Dr. Károly Mirnics With New Insights Into Autism and Brain Development

Transcribed automatically and lightly edited.
Michael Lyon:  This is Heartbeat, conversations about medical science, research, and the discoveries that touch our lives in collaboration with the University of Nebraska Medical Center. I'm Michael Lyon. My guest today is Dr. Károly Mirnics, dean and director of the Munroe-Meyer Institute at the University of Nebraska Medical Center. The institute is dedicated to transforming the lives of individuals with intellectual and developmental disabilities and complex healthcare needs. Welcome.
Károly Mirnics: Oh, it is a pleasure and privilege to be here.
Michael Lyon: Oh, well, likewise for us. For listeners who may not be familiar with it, what is the mission of the Munroe-Meyer Institute and who does it serve?
Károly Mirnics: So, we serve all individuals with intellectual and developmental disability and complex healthcare needs, and we do this through our four pillars: community engagement clinical services, research, and education. And we are from cradle to grave, a life span.
Michael Lyon: That's interesting because when people hear developmental disabilities, that term, they often think only about children. Um, from cradle to grave, what does that mean to you? What sort of services and support does the institute provide across a person's lifespan?
Károly Mirnics: Oh, my goodness, that's a tough question to answer in a very short period of time because we have over 40 different kinds of services, and they range from occupational therapy to psychology to genetic counseling to pretty much anything that we can organize in our community.
Michael Lyon: What are some of the biggest challenges currently facing individuals with intellectual and developmental disabilities and their families?
Károly Mirnics: So, I would break it down to probably three categories. The first will be awareness. I think that we have done a lot in that arena. The second isreally acceptance, and the third are opportunities, and we are somewhere stuck in between just before the opportunities that are available for our families.
Michael Lyon: How does the institute balance patient care, education, community outreach, and research?
Károly Mirnics: Those work together. You cannot separate one from another. Um, that's one integral institute and that is very much reflected also in our funding sources. We have big grants. We have significant clinical services, about 140,000 clinical visits each year. so I don't think that there is a specific balance. We do everything all together.
Michael Lyon: Autism spectrum disorder is one area where the institute has developed significant expertise. What have we learned about autism over the past decade that the general public may not fully appreciate?
Károly Mirnics: Oh, we learned a lot. The usual saying in the community is that if you have seen one child with autism, you have seen one child with autism because this is a spectrum disorder. their patients are very different from each other in their strength and in their needs actually, and we need to address them, so we individualize every treatment. What we learned a lot about the causes of autisms, how to diagnose it early, what are the best treatment methods, and that is life-changing for the families, and as well how to integrate the individuals with ASD into our community. Despite this sort of increased awareness, there are still many misconceptions about autism. What are some of the most common misunderstandings you encounter? Oh, probably I would say the relationship between autism and intelligence. First, a lot of people think that if you have a diagnosis with autism, that somehow you are not that smart, and these individuals are amazing and they have amazing strength. They are just not typical, and they are trying to make it as neurodiverse kids in an environment that is built for neurotypical individuals.
Michael Lyon: Much of your own research has focused on brain development and the biological factors that influence it. What question are researchers most urgently trying to answer today about autism?
Károly Mirnics: I think it's a balance between the genetics, between environmental factors, lifestyles, medications, chemicals, and why is this tremendous rise in the frequency of autism in our population? And as well, what are the best treatment methods that can help individuals to integrate well into the community?
Michael Lyon: In April, you and your colleagues published a study that attracted national and international attention. Give us an overview of what the research team set out to investigate.
Károly Mirnics: We looked at a set of medications that have an intended or unintended inhibition of sterol biosynthesis system. Now, cholesterol, you know everything about it. It's bad your-- for your heart. But the brain loves cholesterol. It's only two percent of the body weight, but it contains twenty-five percent of lipids. Um, and it is an essential building block of life. Without cholesterol, there is no life, So we looked at this set, a set of medications that have an intentional or unintentional side effect to inhibit cholesterol biosynthesis. And what we found that there was a significantly elevated chance of the child having autism if the mother took these medications during pregnancy. This further increased if they took two or three of these medications.
Michael Lyon: You've described this specific biological pathway being of particular interest to your research-search group. Why was that? How did you come to select that?
Károly Mirnics: So, we went from all the way from basic science to basically clinical implications. Initially, we were interested in how the brain connects, how it develops, and there is also one particular developmental disability that is called Smith-Lemli-Opitz syndrome that arises from mutations or how-- nowadays we call them pathogenic variants in the c-cholesterol biosynthesis gene. And 75%, up to 75%, I should say, of individuals were on the autism spectrum. Now, we were investigating this process and what does the mutant or the gene do, and how does it affect brain development? And then we found a set of medications that were mimicking the same bio synthesis inhibition that are seen in these patients. And then we screened the big library, what are the all the chemicals. And after that basically we went and we looked in a 10-year span at all the mothers in the database who took or who were prescribed these medications and had linked maternal child records. and this is not a small sample size. this was about six point one million linked records, and it was about one third of the birth in this period of 10 years in the whole United States.
Michael Lyon: That must make it one of the largest investigations of its kind. Did that kind of enormous data set give you or, or the researchers the opportunity to examine things that smaller studies couldn't?
Károly Mirnics: Oh, absolutely. There is power in numbers. And we had an incredible team of a neonatologist, who is the lead author Eric Peeples, an amazing bioinformatician Jerrod Anzalone, um Ran Dai, who was an amazing biostatistician Zeljka Korade, who was the molecular cell biologist, a professor of pediatrics. And these expertises came all together and we really worked on this for a couple of years, just on this database before it was ready for publication.
Michael Lyon: So, in a nutshell, what were the findings of this study?
Károly Mirnics: If mothers were prescribed these medications, their children had a significantly elevated chance to have a diagnosis of autism later in life. The second thing is that if they were prescribed two or three of their medications, it further increased this risk. Now, the other interesting finding is that these medications ten years ago were prescribed less than five percent to pregnant women, and that has almost quadrupled over the last ten years.
Michael Lyon: I think it's probably important for us at this point to talk about the difference between finding an association, which I believe you're just describing and proving causation. Can you talk about this study in that context?
Károly Mirnics: So, we cannot show causations. Causation will nobody be able to show in these human populations because ultimately, we don't do experiments on humans, right? So but the point is that we went through from the mutation disease association to cell cultures, to pregnant animal studies, mouse studies, to human biomaterials from blood from pregnant women, from human dermal fibroblasts, and every single model uh that we had access to, and we slowly built actually the basis for the study. So, this was from basic science all the way to translational s-science to the human population studies. So, I think that that biological plausibility is very important. And if you look at the inserts of the drug manufacturers that are included with each medication, they also report significant developmental effects during pregnancy for many of these medications in animal studies and some in human studies. I think that we became a little bit numb to all the warnings that we see on the labels.
Michael Lyon: You've described that when multiple medications affecting this pathway were prescribed at the same time that that increased the risk. Um, does that tell you something about the possible biological mechanism involved?
Károly Mirnics: Yes. It tells a lot about various things. First, there is a biological me- mechanism that this elevates one particular substance in the blood and in the tissues, which is known to be extremely unstable. It falls apart, and it's toxic for cells. So, the more of these medications you get the bigger of this rise is. but it also tells us clinically that we should be aware of it what are... what different specialties prescribe. Because you can get a medication from a cardiologist, and you can get a medication from your general practitioner, which are both inhibiting this pathway, and you are not even thinking about, or they are not even thinking about the interaction of these medications.
Michael Lyon: Some listeners may hear about these findings and become alarmed, particularly if they took one or more of these medications during pregnancy. What's the most important context they should understand before drawing conclusions? And the study, I know, specifically cautions against stopping prescribed medications without medical supervision.
Károly Mirnics: You always have to discuss your medical choices with your provider. Don't stop your medication if you are-- don't want to become pregnant or you are pregnant. It's always a balance between your own health and the health of the unborn child, right? The future health of the unborn child. And our basic science studies suggest that if you have a particular genotype which is about 3% of the population, you might be much more susceptible to the effects of these medications. And I would guess, based at least on the animal studies, that that population of human that segment of the human population would be probably the most vulnerable to the side effects.
Michael Lyon: Was your team able to account for other factors that might influence autism risk? And what limitations remain even in a study of this scale?
Károly Mirnics: There are many limitations here, and I'm not saying that we addressed them all. the power of a big database is that you have the numbers. The weakness is that you don't have the specificity. So, we don't know anything about the father's habits. We don't know anything whether... We don't know how much medication the women took. Did they take it every day? What was the dose? We don't know necessarily all the other confounding factors, their genetics. we so, um... It's even nutritional habits. Um, we tried to control for many variables, as many as we could, but we were not perfect.
Michael Lyon: Where does the research go from here? I mean, do you anticipate future research focusing on identifying which mothers and children may be particularly vulnerable to these medication effects, maybe because of those underlying genetic factors?
Károly Mirnics: Yes, I would say that that would be one of the priorities, you know. Um, and further dissecting this interaction between medications and genetics. That's definitely one of the main directions. I would also love to see that is there a paternal risk if the fathers took these medications ultimately, and whether that would also predispose a child for developing autism. But beyond that there are so many unanswered questions about pretty much the biochemical pathway, the exact inhibition from basic science all the way to the clinical. Are the kids who have the autism diagnosis whose mother took these medications, are they presenting with slightly different symptoms? Or is there a chance that based on your genetics, these medications would predispose you to developing ADHD, OCD, learning difficulties? We don't know anything about that at the current time.
Michael Lyon: Finally, if there is one takeaway you would like physicians, expectant parents, and the public to remember from this study, what would it be?
Károly Mirnics: A couple of them. Talk to the providers who prescribe the medication and ask, "What is my risk about any medication that you are taking during pregnancy?" And discuss it honestly, what is the risk for you, what is the risk for the child? The second is that I think that the, one of the main take-home messages is here that don't think about a blame game fathers should not blame the mothers. Mothers should not blame themselves if they took these medications and they have a child with autism. Um, think about it this way, a chance, increased chance is not certainty by any means. If I may make an analogy, the lottery chance of hitting it is one in, I don't know, 200 million, right? Now, if you won the lottery, it was 100% for you, right? So, population findings cannot be translated all the way down to individual risk. So, there are many women who never took these medications and have a child with autism, right? And there are many women who took these medications and do not have a child with autism. So, keep that in mind. This is research, and the impact of it certainly should not be overstated at the individual level.
Michael Lyon: I've been speaking with Dr. Károly Mirnics, Dean and Director of the Munroe-Meyer Institute at the University of Nebraska Medical Center. I'm Michael Lyon, and this is Heartbeat.