Abstract
Autism spectrum disorder in children is a group of neurodevelopmental disorders characterized by difficulties with social communication and behavior. Growing scientific evidence in addition to clinical practice has led the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) to categorize several disorders into the broader category of autism spectrum disorder. As more is learned about how autism spectrum disorder manifests, progress has been made toward better clinical management including earlier diagnosis, care, and when specific interventions are required. The 2014 Neurobiology of Disease in Children symposium, held in conjunction with the 43rd annual meeting of the Child Neurology Society, aimed to (1) describe the clinical concerns involving diagnosis and treatment, (2) review the current status of understanding in the pathogenesis of autism spectrum disorder, (3) discuss clinical management and therapies for autism spectrum disorder, and (4) define future directions of research. The article summarizes the presentations and includes an edited transcript of question-and-answer sessions.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1887-1920 |
| Number of pages | 34 |
| Journal | Journal of child neurology |
| Volume | 30 |
| Issue number | 14 |
| DOIs | |
| State | Published - Dec 1 2015 |
Keywords
- autism
- developmental delay
- language
- neurobiology
- social communication
ASJC Scopus subject areas
- Pediatrics, Perinatology, and Child Health
- Clinical Neurology
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In: Journal of child neurology, Vol. 30, No. 14, 01.12.2015, p. 1887-1920.
Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Recent Advances in Understanding and Managing Autism Spectrum Disorders
AU - Germain, Blair
AU - Eppinger, Melissa A.
AU - Mostofsky, Stewart H.
AU - Dicicco-Bloom, Emanuel
AU - Maria, Bernard L.
N1 - Funding Information: DR HIRTZ: So now I would like to introduce the panel that we have here. We have a wonderful, illustrious panel to end the day of people with various expertise and each one is going to talk just for a few minutes, and then entertain discussion and questions. So just to introduce, this is Bob Schultz in the far end from University of Pennsylvania. Nancy Minshew from University of Pittsburgh. Marshalyn Yeargin-Allsopp, who actually is from the CDC. It is Atlanta, but not Emory. It is the CDC. And the next is Omar Khwaja. Did I say it right? Okay. Who is from Roche Pharmaceutical Research. Mike Johnston from Hopkins. And Ashura Buckley who is from NIH, both NIMH and NINDS. I think we’ll start maybe with Ashura and go that way. And we’ll have just a few minutes of what future directions she thinks are important. DR ASHURA BUCKLEY: Good afternoon. Can everybody hear me okay? Okay. So I’m just going to take a couple of minutes to highlight take-home future directions for research; highlight some of the current NIH efforts that’ll help us get there; and just briefly outline a new approach that Sarah Spence alluded to at the end of her first talk. So just very quickly, I think the models to identify and correct neural dysfunction are right up there as the most important things that we need to be looking at, and to include people with intellectual disability in those trials. We need to put newly identified ASD genes in context with what we already know about molecular pathways and brain circuitry, and we heard some great talks today really focusing on those. And we need to continue to explore—I know Deb said it and we’ve talked about it today. I’m just going to underline it again. The co-occurring conditions that we see in ASD. So for those of you who are clinicians, this is really what’s bringing patients into your office. Whether it’s seizures, it’s the monogenetic disorder that comes with other things. And something we didn’t talk about today, the incredible prevalence of sleep abnormalities in this population, whether it’s sleep-wake transitions, the rhythms that are off. There has been some work in melatonin abnormalities, things like that that will help us walk backward to where these abnormalities in the disorder might be coming from. Just to switch gears very quickly, current NIH efforts. The NIH is, obviously, very involved and very interested in ASD and helping us get to some solutions. We heard from Dr Chugani who is NINDS funded and we’ll be analyzing her PET studies with buspirone looking at some of the very early biomarkers in serotonin, and that was great. We’re looking forward to that. I’d like to mention the Norway Autism Birth Cohort Study funded by the NINDS and Norway, obviously. Very large case-control study integrating prospective health data—integrating that with the broad-based profiling of immune molecules, analysis of infection, fever, medication use, genetics, really looking at genetic and environmental interaction in ASD. It’s a great study; longitudinal. Looking forward to that. We heard from Dr Sahin and Dr Buxbaum who are recent recipients of NINDS, NIMH, and NCATS funding for the rare diseases clinical research network developmental synaptopathies associated with TSC, PTEN, and Shank3 mutations. And one last thing. Just very recently, last week, actually, the biomarker consortium RFA was just announced, and this is actually very exciting. It’s a multisite trial really intended to establish standards for ASD biomarkers. What’s really important here is that we all use the same language when we’re talking about ASD. This is an effort to do that. So it’ll standardize both the collection and the analysis of data. It’s supposed to qualify biomarkers for specific application in clinical trials, diagnostics, therapeutics. So the general areas that we’re going to be looking at are focused on eye tracking and electrophysiologic paradigms. It’s supposed to make results broadly available to the scientific community, and this is also really important. The data that’s collected will be deposited in NDAR, which is the National Database for Autism Research, as well as NIMH’s repository for genomics research database. And that should help us really further our research and all get on the same page about what we’re talking about and what populations of autism we’re talking about. And, last, I just want to mention the research domain criteria or RDOC. If any of you have heard of that, that is spearheaded by Dr Tom Insel who is the head of NIMH. It started in 2009. And it’s a work in progress. But really—and Sarah talked about this a little bit when she put Isabelle Rapin’s recent paper. Really, it’s a project to redefine the research agenda for behaviorally defined disorders. So it should be complementary to DSM-5 and not replace it. But the major goal is to accelerate the pace of new discoveries by fostering research that translates findings from basic science into new treatments, addressing fundamental mechanisms across diagnostic categories. So sort of getting away from just the behavioral self-reports diagnosis and really looking at the mechanism, the abnormality across very many diagnoses. So you would be looking at maybe patients who had anxiety who also had a diagnosis of ASD and schizophrenia, or someone who had anxiety because they had OCD, and what does that look like; are those the same or different constructs in behaviorally based syndromes. So I invite you to actually look at the NIMH Web site and RDOC and you can just Google that and it’ll go through the matrices with you and what that approach looks like. I think it’s sort of a formalization of what a lot of the researchers have been talking about already today. Just sort of a different conceptual approach that may help us walk these back and, hopefully, come up with some new categories that will be generated from this basic research. That’s it. DR MICHAEL JOHNSTON: I really liked this symposium and I’d like to hear it again tomorrow, so I hope to watch all the recordings. I thought it was terrific. There wasn’t a dull moment. I came away with 3 clinical pearls. The first was that someone in the audience asked how does ABA therapy work. After listening to the speakers today, I think it works through synapses. The synapses are inefficient, they’re aberrant, they’re distorted and this therapy somehow shapes the synapses and maybe you have to turn up the volume and give it over and over again, but somehow I think that’s probably where the ABA therapy works. You’re giving sustenance to synapses that are having a hard time on their own creating memories and networks. The second thing that I found most interesting was the work on mTOR and mTOR being increased in tuberous sclerosis brain. And I have some interest in that myself. I think someone asked about whether this had been found in brains of children with autism. I read before I came here a paper by Tang in Neuron , September 2014. It’s a great paper. And, basically, they used postmortem brain of individuals with autism and say that they did find increased elevation of mTOR enzyme. And they linked this to the increased size of dendritic spines through a process called macroautophagy and a disruption. I found this so interesting because we all know that the brains of children with autism are bigger when they’re younger and that’s a characteristic that’s been documented. This paper would suggest that that’s because of increased mTOR, and this mTOR reduces the amount of autophagy that’s reducing synapses and makes them too big. So this could link the mTOR with the size of the brain and the synapses. I think that it’s a beautiful paper. I would urge you to read it. It really ties together what we’ve been talking. Especially the link between autism and—idiopathic autism and tuberous sclerosis. Tuberous sclerosis may be a model for autism. Finally—oh, and I wanted to mention in addition to the mTOR that Tanjala Gipson, who is a young investigator, pediatric neurologist at Kennedy Krieger at Hopkins, and has an … award, presented award yesterday is studying patients with tuberous sclerosis that function at a lower level and have self-injurious behavior. These patients can have very severe seizures and self-injurious behavior, and she has preliminary data that mTOR inhibitors can reduce that behavior and can reduce seizures. I think that’s worthy that there may be some hope that patients, even the lower-level patients, may benefit by this therapy in the future. And, finally, Rett syndrome, I loved David Katz’s talk. Every time I hear him I love it because he talks about excitation; glutamate. That’s a subject that I love. And he says that the problem in Rett syndrome is either too little inhibition or too much glutamate. We think so, too. The Rett syndrome brain, both in humans and in mice, has too much glutamate. So not only are the receptors increased, but there’s too much glutamate. They have about 50 to 100% more glutamate than they should, which is bizarre. You would think the receptors would go down. The reason I mention this also is that SakkuBai Naidu, who has done research in Rett syndrome for years has an FDA RO1 grant to study dextromethorphan, a very simple, over-the-counter inhibitor of the NMDA receptor, and she has 30 subjects that she studied. What she’s studying is the ability of the dextromethorphan to enhance the performance. Preliminary work suggests that indeed dextromethorphan does help performance. She has 30 subjects. She needs 30 more. If any of you know of subjects, I would make that appeal to contact Sakku. I thought it was a terrific symposium and I’m going to be dreaming about it. DR OMAR KHWAJA: Thanks. So, certainly, too, I want to echo that. I want to thank the organizers and congratulate them. I think it’s been a really fantastic survey of where autism research is. So I guess for me the highlights, what I’d like to do is sort of pick 2 things that I saw. One I saw and the second I heard today. The first one where I think really is where the future lies is in a slide that Mustafa Sahin presented where he showed that at one end we have the genetic pathologies that I think Jonathan Sebat and others very elegantly alluded to. These converging genetic pathways and mechanisms that relate at least to part of the etiology of autism. And at the other hand, this simplification of the behavioral criteria that are necessary to diagnose autism that Sarah Spence presented and others have talked about. But I think the sweet spot, if you like, for the future of developmental autism therapies, at least in the near and medium term are that point in between. In other words, not necessarily single treatments for single genetic disorders and not necessarily behavioral treatments for a constellation of behavioral complaints. But, essentially, this middle area that I would talk about as perhaps circuitry. I think that Dr Buckley very wisely—I think this has been a great initiative of the NIH to introduce the research domain criteria, and I would think that this is something that we as child neurologists should certainly start to look at and try to look at disorders that we encounter, not just autism, but other developmental disorders through the lens of. The other thing was that Joe Buxbaum said it’s a great time to be a child neurologist, and I think that’s certainly true. I think we are at this—a number of people have used the term—revolution. I think we’re at this really incredible point where we’re child neurologist with a grounding in neurobiology and neuroanatomy, but also an understanding of the developmental tempo of what’s happening in the brain. I think we’re really ideally placed to try and make the next push in the treatment of the disorders. So want to spend 1 minute just expanding a bit on that. Just to level set a bit, though. I look at things now through the lens of industry and biotech and knowing that neuroscience products they take essentially—for 1 new molecular entity to launch is an investment of somewhere now north of So want to spend 1 minute just expanding a bit on that. Just to level set a bit, though. I look at things now through the lens of industry and biotech and knowing that neuroscience products they take essentially—for 1 new molecular entity to launch is an investment of somewhere now north of $1.8 billion for 1 molecule. And the likelihood of success, the probably of launch is around 6%. In pediatric neurological disorders, much lower than that, and, essentially, it’s incalculable because there really haven’t been any. I think that we’re often looking at medications which are being repurposed. .8 billion for 1 molecule. And the likelihood of success, the probably of launch is around 6%. In pediatric neurological disorders, much lower than that, and, essentially, it’s incalculable because there really haven’t been any. I think that we’re often looking at medications which are being repurposed. We heard about the epidemiology this morning. I mean, this is a prevalent disorder with an incidence for reasons we don’t fully understand that’s increasing. Probably more common than schizophrenia, at least 1.5 to 2 times more common than schizophrenia. If you look at the industry pipeline for new molecular entities for autism, it’s vanishingly small. If you look at it for schizophrenia, it’s dramatically larger. We have to ask about why. I think where can we go, really, with this? I think what I’ve heard today where I would say that we could best put our resources as a community would be to try and understand these domains of behavior that relate to social impairment and repetitive behaviors. In other words, these, I think, are highly targetable. I think they’re tractable from a drug development standpoint. And the presentations by Tim Roberts, by David Katz, for example, I think one of the things that we really urgently need to look at is to try to understand the excitation imbalanced circuitry in the brain, because these are ideally targetable by compounds that are already available, at least in screening libraries or in already-existent, safe compounds. So those that modulate GABAergic and glutamatergic systems. The other that we haven’t heard about today, but I think is important, are the social neuropeptides, so vasopressin and the oxytocin system. I think in the near term these are highly targetable. I think one of the other things that the NIH has done, which is a great beginning, is the development of Fast-Fail Trials using biomarkers such as electrophysiology, which can be easily applied to children. So there is a challenge for us, I think, from a drug development standpoint. In industry, this is something which is high risk and that’s why not many people are going into it. But I think what this is really a peak time for us to seize the initiative and go forward. I think that this sweet spot between behavior and between genetic pathology is really, from my standpoint, where the highest likelihood of progress is to be made in the coming 2 to 5 years. DR MARSHALYN YEARGIN ALLSOPP: As Deborah said, I’m at the Centers for Disease Control and Prevention. I’m a medical epidemiologist. Our discipline is epidemiology and we use that within a public health framework. I feel that we are doing a number of studies and activities now that allow us to be well poised to contribute to some of these really important questions about autism. I’m just going to point a few of them right now. The first is in the presentation about DSM-5 . As Craig Newschaffer explained how we collect data on children to determine the prevalence of ASD in 8-year-olds in the United States, known as the ADDM Network, we are now going to be able to continue to collect data in such a way that we will be able to look at the prevalence of ASD in children diagnosed or at least, for our surveillance purposes, determined to be cases under DSM-5 and DSM-IV criteria. So we will be able to tell you what the difference is. We’ve already done a preliminary study that has shown that the prevalence was about 20% lower. That was using the methods that we have established now and, of course, DSM-5 was not in the field, and so we don’t know how this is going to play out from the standpoint of clinical practice. But as that occurs with our next study year we will be able to report both. So stay tuned for that. We’re looking forward to being able to inform this conversation about what happens when DSM-5 criteria are applied at a community level compared to DSM-IV . The second area that I wanted to highlight was from Craig’s presentation where, of course, everyone is continuing to ask the question why is the prevalence of autism increasing. And it is the ADDM Network from CDC that has reported, as Craig said, 5 surveillance years and our most recent report in March of this year was the 1 in 68 children. Why? We don’t really know. But we do know that there’s a lot of geographic variability. We also know that this group of children who do not have intellectual disability seems to be a growing group and seems to be contributing more to the increased prevalence than previously. One of the questions that we are trying to answer, of course, is whether there is an increase in risk factors that are associated with ASD. Not just the recognition, increased recognition, but is there an increase due to an increase in risk factors. Some of the scientists at CDC, I was included, did a literature search and came up with a number of perinatal factors that from the literature are important or have been associated with an increased prevalence of autism, and we selected 3. One was being small for gestational age, being low birth weight, and having had a C-section. And when we looked at these factors, we found that all 3 of these factors, one or more of these, only contributed about 12 to 13% of the overall prevalence of ASD. So we do feel that there are multiple factors that contribute small amounts and that there’s no one big factor that is responsible for this huge increase, although, we are continuing to study that. We have a case control study that we’re doing on young children. It’s called the Study to Explore Early Development. In addition to a range of medical information from records, questionnaires of the parents, clinical examinations of their children, we are also collecting biospecimens. And as we begin to analyze those data, we hope that we will be able to answer some of the questions related to what are risk factors and potential causes of autism. I was also interested in Lonnie’s presentation where he pointed out that the median age of diagnosis of ASD has not changed. From our ADDM data, the first report was in 2002, it still remains at about 4.5. We have a program at CDC called Learn the Signs Early, in addition to the work with the American Academy of Pediatrics, and many of the work that you and others are doing to identify children earlier. We haven’t really moved that needle very much over time. What we found that there are more children being diagnosed at every age, but, again, the median age has not changed, and we know that there are disparities, racial and ethnic disparities in terms of recognition of autism. So we are still doing a lot of work in that area and there’s a lot more to be done. The last area that I wanted to emphasize is this overlap between autism and epilepsy. This is an area that we’re very interested in. We’re not doing a lot in this area now. We are looking at the co-occurrence of epilepsy with cerebral palsy and we do surveillance for cerebral palsy as a primary disability in children with autism as well. But we are starting to look at this and to see if we can incorporate more about the co-occurrence of epilepsy in the children that we have identified with autism. Overall, we have a lot of cohorts now. We have cohorts that we have identified from our surveillance beginning in the year 2000. We also have cohorts of children from our case control study. So I think it’s going to be important for us to use the cohorts that we have already assembled, whether it’s longitudinal studies or other special studies, to try to answer some of these really important questions related to autism. DR NANCY MINSHEW: Thank you. I’m Nancy Minshew from the University of Pittsburgh. It’s getting late, so I only want to make a few comments. I’ll try to be a little briefer. Just to be provocative, I think we could say the prevalence ranges from 1.5 to 3%. The 3% being if you take the Korean study seriously. And then as Marshalyn just said, a lot of the increase has been in the improved recognition of those individuals with ASD who have intact formal language and average or above IQ scores. There is a wide variability, as you know, in expression. If you’re the practicing neurologist and you have children come in—and remember they can be adults. There’s a lot of adults out there now. Are you comfortable recognizing autism across the spectrum? If you’re not, you have to see a lot of kids to get really comfortable with the full spectrum, and that may not be something that’s achievable in your particular setting, but you could at least watch the movie about Temple Grandin. John Robison who’s as smart or smarter than, has written some books that are just hilarious. You can take a walk in a couple hours you’ve listened to them. His last book was Raising Cubby . Fascinating. Makes me laugh out loud. He’s writing a book called Switched On about the impact of RTMS on his capacity to recognize face emotion, which is really interesting and provocative in terms of the potential for future treatments. So that’s that. With regard to the switch to DSM-5 , there was 1 large study and we did a smaller study, but covered the whole spectrum of age and IQ. Those who received a diagnosis of autism under DSM-IV also received a diagnosis under DSM-5 . We were about 93-plus%. And the few percent that didn’t make it on DSM-5 , we just didn’t have the right information in the records as we corrected them. But I think the gentleman that asked the question about how well are the community clinicians doing when they use these criteria to make a diagnosis how likely is that to be accurate. I think that’s really an excellent question and one that we do somehow need to look into, which suggests to me also the possibility that if clinicians had a questionnaire or 2 that’s kind of backup support that they’re on the right track that would be very helpful. I think generally, neurologists haven’t focused on the kinds of complex behavior issues that characterize autism. So we’re not as familiar with the intricacies of social interactions or pragmatic language, perhaps, although, Isabelle Rapin certainly educated us on that, or repetitive behavior or concreteness or whatnot. That was not our training. Most of us didn’t get any training on autism, and I’m not sure that’s changed very much, which is very unfortunate. You might try to see if your center would have at least 1 speaker a year who’s more clinically oriented to come in and help you to understand what are the current treatments, what are the ones that are available in your area; what are the target manifestations across the age and severity spectrum. Aside from that, I would say that neurologists, when you receive a referral you need a specific question. And the question, Does my child have autism or not, may not be the best question for them to be addressing to a neurologist. But there are questions that only neurologists can answer and they have to do with where in the brain does this live; and what might have caused it; and, by the way, my child is one of the extreme preemies and he had this periventricular stroke and now he had that right hemiparesis, but he also has autism, and did it all come from that right periventricular stroke. You can answer those questions, but nobody else they see can answer that. So questions about cause are ones that you can certainly address. I think with confidence you can address issues about vaccines. That may be also last year for a lot of people, but it’s not out in the community. There are still people afraid of that. But if you look at the neuropathology, and you look at the underconnectivity of the brain, and all of the genetics, you’re in a position to confidently say none of the evidence fits that. I think certainly the studies of infants identifying findings by 5 to 6 months and epidemiology implicating in utero is helpful, but I think families need to understand that there are things going on in the brain in the first year of life, and it’s not until you get to the second year when all that scaffolding for higher-order functions is coming online. That’s when you’re’ going to see the majority of the symptoms. We wouldn’t expect them to see in the first year, just like with dyslexia. We know that that’s highly familial, but do we expect to make that diagnosis in the first 2 or 3 years? No. If it shows up at 5 does that mean there was some event? So at any rate, you can do that. Now, I think what I’d like to know from the geneticists is we need to know which genetic test to order that will give families the latest information knowing that a year or 2 years from now there will be more information. I know Bernie Devlin at our site is not happy with the policy that’s been put up by the organization. So my challenge to the geneticists is you tell us what should be done and then the societies need to get behind it in order to advocate to insurance companies to insist that they do this. And then last, I would say that if we’re going to look for more brain donations, most of these kids live a normal life span and we’re going to have to turn to the adults, many of whom are very popular, Temple Grandin or, as I said, John Robison, and ask them to get behind this. The adults, when they do pass, many times their parents are already deceased and nobody is around who even knows that they have autism, let alone is in a position to advocate. So I think if we’re going to look for more donations we’re going to have to go at that level as well. DR ROBERT SCHULTZ: Hi. I’m Bob Schultz. I’m from the Children’s Hospital of Philadelphia. The privilege of going last, which means I get to be the shortest. Oh, I need to be closer according to Manny. I want to reiterate that I go to a lot of conferences and a lot of symposiums. This was really a terrific symposium. I want to really congratulate the organizers. I especially liked the emphasis on biomarkers and genetics. I was thrilled with Joe Buxbaum using the word that we have a revolution going on in our approach and thinking about treatment. So genetically informed treatment. I think I’ll use that in my next grant application. I also liked Sarah Spence’s explaining to me why we used a numeral 5 rather than a Roman numeral, so that we can get the extensions of point 1 and point 2. That was always puzzling to me. But as we think about treatments for autism and we think about these wonderful treatments that are being done in animal models, I just want to throw out a caveat that in animal model research we always have a common genetic background. In people with autism, we don’t have a common genetic background. So someone who has a Shank3 mutation is not going to be against the same background. And so the task as we move forward with these trials into clinical practice, let’s say in the near future, that would be optimistic, is that we have to treat individuals. And, ultimately, what we have to understand is how to make predictions at the individual level. I believe that it’s going to be quite a multivariant prediction problem. We may have signals for MEG; we may actually know what genes are involved but only some of them, because a lot of the variance is going to be due to common genetic variants, and I’m not sure how we’ll ever be able to kind of accurately or articulate what that common genetic variance is, but we may have biomarkers, we may have genetic markers. One of the things that seems to get short shrift and I’m a neuorimager, but I always like to proclaim this point, is actually behavioral markers. If we’re treating kids with autism we don’t really want to treat a biomarker because that’s not what brought the kid into the office. We want to treat the child’s behavior and the behavior that they or their family finds troubling. And there is another revolution going on, I think, in measuring behavior that I want you to be aware of. The people in the computer science community will call it the quantified self. So how do we actually get big data on individuals? We want to measure their movement throughout time. We want to measure and sample language continuously and there’s recording devices for this. We are deploying gaming systems in the home like the Connect video game, which can really accurately quantify movement in 3 dimensions. And we want to apply machine learning, big-data approaches to understanding the behavior of individuals with autism. This is in addition to the gold standard and in many cases can precede the gold standard kind of characterization because it may be done more cheaply because it can be done remotely. As many of you know, it’s very expensive to bring kids into the lab to do research. It costs between 5 and probably As many of you know, it’s very expensive to bring kids into the lab to do research. It costs between 5 and probably $10 000 per person once you add up all the costs associated with that. So the idea of reaching out into the family and into the community to start the measurement process ahead of time is probably a really cheap way to do research, and will allow us to get more quantified on the behavioral end. 0 000 per person once you add up all the costs associated with that. So the idea of reaching out into the family and into the community to start the measurement process ahead of time is probably a really cheap way to do research, and will allow us to get more quantified on the behavioral end. The other thing that’s a shame that I want you all to recognize is that even though the people who prescribe a big-data approach often say we’re going to use the electronic medical record. For autism that really doesn’t work that well because autism—hospital systems is not the medical home for kids with autism. So that, again, gets back to the point we have to find ways to reach families in their local environment to do these kinds of measurements. One of the most difficult things for clinical researchers, such as myself, is actually acquiring samples. We get a grant, we say we’re going to see 100 kids, and then we spend most of our time talking about how we’re going to increase recruitment. It would be nice if there were supports at local and national levels for research registries, and if we could get the word out to families about how important research is so that they could participate at higher levels. Finally, I think a lot about treatment and when we eventually get to the point where we have these wonderful treatments that target genetic mutations and biological pathways. It’s probably likely that these treatments are not going to be magic bullets; that they’re going to need to be done in combination because kids, at whatever age we give the treatment to, are going to be deprived of certain experience-dependent learning opportunities. So it’s probably going to be combing behavioral treatment with a medication. That medication will unlock a biological impediment to their profiting from experience the same way that typically developing kids do. So I think we need to think behavioral treatments that will be matched with different biological pathways now, because I, like Joe, I love this idea that it’s a revolution. I’m optimistic that in the near future we may be actually using these and we’ll have to be responsible about how we combine them with existing therapies. So I’ll stop there. DR MINSHEW: And I think I would add to that. One of the concerns is that we’ve had quite a few advances in interventions, but unless you live within an hour of the few sites where that was developed, you’re out of luck. So there’s a real obstacle in how do we disseminate the treatments that we do have that are effective and we need to really do that. There are more treatments in development designed to be combined with whether it’s a brain stimulation approach or guided pharmacologic approach, but we’re going to hit the same wall if we don’t figure out how to support dissemination of treatments that we’ve demonstrated do have efficacy. DR HIRTZ: I want to thank the panel very much. I think those were excellent comments. I would also like to open up the floor if anybody has any questions for the panel. Bernie, you start. DR MARIA: I would like you to address the pragmatics of evaluating a new child. So you have high clinical confidence that the child has autism. Say the child is 2 years of age. It’s a young family. They’re thinking perhaps of having other children and they have a lot of questions about genetics and also about what kind of additional diagnostic steps need to be taken. So we heard earlier that MEG, for example, is not ready for prime time, but I haven’t heard a clear answer about whether MRI is really standard of care. So I’d like that question to be answered. In the absence of any kind of seizure history, should EEG be included or not included; or video EEG be included or not included. I’d like to hear that. And then on the genetic testing, for counseling reasons are obviously good reasons to be getting that kind of data, but is there a case to be made to the families that if a specific mutation was identified that that wouldn’t just be useful from a counseling perspective with additional children, but it might also be predictive of how that child would do over time by virtue of families interacting around the world using the Internet, linking up based on what mutation they have. So if they have an SCN mutation, is that likely to be predictive of the clinical course? They ask about mental retardation, for example. That’s one of the things that drives their concern. Is that likely to be predictive or not? DR HIRTZ: Nancy, do you want to start? DR MINSHEW: Yes. I would say that routine imaging is not indicated. If there’s an argument, we’ll go ahead and argue that. But for the most part, we don’t expect to see some gross brain abnormality or anything treatable on these scans, and there’s been enough done to know that. So in the absence of some focal findings or something else going on, no on the MRI scan. I think the EEG is another where unless you have some good reason to think it’s an epileptic encephalopathy or strong clinical suspicion that there are seizures, then I wouldn’t do that either. And the same for the blood and urine amino acids unless there’s a specific suggestion that one of those syndromes is occurring, then I wouldn’t just send those out either. The only thing that I think is really valuable is the genetic studies. My question is I don’t think we do have the most sophisticated recommendation yet, and we don’t have the insurance companies reimbursing, but that would probably be the only thing. I think there will be growing value in parents knowing. I think first of all, there’s always a relief when parents can say it’s that, there is that right there. They do need this new understanding of what genetic means. It can be a de novo mutation. And many parents I see they’ll say oh, that comes from my side or oh, that comes from my side. So that’s what I would say. DR MARIA: Is there predictive validity to given mutations in terms of prognosis or not? DR MINSHEW: I think there’s some. I think we have to gather enough of them together to be able to consider the variation. I think if you look at the Simon’s experience with 16P11, they thought the genetic homogeneity would give them great phenotypical homogeneity and it didn’t, but that’s because it’s just too course at this point. DR HIRTZ: Thank you, Nancy. Number 3. DR AMY GOLDSTEIN: Hi. Amy Goldstein from Pittsburgh. Nancy, if last year’s concern was vaccines and autism, I would say this year’s concern that we’re seeing in our clinic is MTHFR in autism. There are a number of parents coming in where MTHFR testing has been done and the parents want to have explained to them how the methylation defect is causing autism. Could you please give us some guidance as to how to answer this question? DR MINSHEW: Parents know it before we do, don’t they? They know that that thought is out there that there be an alteration in methylation, especially during pregnancy that may result in the expression. I think we need others that know more than I do to speak up, but I think they’re too soon on that and they’re at risk of doing the wrong thing and making it worse would be my concern. But who knows— DR HIRTZ: [Interposing] Anyone else on the panel have any comments about that? No. No takers. DR MINSHEW: We must have a methylation person here, isn’t there? No? DR HIRTZ: All right. DR MINSHEW: Sorry, Amy. DR HIRTZ: Let’s go back to number one, please. Your next question. MALE VOICE: It’s regard to the prodromal symptoms and I’m interested in the predictive value of seeking out these patients with recurrences in families. Now, for some of the white-haired fellows over here, white-haired fellows, there was a German, Brazelton, who, in Boston, about 45 years ago did some visual preference studies or visual orientation studies in newborns. In fact, in the first 48 hours comparing normal newborns and those—I believe the other control was the anoxic encephalopathies. And then these 2 groups very, very definitively identified the preferences, the normal preferences shown by these normal kids. My question is, looking at recurrences, and we’re still a few years off with genetic studies, would there be any value in these visual boxes in looking at potential patients in the recurrent families? DR HIRTZ: Who would like to answer? Bob? DR MINSHEW: I think they’re doing that. DR SCHULTZ: We are, and Lonnie mentioned it this morning, so that’s the whole baby sibs kind of approach. You take a child that there’s already an index case and you have the opportunity from early in life to be able to observe the unfolding of potential autism. If the recurrence risk is 15%, you get a sample of 100 and you have 15 cases where you can watch it carefully and measure it carefully. So Ami Klin is doing it down in Emory where he’s using eye tracking every month for the first 6 months, and I think every 3 months after that. Our infant brain imaging study, which is headed by Joe Piven, but there’s 4 data collection sites is actually doing brain imaging at 3 to 6 months of age at the first time point, and repeating it 4 to 5 times up through age 24 months, and then following the kids behaviorally out to 48 months. I think there’s a huge value and it’ll tell you about multiplex autism. It might not tell you about simplex autism, which is only occurring in 1 family member. But huge value in understanding it because the retrospective bias that it’s ordinarily there by trying to figure out what happened from history. DR HIRTZ: Thank you. Number 3. MALE VOICE: I have a question for Omar. So the billion dollar price tag for developing a drug is an incredibly daunting prospect. I wonder is there ways around that? Did the Orphan Drug Act that the US passed in 1983—was intended to try to provide incentives to encourage the development of drugs for small populations. Are there strategies, such as the ones encouraged by that legislation that you can apply? DR KHWAJA: Yes. So there are incentives which have been made, particularly here in the US and similar ones in Europe. The Orphan Drug Act is one. The more recent revision of the FDASIA, the PDUFA V and the pediatric legislation here in the US, for example, also incentivizes drug development in terms of extending patent life and intellectual property protection for drug developers. And that certainly helps incentivize, but given the paucity of drugs in the pipeline at the moment it certainly hasn’t been enough to really incentivize it sufficiently. The biggest cause of failure—I mean, the biggest point of failure in drug development in neuroscience is in Phase II. So we have drugs which have some efficacy in animal models and I think there’s a whole discussion about what animal models potentially contribute in the drug development process in autism or, I guess, orders of higher hold or of human functioning, social functioning. And a lot of drugs make it through the safety barrier through the GLP Toxicology in Phase I type of studies. Where they really fail is in Phase II and that, I think, is where the initiative like EU-AIMS and others that Paul Wang talked about have the biggest role to play. In other words, how do we gate the drug development process so that we discontinue development of drugs which are unlikely to show benefit in larger expensive Phase III trials or how do we progress drugs so that we can build a sufficient evidence of efficacy to get them through that Phase II hurdle. I think that’s the approach that we and other companies are taking, which is to really build these experimental medicine studies, proof-of-mechanism and proof-of-concept studies, to essentially gate the Phase II process before taking very expensive investments in Phase III. I think it’s a combination of external regulatory incentives, advocacy, and patient groups demanding. I think a recognition of the economic costs, I mean, now the paper that came out in JAMA suggesting lifetime—societal costs per annum of suggesting lifetime—societal costs per annum of $127 billion that autism costs in the US; 60 billion to 90 billion in the U.K. These are really very large figures. 27 billion that autism costs in the US; 60 billion to 90 billion in the U.K. These are really very large figures. But for industry, I think it’s about addressing the risk of taking drugs into expensive Phase III trials is how do we actually increase the potential for success or discontinue development in Phase II early enough that we haven’t unnecessarily invested large amounts of money. MALE VOICE: It sounds to me, based on what you say, that we need more drugs in the pipeline at Phase I. DR KHWAJA: We do and that’s where the pipeline is really empty. There are a lot of discovery initiatives based on genetic pathologies, on synaptic pathologies, on potentially extrapolation from other mechanisms. But where there really is, particularly for pediatric drug development, there is a real paucity of drugs. Entry into GLP toxicology, entry into human, entry into Phase I, Entry into Phase II, there’s essentially nothing really at the moment, and it’s how do we fill that. And what is the process of filling it? It isn’t that there’s an absence of molecules to go into that pipeline, its’ an absence of evidence to actually progress them along that. This is where I think the role of biomarkers, particularly, has for understanding that a drug is going to be efficacious in the human brain that is penetrant to the brain. There was a discussion about the IGF1 studies in rats about understanding dosing. I think Manny talked about this idea of there being this old concept if a drug a dose-response relationship that’s essentially linear or geographic or whatever, but, essentially, it’s likely more U-shaped or some version of U-shaped, and how do we actually address dosing, how do we address dosing in the developing brain. I think these are all the issues that we struggle with in industry the most is how to actually progress molecules of which there are multiple, but how do we get them effectively through Phase I and Phase II. DR JOHNSTON: I’d like to point out one low-cost … that was reported in Proceedings in National Academy of Science last week. Andy Zimmerman and his colleagues from Hopkins and Mass General reported the use of broccoli sprouts as a cure for autism. It’s an interesting paper. The active compound has been purified and it’s got a strong effect, but I don’t know how far it’ll go. DR KHWAJA: Yeah, I mean, there’s an interesting… MALE VOICE: You’ll need to teach kids how to eat their broccoli. DR KHWAJA: I think mothers everywhere probably are going to be happy about it. I won’t comment on the efficacy of that particular compound. But I think what that paper very usefully does is give some important information, which is one of the big killers of autism trials is placebo effect and expectation and the bias and trying to understand that. I think that study actually very interestingly showed with the outcome that they chose as one of their primaries, the SRS, was actually the lower than anticipated placebo rate in that, and I think that’s very interesting compared to more traditional measures, such as the ABC. I think the other thing about it is that it is realistic to actually do these trials in children and that’s often been a big barrier is that actually doing studies in children with autism is difficult. There are parents that are willing to enroll their children into these studies as long as they’re safe, and that they’re well controlled, and that they’re well designed, and that they weed out early enough. The other thing I did want to say is that we also, with this revolution, in industry we’re looking a little bit now at a number of failures in Fragile X particularly, which is whether the GABA-B and the mGluR5 hypothesis has really failed. There have been now a large Phase II and Phase III failures in Fragile X. People are saying well, you guys came to us and said this is a clear mechanism, we have a nice animal model, we have safe compounds. You put it into your patient population and it doesn’t work, so why should we continue to invest in this company and in this idea that we can mechanistically address autism. And we also have to back translate now and really try and understand why those studies failed. Did they fail at the endpoint? Did they fail because they were the wrong populations; wrong duration of treatment; or was there something about the mechanistic hypothesis that was wrong as well? DR HIRTZ: Paul. DR PAUL ROSS: Paul Ross from Boston. First of all, Brussels sprouts taste a lot worse than a ketogenic diet. DR JOHNSTON: No. You got to be careful. It’s not Brussels sprouts. It’s broccoli sprouts. DR ROSS: That’s even worse. I really liked Dr Minshew’s answer to the question as to what you do about working up these patients. I see a lot of children with autism and most of the times I think no testing is indicated. But I think it depends on your examination. If a child, for example, has microcephaly and is 2 years old, you do want to get an MRI. There’s no point in getting amino acids if they’ve been checked in the newborn period. I think if a child undergoes a really impressive autistic regression, you have to think about the possibility of an epileptic encephalopathy and I’d get an EEG then. With regard to the genetic testing, the microarray most of the time shows abnormalities that are innocent and have nothing to do with the autism, and you’re really obliged then to get a microarray on both parents to see if this is a benign genetic aberrant. This costs a lot of money and many of the families can’t afford it. And if the family is older and don’t plan to have additional children, there’s no real compelling reason, as far as I’m concerned, to get genetic testing. So I think most of the time, a careful neurological examination will determine whether or not any additional testing needs to be done. DR HIRTZ: Thank you, Paul. Number 3. MALE VOICE: I think we have an excellent day of presentation. I wish and I understand the limitation of time. I wish there was room for brief presentation from the clinical point of view to help us out as far as what’s available for the intervention that all these parents come—hyperbaric oxygen therapy recently and NMDA or anything like that. So I really think it would have been a very helpful thing for us in clinical practice how to answer. You understand? They bring me an article about hyperbaric oxygen therapy or other therapies, how shall we respond? I think that would be very helpful. DR HIRTZ: I think you’re right. I think there just wasn’t time to fit everything in about autism. But, clearly, that’s something that would be very useful at the CNS meeting in some form. Maybe we can have a breakfast symposium or something like that. Mary. DR DECICCO-BLOOM: Number 2? Marshalyn, since I don’t do epidemiology, as you well know, and we think about environmental factors, many of which are ambient, whether it’s flame retardants, it used to be lead in the gasoline, it’s certainly pesticides. So I always use as a teaching model how lead levels in the environment, in the blood have an impact on IQ, and then we cleaned it up and all those things improved. And so environmental factors clearly can be detected by population studies. Can you, the CDC, are there mechanisms in place to ask a similar question about the flame retardants, the pesticides or do we no longer have these structures that allow us to do that kind of a study or am I thinking about it wrong? DR ALLSOPP: So Manny’s question pertains to what we can use to measure environmental exposures, if I understand you correctly. To be honest, I don’t think we’ve made much progress in that area. So all of the environmental studies that I’m aware of that look at autism are looking at very gross environmental measures. They’re looking at the HAPs System, which is by the Environmental Protection Agency, which may look at a geographic area and may show that there are elevated rates within a geographic area, but it doesn’t get to the level of the person. So with the National Children’s Study the original proposal was to really try to measure environmental toxins within individuals so that you would get more to the person level in understanding what the impact would be of an environmental exposure. But we really don’t have data and so there are suggestions. There are a couple of studies out there where they’ve looked at these—what we call ecological studies that are looking at measures of the environment overall and are showing some elevations, and then looking at, say, an outcome, such as autism, and trying to draw some correlation. But we still have a lot of work to do in that area and I think that, again, that there are still—it’s an area of interest, but I think that we really don’t have good measures yet that allow us to say whether specific environmental exposures are related to autism or other developmental outcomes for that matter. DR DECICCO-BLOOM: And I had a second I might—because of this—and it’s not for you. It’s for everybody. Families come to us as neurologists to be the advocates for the child. So now if you come in the door with autism and you leave with that diagnosis we are entitled and feel obligated and pleased to support a child with 25 hours a week or more of therapy because we’ve done this. But we all know that this has been societally driven, advocacy organization driven. Since the genetics and the environmental factors contribute to multiple disorders, I know you and I have had conversations of this offline, it is likely to be true that this will have the same consequences for intellectual disability. So we’ve been seeing twice as many of those children over the years and they would likely benefit from those 25 hours or more of directed. It would likely be true that if the families and society and the health care profession consider that those interventions are valuable and are deserved, and we’re the small community that actually kind of knows the secret. I was just wondering when and how and whose mission it is to say that; that we could have a tremendous impact in intellectual disability, which we kind of say oh, intellectual disability never going to get better, go home. But no, put them in the autism classroom. So I don’t know who wants to discuss that. DR ALLSOPP: Well, I’ll just start and I think that Manny knows that we’ve been studying developmental disabilities for more than 30 years, and have been studying intellectual disability, cerebral palsy, and sensory abnormalities, hearing loss, vision impairment. And we’ve only been looking at autism in the last 15 or so. So I think it’s extremely important that we not forget about the other disabilities and not that they’re comorbid with autism, but these are primary disabilities of great concern with serious consequences and prevalence, for example, of intellectual disability, which, historically, has been higher than with autism and now may be equal. So I do think that some of these interventions would be effective for children with other disabilities as well, and I continue to ask where’s the advocacy for the other disabilities that we see with autism. DR KHWAJA: Just to add to that, I fully agree. I think this has been a personal bugbear of mine for a long time is that children with other types of developmental disability, particularly intellectual disability have been … that I think children with autism were seen at once, which this is a static and there’s nothing you could do about it other than provide some type of schooling, etc. You look at prevalence overall of neurodevelopmental disabilities; that’s 13% of the population. When you take children with cerebral palsy and nonsyndromic intellectual disability into account it’s a magnitude greater than autism alone. I think one of the things that is moving, at least within, I would say in the pharmaceutical and biotech industry, is the understanding that autism and intellectual disability and schizophrenia and the intellectual disabilities associated, for example, in Down syndrome in cerebral palsy that these are half of biological and depending that’s addressable through medication together with behavioral therapy. So, for example, in our company we have a program in autism. We also have a program with a new molecular entity for intellectual disability in Down syndrome. I think there is a move in industry to expand beyond autism because commercially, obviously, it’s a bigger case, but I think Marshalyn is right. I think it’s who owns the advocacy for those children outside of autism, which I think has been extraordinarily successful in advocating for itself. But I think it’s that broader community of individuals with intellectual disability that still are neglected from just the day-to-day clinical care, intervention, schooling, additional therapy standpoint. DR HIRTZ: Bob, do you have a last word to add? DR SCHULTZ: Very briefly. What’s interesting is that you mentioned ABA and 25 hours a week of intensive treatment. If you look at the treatment trials, the outcome measure that changes is IQ. So you go back to Lovaas, it’s IQ. Go back to Early Start Denver, it’s IQ. So you might say well, it’s going to work in intellectual disability, but that’s actually a test to the specificity of the treatment as well. So even an autism researcher should be really interested in trying this in kids with developmental disabilities to understand this issue. DR HIRTZ: The last 2 questions. I think that Joe was up there first. MALE VOICE: Yeah, he was up there first. I was watching. You’re so polite, Joe. So I’m going to sort of make a point and a question that’s—since one of the organizers of this—I’ll sort of criticize my own organization. I think that this symposium was really exciting in that amongst other things it demonstrated the enormous potential for novel therapeutic approaches that leverage recognition of specific biological mechanisms that could be affecting subsets or in some ways, perhaps, as Dr Johnston pointed out with mTOR, perhaps the broader autism spectrum. I think what this symposium lacked and I want to sort of see—Dr Schultz started to—I have to stop myself from calling him Bob in these formal settings, but Dr Schultz sort of referred to some of this, but I think it would be good to get commentary from the panel about this about leveraging some of the findings from neuroimaging and other studies to really develop novel behavioral therapeutic approaches and other sort of more neural circuitry approaches potentially with TMS, TDCS, other kinds of brain stimulatory approaches that could possibly combine—of course, be combined with these medication pharmacologic approaches. Dr Schultz alluded to this. We are ourselves very interested in visual-motor disconnectivity in autism and its relation to autism. We are ourselves thinking about connect system models for therapeutic intervention leveraging—knowing and having identified these abnormalities in connectivity and wanting to use that and potentially brain stimulatory approaches. So I would be curious if the panel had any other thoughts about the opportunities for novel behavioral interventions. DR MINSHEW: I think that’s another half day or a couple of hours. There are certainly ones in development. DR SCHULTZ: I’ll just mention one of the new ones that we’re doing now in the last couple years is constraint-based therapy for cerebral palsy. That would be kind of an example. And there it’s clear that in order to get results you need a behaviorally salient task for the kids to do. You just can’t have the arm constraints. So it’s a real plasticity therapy. Also the evidence that you can inhibit the good hemisphere in a hemiparetic child and that will prevent that from inhibiting the bad hemisphere, and with TMS, so that becomes more—so there’s a lot of objective evidence now that on which to base that. DR KHWAJA: Just a short comment on that. I think from a drug development standpoint that’s also a very critical issue because the bottom line is that pills are not going to teach skills. So that development of behavioral paradigms are all going to be—treatment paradigms are going to be the foundation of treatments of children with not just with autism but intellectual disability and other forms of developmental disability. I think that Dr Minshew alluded to the real challenge now and also related to Dr Buckley’s comments on the RDOCs, which is for neurologists and child neurologists in particular to become a lot more sensitive to the specific neuropsychological underpinnings of the behaviors that we’re seeing in the clinic, and being able to understand those. Because development of treatments is going to be really dependent on fully understanding those individual components, I guess, of the spectrum of behavior that we see in children. MALE VOICE: So I guess I just want to mention that obviously … with use of TMS, for example, in depression and just identifying specific neural circuitry and neural pathways at this sort of more larger scale level that may be—as opposed to microstructural level that may be impaired may be really, really crucial for more specific highly targeted behavioral interventions, as well as potentially other right-brain stimulatory efforts. DR HIRTZ: Okay. Thank you. One last comment/question from Joe. DR BUXBAUM: And I’ll try not to make it too long winded. But I thought there’s been a lot of statements about genetics and I’m a research geneticist and not a clinical geneticist, but maybe I’d like to kind of answer— DR HIRTZ: Is the mic on? DR BUXBAUM: It’s not on? I hear it. DR MINSHEW: Bend over so we can hear you. DR BUXBAUM: So the question as to the positive predictive value of genetic testing depends on the genetic variant. There are some where you’re pretty much guaranteed a severe neurodevelopmental disorder and there are some where the risk is 3-fold. So there’s no one answer to that. It’s also important to recognize that most of them, as Nancy mentioned, with 16P they don’t track perfectly with autism and they could have broad phenotypes. And so it has really been shown very clearly when you look at families with, for example, an … mutation in multiple generations that you really can’t say for sure it’s going to be intellectual disability or autism or both, and you can’t say either whether there’s going to be dysmorphologies or not. So the idea that we have a perfect neurological or genetic test that will say—clinical genetic test that will say this person should go forward for genetic testing, that’s been excluded in almost every study done to date. So the reason to do genetic testing is because there is a developmental disability. And the benefits are subtle. I put up the slide of the 3 benefits; patient, family, and society. That’s kind of the bioethical frame. It’s going to be rare that you’re going to look at a child and say this child will have Long QT syndrome because of this deletion, but you will make those claims sometimes. But for the family who then can call or who can Google and can advocate, that’s game changing. It’s also the source of a lot of our funding and drive. Also, the genetic testing gives us the data about the odds ratios and about the PPV. If nobody tested, we would know nothing. So I love this idea that Nancy mentioned that it’s up to this group to make the insurance companies—give them the baseline that they should be funding or should be paying for and then have it driven that way rather than people attempt to get genetic testing done and have it turned down by insurance. I think that the benefits are subtle, but they’re so critical. And if you think about Fragile X, how much good can we do to Fragile X and yet we test all the time. It’s because testing benefits the larger community. Publisher Copyright: © SAGE Publications.
PY - 2015/12/1
Y1 - 2015/12/1
N2 - Autism spectrum disorder in children is a group of neurodevelopmental disorders characterized by difficulties with social communication and behavior. Growing scientific evidence in addition to clinical practice has led the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) to categorize several disorders into the broader category of autism spectrum disorder. As more is learned about how autism spectrum disorder manifests, progress has been made toward better clinical management including earlier diagnosis, care, and when specific interventions are required. The 2014 Neurobiology of Disease in Children symposium, held in conjunction with the 43rd annual meeting of the Child Neurology Society, aimed to (1) describe the clinical concerns involving diagnosis and treatment, (2) review the current status of understanding in the pathogenesis of autism spectrum disorder, (3) discuss clinical management and therapies for autism spectrum disorder, and (4) define future directions of research. The article summarizes the presentations and includes an edited transcript of question-and-answer sessions.
AB - Autism spectrum disorder in children is a group of neurodevelopmental disorders characterized by difficulties with social communication and behavior. Growing scientific evidence in addition to clinical practice has led the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) to categorize several disorders into the broader category of autism spectrum disorder. As more is learned about how autism spectrum disorder manifests, progress has been made toward better clinical management including earlier diagnosis, care, and when specific interventions are required. The 2014 Neurobiology of Disease in Children symposium, held in conjunction with the 43rd annual meeting of the Child Neurology Society, aimed to (1) describe the clinical concerns involving diagnosis and treatment, (2) review the current status of understanding in the pathogenesis of autism spectrum disorder, (3) discuss clinical management and therapies for autism spectrum disorder, and (4) define future directions of research. The article summarizes the presentations and includes an edited transcript of question-and-answer sessions.
KW - autism
KW - developmental delay
KW - language
KW - neurobiology
KW - social communication
UR - http://www.scopus.com/inward/record.url?scp=84947074401&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84947074401&partnerID=8YFLogxK
U2 - 10.1177/0883073815601499
DO - 10.1177/0883073815601499
M3 - Article
C2 - 26336201
AN - SCOPUS:84947074401
SN - 0883-0738
VL - 30
SP - 1887
EP - 1920
JO - Journal of child neurology
JF - Journal of child neurology
IS - 14
ER -