The Genetics of Autism

The Genetics of Autism

Contrary to popular belief (and Jenny McCarthy), autism is the most genetic and inheritable of all neurodevelopmental disorders. Identical twins have >80% chance of shared diagnosis, versus a much lower ~10% chance in fraternal twins, a classic indication of underlying common genetic cause. 

What is autism? Classical autism is part of a broader group of autism spectrum disorders (ASD) characterized by (i) impaired social communication and interaction, (ii) absence or delay in language and (iii) restricted, repetitive behavior. These features vary hugely, from severe intellectual disability to mild personality traits. Intellectual delays occur in 30-60%, and 30% also suffer seizures. Current rates of diagnosis are 1 in 88 children. This is partly due to a broadening of the diagnosis but could also reflect impact of changing environment on genetic susceptibility. 

Monogenic cases of autism are known as syndromes. About 10% of children diagnosed with ASD have mutations in a single gene. The most common is Fragile X syndrome (FXS), which accounts for 5% of autism cases with as many as 50% of individuals with FXS meeting criteria for autistic disorder. Other syndromes that present with ASD are Tuberous Sclerosis, Retts, and Neurofibromatosis. Although the primary diagnosis is not ASD, the symptoms include ASD. 

Polygenic disorders are caused by additive effects of multiple genes. Because inheritance patterns of autism are not Mendelian, it was initially thought to be polygenic, like traits of hypertension, height or skin color. Austism superficially fits this definition because of the continuous spectrum of characteristics. But, it’s a lot more complex because no single gene appears to account for more than 1% of the non-syndromic cases. 

Heterogenic disorders occur when mutations at any of a number of different genes can give rise to the same phenotype. In autism, many of the mutations are unique, rare and arise de novo, not being found in parents or recent ancestry. Most mutations occur on only one allele (one of two copies of the gene). Many are copy number variations, affecting gene dosage, caused by insertions and deletions in the chromosome. The emerging theory is that many different mutations converge on a common function: synaptic transmission

The synapse: Information transfer occurs at the synapse or junction between neurons. The first synapses in human cortex appear 40 days after conception. The most dramatic change takes place around birth. During the first three years of life, more synaptic contacts are formed, but only some will be stabilized. Many genes implicated in autism (image) function at the synapse, and the timing of appearance of autistic characteristics coincides with synapse maturation.

REF: Autism and Brain Development. Walsh et al., Cell (free read)


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145 Responses to The Genetics of Autism

  1. Great summary!  I love the graphic of the synapse. I spend a lot of time in class talking about neurotransmitters like acetylcholine, but I did not realize there was a connection to Autism.  

  2. Rajini Rao says:

    LOL, David Haddad  for recurring nightmares check the comment stream on this:

  3. Rajini Rao says:

    Thanks, guys. It’s the most abbreviated summary I could come up with, so there’s a lot I’ve left out. Re. the synapse, there is general agreement that a lack of balance of excitatory and inhibitory signaling underlies much of the autism spectrum traits.

  4. Rajini Rao says:

    Bwahaha, awesome chart of correlation, Feisal Kamil . Excellent documentation of the high points of her career as well. 

  5. Rajini Rao says:

    David Haddad , there are many forms of diagnoses other than behavior but they are not universally applicable because of the wide range of ASD. If it’s a syndrome, there are metabolic markers, or brain MRI scans. Genetic tests are increasingly applicable, so a child could be screened for known genetic risk factors. Also, I believe behavioral tests can be quantified, so they are not as qualitative any more. 

  6. The anti-vaccers may still be barking, but at least (I think) it’s safe to say parenting is no longer considered a cause of ASD. No great consolation to a generation or two of mothers who were told to blame themselves. 

  7. Rajini Rao says:

    Shaker Cherukuri , on the one hand there are reports of a paternal component to inheritance of autism (3x higher for 40+ year old fathers compared to those in their twenties). On the other hand, a study showed that the skewed gender ratio for ASD in males decreases with paternal age from 6.2:1 among offspring of fathers less than age 30 years to 1.2:1 among offspring of fathers aged 45+ years. 

  8. Rajini Rao says:

    David Archer , was maternal care one of the early suspects? Too bad. I’m not coming across any references to parenting in the scientific discourse these days.  

  9. Nandlal Shah says:

    Great info Rajini Rao excellent illustration and I hope that debunk some of myths about causation of ASD.

  10. Chad Haney says:

    That is so much #awesomesauce  Feisal Kamil 

  11. Matt Kuenzel says:

    The genetics of autism seem to illustrate the “missing heritability” problem:

    “Large-scale genomic studies over the past five years or so have mainly failed to turn up common genes that play a major role in complex human maladies. More than three dozen specific genetic variants have been associated with type 2 diabetes, for example, but together, they have been found to explain about 10 percent of the disease’s heritability—the proportion of variation in any given trait that can be explained by genetics rather than by environmental influences. Results have been similar for heart disease, schizophrenia, high blood pressure, and other common maladies: the mystery has become known as the “missing heritability” problem. Francis Collins, director of the National Institutes of Health, has sometimes made grudging reference to the “dark matter of the genome”—an analogy to the vast quantities of invisible mass in the universe that astrophysicists have inferred but have struggled for decades to find.”

    The Genome’s Dark Matter

  12. Rajini Rao says:

    Matt Kuenzel , dark matter of the genome sure does sound glamorous 🙂 My hard-earned understanding of the literature is that very large-scale autism studies of genome wide associations or sequencing struggle to find common variants with high enough linkage scores. When they do, they locus will not be replicated in another large study. The reasoning for this frustrating difficulty in pinning down a specific genes is the heterogeneity I mentioned. Many different genes converging on a few common pathways, with no single mutation contributing more than 1%. Apparently, this feature (including some of the genes) is shared with other complex disorders of the brain..including intellectual disability and schizophrenia. 

    I’m struck by the recent finding that 80% of the genetic differences between individual people consists of rare variants. This is going to make unraveling the genetic basis of our traits much more difficult. It does keep me in business longer though 😉

  13. Rajini Rao says:

    Also, Matt Kuenzel , there is the contribution from epigenetics, immune system and the gene-environment interactions that are being actively studied in all these complex but common human maladies you mentioned. 

  14. From a father of a child with Aspergers, very interesting. A bit over my head with some of the science. The more we know the more we can aid sufferers. Its a pity that its only the behavioral tests that are generally used for diagnosis, or has that changed. Seems to me their are reasonable screening and generic qualifications that could be watched to improve capture at early stages of development. 

    I’d like to think that some of the high functioning cases of ASD are actually contributing to the medical profession of this, and I’d assume they know their own diagnosis ????

  15. Rajini Rao says:

    Damian Clarke , I think that in the future the purely behavioral tests will either become more quantitative or have additional components of biomarkers (genetic and metabolic). The science community is definitely looking for them.

    I’m quite sure many of the high functioning autism/Aspergers individuals are contributing to the research on this (and other topics). I was sitting next to one at a conference on autism about a year ago! At the same conference, speaker Ricardo Dolmetsch (Stanford) asked for a show of hands in the audience (other researchers) having a family member with ASD. Astonishingly, about a third of the audience raised their hands. 

  16. Rajini Rao Psychologists applied a handful of logical fallacies and pronounced that a damaged emotional bond between mother and infant son induced autism. This derived from observational data that mothers of autistic sons had an impaired affection for them, and were emotionally distant. Thus causing neurological problems. More compassionate (and scientifically informed) researchers might (and did) conclude that mothers are human, and having a child that responds extremely poorly on most social levels is hard to feel normal affection for. But a lot of profound damage was done while this theory was in vogue.

  17. Rajini Rao says:

    Awww, how sad David Archer . I’m a late comer to this field (only got interested after one of the genes we work on became implicated in ASD), so I missed much of the common misconceptions other than the vaccination theories. 

    Actually, it’s the moms who first notice something as little as a baby not meeting her gaze that eventually leads to a diagnosis. 

  18. Mary T says:

    Excellent and very informative post, Rajini Rao ~  I’ve known someone with fragile X.

  19. Rajini Rao says:

    Thanks, Mara. I was planning to follow up with a post on why  more males than females are diagnosed with autism. 

  20. Thanks, Rajini Rao for this post. Given the amount of ignorant superstition in circulation about autism it is very important to get the facts out there.

  21. David Archer I think in France, where Freudian and Jungian psycoanalysis are strong, they still blame the “refrigerator” mothers.

  22. Víktor Bautista i Roca Appalling if true. That “theory” has been thoroughly discredited for a long time now.

  23. Rajini Rao interesting to see how many books and articals have been written on how it is now perceived that major influencing characters within history, are thought to suffer.

  24. It must be very challenging for researchers if the causes are due to a very large set of combination of genes. Matter will be worst if some gene variations may be pronounced by environmental factors.

    Very helpful summary. Wondering if we all should get our genome (partially) sequenced by companies like 23andMe.

    Any thoughts from experts here?

  25. I appreciate that the “conventional wisdom” of people working in the field of autism genetics is that autism is mostly genetic. However I am pretty sure that this idea is not correct.

    The twin data is not compelling because twins also share an in utero environment, and DZ twins are much more concordant in ASDs than are full siblings, indicating that a shared in utero environment also contributes to a shared ASD diagnosis.

    I appreciate that high MZ concordance data is considered “classic” evidence for genetic causation, however that assumption is misguided. The phenotypes of cloned animals are much more different than the phenotypes of the donor animal and from unrelated conspecifics, even though they have identical genes. What cloned animals don’t have is identical epigenetic programming. If differential epigenetic programming can cause greater phenotype differences in an identical genetic background than can differential genetics (cloned vs unrelated conspecifics), then assuming a shared phenotype is due to shared genetics (without correcting for epigenetic programming) is unwarranted.

    Highly inbred strains of animals do show dispersion in phenotype. Presumably they have identical genetics, the differential phenotypes must come from something else that is different. Presumably it is differential epigenetic programming that occurs during development.

    The only difference between different somatic cells is their epigenetic programming.

    There is some evidence that transposition occurs during brain cell differentiation and development. If so, then the genetic structure of the brain is much more complicated than appreciated.

    Rett Syndrome is caused by the loss of the MeCP2 protein in some cells (the gene is on the X chromosome, females are mosaic in which X chromosome is inactivated, active MeCP2 in some cells “rescues” the phenotype from death observed in MeCP2- males). In the mouse model, reactivation of MeCP2 seemingly completely resolves the symptoms. The function of MeCP2 is to regulate the binding of transcription factors to methylated DNA. MeCP2 modulates the readout of epigenetically programmed DNA. If the severe symptoms of RS can be resolved (in mice), simply by restoring a more “normal” epigenetic readout of methylated DNA, then what basis is there for suggesting that the milder symptoms of ASDs are due to “genetics” and not “epigenetics”?

    Epigenetic programming is known to happen in utero. In utero epigenetic programming due to maternal environmental exposure is known to affect the phenotype over the lifespan (see the Barker Hypothesis). ASDs can be caused by teratogens, valproate, thalidomide, maternal stress, low maternal folate and some others. Those teratogens are not acting by changing the genes. They can only act by changing the course of proliferation, differentiation and epigenetic programming.

    Most large GWAS are not able to find “the genes” for common disorders. My interpretation is that those disorders are fundamentally not due to “the genes”, but are due (most likely) to epigenetic programming.

  26. Identical twins have >80% chance of shared diagnosis, versus a much lower ~10% chance in fraternal twins

    This means that dominant cause may be genetic, but genes work in environment. Perhaps we added something in environment that activates predisposition? How about separated identical twins ? 

    For instance the fact that 30% suffer seizures might mean that we overloaded nation with carbs, since ketogenic diet controls it the best.

  27. Rajini Rao says:

    mandar khadilkar , genome sequencing will become routine eventually, possibly in our lifetimes. 23andMe will provide info on common risk factors for a number of diseases. Matt Kuenzel was planning to try out their services, I don’t recall if he did and whether he found it useful.

  28. Víktor Bautista i Roca Thank you for that. Perplexing and appalling. 

  29. Robby Bowles says:

    Great post as always Rajini Rao!  How long have you had research interests in autism?

  30. Matt Kuenzel says:

    Rajini Rao I haven’t done the genome scan yet – too worried about what the results might show! David Whitlock Good information on the puzzle of autism’s heritability. From what I’ve read, it seems that sibs of autistic children have something like a 20-fold increased risk. Part of the problem with the data may be the fuzziness of the condition and difficulty in standardized diagnosis.

  31. Rajini Rao says:

    Robby Bowles , we study ion transporters that exchange sodium (and potassium) for protons. A subset of these reside on endosomal membranes where they regulate the pH in the lumen. NHE6 and NHE9 have mutations associated with Angelman syndrome, autism, attention deficit hyperactivity disorder and addiction (enough to get our heads whirling!). We suspect that they regulate trafficking of neurotransmitter transporters and receptors to the plasma membrane. We just completed a study where we tested the variants found in children with autism and showed a loss of function. Now that it’s time to write the paper, I must read up on autism so I can sound half-way intelligent about it 😉

  32. David Archer In case you understand French, here you have the censored documentary (in a Russian server)

  33. Víktor Bautista i Roca My Spanish is better than my French, but I’ll take a look at this.

  34. Rajini Rao Did you included ADD inattentive type in your studies when you say ADHD?

  35. Rajini Rao says:

    David Whitlock , autism is not “mostly genetic”; rather, it is the “most genetic” of complex neuropsychiatric disorders. There are some nice reviews (one in Nature Reviews Genet) that compare the heritability of ASD with schizophrenia, bipolar, ADHD, etc. This post is about the genetic component of ASD. Certainly there are epigenetic, environmental, immunological components as well. I see no persuasive reason to put epigenetics as the center of the disease etiology when gene dosage and gene expression effects (essentially what epigenetics controls) can occur just as well by “conventional” copy number variants that have been documented by patient pedigree analysis and backed up by animal models. I don’t think anyone disagrees that the challenges posed by ASD come from the extreme heterogeneity in both genetics and clinical diagnosis (as Matt Kuenzel mentioned). If GWAS fail, there’s cytogenetic analysis, linkage, homozygosity mapping, copy number variation and DNA micro-array analysis that have been quite productive in finding potential genetic components. 

    I’ll get back to you in a bit re. your other point, since I don’t like long comments, thanks!. 

  36. J. Hancock says:

    Rajini Rao and David Whitlock: often a parent (most often male) is diagnosed by association when a child (most often male in this case of concurrent diagnoses) is diagnosed.  a genetic component is very evident, and in my family my son was diagnosed at 12, and his father was then diagnosed, and then his father as well.  their looks are similar, but their behaviour patterns are strikingly similar.

    thanks for posting this Rajini Rao!

  37. Rajini Rao says:

    J. Hancock , your example, while anecdotal, also brings up the issue of male predominance in ASD. I’ve seen the pedigree charts where the females act like “carriers”, even though the genetic variation being followed is not on the X chromosome. There are some fascinating theories to explain this (of course, there’s also a bias in referrals of males to females). 

  38. J. Hancock says:

    yes, sorry Rajini Rao, I don’t have the references.  I was shown the studies 4 years ago when my son was diagnosed.  I had a lot to take in at that time (and a lot to cope with!) so I didn’t make notes on the articles.  

    so yes, I present the comment as anecdotal, because I can’t do anything else at this time.  but my son’s genetic heritage clearly shows itself to anyone who knows (or meets) all three individuals.

  39. Robby Bowles says:

    Interesting to hear how your work in ion transport relates to disorders such as autism and others.  I’m always curious how researcher’s careers have progressed and evolved as their careers have advanced.  Even more interested now that I’m moving towards my own lab.  Sometime, would love to hangout with you, Allison, and Chad and discuss your philosophies behind managing labs, research directions, etc.

  40. J. Hancock says:

    a great book (by a man who also talks about being diagnosed when his son was diagnosed) is ‘Asperger’s From the Inside Out’ by Michael John Carley.

  41. Rajini Rao says:

    J. Hancock , Damian Clarke , how do you feel about Asperger’s now being folded into the broader ASD category instead of being it’s own class? I found this interesting: “Members of the Aspergers community are afraid the new label will saddle them with a stigma and make it even harder for them to function in an already difficult society.  At the same time, some parents of children with “classic” Autism are also concerned about the change.  “People already have an idea in their heads that my autistic son is like Rain Man,” said Dallas parent Cheryl Starkey “I think putting Aspergers in the same category as lower functioning autistics will just add to the false stereotype that everyone with autism is gifted.”  

    Cheryl Ann MacDonald would know more about this too.

  42. Joe Repka says:

    I apologize for going off-topic and not contributing, but I really feel compelled to just thank Dr. Rao and all commenters for a great post. This is what G+ is about for me.

  43. J. Hancock says:

    I think it’s full of problems too Rajini Rao.  Asperger’s needs a different set of treatments than Autism.  I’m glad Asperger’s is under the Autism umbrella because (in my country) that’s the only diagnosis that has significant funding attached to it.  but the approach to treatment/ teaching coping skills/ life skills is vastly different

  44. Peter Langdon you might be interested in this.

  45. Rajini Rao says:

    Joe Repka , this is what G+ is for me too. First, it’s the exercise of posting that gets me to marshall my ideas on a subject. Then, it’s the thoughtful comments, questions and alternative ideas that make me go back to reading and revise my understanding. 

  46. Rajini Rao As the mom of an Asperger’s son, I too dislike lumping them in with classically autistic kids.  I’ve worked with both, and the experience of working with each is very different.  Also there is a stigma and I’d love to spare my son that.  He is atypical and most won’t notice his Asperger’s unless they know what to look for in his behavior. Labeling him autistic would only hinder him.

  47. J. Hancock says:

    Bill Collins, thought you might be interested in this post/ comment thread.

  48. Rajini Rao says:

    Angie Creasy-Thompson , thanks for that insight. So the potentially greater access to funding would not compensate for the labeling issues?

  49. Rajini Rao Not to me.  Insurance covered behavioral therapy for both when he was younger (in WI) so it wasn’t an issue.  By the time we moved back to VA (horrible coverage here), he was functionally well on his own.  An example of how far he’s come is that he is being promoted to Patrol leader in Boy Scouts at 13 years old by the older boys who are “very impressed” with him.  However, his default social group is still men in their 60s-70s.  That’s who he is most comfortable with.  (Think a young Yoda 🙂  )

  50. J. Hancock says:

    just to clarify Rajini Rao, Asperger’s was under an umbrella of Autism, but a separate entry under the heading of Autism .  removing that separate entry won’t (I hope) change the funding, but it will make some resources harder to access, and alter people’s perception/ the stigma of each disorder.

    and J. R. Nova.

  51. J. Hancock says:

    I love the description Angie Creasy-Thompson, of the young Yoda!

    it really is amazing how some age groups are indifferent to the Asperger’s traits, isn’t it?

  52. Mad B says:

    Thank you for another great instructive post Rajini Rao 

  53. Rajini Rao says:

    Ok, I’m getting the classification now, thanks to both Angie and J. Hancock. I do know many wonderful young people who identify best with older folks (including my daughter). One of my best students once remarked that she was “old at heart” 🙂

  54. Yep, J. Hancock he’s always been an old man when it comes to hanging out.  He’s been a Ruritan (civic group) member since he was 9.  Before him the average age was 65 ish.

  55. Rajini Rao Just to correct you on something. The 1 in 88 number is not  for classic autism, but all autism spectrum disorders, including the very common PDD-NOS, as well as Aspergers Syndrome, both of which do not feature the intellectual disorders (quite the opposite in fact is true, there is often a rate of average to above average intelligence in this group).

    The rates for classic autism are much lower than this, 1 in 1000. I am saying this because one of the common misunderstandings regarding the data regarding autism spectrum disorders, is that classic autism, which is often far more severe and non-functional, rates have essentially remained stagnant, and relatively low. While the increase in the numbers is largely because of the diagnostic inclusion of pdd-nos and asperger syndrom in the DSM-IVtr, but also eliminating the requirement of intellectual disabilities in a regular autism diagnosis (high-functioning, mid-functioning, where intellectual disability is not present). Part of the reason autism spectrum disorders have gone up in rates to 1 in 88, is because of the broader diagnostic criteria, and an increased understanding of autistics. While 1 in 88 number is true for all autism spectrum diagnosis, it is not an accurate number for classic autism, which has a far smaller number. 

    This is going to change even further though with the DSM-V, and I am not sure tracking classic autism will even be easy.

    Sorry as somebody who is familiar with this data, I had to call you out on this. Please correct it. 

  56. (It is a little out of date, but being familiar with the data from the feds, the numbers for classic autism have remained stagnant.)

  57. Rajini Rao The other part of the Aspergers kids, is the social awkwardness with kids their own age. An  almost “cluelessness” about how to  interact with their  peers.  

  58. J. Hancock says:

    and Angie Creasy-Thompson, isn’t it amazing to watch that peer group difficulty bar go up through age with them?  (as in the peer thing remains constant, no matter what their age is!)

  59. Rajini Rao says:

    I agree, thanks for that clarification Christine Paluch ! I had originally put down both rates for classical autism (I had it at 1:300) and ASD but then cut back on length. It’s an important distinction. I don’t have a sense for whether classical autism is stable or increasing, so I’ll look around and chime in. 

  60. Bill Collins says:

    This is a really helpful explanation! Thank you so much.

    (Incidentally, my 10 year old Aspie kid is in the other room doing dramatic readings to his Aspie friend. They understand each other just fine. 🙂 We here  in the neurotypical world are a bit like regularly visiting the Moon for them.) 

  61. Rajini Rao I’m not so bothered about the labeling.

    My wee man is high functioning, but classed as on the cusp of Autism. My understanding as I picked it up is that it is a spectrum, and the traits attributed to points on this spectrum are, by ASDs very nature, not exclusive, and that patient traits can vary depending on a number of factors. There is no doubt that opposite ends of the spectrum will vary immensly. Surely the issue is that funding and assistance in whatever form required is administered, impartially and with the only goal of allowing the patients to fulfill a life as socially inclusive as possible. Also I believe that early diagnosis is critical for the successful application of the many therapies required to deal with a patient,  

  62. Rajini Rao  I don’t dispute any of the data showing association of ASDs with genes and CNVs. However, there are cases of ASDs that are associated with environmental exposures. That strongly implies non-genetic mechanisms. My presumption is that the common ASD symptoms are due to final common pathway(s) that is/are activated by CNVs, the genes found to be associated with ASDs, and the multiple environmental exposures. Because that final common pathway(s) can be activated independent of genetics (there is not 100% concordance in MZ twins), that final common pathway must be something non-genetic, yet has life-long effects. That pretty much implicates epigenetics. I appreciate that epigenetics is much more difficult to study than genetics, and mostly it can’t be done on humans because the relevant tissue compartment is the brain, and the assays are all destructive.

    My own feeling is that being on the autism spectrum is a trait all humans share, like height. Everyone has a height, only at the extremes is being too tall or too short considered a “disorder”. At one extreme of the spectrum is autism, at the other extreme is schizophrenia and in the middle is neurotypical. There are many dimensions to this however, but my hypothesis is that it mostly relates to a trade-off of a theory-of-mind with a theory-of-reality.

    That trade-off happens in utero because that is when the fundamental structure of the brain occurs, and brain size is limited at birth, so it can’t be big enough to do everything; there have to be trade-offs.

    I think trying to pin all, or even most of the “cause” of autism on genes is fundamentally misguided approach. Development of a phenotype is not (and cannot be) solely a product of “the genes”; development of a phenotype occurs via an interaction of the genome with the environment. That interaction is non-linear, and to try and force-fit it to a linear model (as in Z% from this gene) is fundamentally a flawed approach. That interaction is chaotic and exhibits the butterfly effect which makes some predictions not possible.

    I understand why autism research has gone in this direction. Following the unfortunate refrigerator mother idea, the Wakefield fraud, the mercury fiasco, and the anti-vaccine debacle, researchers who were trying to do credible work in autism were marginalized by their scientific peers, and threatened (sometimes with death) by parents of children with autism. The field went to indisputably rigorous science, which genetics is. Unfortunately we are finding out that the genome and how the genome works is a lot more complicated than was thought before we had all this data (most of which is still not understood (as in the hyperconserved non-coding DNA regions)), hence the idea of “missing” heredity.

  63. Cameron Jose says:

    My first born son is 10 years old and autistic. He is a genius at solving puzzles in games and can memorize books front to back. The thing that kills me is when he asks ” When can I have a family of my own dad ” ? I hope there is a cure one day because I hate knowing he is alone in his own world let alone being left alone in the world we live in.

  64. J. Hancock says:

    I think David Whitlock, that there is a genetic connection, whether it is a predisposition, or a genetic proclivity to sensitivity to environmental/ dietary/ other factors.  with what I have read and seen (and what I live with everyday), there is no doubt in my mind that genetics play a role.

    I also completely believe that allergies and or sensitivities play a large role as well.

    removing certain things from my son’s world, and introducing some others, have reduced his symptoms/ problematic behaviours by half.

    the science on these things may not be solid yet (and may never be solid), but my daily life (and that of my son) has changed dramatically with a few adherences to non medical interventions.

  65. J. Hancock says:

    Cameron Jose I dread the same thing for my son.

    Einstein said (paraphrased) “It’s strange to be so well known and so lonely.”  I thought of that when I read your comment.  

  66. One of my sons has autism. Interesting.

  67. Bill Collins says:

    I have to say that I am convinced that both epigenitics and genitics are factors, both from the reading that I’ve done and from observations (biased admittedly) of my son, my wife, her brother, her mother and others in their family. 🙂

  68. Rajini Rao says:

    David Whitlock , we may be at cross purposes here. I’m not disagreeing with your points regarding the importance of epigenetics, and you raise some very interesting and provocative ideas as well. MZ twins have been shown to have within-pair differences in copy-number-variation (CNV) profiles and other de novo mutations that alter their phenotypes. Second, epigenetic differences between the two would be likely and expected, given the stochastic nature of the epigenetic events. In female monozygotic twins, the random pattern of epigenetic deactivation on the X chromosome will also contribute to genetically based differences. Amazingly, differences in MZ twins due the timing of twinning have been observed. So, definitely, both genetic and epigenetic differences contribute to distinct presentations of ASD in identical twins. I am also in accord with your view that multiple mechanisms converge on a few common pathways- there is actually solid developmental biology behind that concept. 

    I have to disagree with your views of scientists taking a “conventional” or even misguided approach. There is no unified approach that the hundreds of labs and possibly thousands of scientists working on this topic are taking. Each lab and each investigator is following some independent and unique line of questioning, by the very nature of the scientific enterprise. Also, you’re reading too much into one single post on the topic! I did state very clearly in the comments that I was only covering a very small section of the subject. I would love to talk about this topic more, but not at cross purposes.  

  69. Have you guys ever had to raise a autistic child it is very hard more time involved but very rewarding at the same time.

  70. Rajini Rao says:

    Several commentators on this post have shared their experiences, Deborah Dawson . So the answer is yes 🙂

  71. Sorry not tryi g to be smart but i have a nine year old girl that has autism love her dearly.its hard my husband has cancer so i deal with a lot but still i am blessed.

  72. Thank you for your post enjoyed it so.

  73. J. Hancock says:

    @ Deborah Dawson many of the commenters on here (myself included) have stated we are parents of an Asperger’s child.

  74. Rajini Rao says:

    {Hugs}, Deborah Dawson , thank you for sharing your thoughts. We love our children and family whether they are “perfect” or not. Who’s perfect anyway?

    As a scientist, it’s easy for us to be discouraged because everything we do amounts to so very little! One way we keep engaged and focused is by pitting our brains against nature and trying to figure things out. This makes us seem somewhat abstract and emotionless, arguing about minutae, but it’s our way of dealing with challenges of our work. I hope you don’t think we don’t care, I’m a mother too. My best hopes for your family’s health.

  75. Deborah Dawson raising any child is highly rewarding if you are doing it right, which means paying attention to the child’s needs, not to your wants. 

  76. Bill Collins says:

    Is that the entire picture though David Whitlock ? (And note that she’s got a husband suffering with cancer, which may mean a looming – or present – caretaker burnout.) Isn’t it also true that one must take care of one’s own needs? When members of one’s family need more of one’s time and attention, a caregiver might not pay proper attention to their own needs. Or might feel too busy to do so.

  77. Rajini Rao  I have been doing research in this area for about 8 years, so it isn’t just this one article.  I am located in greater Boston, so I regularly attend some of the local autism research events, and with the proximity of the big gene labs, the idea that “genes are the most important thing that there is” has a lot of implicit support, more than I think the data supports.  😉

    A lot of the early funding for gene studies on autism was “sold” with the idea that once the genes were identified, there could be prenatal genetic tests, so that fetuses that were going to be born with autism could be aborted. It was pretty clear to me early on that that approach would never work. The liability for a false negative would be so high (millions) that the test would have to be skewed to have a high false positive rate, so any test supplier would have to have many false positives to avoid false negatives. Since many multiplex families have multiple ASD siblings, they might not be able to produce a fetus that “passes” the excess false positive skewing that any commercial test provider would require.

    If I came down too harshly, I apologize.  Physiology is ever so much more complicated than most researchers appreciate. 

    Just recently there are a few posts about the role of lead exposure on future criminal behavior.  I suspect that the effect is real, and it derives from lead interfering with regulation of receptor populations due to interference with receptor recycling, possibly via the pH things in endosomes that you are looking at.  Lead substitutes for Ca, and causes oxidative stress. Oxidative stress inhibits the V-ATPase, which slows the progression of pH during autophagy and endosome recycling and (?) affects downstream signaling of what ever the products of those processes signal (which is not well understood). There could be similar effects of lead on ASDs. Maybe with a longer lead time, corresponding to maternal exposures in utero skewing epigenetic programming of her eggs while she is in utero? That also may be how NHE’s mediate effects, through differential signaling via time-progression of pH changes.

    My schtick is nitric oxide, so I tend to see everything in terms of nitric oxide signaling.

  78. Bill Collins no disrespect or criticism was meant on my part, just that raising any child can be highly rewarding, and is one of the most important (if not the most important) things that adults can do.  It is only by raising children that the human race continues. 

    It is very unfortunate that our society (in the US) does not value raising children or taking care of those who need taking care of. 

    I am on the spectrum, so my communication of emotional things can be stilted. 

  79. Bill Collins says:

    I didn’t think you meant that David Whitlock . 🙂 I was just trying to offer some additional perspective. 

  80. Great link Rajini Rao! This one probably relates to how the gene is expressed and may link to some environmental conditions. Just because there is a genetic tendency does not mean that the disease will be expressed, right??

    I am OK also with Aspergers being included in the Autism Spectrum and it is just IMO but many emotional disorders especially the Personality Disorders should be on a spectrum. This will lead to less diagnosing only from symptoms and will now include environmental stressors which may lead to the expression of symptoms. (Means less over diagnosising of people)

    The problem area’s that we now need to address in the field are finding treatment specialists for those with mild, moderate, severe autism. Treatment success should improve. Time will tell, but no diagnosis IMO can be simplified into stating this is just genetic. What we want to fix is how these genes are expressed: example Someone with a genetic family history of Diabetes Type 2 should be careful with eating habits.

  81. Rajini Rao says:

    Yes, that’s right Cheryl Ann MacDonald . For the most part, they are susceptibility factors. In the lingo of genetics, some mutations are highly penetrant and others are less so. Another way of thinking about it, is that it must take multiple weak hits to show symptoms. 

  82. Wow really .like this my son has autism

  83. J. Hancock says:

    with what I’ve seen with diet and environmental controls, I sure can attest to the impact those have on the genetic condition of Asperger’s Cheryl Ann MacDonald and Rajini Rao.  I was skeptical about dietary changes, but I was also willing to try anything.  and what a change!  dietary changes alone can account for up to 50% improvement in my son’s ability to cope in the world.

    it’s not easy to stick to such a strict regime of food consumption, especially when he was younger, but the older he gets the more he regulates himself.  he says he just feels better (less anxious/ stressed) when he sticks to the diet.  the trick is now to convince the relatives to follow our lead.  that’s proving a little more difficult.  =P

  84. Rajini Rao says:

    Haha, I like how blunt you are! Good to see you here Ms. Feathers! I’m so glad that your 15 year old is an advocate. 

  85. Great info on the genetic’s Rajini Rao    ….because now we (psychology) can try and figure out what those multiple hits are with ASD’s.

    All of us meet very successful people with ASD’s probably very frequently (some well known Scientists, Surgeons, Psychologists, Authors, etc)  We need to decrease the stigma associated with both emotional & physical disorders as the tendency to combine disorders on spectrum’s will continue to forge on.

    Great J. Hancock it seems like you are making good progress with diet changes, I am assuming decreasing Sugar intake and what else works? This will ultimately lead many down the path of not having to take medications and learning ways to decrease that genetic expression.

  86. Rajini Rao says:

    Cheryl Ann MacDonald , do you worry that public perception of high functioning autists, who are often savants actually, makes it difficult for parents with more severely affected children? 

  87. J. Hancock says:

    the assumption of savant is rampant when the word Asperger’s is mentioned.  I know that from the amount of people who quiz me and my son on what his ‘specialty’ is.  

  88. Rajini Rao says:

    That’s what I suspected, J. Hancock, a kind of glamorization. 

  89. J. Hancock says:

    yes Rajini Rao, it’s almost crushing to see people lose their enthusiasm for interacting with my son when they find out he can’t do ‘card tricks’, or recited calendar ‘days of the week’ for any specified year. 

  90. Rajini, are there any stats for the likelihood of passing on Asperger’s Syndrome? I see this is for classical autism. Also have you come across any sort of stats for autism in siblings (non-twins)?

  91. In what way do you mean Rajini Rao “making it more difficult”?  It may make it difficult for Higher functioning ASD’s too?  Savants have been over glamorized and are very rare…..this brings the savant (very old diagnosis) category back down to where it is considered a disorder, as they have multiple problems despite maybe being successful in one specific area.  

    Savants (I have worked with only a few in 15 years) are in general very unhappy in life especially socially….

    I don’t know if I answered your question, thou…

  92. J. Hancock , we noticed extremes of behaviour (daughter with Asperger’s Syndrome) with sodium not sugar. It was almost the type of thing we would be afraid to mention to people because No One really believed us. But it’s there. I’m sure of it. 

  93. Sandi D says:

    I wondered if anyone has tested to see if the rate is higher in males due to females are responsible for birth control? So if at risk to have a child will take per-cautions to avoid this happening.

  94. Do not worry about what other people think on this one Jennifer Purvis 🙂 do what works is the motto. And good for you. Interesting decreasing sodium intake….not sugar.

  95. Rajini Rao says:

    The numbers I see don’t specify Aspergers, Jennifer Purvis , they just cite ASD:

    Siblings have a 25-fold higher chance, if I recall correctly, but the actual percentage is 2-18% according to that link. 

  96. Thank you Rajini Rao . I find it very hard to find numbers indicating Asperger’s, especially as some don’t identify it as ‘autism’ and some include it with ‘autism’. 

    Both my husband and I have family members affected by Asperger’s Syndrome and we have a daughter who has Asperger’s. It’s been a very long, hard 7.5 years and I know she is desperate for a sibling. I just don’t know how we as a family would cope with a child who is also on the spectrum. It is interesting to see my mother’s siblings with Asperger’s, my husband’s siblings with Asperger’s, aunts and uncles with Asperger’s, all in hindsight of course. 

    I am desperate for science to not only help with diagnosis but to aid in the coping, the appreciation of the gifts of those with autism, as well as helping those ‘affected’ (as it’s called) to live a fun, happy, and productive life. I know many AS adults who feel overwhelming sadness and loneliness and it should be all we can do to help. I consider myself on the Spectrum with no formal diagnosis and it wasn’t until my daughter was diagnosed that life started to make sense.

  97. Sandi D says:

    Yes, thank you for the article. It helps to understand for us older parents

  98. Chad Haney says:

    How do ya do, David Archer ?

  99. I do dinner, Chad Haney. 

  100. Chad Haney says:

    I had another imperial pilsner with lentils and rice.

  101. Ooh – that reminds me. Look for a post shortly. 

  102. J. Hancock says:

    @ Jennifer Purvis: if you suspect anything  is a contributing confounder, take it out of the diet for a minimum of 3 months, and see if there is any effect.  

    my personal research kept showing up one factor to change, but making that change didn’t prove significant with my son.  that is until  I attended a seminar where the presenter said “3 months” .  “Do this for 3 months , then “see if it works” she said.  

    it was the magic number.

    three months became my benchmark from that day forward.  that ‘benchmark’ has served me well for determining if a change is ‘useful’/ ‘helpful’.

  103. J. Hancock What was the dietary item you removed?

  104. J. Hancock says:

    @ David Archer: truth be told I am not yet ready to publicly declare my findings.  I am more than willing to share these things privately, and I am working on an article that covers my personal experience, to be shared (privately) “soon”.  

    there is research behind what I did/ am doing, but my methods severely lack the ‘controls’ necessary for a ‘scientific’ method.

    I am more than willing to include you in my ‘share’ of my ‘article’, as long as you agree to respect the personal nature of the ‘research’, and acknowledge that there is no scientific basis.

    note, please, that I have a scientific background, but my research/ post doctoral studies were interrupted by the arrival of my special needs kids.  my education/ life experience has been applied (profoundly) to the outcome of their individual cases.   

  105. Ping me or something J. Hancock when you are ready to share. Please?

  106. J. Hancock says:

    I will Cheryl Ann MacDonald.

  107. Sandi D says:

    Christine Paluch I agree there is a few conditions like down syndrome & cerebral palsey that have these traits. But not the classical autism Kanner first outlined or Asperger?

  108. Thank You J.Hancock and Raj this post is a winner… 🙂 even the comments!

  109. Thanks for the very interesting information Rajini Rao .How is Asperger syndrome different from classical autism or is it the same genetically?

  110. That’s why Hindus have “Gotra” to overcome!

  111. Rajini Rao says:

    Siromi Samarasinghe , Aspergers is a high-functioning form that lies on the milder end of the autism spectrum. Genetically, the same genetic variants can be found in both milder and severe forms of ASD, which is part of the complexity and confusion. For example, siblings may share the same genetic mutation or copy number variation but be diagnosed with different forms of ASD. This could be due to epigenetic differences or modifying effects of other genes, for example. 

    PradipKumar Chakrabarty , “gotra” considerations prohibit intermarriage on the paternal side, but not on the maternal side because the family name is different. That’s not very scientific! 🙂

  112. Rajini Rao says:

    Mark Bruce , there is a push to find biomarkers although they will likely to be specific for clinical sub-types of ASD, given the heterogeneity. There are several candidate neuropeptides that appear to be elevated in ASD newborns: neurotensin, VIP, BDNF, CGRP, neurotrophin 4/5 and serotonin.


    For the syndromes, because they are better defined and monogenic, it’s going to be a lot more feasible to find biomarkers, although genetic testing would be more straightforward. 

  113. A subject close to my heart – my stepson is autistic.  It has been maddening to hear all the misinformation poured into the public’s ears over the years.  He’s nearly 17 and a giant – a gentle giant now, thankfully.  

    Here’s to those who study autism and seek to find a cure.  You’re all heroes to me.  Thanks, Rajini Rao!

  114. How many almonds u take daily Rajini..?

  115. Sandi D says:

    I wonder if this article will be re-posted ?

  116. Sorry i didnt mean to put my problems on anyone just saying its really hard to have a sick husband a autistic child and two adhd boys ages ten and eight but i love all my kids really do autistic children are really smart. What a joy they are.i do the best i can do to take care of my husband and my three kids but its what god gave me so yes i am blessed i have a lot to do but with gods help i manage.we have no family they are a certain religon so they dont believe in treatments and they dont associate with us because we do.sorry but we do with what god gave to us we love our god we love autistic kids they are speciial.thanks for comments.i tell my chil every day god made her my special girl and it would not be her if she was different. Thanks everyone my site is deborahdawson22@

  117. Rajini Rao Does ADHD and ADD (Inattentive) considered sub classification of ASD? DSM III to IV changes were related to this classification change?

  118. Rajini Rao says:

    mandar khadilkar I don’t keep up with clinical categories since my work is mechanistic rather than descriptive 🙂  I’m curious about that distinction too, so I’ll google that for you in a bit, off to teach a class now.

  119. Matt Kuenzel says:

    Teach a class at 7:30 am ??? That is just plain cruel both to you and the students !

  120. Rajini Rao says:

    mandar khadilkar “DSM-V — which is currently in the planning stages and is slated to be published in 2013 — will bring changes for the attention deficit and hyperactivity disorder (AD/HD) community, perhaps by treating these as two separate disorders, rather than subtypes of the same condition.” More:

  121. Rajini Rao says:

    Matt Kuenzel , thanks for the sympathy! Medical school lectures are indeed painful: they start at 8 am and given my half hour commute, plus time to walk across campus to a fancy new teaching building and time to set up the sound/vid/clicker systems, this means an early and chilly morning. Much better for the PhD lectures, which are down a quick stairway from my office and don’t start until 9 am (everyone knows that grad students are lazy) 🙂

  122. Chad Haney says:

    Having said that, for BioChem, there was a multiple choice exam and an essay exam. The med students took the multiple guess and the grad students took both. #justsayin  

  123. Rajini Rao says:

    Med school at Hopkins is now pass now or pass later. There is no fail. 

  124. Chad Haney says:

    Sad. None of the students in  UofC’s MD/PhD program have impressed me. Having taken some of the same courses as the med students, it’s scary to think of how they perform after med school. It’s all memorization and socialization. Don’t get me started about the pharmacy students either.

  125. Rajini Rao says:

    What is sad is that the med students start off all honed and sharp- they are actually a cut above our grad students in quality because we rank #2 for med schools but further down for grad programs. Then we dumb them down…

    As for the socialization, it’s a bit out of control! They actually get put into Houses, like Harry Potter, with cozy little sofas and kitchenettes in the teaching building. 

  126. Rant day for Chad Haney  and Rajini Rao 

    ….btw… I go through this myself few days of the week and then think that my Seniors said that about me too…….then I say, BAU 🙂

  127. Rajini Rao says:

    Hehe, beg pardon mandar khadilkar . We are airing our dirty laundry here, tsk.

  128. E.E. Giorgi says:

    this is fascinating, don’t know how I’d missed it! thanks for sharing!

  129. Guitar Dave says:

    It is a Very Important fact to know because so many Children all over the World Are affected by this disorder . Hopefully many of those who are misinformed will see this . 

  130. Rajini Rao Do you mind if I share some of your posts on the business site? I would like to share this one.

  131. I am so glad that people keep coming and read the posts even after the post is lil old.

    That shows the value author added….thanks again Rajini Rao.

  132. Rajini Rao says:

    Of course, feel free Health Psychology of San Diego . I was planning to do a post on gender differences in autism (prevalence is 4x higher in males) and have not got around to it. I wanted to sum up the various theories proposed for this difference.

    Thanks, mandar khadilkar ! Hope you are well?

  133. Great thanks Rajini Rao I have to ask because it is a business page (my own thoughts). I want to share the medical posts.

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