Sunday, June 19, 2011

What if Autism Isn't a Neurodevelopmental Disorder?

Picture from Wikimedia Commons
Autism is typically thought of as a neurodevelopmental disorder.  It is assumed that something goes wrong early in a child's development and that the brain doesn't develop properly and that the result is permanent.

But what if that wasn't the case?

According to some recent research, the symptoms of Rett Syndrome (a form of autism) might caused by the continuing lack of the protein MeCP2 rather than problems with growth and development of the brain caused by the lack of MeCP2.  If that seems like splitting hairs, it really isn't.  That simple distinction means that Rett's might not be a neurodevelopmental disorder after all.

For those of you who don't know, Rett Syndrome is (currently) one of the five conditions that together make up what is known as the autism spectrum.  However, Rett's is somewhat different from other forms of autism.  It is rather rare (1 in 10,000) and effects girls almost exclusively.  It also tends to involve physical issues such as loss of motor control, severe digestive problems, and heart problems.  However, unlike other types of autism, a probable mechanism for the problems of Rett Syndrome has been identified - mutations in the methl-CpG-binding protein 2 (MeCP2) gene.

Because there is a known genetic mutation as well a known biological pathway that is disrupted, researchers have been able to create a number of different model of what Rett's looks like in mice.  Using these mice, researchers have been able to test a number of different theories about Rett's and this work has lead to a better understanding of the condition.

Early last year, researchers demonstrated, using mice that were deficient in MeCP2, that if you could restore the levels of MeCP2 in the brain that the mice's Rett-like symptoms would be reversed.  That part isn't too surprising but it does show that Rett's is an ongoing process.

What is more surprising is work done just this year.  This time researchers took mice that developed normally with the proper level of MeCP2 and removed their ability to produce this protein as an adult.  Once the protein was removed, these mice developed the same Rett-like symptoms as mice that were MeCP2 deficient their entire lives.

As a result, researchers are now shifting from thinking about Rett's as a condition that is caused by the lack of this protein during critical developmental periods (i.e. neurodevelopmental) and instead thinking about it as a life-long condition that is caused by the lack of this protein.

Or in other words, even though Rett's is "genetic", it is caused by an ongoing biological process and it should be possible to "cure" the condition by correcting this process.  So while there is not yet any cure for Rett's, the possibility of a cure for everyone with Rett's just got a little closer to reality.

What I find interesting is that Rett's isn't the only known "genetic" cause of autism that works like this.  In recent years Fragile-X, the leading genetic cause of intellectual disability and autism, has been shown to be reversible in adults and there are actually drugs in the works that might be able to do just that.

So what if other forms of autism aren't neurodevelopmental disorders either?  What if, like Rett's and Fragile X, other forms of autism are caused by an ongoing biological process rather than caused by something that went wrong during early development?  I think there is certainly enough evidence of ongoing biological disruptions in people with autism to make this a possibility.


  1. Great post!!! Our child's drastic response to omega-3 and the SCD diet has always had me suspecting this. I know not all kids are diet kids, but it had me wondering if one of two missing items were enough to cause autism. If you look at the history of things like scurvy and beri beri, a simple dificiency was enough to cause tragic mysterious diseases much like we have today with autism.

  2. "In recent years Fragile-X, the leading genetic cause of intellectual disability and autism, has been shown to be reversible in adults"

    Just to clarify, that's adult *mice* right?

    The Rett's and FX mouse work is really exciting but it's still a big leap to humans.

    Thanks for a thought-provoking post.

  3. Hi Jon,

    You are correct, the fragile x reversal has been in mice, not humans. Although I think that there are some drugs under development that aim to do something similar in people. But I don't really know how far along these drugs are or even if they are out of the abstract idea phase.

  4. This is an interesting question, but I'm not sure the analogy works. First of all, autism is probably not one disorder, but a collection of common symptoms that can stem from many causes. Thus, just because something is true of Rett's or Fragile X (which probably should be distinct disorders in their own right) doesn't mean it applies to autism as a whole. Indeed, genetic studies of autism seem to suggest there are a number of different genes involved, at least 40 IIRC, at several different locations (

    BTW, The authors of the recent CNV study say they're "involved in cellular motility, proliferation, and communication pathways" and I think it's fair to say proliferation, at least, is much more common early in development than in adult life.

  5. A very thought-provoking post indeed. I agree also with all the comments made from your contributors - autism is not autism but rather autisms.
    This issue takes me back to the example of PKU (phenylketonuria) - and how a genetically led in-born error of metabolism condition is solved to a large extent by a simple manipulation of diet (combined with supplementation of the deficient amino acid, tyrosine) and the knock-on effects it has had on thousands of people since Dr Folling's first discoveries.
    Regarding the comment about mouse models and big leaps to humans, I agree it is a big leap, but a leap that autism research is readily embracing in its various endeavours (as witnessed by the special edition recently posted in the journal Autism Research)

  6. This kid doesn't appear to be a mouse...,0,7738702.story

    but maybe not the same as subject.

  7. Hi Emily,

    I would agree that it is very likely that there are many autisms rather than just one form of autism and that different forms are going to have different causes. But I don't necessarily think that invalidates the point.

    Many of the other "known" causes of autism work the same way as fragile x or Rett's seem to. For example, Smith-Lemli-Opitz Syndrome is a metabolic disorder involving cholesterol that can cause autism. The symptoms of autism (and the other problems) can be helped by giving cholesterol. Or take the group of three related conditions that involve problems with creatine metabolism - two of the conditions can be helped with supplements while the third (creatine transporter deficiency) might be able to be helped if you could sneak something past the blood/brain barrier.

    According to a recent article in Neuron (and other sources), up to five percent of all cases of autism might be metabolic disorders like these two.

    The same article goes onto suggest that an additional 5 to 7 percent of cases are single-gene disorders like Rett's or fragile x. Both of these conditions were once though to be permanent developmental conditions and now they aren't.

    As for the estimated 7 to 20 percent of cases that are "caused" by CNVS, I think the results there are mixed. There are literally hundreds of almost unique CNVs that have been found in children with autism. I have a very hard time with the idea that all of these disparate mutations could all lead to a very similar clinic presentation. Especially since each child's mutation is almost unique and very little overlap has been seen in the several large CNV studies.

    Then there is the fact that my two identical twin daughters have different CNVs yet both have the same severity and core features of autism. If only one of them was in a gene study, I could easily see their autism being blamed on the CNVs (and actually, one the CNVs that one of the twins has was implicated as a possible cause in one study). Yet I don't think that two different sets of CNVs are going to cause autism that has the same core features.

    And then there is the at least 70% of cases of autism were no definite cause (single gene mutation, metabolic disorder, CNVs, etc) can be found. In these cases something has to be forcing the abnormal development and/or symptoms of autism. And if the cause isn't written into the genetic code then something else is causing it and presumably would need to exert a constant pressure to keep the body from reverting its genetic programming.

    OK, maybe that is a gross oversimplification and ignores things like the inherited epigenetic layer than can regulate the genes, but you probably get the idea.

  8. More logical and more probable:

    What if Rett's isn't a form of autism at all but just something that looks like it?

    Strange people, they accept something as a fact and then when that thing doesn't conform to the majority of Autism cases one assumes that therefore that autism is more like the thing instead of reaching the obvious conclusion the the thing was wrongly classed.

    Never ceases to amaze me.

  9. Hi Petrossa,

    If I an understanding you correctly, what you are saying is that conditions that look like (i.e. have the behaviors of) autism aren't always autism. The problem with that idea is that all forms of autism (except possibly Rett's) are diagnosed entirely on the appearance or absence of behaviors.

    If you have enough observable behaviors at the correct time in your life to meet the criteria for one of the (currently) five forms of the autism, then by definition you have autism. There is not an exception in the DSM IV (or V) that says that if you have a known genetic defect that you don't have autism. So if a condition looks enough like autism then it is autism.

    The thing that distinguishes Rett's from other forms of autism are additional physical difficulties and the probable (but not definite) presence of a known genetic mutation.

    Consider what happens when you apply your line of reasoning to fragile x, which I also mentioned. Would you say that children with fragile x can look like they have autism but don't? And if not, what exactly is the difference between fragile x and Rett's?

  10. The other thing I should probably add is that there is nothing that looks like the majority of cases of of autism cases because that concept does not exist.

    Each person with autism has an almost unique combination of traits that makes up what autism looks like for them and there is no single identifiable trait that a majority of cases have in common.

    As the saying goes, if you have seen one person with autism then you have seen one person with autism.

  11. MJ

    Autism is badly classified i agree. DSM IV nor V offer no real solution.

    Having Aspergers to a high degree i do have some insight in the matter. That and having read anything and everything over the last 35 years even vaguely pertaining to the matter.

    Autism is imo, and this is supported by many studies, a result of white matter anomalies causing the brain to develop differently during and after gestation.

    The pruning and re-enforcing system just causes the brain to have completely different way of processing information. That in itself is a good thing. A positive genetic adaption. The neo-cortex gets to be less a extension of the limbic system and more an autonomous entity.

    The negative part of all genetic adaptations is that many come up and few are viable.

    That what DSM labels autism is just some of the symptoms of various adaptations not panning out. Symptoms shared by a slew of other disorders.

    This makes it a tricky business properly diagnosing 'real' autism.

    Various other disorders just overlap and are classed as autism just on the basis of those symptoms leading to pollution of the data.

    The title of your artical would be better named: Rett's syndrome isn't part of the autism spectrum.

    Your next article might be titled:

    There is no autism spectrum, there are just many disorders classed as such.

  12. Petrossa,

    Sorry, but I have to disagree with you. While it may be true that in some forms of autism there are white matter anomalies and issues with neural pruning, I don't think that evolution or genetic adaptation has anything to do with it. I think it instead speaks to an ongoing biological process that is preventing the brain from growing properly.

    For example, consider that if the immune system is chronically activated in the brain (as has been shown in some studies), it can affect how synapses form -

    Or look at results that suggest that genes relating to immune function and brain growth are either over or under expressed in the brains of people with autism -

    Neither of those changes is pure genetic drift and both could be heavily influenced by environment (or epigenetic) factors.

    So when you look at Rett's and fragile x and see that neural function can be restored by correcting the imbalance created by the condition that suggests that something is preventing the brain from functioning properly. When that thing is removed, the brain seems to start going back to how it is supposed to function. As a result, I think that the neural differences are more a symptom than a cause.

    As for Rett's not being autism, I have to ask, have you ever met a child with Rett's? I have and from casual observation I don't think I would be able to tell the difference between a child with Rett's and a child with autism. Rett's obviously has other symptoms other than just autism but the symptoms of autism are definitely there. I think the same could be said of CDD but having never had any first hand experience with it I can't say for certain.

    Although you do have a point about their not being a single form of autism but rather many different conditions. But until we get a way to differentiate the different forms of autism the point is somewhat moot. For know, if it looks like autism we have to call it autism.

  13. See also the mouse model of Tuberous Sclerosis (in humans more than 50% of cases also have autism) where learning/cognitive deficits were reversed.

    There are many many pathways to the autism-related phenotype, with one 'cause' leading to a wide range of outcomes, but also many different 'causes' that lead to the same outcome (multifinality and equifinality).

    Moreover, even if autism is an on-going process doesn't mean it is not a neuro-developmental disorder: critical/sensitive periods of neuroplasticity in early life mean that early deficits or differences will have long lasting and sometime immutable effects. Development is also lifelong, not limited to just childhood.

    “plasticity is a double-edged sword; the more flexible an organism is the greater the variety of maladaptive behaviours it can develop” (Symons 1990; p.233)

    Saying that, the brain is exquisitely flexible throughout life, and I have hope that such findings as you have reported on (and others) will advance the possibility of prevention or habilitation.

  14. no disrespect but I think people like to hold onto a possibility of curing autistic spectrum disorders! can you please just except that this is how they were born and that you should be enabling people on this spectrum to enjoy the best that is possible in life. It can be managed, People on the spectrum don't always have the same symptoms , neither do they experience the same severity, they are individuals OK not test specimens. we all have ASD traits somewhere in us. I have a child with ASD and I am sick of hearing people discussing cures like it is some sort of disease. Yes they are different but with all disabilities whether they are mental, physical or learning , it is not the individuals that have the problem it is society it self. we live in a world where we are expected to behave in a certain way and if we abscond from this norm we are deemed abnormal. society have a way of creating labels. labels have their pros and neg's but that is another topic altogether. I know that in a perfect world we would all like to be perfect but that is not how the world is.

  15. may I also point out that scientists are still no closer to identifying the cause of ASD's, people just like to clutch at straws and hope that some crazy thing they have read is true!
    unless what you have read is hard medical evidence that is evidence based (scientific) then please try to relax regarding ASD and Retts. There are aspects of the occurrence of retts that are still not explainable

  16. Thanks so much for sharing this information. I can't believe it took me so long to find this post. My cousin has rhett syndrome and this gives me hope!

  17. The genetic markers for PKU are not outdone by the beautiful simplicity and low cost of the blood samples. Also, diet allows a somewhat normal life, something that knowing how to accommodate the biological "error" (can't think of a good terminology) only can do. What good does it do to know the pathways if we have no treatment?

    The complexity of the human organism, the ease with which homeostatis can be thrown off, is as important or moreso than genetics to me.