Since accepting its first patient in 2015, the Undiagnosed Diseases Network (UDN), which is funded by the National Institutes of Health, has been working to find answers for patients with unknown disorders that have nowhere else to turn. The 13 UDN sites across the country conduct basic and clinical research to improve the level of diagnosis and uncover the underlying disease mechanisms associated with these rare conditions. The UDN is an expansion of an Undiagnosed Diseases Program initiated in 2008 at the NIH Clinical Center in Bethesda, MD. Many liken our work to the popular television show House M.D., although we would argue that diagnosing a rare disease in one hour is pretty much impossible!
Rare diseases aren’t that rare. The National Organization for Rare Disorders (NORD), as well as the Rare Diseases Act of 1983, defines a rare disease as one that affects fewer than 200,000 people in the United States. It has been estimated that approximately 25 million Americans have a rare disease. This week, we and others around the globe will be celebrating Rare Disease Day. We’re doing this AMA to raise awareness about rare and undiagnosed diseases among the scientific community and share information about rare diseases and their impact on patients and families.
A bit more about us. We are:
Dr. Loren Pena: a clinical geneticist and Associate Professor of Pediatrics at Duke Medicine, one of seven clinical sites within the UDN. I see patients in the Duke genetics clinic and evaluate patients enrolled in the UDN at Duke.
Mr. Jamie Mills: the father of Quinn, a 3-year-old boy diagnosed with an extremely rare genetic disease by the Duke UDN team last year. Quinn’s particular mutation is so rare that at this time there are only 10 known cases around the world. I am also co-chair of the UDN Participant Engagement and Empowerment Resource (PEER), a group of participants and family members who have participated in the UDN.
We will be answering your questions at 1 p.m. ET – Ask Us Anything!
UPDATE: Thank you for such thoughtful and engaging questions! We had a great time answering them and hope to do this again sometime. You can learn more about the UDN at https://undiagnosed.hms.harvard.edu/. Cheers /r/science, have a great week!
Hi and thank you for doing this AMA. A couple of questions:
How has genome sequencing impacted the diagnosis of rare diseases? At what stage in the clinical workup do you begin to think about sequencing the patient and the parents?
Can you talk generally about the genetics of rare diseases? Do they tend to be monogenic or polygenic? Inherited or de novo? Or is there no real trend?
Genome sequencing has really opened the door to identification of genes involved in known disorders, and discovery of new genes involved in human disease. The approach is quite different in terms of when to send genome sequencing and is dependent on the provider and the institution. Some providers prefer to start with genome sequencing, others may choose a targeted approach prior to genome sequencing. The genetics of rare disorders are quite varied and we are still learning whether there are specific trends. - Loren
While I can't get into specifics about the field of genetics, I can say that it has been amazing to see how having Quinn's whole exome sequencing being put into a database at GeneDx in December 2015 led to the discovery of this rare mutation in mid-to-late 2016, because other children's whole exome sequencing came into the same database, and the mutation could be cross-referenced with the clinical presentations. Pretty amazing. - Jamie
For those with rare genetic conditions like Quinn's, what options for treatment are there currently? And how does that process correlate when trying to find a cure
Treatment for some rare disorders depends on the symptoms. In recently described conditions, we need to understand the mechanism of disease before development of a therapy that is specific for that disorder. Model organisms play an important role in development of new treatments for rare disorders. - Loren
There is nothing available at the macro-level yet, in terms of treatment. We are able to treat some of Quinn's symptoms with help from secondary physicians (who we sometimes think are guessing as much as we are), such as Neurology (to treat and contain Quinn's seizures), GI (discomfort/pain, slow gut, constipation, reflux), Sleep Neurology (lack of regularity with sleep schedules), and others. To be honest, I feel like we are always playing defense with Quinn's condition - we try to respond to issues as they come up and we roll with Quinn's moods, without really having a good overall treatment in mind or advance knowledge of what could be coming next. We have really enjoyed getting to meet and talk with some of the other NACC1 patients' parents, to understand a little bit more about what makes these kids unique and special (so far we've met 4 other families out of the total of 10). We also are lucky in that Quinn's maternal grandparents are research scientists who study Huntington's Disease, and are able to use some of their research discretionary money to devote to researching Quinn's mutation. They are in the process of cultivating a mice colony with Quinn's mutation, so this will likely be a long process. We know we are lucky to have family that are researchers; but we are just starting to think about ways to encourage fundraising for research for Quinn's mutation. We are hopeful that eventually there is something available clinically that can help Quinn. - Jamie
What are your thoughts on possible prevalence of undiagnosed rare diseases? How many Americans might suffer from an undiagnosed rare condition because of missed diagnosis?
Rare disorders are thought to affect about 10% of the US population, approximately 30 million Americans. - Loren
Thanks for coming to talk with us! Dr. Pena, I'm interested in understanding more about the kind of work you do and how physicians are rewarded for their work (both financially and otherwise). Does the socio-economic structure of medicine today make it hard to spend so much time on each unique case, or are there ways around those issues?
Genetics is an exciting specialty and combines quite a bit of laboratory knowledge (biochemistry, cytogenetics, molecular biology). With the emphasis on personalized medicine, I think genetics will become more popular. A genetics visit tends to be very thorough, so efficiency is very important to make sure we are in sync with our expectations for efficiency. - Loren
My daughter has a CACNA1A mutation, specifically R1349Q. This partially answers how she presents. She has dysmorphic features, which isn't documented with this. There is such little knowledge about SHM or what I think more describes her but hadn't been mentioned by her geneticist, AHC. We just don't know how to best advocate or help her, always feeling like we educate her local health care team. It's a weird place to be in as parents. Any advice other than traveling to see someone?
This is going to sound pithy, but maybe you could try to make some friends with some medical researchers? You could ask your geneticist if there are people that might be interested in studying a rare disease. If you get professional researchers to be interested in this, then they are going to have the resources and capacity to study the disorder and apply for funding to support the study of the mutation and its treatment. - Jamie
The UDN team at Baylor College of Medicine recently published a paper about gain of function variants in the CACNA1A gene (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5557584/). Although they did not report any patients with your daughter's specific gene variant, it may be worth reaching out to the corresponding author to ask about any ongoing research (email address is listed in the article) 2.) Are you aware of the CACNA1A Facebook group? We know that the family of the UDN patient in the article above has found it really helpful to connect with others: https://www.facebook.com/groups/cacna1a/ 3.) Have you met with a genetic counselor? If not, it may be worth looking into- they are experts at helping patients and families navigate this process. Here is a tool you can use to find a genetic counselor in your area: https://www.nsgc.org/findageneticcounselor. Good luck! - UDN Coordinating Center team
How often are rare diseases discovered? Do you think there are still a lot out there that haven't been identified yet?
Yes, there are probably many conditions out there that have not been identified as a specific rare disorder! It is difficult to know how often rare disorders are discovered, but large throughput sequencing methods such as exome or genome sequencing have been instrumental in accelerating the pace of discovery. It is truly an exciting time to be a geneticist! - Loren
How long does it take for someone to get a diagnosis and proper treatment for a rare disease? If the symptoms of a disease or disorder tend to follow other more common diseases, it seems likely it would be consistently misdiagnosed before someone decides to test for the rarer/less common disease.
My limited knowledge in this leads me to believe that from initial diagnosis to delivery of a clinical treatment of a rare disease, it can be many years. From my discussions with my in-laws (who are at the very first stages of studying Quinn's genetic mutation), it will likely be in the 5-10 year range (at least) before we arrive at this option for my son. My in-laws have been developing a clinical treatment for Huntington's Disease (they are doing primate testing of a treatment right now) for over 30 years. They have made more strides recently, as technology and knowledge has increased, but this is a painfully slow process, necessary due to the implications of doing something wrong! - Jamie
I have been very sick for over a year and have desperately been trying to get a diagnosis. What is your advice for getting a doctor to not just check boxes and dump you onto specialists that just turn around and dump you when the problem is not in their specialty? It feels like if they can't figure it out they don't seem to care anymore. How do you encourage them to dig a little deeper to see if it is a rare disease?
Three questions: 1.) Do you have a champion/central person managing your care that could do this for you (i.e. your primary physician or someone who you fall back to when the specialists dump you)? Our pediatrician fills this need for us often-times, as well as the Complex-Care team at our hospital, which helps to manage cases with complex medical needs (they're like the hub at the center of the wheel, with the specialty docs being the spokes); 2.) Have you seen anyone in genetics at your hospital yet, or tried to be referred to a genetics group in another hospital? They would look at what is known clinically about your condition (if it can be diagnosed); 3.) Have you applied to the UDN? This would help with research endeavors if your condition cannot be diagnosed clinically. You can read about the application process here: https://undiagnosed.hms.harvard.edu/apply. - Jamie
Is there research concerning how likely you are to receive the right diagnosis from a GP?
None that I am aware of. I think it would be difficult to assess the accuracy of a diagnosis obtained through a GP, and this may be one of the reasons for the lack of information. - Loren
What should the medical community be doing differently to better diagnose rare conditions?
I think the biggest obstacle to diagnose more quickly/efficiently is the lack of qualified genetic physicians/counselors/clinicians to serve those who need to be seen/diagnosed. Even at Duke University, appointments are scheduled 4-6 months out, unless the person is in-patient. If my memory serves correctly, most of the genetic physicians wear multiple hats (i.e. cardiology and genetics). This would probably speed up the process for most people, if specialization in genetics was pushed more in medical schools. DISCLAIMER - I am not a medical professional; this is purely observational. - Jamie
I think referring to the appropriate professional is a very important on the road to diagnosis. This occurs frequently in pediatrics, and I agree with Jamie that access to the appropriate healthcare provider may be a rate-limiting step. - Loren
Do you see artificial intelligence playing a larger role in diagnostics in the coming years? Have we reached a point where no single person is capable of seeing the large picture of a history of symptoms to make a proper diagnosis?
We are seeing some efforts in the use of automated methods for developing differential diagnoses. There are several apps that we can use to assist us in development of a list of candidate conditions. Some of the programs require us to enter symptoms and physical findings, and others are based on photographs. These are very useful tools for clinicians. - Loren
What are the most difficult rare diseases to diagnose?
Probably those that are ultra-rare and have very limited information available in terms of symptoms and physical findings. Another category that is difficult to diagnose is disorders with many different symptoms that vary from person to person. - Loren
Do we need to do more genetic testing as part of regular physicals? Or should that remain specialized?
Genetic testing is complex and should always have an indication for use. Providers that offer genetic testing to patients should be able to offer pre-test counseling in terms of what types of results could arise, how the potential results could be interpreted and utilized for care, and the limitations of the test. - Loren
What I liked about our process was that it started basic and expanded outwardly. The screenings started with more generic testing options, and when nothing came back, the screenings become more extensive, until we finally reached the whole exome sequencing. I think this approach is best because these tests are expensive and time consuming, and if the basic tests can eliminate the need for the more extensive tests like whole exome sequencing, then that's all the better. On the other hand, as a parent wanting to know results, the waiting involved in this approach can be maddening as well. I don't want to gloss over that aspect of the process. - Jamie
I need information on HLA-B27, my 13 year old son was diagnosed at age 7 with sialadentits and now has dental cyst. Trying to find out if there is a connection. The oral surgeon has no information for us on the topic.
The NIH Genetic and Rare Diseases Information Center (GARD) is a good source of reliable information. We found this page on there website that may be of interest: https://rarediseases.info.nih.gov/diseases/7638/sialadenitis. If you still have questions, you may want to consider reaching out to one of their information specialists.
Hi and thanks for joining us today!
What are your thoughts about the lack of national surveillance for many rare diseases like Guillain-Barre or myasthenia gravis?
From my experience, the less common the disease (cluster of symptoms), the less likely there is some type of network available to support those with the disease and the less likely there is knowledge about the disorder. A good example: someone from the Duke University Undiagnosed Disease Network gave a presentation about rare diseases discovered by the Duke UDN team to a group of new pediatric residents at the hospital (without identifying children by name, just the name of the mutation). One of the residents at the presentation knows our family and knows our son, but it wasn't until months later that she made the connection that one of the children discussed in the presentation was our son, whom she knows well. I think we will have to continue to advocate, educate, and publicize information about these rare diseases. - Jamie
Hi UDN, what would you suggest to a patient who has an identified mutation, but cannot find a specialist within the state they live in that is familiar with their disease/willing to treat? Do you have patient coordinators who help patients find specialists, by any chance?
And one last question: how can we help and how can we get involved? How can we volunteer or serve UDN better?
Because of the rarity of some conditions, specialists are frequently at different institutions. The good news is that technology has facilitated so many of our interactions! In the UDN (and in my clinical practice outside of the UDN), I share information regarding existing resources with families. We also try to connect the families with the provider or investigator, and find out for families what type of research or visits are available. I suggest having a conversation with your provider about existing resources. It may be helpful to have specific names or institutions. Even if you are unable to travel, there may be opportunities for participation, or input, that don't require an actual visit. - Loren
I agree with Loren. I think making it known to your provider that you are willing to talk to others is really important. We made it super-clear that we wanted to talk to others like Quinn. But, we have found out that another family in the initial cohort of children found with the NACC1 mutation (discovered summer 2016, published January 2017) was only plugged in to the network of other families (started with us, then we connected them with other families) a few weeks ago. She said she made it clear that she wanted to talk to other families a long time ago, but it just didn't happen. I suspect that this is probably something that patients/parents need to advocate for regularly, to remind providers that they want to talk to others with their conditions. - Jamie
Regarding your last question, we are not actively looking for volunteers but appreciate your support and help spreading the word about the UDN. The NIH UDP (now 1 of 7 UDN sites) has existed for 10 years and we still hear from people that have never heard of it or its expansion to a national network! If you are a health care provider, there may be other ways to get involved- feel free to reach out to us at UDN@hms.harvard.edu. Thanks! - UDN Coordinating Center team
I was diagnosed with a rare disease as a teen, and for the next decade felt like 1) I had to rely on referrals and doctors that I had no way to vet (resulting in some really unfortunate treatment decisions), 2) I had no support from people who understood my situation, and 3) I didn’t know how to process and plan for my disease. I’ve since found a community of people with my disease that have helped with all the above, connecting me with a doctor who understands my condition, and being able to ask/answer questions. However, I don’t understand why I wasn’t given, upon diagnosis: 1) information about the top specialists who work with my condition, 2) connection to social supports, 3) a referral to mental health professional to help me process this news and plan for the future. In your opinion, what kinds of supports and options should be offered to newly diagnosed patients, and who is in the best position to offering those options and supports (diagnostic team, specialist, PCP, hospital social worker, etc)?
From a parent perspective, I feel like getting the diagnosis and seeing the published paper was really helpful when we were able to see the phenographic chart that showed all of the other children (like our son) has common issues. I found it really helpful to read the case study information at the end of the article to know what the other children/young adults had gone through or were currently going through. It was helpful to be able to point to some of Quinn's issues and know that they were related to his disorder. Speaking with other families - which has been more difficult than I anticipated - was also really helpful. For example, Quinn sometimes sleeps for multiple days/nights in a row, and we used to be concerned about that, until we found out that the other NACC1 patients do that as well. So, to answer your question, it would help to have some type of common issues/problems that are related to the rare disorder, so that you could know what is likely related to the disorder and what is not. I have been thinking recently about how to make managing the NACC1 disorder easier on parents in terms of therapeutic responses to common problems, such as creating a Google Doc that shows how the various families have treated seizures, sleep irregularity, visual impairments, extreme fussiness, etc., so that we could share this chart with families who are new to getting the diagnosis. But that brings up a very good point that you raise: how do we get this information out to the wider community to be able to share more easily? I wonder if the internet can be tapped into to make this more readily apparent and visible to the wider community. For example, we often get contacted by our genetic counselor when a new NACC1 person is found, and we are usually given the opportunity to contact them (via email or phone) if they are willing too. If they have been willing, we usually invite them to join a private Facebook group with other parents of NACC1 kids (or to be connected via email or phone with other parents, if they don't have Facebook). So, to answer your question, I think we need to leverage technology and parent/patient involvement to help better educate newly-diagnosed individuals. - Jamie
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