Transcription:
Developmental Disabilities

Dr. Greg Fritz: Ladies and gentlemen, this is a first for Mindcast. We have a real live rockstar in the house today. Welcome, Dr. Daniel Moreno-DeLuca and your participation in the podcast today. While we'd love to hear him play his guitar and sing his latest hit, we've invited him here to talk about developmental disabilities. Daniel's unique professional background, as opposed to musical, bridges neurosciences and genetics, precision medicine and psychiatry. Daniel is a tireless advocate for genetic testing for children with disabilities, basically to help explain outcomes and even influence types of treatment. It's so fascinating. We can't wait to hear about it. And it's really the wave of the future and you're going to enlighten us today.

Daniel is a child and adolescent psychiatrist at the Verrecchia Clinic for children with autism and developmental disabilities at Bradley Hospital. So, welcome from those duties.

This is Mindcast: Healthy Mind, Healthy Child, a podcast from the mental health experts at Bradley Hospital, leaders in mental healthcare for children. I'm Dr. Greg Fritz and my colleague, Dr. Anne Walters, is with us.

Dr. Anne Walters: Daniel, thanks so much for joining us today. To start, it might be helpful to define developmental disabilities for our listeners. These encompass a wide range of conditions that affect an individual's development across the areas of learning, language and/or behavior. When we talk about the range that a developmental disability could take, we can think of autism spectrum disorder, ADHD, learning disability, or even Tourette's disorder and many others. And of course, there are varying pictures of strengths and needs in each of these conditions. So for our first question, could you tell us a little bit about what do we know about the causes of different developmental challenges?

Dr. Daniel Moreno-DeLuca: Thank you. Thank you very much for having me here. I love talking about this subject. We often talk with our families and the kiddos on the spectrum about each having their own interest and their niche passion that they like to pursue. And I like to think of autism as one of my niche passions. So if I get too carried away, just let me know.

But going back to your question about the origins, we know that autism spectrum disorders and developmental disabilities have a very strong genetic component and in fact is one of the mental health conditions with the highest heritability. Now, heritability does not mean inherited, and that's going to be a key concept all throughout our talk, but it does mean how strongly genetic any given medical or mental health condition is. So there is a strong, a very strong genetic component. It is not the only potential cause of autism or developmental disorders. There are also perinatal infections and exposures to different toxins during pregnancy. But the overwhelming emphasis is going to be on genetics as a genetic cause can be identified in up to one out of every three kiddos with either autism or developmental conditions.

Dr. Greg Fritz: So does the use of genetic testing lead to improved health outcomes in patients with developmental disabilities compared to patients who did not? That's really the jumping to the bottom line here a little bit quickly. Fill us in on what we know about that.

Dr. Daniel Moreno-DeLuca: I would be happy to do so, because it's a question we hear about from our colleagues in the clinic very often. And my argument is that it totally does if you know how to quantify and how to think about those outcomes that can be affected by having a genetic result. So we just said that approximately 30% or of kiddos are going to have another underlying genetic condition. We also know that genes don't care about the DSM, meaning that it's not like they're only going to go to the brain or they're only going to affect behavior. They can actually have what we call pleiotropic effects, meaning that they touch upon many different organ systems. And we know that many of the treatments that we use are also going to potentially touch upon not only brain, but several other organ systems.

So the way that I like to think about this with the families in the clinic is, one, let's make sure that we understand you completely as a person and not focus only on one single aspect of what's going on. Let's say if you have autism and you have a genetic condition that also increases risk for heart anomalies, let's make sure that we check out your heart and that's working okay before we start any given medication that could potentially affect how quickly your heart beats. Or if there's anything that has yet to be uncovered, let's use this opportunity to figure out what other organ systems could be affected.

Now, the second thing is that we're getting to the point where genetic conditions are associated with very unique developmental profiles. So we know by seeing kiddos and adults on the spectrum, that once you've seen one person on the spectrum, you've seen one person, meaning that they are going to be very different. That is reflected also among their genetic causes. So that 30% is actually composed of hundreds, if not thousands, of individually rare genetic changes that may affect different organ systems in different ways. And that may affect behavior and their mental health presentation in different ways.

So one good example could be that if you know that a kiddo that you're seeing in the clinic has, let's say, SHANK3 mutation. This is one of the classical genetic changes that has been associated with autism, but then you realize that profile is also underscored by some more challenges on expressive verbal language. And if you know that's going to be that neurobehavioral profile, then maybe you could prioritize other ways of communication that are not necessarily through spoken word. So just keeping in mind, not only what the deficits are, but also what the strengths could be, could potentially get you a better bang for your buck. And this is not even going into the huge network of supports that was previously invisible for families that now is a real possibility since the world is a pretty large place and they can connect with other families with similar genetic conditions or how they can make informed decisions about their family outcome, who else is at risk, are the risks going to be higher or lower, which is something that people don't think about for a future pregnancy or for a future family member that may not necessarily be immediately related to that close circle. So there are a lot of nuances and there's a lot of information that in my view is actionable now that can come from those genetic testing results.

Dr. Greg Fritz: So you're saying knowledge is power for these families and that knowing their genetic background and so forth is helpful in broader ways than just a medication choice or something like that.

Dr. Daniel Moreno-DeLuca: Absolutely. I like to think of genetics as one of the additional things we do for clinical care for our patients. It has very unique implications that we can potentially talk more about in the sense that it feels very personal and it's a little bit more nuanced in the way that we have to care for that information from a privacy perspective. But it's the same thing that we would think of when doing a workup for any medical or mental health condition, where if you identify something, let's say, low vitamin D, then you treat that and that can improve. Although the link may not necessarily be as direct with several of these genetic conditions, it's not exceptional. Like I hear often about this genetic exceptionalism that it's something that it feels very far removed from reality. And the truth is that there are actionable clinical interventions that we can do now based on that information for the families we're seeing today in our clinics.

Dr. Anne Walters: So how about the field of developmental disabilities? And treatments in the field certainly have changed a lot over the last five or 10 years. And what are your thoughts about the contribution that genetic testing has had on changes and/or availability of treatments?

Dr. Daniel Moreno-DeLuca: That is a good question. I'm an optimist and I wish we were a little bit closer to a striking change in regards to novel treatments that are genetically informed. Like my dream would be that we would have compounds either medications or behavioral therapies that would tailor these specific profiles more precisely to help the kiddos.

So I think there's two levels to that question. One, I think it can affect treatment now by using the information we just discussed. If the kid in the clinic has a cardiac anomaly, then be pretty sure about that before starting an alpha agonist for hypertension, like with some of the medications that we use or a medication that is going to make the heartbeat a little bit more slowly. So that is a direct effect that's going to happen now.

Now, in the future, I'd love to see more of the examples of behavioral therapies that are taking into account the unique neurobehavioral profile of people with these individually rare genetic conditions. And I would also like to see some medication interventions that tailor these underlying biology a little bit more precisely. So we are actually doing a study right now on families who have a little piece of their chromosome 15 missing at 15q13.3. It turns out that genomic region includes only a couple of genes. So genes are akin to the words in our book of life. And these families have one less of those words. And that specific gene encodes for a receptor for a neurotransmitter called acetylcholine. So we know that our brain communicates in very special ways by using these neurotransmitters, these substances to transmit a message between one neuron and the next. And we know that these families have one less recipient of that message. So then very crudely, we hypothesize that we could increase the loudness of that message to see if the following neuron could hear it a little bit better. And there are medications that allow us to increase that loudness in a way. So we have been using galantamine, which inhibits the breakdown of acetylcholine. So it just keeps the volume up there and that it helps fine tune how the message is going to be received by the next neuron. So all of these biologically informed use of a medication that's out there readily available has been tested and proven to be safe in kids, adults, even though it was originally intended for people with cognitive decline and dementia. We could be considering a repurposing of one of those medications now based on those generic changes.

Now, ideally, we would follow this up with a clinical trial and that is our aim. But these are ways of thinking about affecting treatment with readily available resources. And that's even without getting into the more cutting edge technologies like CRISPR or gene therapy that are very big topics on their own.

Dr. Greg Fritz: So, it's true that the genetics has become sort of mainstream. It's almost part of the pop culture as well as the medical culture. And there's that home genetic test. I know somebody few months ago gave me an Ancestry.com test for my birthday. And all that stuff is gaining popularity. People seem to be fascinated to know either their origins or if they have a long lost sibling somewhere, but it's in the water, so to speak. But do you see any negative aspects to this, any problems associated with it, or are there any harms that you've seen people experience or cautions you have?

Dr. Daniel Moreno-DeLuca: So I really like this question because it allows us to drive a couple of points home. And you're right, that right now, genetics is in the forefront of people's minds and like the latest TV shows are all covering some version of genetics. And my argument has been that genetics is not one thing, and genetic testing is not one thing, but it's actually quite a few different things put together under the same bag.

I would like to let us know, open the bag and see what types of things we're putting in there. So one of them is the one you mentioned, Greg, which is ancestry testing. That one tests for common genetic variants. We all have a different version of that. It could influence how tall we are or our eye color or things like that. And it can also be used to see back in the day where someone's potential genetic origins were from, with an asterisk that there are going to be some caveats to that. And that is the one that you can get in your favorite supermarket as an off-shelf genetic test. Now, because it looks for common genetic changes, it is not going to be identifying the rare clinical-grade genetic changes that we talked about just a little while ago. So these tests, for the most part, don't have what we call a clear certification, which is a clinical certification, and they cannot deliver clinically meaningful results except in very limited circumstances.

So for example, some of the companies that I won't name started offering some potential clinically actionable results. And that's where I see some of the harm. This conversation needs to be done in a way that families can ask those questions. They can understand the nuances of the results, know what to expect and be well-connected with resources once they get the result. And in my view, that hadn't been happening. It's improving in some of these direct-to-consumer testing, but it is the norm and it is the expectation with a very high bar of clinical care and is much different in common genetic testing.

So one typical example could be if one of these tests is going to test for, let's say, the BRCA gene that increases risk for breast cancer. You take the test and you see that nothing came up, so then families can think, "Well, I'm of the hook. Even if I have a strong family history of breast cancer, I took this test and I'm totally done." What they don't tell you is that, one, it's not a clinical test. And, two, they look for one change and not necessarily the hundreds of different changes that can explain that. So that's why genetic counseling is so important so that people understand all of those nuances.

On the other part of the back, we have clinical genetic testing done for rare genetic causes. So instead of common, this is for rare causes and that's all that we've been talking about at the beginning of our podcast. This is a clinical-grade test that you can only get through your doctor that is going to give you all of this information. And it's usually administered as a part of a genetic counseling session. Then, we have other things like pharmacogenetic testing that supposedly are going to tell you how well a medication is going to work for you or how quickly or slowly you're going to metabolize it out of your system.

There is promise in that field, but I don't necessarily think that it is ready for prime time just yet. And then, there's epigenetics, which is not even looking at the genetic material. But looking at the alterations on top, that's the name epi, on top of that genetic material that can alter whether someone with a genetic change is going to express it or not, whether they're going to have symptoms or not.

So when you say genetic testing, all of that comes in the same bag for families. And those are some of the nuances. And for rare genetic testing, which is the one we do clinically, we didn't want to assume that we knew what the families thought about it. And we did a very large study that we're close to publishing where we went ahead and asked them, like, "What is your knowledge about all of these genetic concepts? What are your impressions on genetic testing? What are your attitudes? Would you recommend these? What are your concerns?" And it's been very interesting to do that study and see that the overwhelming majority of families are interested, have heard about it, may not necessarily have a very granular knowledge of all these fancy generic terms that we've been using, but they are driven to learn more and they want resources to make an empowered decision that they themselves can make once that's clear for them.

Dr. Anne Walters: So that sort of takes us right to thinking about our families and children that we work with here at Bradley. Do you have a set of criteria that you might use when thinking about who would benefit from that sort of testing? How do we best make that decision and who do we refer to you?

Dr. Daniel Moreno-DeLuca: So it's good to be clear, and it's a very simple process. Like if one of our patients, either a kiddo or an adult has a diagnosis of autism or a developmental disability, that triggers the professional recommendations by all of these professional societies of doing genetic testing. So it's not super complex or it doesn't get super fancy as an algorithm that you have to include whether there's intellectual disability along with autism or whether there are congenital malformations. No. If those diagnoses are met, that triggers the recommendation of offering, not doing, offering genetic testing to those families to have that conversation. And then, once you sort of know that this is a road that you want to pursue with those families, you can send them our way.

We have several services that we've developed here from Bradley that are very unique, I would venture to say not only in the country, but even in the world, where we have a genetic counseling service that's entirely housed within a child psychiatry hospital with our genetic counselor, Molly Goldman. And we also developed a genomic psychiatry consultation service, so that when we get an abnormal result, we can do all of the things we were just talking about. Like we can put our heads together with the primary clinician team and think what parts of the algorithm that we need to modify, taking into account this rare generic result. And we created that as a consultation service so that we can benefit the broadest amount of kiddos and adults without necessarily being clogged up with longitudinal care, which we know happens unfortunately often when longitudinal services are put in place. So that's how we would go about it.

Dr. Anne Walters: That makes a lot of sense.

Dr. Greg Fritz: So once you do that and that family has agreed and undergone the testing and you've interpreted that to them, not you by yourself, but what are the next steps? How can treatment vary once you have these results?

Dr. Daniel Moreno-DeLuca: So we can start putting in place several of the strategies we talked about a little bit earlier, so maybe it's easier if we just pick one of the examples, knowing that it's going to be very individual with different generic changes. But let's say that we have a kiddo who we tested because they had autism, a six-year-old boy. And then, we found that they had a 22q11 deletion. Low and behold, we know a lot about 22q11 deletions. It's actually the deletion that causes DiGeorge syndrome, and we know that it causes several behavioral and mental health comorbidities or symptoms. And it also causes some heart problems, going back to that. And it has a unique profile of things that we need to be mindful of. So it turns out that this deletion is one of the highest, if not the highest genetic risk factor for psychosis.

So if we keep that in mind, if we start seeing that this kiddo, when he turns 12 or so, starts reporting some things that we may more quickly interpret as developmentally appropriate, I don't know, fantasies or things like that. This is a kiddo where we need to be a little bit more mindful that they could be heading the route of psychosis to start putting in place the evidence-based interventions that can prevent that. This is a kiddo for whom we need to make extra sure that they don't have the heart problems or any of the other medical problems that are seen with 22q11 deletions, that we keep their calcium at a good level, because that's one of the problems of people with DiGeorge syndrome or knowing that they are going to have frequent infections. And if we're treating them with a medication for which the values are going to change based on whether you are dehydrated or not, then those are also things to keep in mind in there too, or even thinking about trying to put in place strategies to prevent transition to psychosis in ultra-high risk individuals.

So I feel that every month we have something that either supports or contradicts one of these strategies. And I'm thinking specifically about omega-3 fatty acids in that patient population. And there's been some studies done in specific cases of rare genetic conditions that have been showing promise to prevent transition to psychosis, which again, if your intervention from a genetic test is that you're using fish oil to help a family, it sounds pretty benign and sounds like you could have a strong impact even without getting as fancy as gene therapy or CRISPR. Now, the important thing is to go back and see if that's currently supported by the literature and keep updated. And that's why we offer these services precisely.

Dr. Greg Fritz: In a big autism clinic, what percentage of the kids would have this particular syndrome? I mean, ballpark, not...

Dr. Daniel Moreno-DeLuca: Very tiny. So I can say that we have two kiddos with that deletion and two kiddos with the duplication, so they're opposing genetic change of that region.

Dr. Greg Fritz: I mean, 1% to 2% tops.

Dr. Daniel Moreno-DeLuca: But I would like to add that probably 70% of my clinic has an identifiable genetic change that explains their autism or their developmental challenges, again, because it's enriched by design. That's what we're looking for and that's how we're building our clinic. So we need to keep abreast of the literature in quite a few different conditions.

Dr. Greg Fritz: Yes. And that was what I was going to get at. I mean, autism is sort of the final common pathway manifestation that many different genetic presentations can contribute to, right? And so, you're going to have a clinic with a lot of children with rare syndromes once you can identify many, many of them, but it's not like one genetic picture is going to explain half of autism or something? That's never to happen.

Dr. Daniel Moreno-DeLuca: No. The most frequent rare genetic cause of autism explains maybe 1% to 2% of the cases and that could be fragile X syndrome or a 15q13 duplication. And that's just being generous with that frequency. So it's actually a lumping of many rare general conditions that converge on a diagnosis of autism.

Dr. Anne Walters: And I think what I'm taking away from this in terms of working with a population of children day to day that we may recognize later in life have a diagnosis of autism. So maybe they're 10 or 11 or 12, and they're kids that have functioned, you know, effectively and well in school for the most part, but who have really struggled socially. Sometimes parents will ask, "Well, now that we have this diagnosis, we don't know that there would be a benefit to knowing more about genetics." And so for me, it's really helpful to think about being able to say, "Well, it's possible. You know, it's up to 30% of children that have some identifiable genetic causes and also will influence treatment so importantly in a variety of ways," whether it's physiological, as you mentioned, with some of the conversation about heart conditions or other sorts of things that would be super important to know about for a parent.

Dr. Daniel Moreno-DeLuca: Absolutely. And I think that's a great point to take home, which is that we will never diagnose autism with a genetic test. It's just a different entry point. So autism is a clinical diagnosis and genetic testing is indicated once a diagnosis has already been made. And I think it's important to see why people may or may not want to pursue genetic testing after receiving a diagnosis of autism, because I think there's a lot of embedded misconceptions in there and my goal is that families can make their better informed decision, their most well-informed decision. My goal is not for all families to have testing, it's for all families to know that testing is indicated and to see if that applies well to their case. So for some families, it could be maybe guilt, that's driving some of that avoidance. Like what if that's something that I did? What if it's my fault? Because I passed something onto my kids, and we are very quick to dispel all of that guilt. There's nothing that you either did or did not do that changed your genes pretty much.

Dr. Anne Walters: And going back to what you said in the beginning of inherited versus genetic. I think the inherited is often a frightening thing for families, you know? So who was that in the family that led this to happen?

Dr. Daniel Moreno-DeLuca: Absolutely. Or we hear the opposite. We hear, "Well, no one in my family has autism. So then, it's not genetic." And we tell them, "Well, actually, the vast majority of rare genetic changes that are causative for autism happen spontaneously in the kiddo," which we call de novo, meaning that those changes are absent from the parents and just happened while the baby is being formed there like at the very early stages. So dispelling a lot of those potential misunderstandings can be quite helpful.

Dr. Anne Walters: And you mentioned CRISPR a couple times. That's not familiar to me. So could you say a little bit about that?

Dr. Daniel Moreno-DeLuca: Sure. So CRISPR is this really cool technology that actually won the Novel Prize fairly recently because it's like a surgical level of precision to edit the genome. Now, again, I would potentially just draw a line of everything that we've been talking up to now and say that this is nowhere near clinical application for psychiatry yet. And it opens up a lot of debates of when and what sense it could be reaching clinical care. But what this says is that you can go into the genome and correct any given genetic change, and sort of change that genetic condition back to its original state.

And again, as you may have sensed, I'm choosing my words carefully because there's a lot that goes behind these genetic conditions as well. So yeah, it's a very cool system that was derived from other organisms that allows us an incredible precision to fine tune and cut and insert or remove parts of the DNA.

Dr. Greg Fritz: I just want to underline taking a very methodical, conservative, cautious position as opposed to a salesman's position. And that's the appropriate approach for everybody to take, don't you think, at this stage of development? I mean, it's hugely important and it's changing very rapidly, but it's complicated and it takes a lot of research to turn it into something that is routine clinical.

Dr. Daniel Moreno-DeLuca: Absolutely. And I'll go ahead and say something that I've been thinking from the get-go, I think it's helpful to clarify that and it is that I don't think autism needs fixing. I want our patients with autism to live their best, absolute life that they can and to build on their strengths and to help supplement some of their challenges. But that's why I've been choosing my words so carefully with the CRISPR technology, because I don't think that the solution is to do away with these conditions, but to actually allow each individual to be the best version of themselves that they can be, and supporting them in that role. So I'm very mindful of like what you said, Greg, of being a little bit more conservative in that stance and just working with the community, with the autism community, along to support them in a way that enhances as much as we can their lived experience.

Dr. Anne Walters: Versus some of the more degenerative sorts of genetic conditions that obviously people would not want children to have to go through and experience, that it's a very different situation with autism. So, great to make that distinction, I think.

Dr. Greg Fritz: So tell us when is your next single going to be released?

Dr. Daniel Moreno-DeLuca: I don't know yet. I need a little bit of downtime to record the next one.

Dr. Greg Fritz: Good, good. Well, we're thrilled that you could be with us today. And if you folks listening found this podcast helpful, please share it on your social channels and check out our entire podcast library at bradleyhospital.org/podcast for topics of interest to you.

This is Mindcast: Healthy Mind, Healthy Child, a podcast from the experts at Bradley Hospital. I'm Dr. Gregory Fritz with my colleague, Dr. Anne Walters. And we both thank you for listening.