there needs to be trust established, as I’m sure everyone understands, there are historical and structural issues of trust that go along with individual, undiagnosed people trusting the ability of whole genome sequencing and other very advanced techniques to make a diagnosis. And the importance of trusting that the information provided by whole genome sequencing will in fact be used exclusively for making a diagnosis and not for any other kind of stigmatization of individuals who undergo whole genome sequencing. So I think that there is access, hopefully that will be accelerated by the reduced cost and the increased willingness of medical payers, health insurance companies, and Medicare and Medicaid to pay for whole genome sequencing. And there are important access issues and education issues for providers who see these individuals who are undiagnosed. And then there are important trust areas to ensure that when this access is offered to undiagnosed individuals, that they will be willing to trust to undergo the test and to trust the fact that that the information from whole genome sequencing will be used for their diagnostic benefit.

Daniel Levine: We also have the ability to diagnose far more diseases at birth than a routine check for as part of newborn screening. Could we cost effectively eliminate the diagnostic odyssey for more people if we expanded newborn screening to include far more diseases than are tested for today?

F Sessions Cole: Absolutely. And I think this area of expansion of neonatal or newborn screening is a very important area that will eventually yield increased improvements in diagnostic rate, and also in the ability to identify and prevent certain genetic conditions from having their most extreme impact and consequences that we’re seeing today. And Michelle might discuss specifically the situation of her son and how an earlier diagnosis might have resulted in an improved outcome.

Daniel Levine: Well, let’s bring Michelle in. Michelle, you have a master’s in nursing, you’re a registered nurse, you’re the program director of UDNF’s newly established Patient Navigation program, but you’re also the mother of a son who died from a rare disease that for a long time was undiagnosed. Your son Mitchell began developing symptoms of a rare neurological condition around the age of 12. What happened?

Michelle Herndon: Yeah, when he was 12, Mitchell had been a quote “normal” kid developing. Typically the only medical problems he had had in his life was asthma, but that had even cleared up. He had played basketball that basketball season, and I think he even won most improved player award that winter. And about February-March, I just started noticing him walking funny. Being a nurse, I have a little bit of, maybe, a hypochondriac—I mean, always jumping to the worst case scenario. And my husband encouraged me to try and let that go. And he was sure it wasn’t anything big and just to not let my anxiety take over. And I had friends telling me, oh, my brother did the same thing when he was 12. He was growing. He got so much taller and he was tripping over his feet all the time. It’s nothing. And so, I tried to not worry, but the nurse and mom Spidey sense in me knew that something was not right. I even had him doing some very basic neurologic tests in my house, and he was failing them all. So I knew something was up. I was very lucky that I was a nurse at a top children’s hospital here in St. Louis at St. Louis Children’s Hospital, which is affiliated with Washington University School of Medicine. And I took him to see a neurologist there. We immediately thought it was a brain tumor, just balance issues. The first thing we thought was brain tumor, and the brain looked fine, but the spinal cord showed some spinal cord inflammation. He at the same time also began to lose his hearing. So those were kind of our first entry into this rare disease, undiagnosed disease world, and really began what for him ended up being about a seven-year diagnostic odyssey.

Daniel Levine: Well, what was that period? What was it like living with the disease that had no name and an uncertain prognosis?

Michelle Herndon: It was hard. There were times when we really wanted a diagnosis and then times when maybe he was doing a little better that we thought, oh, maybe it’s not as important. But I really kept fighting for a diagnosis. And what would happen to us, and this happened a few times along the way, is he would have enough symptoms of something to be labeled as a certain disease, but the doctors might call it atypical. There’s a disease called neuromyelitis optica. And so, for a while, he was atypical neuromyelitis optica, or there’s a disease of the peripheral nerve system called CIDP. And he was atypical, and really [we] ultimately just ended up dismissing all of these atypical diagnoses. So our poor family could not keep up with all these diagnoses. In fact, Mitchell said he spent a really long time learning how to say the really long word for CIDP, which is chronic inflammatory demyelinating polyneuropathy. And he is like, I learned how to say that, and now I don’t even have that. So it was just a lot of up and down going to see multiple specialists, our doctors at Washington University. I had complete confidence in them, but I also admired their humility and realizing we don’t know everything, let’s send you out for a second opinion, third opinion. So just a lot of up and downs, a lot of appointments, a lot of not knowing.

Daniel Levine: And how did that affect your interactions with doctors and your ability to get needed care for him?

Michelle Herndon: It really was unique. First of all, just every time you go to an appointment, having to try and explain this is exhausting for Mitchell and for me, just explaining the history, explaining where we’re at, explaining why the medical record actually says he has this disease or this disease. But we know that electronic medical records are not accurate. And things that were documented years ago still remain in the record. From a practical perspective, there were some things having to do with school and accommodations that he needed at school that if I had a diagnosis, if I could say he has muscular dystrophy, then things would’ve just more quickly fallen into place. Some state support, some Medicaid that he would’ve qualified for much earlier if he had an actual diagnosis instead of just unknown neurodegenerative disease. In a particular instance, he needed a kind of compression device, and our insurance wasn’t going to pay for it. It was going to be a few thousand dollars. And our physical therapist found a grant program that we were excited about. We applied for it, and then we were told he wasn’t eligible because he didn’t have a diagnosis.

Daniel Levine: He was eventually diagnosed through the Undiagnosed Disease Network program. Can you explain what this is and what they did to ultimately get to a diagnosis?

Michelle Herndon: Sure. So the Undiagnosed Diseases Network is a research program venture through the NIH with sites all throughout the United States. And Washington University in St. Louis currently is now a site of the UDN, but at the time, they had not joined the network. This was 2016, 2017, and a physician who had cared for Mitchell earlier had moved to Texas to be on faculty at Baylor College of Medicine. And she contacted me and said, I really think you need to apply to the UDN. I think Mitchell’s case is perfect for the kind of cases that they look at. He had had extensive testing, extensive genetic testing. As Sesh had mentioned, he had the top genetic testing 10 years ago. He had exome sequencing and they hadn’t found anything. And so we applied to the UDN and he was assigned to the Baylor site. They reviewed medical records and ultimately decided he was a good case for their network. The UDN covered the costs for Mitchell and I to travel to Houston for a few days for exams with all kinds of specialists with their team down there. And ultimately, they did his entire genome, the whole genome sequencing for him and for my husband and I, they took a little skin biopsy and they started just studying his genome where they found a variant in a gene. It was a common gene that they knew before, had some disease related to it, but the disease that was related to it was what they call a loss of function, or they did not have a particular enzyme. And the patients who had that disease died in infancy. And Mitchell was so different. He had nothing until he was 12. And so initially they thought to disregard that variant, but the UDN and their team said, actually, we think this is the same gene, but a different variant with a different mechanism. Let’s look at that. And so the cool thing is they took that variant and they modified fruit flies just like the fruit flies you see in your house that you’re trying to get rid of. They modified the genes of a line of fruit flies to mimic and match the variant that Mitchell had. And I still to this day, remember the call when I heard that the fruit flies couldn’t fly, and they were pretty sure that this was the variant that was causing Mitchell’s symptoms. And then after that, they were able to use their network and gene matching to find another patient in the world with the same variant, with a very, very similar picture. So getting that second confirmatory patient was really what really let them know this is it. We’re on the right track.

Daniel Levine: And am I correct that the condition he was diagnosed now is named for him?

Michelle Herndon: It is. So, the technical name is ACOX1, that’s the gene, gain of function, meaning that this ACOX1 gene is producing too much. It’s working overtime. But the initial publication that was published with the UDN scientist Dr. Chung, the lead fruit fly researcher, and Dr. Hugo Bellin, they proposed naming the disease after Mitchell, really just out of Mitchell’s contributions in sharing his experiences, his symptoms [and] being really open to giving the researchers whatever they needed to help understand the disease more. So, it is now known as Mitchell syndrome.

Daniel Levine: Sesh. You’re now secretary of the UDN and had led the center at Washington University School of Medicine in St. Louis from 2018 to 2021. Can you explain how the program works?

F Sessions Cole: Yes. The program works as a research project. So, one of the missions of the UDN is to solve medical mysteries through team science. And as I indicated earlier, one of the important parts of the special sauce of the Undiagnosed Diseases Network is that it brings together many different subspecialists. And in Mitchell’s case, it brought together different subspecialists who had been looking at different parts of Mitchell’s symptoms. And as the subspecialists began to speak with one another, and as the results from the fruit fly work came back, the subspecialists and the researchers began to understand how what they had found in Mitchell’s genome, this gene code variant, gene code difference in this gene called ACOX1 could account for all of the different symptoms that Mitchell was exhibiting. And so, the Undiagnosed Diseases Network brings in individuals with these symptoms that don’t fit into a known diagnosis or diagnostic category. And the process brings these clinicians who are experts in the different symptoms of the undiagnosed individuals or participants and brings them together, almost always uses a complete whole genome sequence, not only of the individual who is affected and being evaluated, but also first degree relatives, usually mother and father, might also include siblings or aunts and uncles who are affected, and looks and compares computationally the differences and similarities in gene code between the individual who is undiagnosed and the members of his family or her family. And doing that and engaging the expert clinicians, the process yields a diagnosis approximately 30 to 35 percent of the time.

Daniel Levine: What does it take to get seen through the program?

F Sessions Cole: Well, one makes out, first of all, a consent at the Undiagnosed Diseases Network website. And that consent provides the network with the ability to bring together all of the medical records of the undiagnosed individual. And as you can imagine, because these diagnostic odysseys have frequently lasted years and frequently involve many different specialists and medical centers, this bringing together the records is an important first step in trying to understand whether there is a possibly genetic problem that could be behind or causing the undiagnosed patient’s symptoms. And then the records are basically brought together and reviewed by the Undiagnosed Diseases Network Center that is closest geographically to the individual who’s undiagnosed. And then the summary of the records is discussed by multiple specialists in a group at the center. And then a recommendation is made to the network as to whether or not it’s likely that the resources in the Undiagnosed Diseases Network will be able to offer this individual a diagnosis. And then if the recommendation is to accept the individual into the Undiagnosed Diseases Network, then the individual is notified and arrangements are made for the individual then to be evaluated at that center by multiple subspecialists and to move forward, if not already done with the whole genome sequencing.

Daniel Levine: We featured a Rarecast in the past with Amy Gray when the UDNF launched, but Michelle, can you explain what the UDNF is and how it works with the UDN?

Michelle Herndon: Sure. So the UDNF or the Undiagnosed Diseases Network Foundation is a patient led nonprofit organization just founded in 2023. We’re committed to improving access to diagnosis, research, and care for the undiagnosed and the ultra-rare. This really grew out of patients realizing that there needed to be more support for the UDN, not only for the patients in general, but also for the sustainability of the ongoing research and funding for the Undiagnosed Diseases Network. And so we work in partnership with the UDN. In fact, next week is Rare Disease Week in Washington DC and we’ll be meeting with a lot of collaborators and partners. And our goal with the UDNF is to ensure that the UDN remains this amazing resource for a very long time.

Daniel Levine: My understanding is the new Patient Navigator program is something that you helped create in part because of the experiences you had. What problem is the program seeking to address?

Michelle Herndon: I think there are a few problems we’d like to address. A big one for me is despite me being a nurse, working at an academic medical campus in a large urban area, very strong family, church, family, friends, just a really great network supporting me and my family and our son, I still felt horribly alone and unsupported during this process. And that really is no slam on any person in particular, our doctors were doing their best, our family was doing their best, but it really is a lonely road being undiagnosed, and it’s hard to not be jealous of other diseases with these massive support infrastructures. And I’m super excited for them. I think it’s great that a ALS has organizations or Muscular Dystrophy Association or the American Cancer Society, that those organizations are amazing, but there was nothing out there for the undiagnosed. And a group of us realized that we needed to be there to support our undiagnosed peers.

Daniel Levine: How does the program work?

Michelle Herndon: Well, we’re very excited to be launching our program. We will be taking in undiagnosed and ultra-rare patients who request navigation services, and we are hoping to provide that. It’s not necessarily care management like you’re used to in a care coordination or clinical management setting. It’s more patient support, helping them get connected to resources in the rare and undiagnosed arena, as well as social support needs. We found that a lot of the patients who are in the Undiagnosed Diseases Network, these things take time. This research takes a lot of time, and during that time, these patients need support and we want to be there. If someone’s in the UDN and they’re waiting for their diagnosis, or maybe they’re getting a model organism study and that’s taking months, or maybe they’re waiting for their actual site visit, what can we be doing in the meantime to support them? So our goal is to walk alongside them, provide supports when needed, and ultimately, if they don’t get accepted into the UDN, we still want to continue to support the community. This is not only for participants in the UDN, it’s for all undiagnosed and ultra-rare patients.

Daniel Levine: I should note the program’s backed with a $2.5 million dollar grant from the Chan Zuckerberg Initiative. What would represent a success for this program? What are you hoping it will ultimately be able to do?

Michelle Herndon: I hope that it will one, bring more patients to the UDN and awareness of the Undiagnosed Diseases Network program. I hope that it will reduce the diagnostic odyssey. I hope that the navigation program, by helping to bring patients to the program, helping to get medical records quicker, that we will play a role in reducing the length of time that it takes to achieve a diagnosis and then ultimately provide emotional, social network support and practical support along the way to these patients and families.

Daniel Levine: And is that the expectation that this will serve as some kind of a pipeline to the UDN and accelerate the process of getting people into that program?

Michelle Herndon: I don’t necessarily think that we are calling ourselves a pipeline, but if there are undiagnosed people who reach out to the UDNF and they say, what is out there for me, I think the first thing we will ask is, have you applied to the UDN? And if the answer is no, then we would be more than happy to provide them with the resources about the UDN, connect them to the coordinating center with the UDN. But if a patient is not appropriate for the UDN, or maybe they’ve already gone through it without a diagnosis, we still are there for them. And we want to be a resource for the entire community.

Daniel Levine: F Sessions Cole, secretary of the UDNF and professor of pediatrics at Washington University School of Medicine in St. Louis, and Michelle Herndon, program director of UDNF’s Patient Navigation program. Sesh, Michelle, thanks so much for your time today.

F Sessions Cole: Thank you very much.

Michelle Herndon: Thank you.

This transcript has been lightly edited for clarity and readability.

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