Gene Mutations Offer Clues On The Autistic Brain

Christopher Walsh, professor, Pediatrics and Neurology, Children's Hospital Boston
Harvard Medical School, Boston, Mass.

Rebecca Landa, director, Center for Autism and Related Disorders, Kennedy Krieger Institute, Baltimore, Md.

Irva Hertz-Picciotto, professor, Epidemiology, UC Davis MIND Institute, Sacramento, Calif.

A trio of studies in the journal Neuron describe genetic mutations that may influence the development of the autistic brain, and how neurons connect to each other. Ira Flatow and guests discuss the latest science on autism, and some of the most successful treatment options.

Copyright © 2011 NPR. For personal, noncommercial use only. See Terms of Use. For other uses, prior permission required.

IRA FLATOW, host: You're listening to SCIENCE FRIDAY. I'm Ira Flatow. New, important clues are emerging about one of the mysteries of the brain: autism. Today, about one in every 110 kids in the United States is estimated to have some sort of autism spectrum disorder, ASD.

A slew of research papers published in the journal Neuron this week shows that autism may be a much more complex disorder than we had believed. Scientists have identified many more genetic mutations that appear to be associated with autism, some more likely to affect boys than girls, other mutations that may influence the very circuitry of the brain, and that - how neurons hook into one another.

And some recent epidemiological studies have turned up some very surprising trends: an association between autism and conception in the winter months, or apparently lower risk of autism if mothers took prenatal vitamins at the time of conception, indicating that some of these autistic switches may be flipped on very early in our development.

For the rest of the hour, we're going to review the latest research on the causes of autism and take a look at some of the best treatments out there, too. And you want to share what works for your kid? Give us a call.

Our number: 1-800-989-8255, 1-800-988-TALK. You can tweet us @scifri. And there up on our Spanish-language site, we've got an interview on the genetics of autism with an author from one of those genetic papers. Check it out. It's in Spanish, at our spanish.com/spanish site. That's sciencefriday.com/spanish site.

Let me introduce my guests: Christopher Walsh, professor of pediatrics and neurology at Children's Hospital Boston and Harvard Medical School. He joins us from a studio on campus. Welcome to SCIENCE FRIDAY, Dr. Walsh.

Dr. CHRISTOPHER WALSH: Hi, Ira. Great to be here.

FLATOW: Nice to have you. Rebecca Landa is a director of the Center for Autism and Related Disorders at the Kennedy Krieger Institute in Baltimore. She joins us from WYPR. Welcome to SCIENCE FRIDAY, Dr. Landa.

Dr. REBECCA LANDA: Hi, thank you, it's a pleasure.

FLATOW: You're very welcome. Irva Hertz-Picciotto is professor of epidemiology at the UC Davis MIND Institute. That's short for the Medical Investigation of Neurodevelopmental Disorders. And she's based in Sacramento. She joins us from the studios of Capitol Public Radio. Welcome to SCIENCE FRIDAY.

Dr. IRVA HERTZ-PICCIOTTO: Thanks for having me.

FLATOW: You're welcome. Christopher Walsh, you were an author on one of the genetic studies in the journal Neuron. What do these three studies tell us about the role that genes play in autism?

WALSH: Well, Ira, these studies add to earlier work showing that autism is very highly genetic. Some people want to run away from that and hide behind notions that autism is caused by vaccines or heavy metals or something, I think because they think of genetics as something unchangeable.

But the second thing these studies show is that autism and genetics is not immutable destiny because some kids - girls especially - carry the same genetic hits that unquestionably raise the risk of autism but develop typically, meaning that the genetics is modifiable.

And then finally, these papers show us that far from being untreatable, autism's genetic mechanism suggests specific ways that people are already developing new drugs that hopefully, in the long run, will be able to treat it better.

FLATOW: When you say that these are genes identified with these autism studies, that there's a lot of genetics involved, are these the kinds of genes you would inherit from your parents, like inherit a gene for eye color or things like that? Because wouldn't then the parents exhibit autism if it was transmitted that way?

WALSH: Well, Ira, that's a great question, and - because, as you say, we tend to think of genetic diseases as inherited diseases, as almost two words for the same thing. But actually, what these studies show is almost the opposite: When it comes to the mutations that cause autism, these studies were specifically designed on the hypothesis that autism might be caused by mutations that are not in the parents, that are not inherited, but are instead spontaneous mutations, analogous to the kinds of spontaneous mutations that might cause cancer. And so it seems like these spontaneous mutations are particularly common as a cause of autism.

FLATOW: Dr. Hertz-Picciotto, you recently published a study associated autism with the time of the year that a baby is conceived. Tell us about that.

HERTZ-PICCIOTTO: Well, we have actually a large program looking at a lot of environmental factors, and the reason we took this on was because there's a bit of the literature in schizophrenia suggesting that the timing - in that case, they looked at season or month of birth and found, you know, some interesting patterns.

And in general, by looking at seasonal patterns, we get clues about what sorts of factors we might want to pursue in greater depth. So in this particular study, we had data from the entire state of California. We were able to link millions of births over more than a decade and which of those children had developed autism based on statewide service databases that we have.

And what we found was that the mothers who had conceived their child in the summer months were - those children were at the lowest risk, and then the risks increased steadily so that in the months of December through March, those conceptions were at the highest risk for autism.

Now, I should add, though, that highest is not particularly higher than the lowest, where - in fact, it was somewhere between eight and 15 percent or so increase over the background. So it's the difference between, say, nine in 1,000 and maybe 10 or 10-and-a-half cases per thousand births.

FLATOW: Any speculation why you'd have more babies conceived in March than, let's say, August, having autism?

HERTZ-PICCIOTTO: Right. Well, when you look around at - so what are the factors that vary by season? You know, the winter are months of, you know, higher rates of infections. The spring and summer can be months of, you know, higher use of certain kinds of, you know, pest control products, both in agriculture and also around the home.

And I should add that even though we were looking at month of conception, it might well be that the critical time, it might be around the time of conception for, you know, whatever factor that turns out to be. But it might also be, say, something that happens in month three or month four of gestation.

So it's simply that there is a block of months in the year that, at some point during that early development of the brain, there may be some factor to which the - you know, some process in brain development is vulnerable.

FLATOW: Rebecca Landa, as someone who has worked for years with kids with autism, tell us what the most successful therapeutic approaches are. How much can you overcome the effects of autism?

LANDA: Well, it's surprisingly that you can actually overcome quite a bit, especially if you begin the interventions early in life. And so the main principles of intervention are to make things simple for the child, to reduce the options, if you will, for the kinds of responses that they make and to create a lot of predictability.

And so some of the labels for some of the interventions that achieve this are applied behavior analysis and some of the developmentally based interventions.

FLATOW: Mm-hmm. And what about the future? Are there any new interventions on the horizon?

LANDA: Well, you know, there continue to be nuances in the interventions, just like Dr. Walsh was explaining, that with genetics, with advances in the neurosciences, you have more and more technology to be able to look at genetic mechanisms.

It's similar in the developmental sciences. So as we learn more about how the brain learns and what typically developing infants know at certain stages of their development, we can begin to apply those principles to trick the brain of children with autism into learning things that it otherwise wouldn't learn.

FLATOW: Mm-hmm. Christopher Walsh, you are saying there are so - there are many, many different genes associated with autism in the brain. Do you see some, though, some common mechanism in place, some common defect? Why do some - why do boys seem more susceptible to autism if they have certain mutations? Are you going to be able to narrow it down that we are all looking for those, you know, magic, few genes? Or is it going to be a constellation of genes all the time?

WALSH: Well, I think it's probably going to be closer to the second answer, the idea of a constellation of genes. However, a large number of the genes we've identified seem to have common functions in the brain focusing around the synapses that connect one brain cell to another.

And therefore, that makes us very hopeful that we might be able to design additional treatments that might regulate the way these synapses function. And, in fact, there's already clinical trials of drugs from several different companies that are actually targeting some of these genes that function specifically in the synaptic connections between brain cells, and they're showing some initial promise.

FLATOW: Can you get a little more detailed about what's going on at the synapses there that's malfunctioning?

WALSH: Sure. Yeah, the synapses are the point of connection between brain cells. And the brain allows us to learn and remember new things by systematically strengthening some synapses or weakening others the way you might sort of rewire a circuit.

And when we experience something, this is represented in the brain as a sequence of electrical activity from one brain cell to another. And if the brain wants to remember that experience, the connection between two active brain cells is somehow strengthened in an amazingly specific fashion.

Dr. CRISTOPHER WALSH: So, brain cells then have a mechanism that registers which cells are active and it turns on specific genes that are normally idle, just for a few minutes or a few hours when the activity's present, and then these time-locked genes will specifically strengthen a particular synapses.

FLATOW: And in autism, what maybe causing the defect? Any...

WALSH: All right. So, it looks like this is a very complicated process. It involves hundreds maybe thousands of genes and it increasingly looks like defects almost anywhere along that process might be sufficient to cause autism. So, on the one hand, that can be a depressing thought, thinking maybe...

FLATOW: Sure.

WALSH: ...do we need to is there enough design a thousand drugs for a thousand kids. However, in fact, recent research suggests that drugs that work for one kid might very well work for another kid with autism with a distinct genetic defect in much the same way that statins will treat high cholesterol, regardless of how we got there whether it's one genetic defect or another genetic defect, or just a dietary cause.

FLATOW: 1-800-989-8255. Let's see if we can get a couple of comments from our listeners. Let's go to Stephen(ph) in Fayetteville, Arkansas. Hi Steven.

STEVEN: Hi.

FLATOW: Hi there, go ahead.

STEVEN: All right, I have some experience with autism in my family and autism related conditions. What we did was we did nutrition therapy, specifically a mineral therapy. Basically we did research into what the body was absorbing through sample tests for hair and so forth, and we started supplementing with a lot of magnesium, a lot of zinc. We used TMG, which is something that helps the body process those, and it has some dramatic effects.

FLATOW: Dr. Landa have you heard of this?

LANDA: I would probably bounce that question back to Dr. Walsh.

WALSH: OK, can't say I'm specifically familiar with that work.

FLATOW: OK, thank you Steven, and good luck to you.

STEVEN: Thank you.

FLATOW: 1-800-989-8255 let's see if we can get another question from Lynn in South Hampton, Pennsylvania. Hi Lynn.

LYNN: Hi I have a five-year-old son who's been thrown out of many schools and didn't start talking until very late due to autism and sensory issues. And I'm interested in - we decided not to go the drug route at this point, didn't really know there was autism type drugs. Two questions: can my embryos be tested - because I had him in vitro - if I want to have another child and find out. And also what kinds of non drug or drug related programs are you finding that are most effective?

FLATOW: OK, thanks for calling. Let's see if we can get some answers here. Can you test the embryos for autism?

WALSH: So, um, when we have identified a specific genetic cause that's present in a particular family, then indeed, the embryo's can be tested. So, for the benefit of this caller, what we would have to do would be to have to get her hooked up with a research program to identify the specific genetic cause associated with her son's condition. And for that, I would recommend that you contact the Simons Foundation or the Autism Genetic Resource Exchange where she might be able to get herself involved in these studies, which I encourage everyone to do.

FLATOW: Um, hum, 1-800-989-8255 is our number. I'm Ira Flatow. This is SCIENCE FRIDAY from NPR. We're talking about autism this hour. Dr. Hertz-Picciotto, another recent study you released linked a lower risk for autism to prenatal vitamin intake. Tell us about that, please.

HERTZ-PICCIOTTO: Yes, this is a study where we had a group of mothers who's child had autism and a similar group of mothers whose child was developing typically. All of the children were between the ages of two and five, and we collected a vast array of information about their behaviors, their exposures, their medication history, their reproductive history, and so forth. And one of the questions we asked pertained to their intake of prenatal vitamin supplements. And for many of these questions, we really need a concerted effort to find out the timing of the behaviors or the timing of the exposures.

So, we asked them when did they start taking those prenatal vitamin supplements and when did they, you know, did they take them throughout the pregnancy and so forth. Well, the results showed that the mothers of children who had autism were less likely to have reported that they took those prenatal vitamin supplements in the three months prior to conception, and also in the first month after conception. And the reduction in risk for those who did take them, was almost 40 percent, suggesting that something going on very early, you know - preconception or right around the time of conception - might be involved in autism.

And I think this links, interestingly, with, of course, the results that Dr. Walsh has been talking about, regarding the spontaneous or sporadic de novo, you know, copy number variance and so forth that are being seen in the genome, and...

FLATOW: Let me just make sure we get that repeat that again because that went by quickly. Women who took vitamins - prenatal vitamins - had a 40 percent lower risk of...

HERTZ-PICCIOTTO: That's right.

FLATOW: ...of having...

HERTZ-PICCIOTTO: And that's right.

FLATOW: ...children with autism?

HERTZ-PICCIOTTO: Yes. And it was the more frequently they took them, in another words, the higher the dose they were getting...

FLATOW: Um-hum.

HERTZ-PICCIOTTO: ...the stronger that affect was.

FLATOW: At the time of conception if they were taking these vitamins, 40 percent were lower risk, wow.

HERTZ-PICCIOTTO: Right.

FLATOW: And you think - wow.

HERTZ-PICCIOTTO: So, those vitamins contain, you know, high levels of folic acid as well as some other B vitamins. The reason women take those is because we - that is the public health and medical recommendation. The reason being that we know that high levels of folic acid protect against what are called neural tube defects. This is a congenital malformation where the primordial brain doesn't quite develop appropriately, and, you know, one of the results - it's called spina bifida. So, that's why women would have been taking them, because that is what is recommended.

But this is interesting, because it's that same time period that seems relevant for autism.

FLATOW: Wow. Wow. Very interesting. Stay with us because we have lots more to talk about, new data about autism. We'll be right back after this short break. Don't go away. I'm Ira Flatow this is SCIENCE FRIDAY from NPR. Earthquakes, tsunami's, oil spills, floods does it feel like we're living the life of Joe? I'm Ira Flatow join me on Science Friday for a look at disasters. Why them seem more frequent and how to prepare plus modernizing our creaky electric grid.

Are you ready for this smart meter? That's on SCIENCE FRIDAY on NPR.

(SOUNDBITE OF MUSIC)

FLATOW: You're listening to SCIENCE FRIDAY. I'm Ira Flatow. We're talking this hour about the causes of autism. More and more genes are being linked to this disorder, as is gender, environmental factors, month of conception. We're hearing about vitamins. Well, women taking vitamins at the time of conception being a reduction in risk factor. Great medical mysteries here, with my guest Christopher Walsh Professor of Pediatrics and Neurology, Children's Hospital Boston and Harvard Med School; Rebecca Landa, Director of the Center for Autism and related disorders at the Kennedy Krieger Institute in Baltimore.

Irva Hertz-Picciotto Professor of Epidemiology UC Davis MIND Institute in Sacramento. Number 1-800-989-8255. Dr. Hertz-Picciotto, you did a study last year on the age of parents as related to the risk of autism. And it was interesting, that you found out and that it depended on how young the mother was particularly, correct?

HERTZ-PICCIOTTO: Right, yes. There's been debate about whether it's age of the mother or age of the father. We certainly are seeing, pretty consistently, that at least one of those does predict a higher risk of autism in the offspring. In our study, we actually had again - similar to the month of conception study - the entire data base of all the births in California. So, we were able to disentangle, a little bit, the mother and the father's contribution - which it's very hard to do because, of course, they tend to correlate. So a small data set is not really going to be able to separate out which of those it is very effectively.

But we found that the father's age was not important if the mother was over 30. Of course, the mothers age being over 30, was itself a risk factor. But when the mother was under 30, that's when the father's age seemed to make a difference.

FLATOW: A mother under 30 and a father 40 let's say or...

HERTZ-PICCIOTTO: Yeah, exactly that seemed to be, you know, the fathers age in that case seemed to elevate the risks. The father, age 40, as opposed to a father aged, you know, 25, or a mother of the same age under 30.

FLATOW: Very interesting Dr. Landa there are lots of alternative therapies out there. Gluten-free diets, swimming with dolphins, stuff like that. What do you tell parents who want to try out things like that?

LANDA: Well, you know... Right. And you can't blame parents for wanting to try these things, because there's a lot of reports on the Internet about miracle cures. The important thing is for parents to keep in mind, are two major principles. One: if you decide to do those things, continue with the evidence-based interventions. And two: be very careful about the ones that can cause harm to your child. So, it's important for things like, if...

FLATOW: Um-hum.

LANDA: ...you do choose something like chelation, which takes all the metals out of the bloodstream and some of those metals are important for good health, you have to really have a good reason for doing that.

FLATOW: Hum, interesting.

LANDA: And if you're going to follow one of the diet therapies, then you want to make sure that you are in close touch with a dietician or a health professional to make sure the child is getting the proper nutrients.

FLATOW: 1-800-989-8255 is our number. Dr. Walsh, with this new knowledge about all these genes that are involved, how do you go - what do you do next? What's the next steps, in your research or anyone's research, in the genetics of it?

WALSH: Well, what these studies published this week did, was really look to make sure all the genes were there in the right amounts. You know, we ordinarily have two copies of each of our genes and these studies were really a very careful inventory to make sure we had two of all the genes we are supposed to have two of, instead of having only one or instead of having too much of something.

So, you could think of it as like taking an inventory of the books in the library and making sure all the stuff was there. And we found that a certain number of kids were missing stuff or had extra genes sitting around that actually cause problems. But what we haven't done yet, is take down those genes, one by one, and open them up and read them and check them for typographical errors or pages missing. And that's the sort of information you get from sequencing the whole genome, because each one of those genes is like a book.

And you have to check all the letters to make sure, because surprisingly, these little typographical errors in a gene - which are called point mutations - are usually sufficient to inactivate the whole gene and make it no darn good. And so, that's really the next step, is to use this fast DNA sequencing to examine these genes, one by one, and we think we'll find a lot more autism related mutations that way. And in fact, there's already some - one or two papers that have come out recently on that subject - that suggest that this high (unintelligible) sequencing will help us explain a lot more of the genetic contribution of autism.

FLATOW: 1-800-989-8255. Terry(ph) in Virginia Beach, Virginia. Hi, Terry.

TERRY: Yes. Hi. Thanks for taking my call. I have a son who was diagnosed at 4 with Asperger syndrome. He's now 17. I knew something was up when he was 18 months old. To me, the best thing that helped my son was my being his number one advocate and learning as much as I could. He was on medication therapy early on. He had a lot of sensory issues, speech issues. He was taking Risperdal and Luvox and Concerta and a lot of things. And we found that he was having hallucinations reportedly, but, you know, it's difficult with these kids because they can't really communicate very well.

He's come a long, long way. He doesn't have as many sensory issues, but, for me, the thing that really seemed to work for him is my vigilance, my insistence on including him in as many things as I could possibly get him into, speech therapy, occupational therapy. And although he was a bit early to get ABA, behavioral therapy, that would have benefitted him but - and I know it's genetic in this case on the paternal side. I also did a lot of research into the family side and found that the autism goes back into other family members, autistic disorders of the high-functioning type but...

FLATOW: All right.

TERRY: Anyway, to me, the medication is questionable, and I didn't go for any of the diets because I knew that it was genetic for one thing. Although I might add that I know that some of the members who have some of the autistic features did have some type of a intolerance to certain foods, but I'm not sure how they adjusted their diets. But I don't think that caused the autism. I just (unintelligible).

FLATOW: All right. Terry, I got to run, but thank you for your comments.

TERRY: Sure.

FLATOW: Dr. Landa, any comments to what Terry had to say?

LANDA: Well, I really take her point, and that is that parents really do need to apprise themselves of what evidence-based treatments are, and they do know their children better than anyone else. And so, you know, when they start to notice these signs of developmental disruption in their children, they really have to persist if they have a sense if their child is not developing well and see a developmental expert and also physicians to make sure there's no known medical cause that can be treated for the problem for autism. And then, you know, they have to aggressively seek the interventions. Like she mentioned, she had her child in early intervention, and that's just pivotal.

FLATOW: How early - let me ask all three of - we've got about a minute left. How early can you check your child for autism? How early can you catch it? How early can you intervene?

LANDA: Well, the signs of developmental disruption can be present during infancy but they're nonspecific for autism. You can start to diagnose it around the time of their first birthday, but some children don't begin to show the symptoms until after that. So, you know, you just have to have ongoing screening for children over time.

FLATOW: Do you agree, Dr. Walsh?

WALSH: Yeah, I agree completely that early on, it's a nonspecific diagnosis. One of the most important aspects of diagnosing it is trouble with language. And, of course, since that usually doesn't develop until age two, it makes it difficult to diagnose it sooner than that. And it's not like, you know, we have an X-ray test or a blood test for it, and that would be the hope, that in the long run, perhaps we could diagnose kids that were at higher risks, so that we could intervene earlier and better.

FLATOW: And what - I'm sorry. Go ahead.

HERTZ-PICCIOTTO: I'm sorry.

LANDA: I just - children are really communicating at the nine-month mark in development, so they're starting to point and gesture and to form words. And so, you know, when those things aren't present at - between 9 to 12 months, there should be some concern.

FLATOW: And what's the first thing a parent should do besides get, you know, panicky?

LANDA: Well, they don't need to panic. I mean, they really do need to tell a professional. That person can be their pediatrician. It can also be a developmental person, in the - what's called the 0 to 3 or early intervention programs where they can get free developmental assessments for their children.

FLATOW: And they know where to find these? They should deal with their pediatrician. A pediatrician will send them to a specialist or different organizations?

LANDA: Well, not necessarily, pediatricians don't always make referrals. Sometimes, they take a wait-and-see attitude so - but if parents remain concerned, they should contact their infants and toddlers program or 0 to 3, it has a different name in different states in the U.S. But it is free, and they can get good assessments there.

FLATOW: Are there support groups for parents that you'd recommend?

LANDA: Yes. I mean, there's the Autism Society of America, and there are - there's Autism Speaks and some other advocacy organizations. And so they can look up either autismspeaks.org, or they can look up the Autism Society of America, and they can find out the local chapters in their area.

FLATOW: And, Dr. Hertz-Picciotto, what about the rest of the family? Does autism affect non-autistic siblings, should you be more concerned about that? If...

HERTZ-PICCIOTTO: Well, I think the family environment is totally modified by having a child who has a disability of this sort. Often, the children who are unaffected lose out on a lot of parental attention, so within the home, you know, there's an entire dynamic amongst the different family members that, you know, can have problematic effects on all of the members of the family.

My work is focused more on the earlier issues of whether the underlying causes, and, you know, people worry also when they're thinking of having another child about what might go wrong. And we do know that siblings do have a higher risk for autism in subsequent children, so those are concerns, I know, that affect families as well.

And, you know, I do want to say in terms of this issue of genetics and environment is that it's not an either-or situation. I think genes and environment interact in multiple ways, and one example, you know, I was talking earlier about the prenatal supplements. We did find that there are women who have certain genetic profiles that put them at higher risk for not - for those women who are not taking the supplements such that, you know, certain case - certain gene - one case in the child, and one case in the mother, if the mother didn't take the supplements, that child was at four- to sevenfold higher risk for having autism.

So we've got to be looking I think not just at opening up the book, as Dr. Walsh pointed, within the genes but also starting to link the two, figuring out how those two operate together. And then we should be able to give some guidance for prevention even, you know, as early as before the pregnancy, during the pregnancy, as well as come up with ways to intervene, you know, after the child is born or showing symptoms.

FLATOW: I want to thank you all for taking time to be with us. Christopher Walsh, professor of pediatrics and neurology, Children's Hospital Boston, Harvard Med School; Rebecca Landa, director of the Center for Autism and Related Disorders at the Kennedy Krieger Institute in Baltimore; Dr. Irva Hertz-Picciotto is a professor of epidemiology at UC Davis MIND Institute in Sacramento. Thank you all for being with us today.

HERTZ-PICCIOTTO: Thank you.

WALSH: Thank you, Ira.

LANDA: Thanks.

FLATOW: I'm Ira Flatow. This is SCIENCE FRIDAY from NPR.

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