Monday, 28 April 2014

Schizophrenia rather than Fragile-X and Retts Syndrome, as a Reference for ASD

You may, like me, have wondered why so much autism research seems to mention Fragile-X syndrome and Retts syndrome.  

Both Fragile-X and Retts are caused by the mutation of single genes, FMR1 and MECP2 respectively.  Autism can be caused by very many, seemingly unrelated things, both genetic and environmental.

When you look at it objectively, there is a much closer comparison for autism, it is schizophrenia.  

I know from the research I am reading that in fact autism and schizophrenia are intertwined and there is no boundary were one stops and the other starts.  Most likely some of the individual biological dysfunctions in autism are present in a greater/lesser degree in schizophrenia and vice versa.  This will be developed in later posts.

For those interested in learning more about schizophrenia here is a nice PowerPoint presentation.

Here are some excerpts:-

·        A biological disorder of the brain which causes disturbances in thinking, speech, perception of reality, emotion (mood), and behavior.

·        Approximately 1% of the population develops schizophrenia during their lifetime.

·        Although schizophrenia affects men and women with equal frequency, the disorder often appears early in men (usually late teens), than women (generally late twenties/early thirties).

The most ASD-like sub-type is called disorganized schizophrenia; and it principal features are:-

      Confusion and Incoherence

      Severe deterioration of adaptive behavior

     Lack of social skills
     Poor personal hygiene & self-care

      Behavior appears silly and/or child-like

      Highly  inappropriate emotional responses

It is not hard to see the potential overlap between ASD and Disorganized Schizophrenia.

We even have a researcher suggesting a very similar strategy for Schizophrenia, to that I am proposing/developing for autism.

The discovery of the pathophysiology(ies) for schizophrenia is necessary to direct rational treatment directions for this brain disorder. Firm knowledge about this illness is limited to areas of phenomenology, clinical electrophysiology, and genetic risk; some aspects of dopamine pharmacology, cognitive symptoms, and risk genes are known. Basic questions remain about diagnostic heterogeneity, tissue neurochemistry, and in vivo brain function. It is an illness ripe for molecular characterization using a rational approach with a confirmatory strategy; drug discovery based on knowledge is the only way to advance fully effective treatments. This paper reviews the status of general knowledge in this area and proposes an approach to discovery, including identifying brain regions of dysfunction and subsequent localized, hypothesis-driven molecular screening.

For psychiatrists, the main difference between autism and schizophrenia seems to be when is the onset of symptoms.  Autism strikes at the age of two or three, whereas schizophrenia occurs much older.  Whether in fact some of the same biological mechanisms might be at work does not seem to be relevant to psychiatrists.  Not surprisingly, they have not made much progress treating either condition.

In the days before the autism was so widely diagnosed, there were many more cases of childhood schizophrenia reported, now it is very rarely diagnosed condition, it became autism.

I did look for some statistics that included autism and schizophrenia, but those clever psychiatrists seem to have separated them, so autism is with developmental disabilities and schizophrenia is not.

But I did find some interesting statistics about developmental disabilities.

When you look at the US statistics (1997 – 2008), based on parent-reported developmental disabilities.

You can see that about 15% of kids have some kind of developmental disability.  Cases of autism increase from 0.2% to  0.7% over the ten years, but those with a learning disability is pretty flat at around 7% and mental retardation (MR) / intellectual disability is also pretty flat at 0.7%.

You also see that the incidence of seizures remains flat at about 0.7%.

According to the medical research, about 30% of people with autism will also have seizures; you would expect to see a seizure “epidemic’, if there had been an autism “epidemic”.  Whereas diagnosing autism is highly subjective, recognizing most types of seizure is not.

So clearly the numbers do not add up.  Perhaps now only 10% of people with autism have seizures?  Or perhaps only 30% of people with autism, really have it?   

The same is true with the incidence of mental retardation (intellectual disability) it remains flat at 0.7%.  According to the WHO, 50% of people with autism also have MR.  So, if there had been a big increase in new people with autism, you would expect an increase in MR.  If the level of MR remains flat it would seem that some people with MR have just been given an additional diagnosis of autism.  Either that, or the 50% figure is now much lower in the US, (which is what I expect is the reality).

With even the most basic figures not adding up, is it really surprising how little progress has been made in the hard part – actually finding treatments?

Autism has changed and now means entirely different things, to different people.  In particular, comparisons across countries are completely meaningless.


Schizophrenia has also changed and is now considered as a family or spectrum of disorders.

Like autism, nobody really knows what causes schizophrenia and most likely many things do, like autism.  There is no single gene, like with Fragile-X or Retts, and there is no cure.

When researchers compared the mixture of genetic dysfunctions in schizophrenia and autism, they found a clear overlap.  This is interesting and perhaps should not have come as a surprise.

In some ways Fragile-X and Retts are actually the opposite of autism.  For example in the case of Retts, the very important substance, Nerve Growth Factor (NGF), is almost at zero, whereas in autism levels tend to be elevated.

Just as we can learn from the comorbidities of autism, I think we can learn a thing or two from the existing research in Schizophrenia.  Indeed I already have.


If anyone was seriously researching treating Mental Retardation (MR), in physically “normal” people, who have not suffered from a brain infection, toxic exposure, malnutrition or any kind of pre-natal or natal problem, we would have another great resource.  It would probably show that, in some cases, MR is caused by a partially-reversible imbalance in the actions of various neurotransmitters, ion channels, hormones etc.  Some of these imbalances will also exist in numerous cases of autism.

According to the well-known expert, Professor Howlin, only about 20% of people with ASD have an IQ in the normal range (i.e. above 70) and 50% have moderate or greater MR (i.e. IQ less than 50).  It would seem that the missing 30% must have mild MR (i.e. an IQ 50 to 70).

I suspect that the cognitive improvement found by treating some types of autism could be replicated in some cases of MR, without ASD.  If there were any clever therapies for treating MR, I would think they would likely be beneficial in autism.  In most countries, as many children have MR as have ASD, so it is strange nobody is looking how to treat it.  They assume the “defects” are hard-wired into the brain; I looks to me that some are not.

Clinical Trials

Even though ASD is a lifelong condition, nearly all the clinical trials are in children, and most often, in quite young children.  Assessing such people is doubly difficult.  Working with adults should be much easier and provide better quality data.

Other neurological conditions like schizophrenia and bi-polar disorder are regarded as adult conditions, so hopefully the quality of the research data is better.  We will see.

Plenty of adults have ASD and the ones with Asperger’s will have no difficulty articulating the effects of any intervention, so it is a pity they are rarely involved in research. 


On a happier note, I believe that if you can tune the autistic brain to its optimal performance, you will see a marked improvement in cognitive ability and, by implication, in measured IQ.  

I have no doubt that a well executed, intensive ABA program, over a few years, could also show a marked improvement in measured IQ, in many cases.  ABA is also a kind of retuning of the brain, but it has to be done right to be effective.

Biological tuning plus ABA should yield the best results.

As for schizophrenia, the biological "overlap" with autism does indeed exist. Two such areas are dysfunctional calcium channels and indeed the glutamate receptor mGluR5.  This will be developed later.

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