Gingerols and Statins (as Farnesyltransferase inhibitors) for RASopathies and Some Autism

Today’s post was driven by another attempt not to take a statin.

Statins are among the world’s most prescribed, and yet most maligned, drugs.  Hundreds of millions of people take a statin drug every day to lower their cholesterol, but a small, vocal minority complain about muscle pains, memory loss and even type 2 diabetes.

Since my Polypill is evidently a therapy, and not a cure, for autism, the odds are that it will be needed life-long.  Regardless of the apparent lack of side-effects, nobody should be taking drugs/supplements that are not really needed.  Atorvastatin (Lipitor/Sortis) is part of my Polypill for the type of autism affecting Monty, aged 11, with ASD.

Every time I stop the statin part of my Polypill therapy, I end up starting it again after only a one day break.  I notice all sorts of little behavioral changes that I really do not want to see.   

These changes involve loss of initiative, flexibility and motivation.  I really do not see how these would be measured in any existing behavioral assessment of autism.  These little changes make a big difference in daily life, so-called adaptive behavior.

In case you are wondering, the types of people with autism that I think might benefit from statins, have high cholesterol and some of the following:-

·        Non-verbal, or people who are slightly verbal, but choose not to speak

·        Poor ability to generalize skills already mastered in 1:1 therapy

·        Great difficulty in separating

·        Great difficulty in coping with change

As with some other elements of the Polypill, there are numerous reasons why statins could/should help in autism.  Today I found yet another one and an interesting non-drug alternative.

Why Statins?

I originally choose statins as a possible therapy, based on their ability to control pro-inflammatory cytokines (e.g. cytokine storms), and their known neuro-protective properties (e.g. reduce mortality after a traumatic brain injury).

I then noted they also affect some autism target genes, such as PTEN and BCL-2.

I did also note that statins were being researched to treat Neurofibromatosis, a single gene condition that is frequently comorbid with an “autism” diagnosis.

Today’s post is really about why statins should help in Neurofibromatosis and what else shares the same mechanism of action. 

Putting aside cytokines, PTEN and BCL-2, this new mechanism (excessive RAS/ERK signaling) might also be active in broader autism and Intellectual Disability / MR.

The other recent development was a study at UCLA that looked at a rare condition called Noonan Syndrome.  Noonan Syndrome and Neurofibromatosis are members of a group of conditions called RASopathies.

The RASopathies are developmental syndromes caused by mutations in genes that alter the Ras subfamily and Mitogen-activated protein kinases that control signal transduction.

Statins reverse learning disabilities caused by genetic disorder

Drawing upon Silva’s previous research on neurofibromatosis 1, another Ras-influenced disease, the UCLA team treated the mice with lovastatin, an FDA-approved statin drug currently in wide clinical use.

When adult mice with Noonan were treated with lovastatin in the UCLA study, the drop in Ras activity dramatically improved their memory and ability to remember objects and navigate mazes.

“We were amazed to see that statin treatment restored the adult animals’ cognitive functions to normal. Traditionally, science assumes that therapy needs to start in the fetal stage to be effective,” explained Silva. “Our research suggests that the leading gene mutation responsible for Noonan syndrome plays critical roles not only in fetal development, but also in how well the adult brain functions.”

According to Silva, UCLA’s approach could help the estimated 35 million Americans who struggle with learning disabilities

The paper itself:-

Mechanism and treatment for learning and memory deficits in mouse models of Noonan syndrome

RAS/ERK Inhibitors

For those of you more interested in the implications, rather than the science, here they are.

Known RAS inhibitors include:-

·        Statins, the popular cholesterol reducing drugs.  The “lipophilic” statins (Simvastatin, Lovastatin, Atorvastatin) can cross the blood brain barrier

·        Farnesyltransferase inhibitors, these are mainly anti-cancer research compounds, but one is the flavonoid Gingerol

Gingerol, is the active constituent of fresh ginger.  It is normally found as a pungent yellow oil, but also can form a low-melting crystalline solid.

Cooking ginger transforms gingerol into zingerone, which is less pungent and has a spicy-sweet aroma. When ginger is dried, gingerol undergoes a dehydration reaction forming shogaols, which are about twice as pungent as gingerol. This explains why dried ginger is more pungent than fresh ginger.

Ginger also contains 8-gingerol, 10-gingerol, and 12-gingerol.

Physiological effects

Gingerol seems to be effective in an animal model of rheumatoid arthritis.

Gingerol has been investigated for its effect on cancerous tumors in the bowel, breast tissue, ovaries, the pancreas, among other tissues, with positive results.

Neurofibromatosis, Behavioral dysfunction and RAS signaling

Neurofibromatosis Type 1: Modeling CNS Dysfunction

Neurofibromatosis type 1 (NF1) is the most common monogenic disorder in which individuals manifest CNS abnormalities. Affected individuals develop glial neoplasms (optic gliomas, malignant astrocytomas) and neuronal dysfunction (learning disabilities, attention deficits). Nf1 genetically engineered mouse models have revealed the molecular and cellular underpinnings of gliomagenesis, attention deficit, and learning problems with relevance to basic neurobiology. Using NF1 as a model system, these studies have revealed critical roles for the NF1 gene in non-neoplastic cells in the tumor microenvironment, the importance of brain region heterogeneity, novel mechanisms of glial growth regulation, the neurochemical bases for attention deficit and learning abnormalities, and new insights into neural stem cell function. Here we review recent studies, presented at a symposium at the 2012 Society for Neuroscience annual meeting, that highlight unexpected cell biology insights into RAS and cAMP pathway effects on neural progenitor signaling, neuronal function, and oligodendrocyte lineage differentiation.

Working memory, which, like attention, depends on intact prefrontal circuitry, is also impaired in both Nf1^+/− mice and in individuals with NF1. Functional imaging studies showed that the working memory impairments of NF1 subjects correlated with hypoactivation in the prefrontal cortex, which may reflect increased GABA-mediated inhibition in prefrontal cortical circuits of Nf1^+/− mice. Remarkably, a dose of a GABA receptor inhibitor (picrotoxin), which caused deficits in working memory in control mice, rescued the working memory deficits of Nf1^+/− mice, a result consistent with the hypothesis that increased inhibition is at the root of the working memory deficits associated with NF1.

Increases in RAS/ERK signaling in Nf1^+/− mice have been implicated in the working memory, attention, and spatial learning deficits of these mice. Genetic and pharmacological manipulations that target the RAS/ERK signaling pathway were shown to rescue the physiological and behavioral deficits of Nf1^+/− mice. Importantly, pharmacological manipulations that impair the isoprenylation of RAS (statins, farnesyl transferase inhibitors), and therefore decrease the levels of RAS/ERK signaling, also rescue key electrophysiological and behavioral phenotypes of Nf1^+/− mice. Indeed, at concentrations that do not affect signaling, physiology, or behavior of wild-type controls, statins reverse the signaling, electrophysiological, attention, and spatial learning deficits of Nf1^+/− mice. Prompted by these findings, clinical studies are currently underway to test the efficacy of statins as a treatment for the behavioral and cognitive deficits in individuals with NF1.

Similar to individuals with NF1, Nf1 mutant mice also show attention deficits. These deficits are thought to be key contributors to academic and social problems in children with NF1. Using an additional Nf1 GEM strain to study attention, in which the Nf1^+/− mutation is combined with Cre-driven homozygous Nf1 gene deletion in GFAP-expressing cells (Nf1 OPG mouse), it was found that reduced striatal dopamine was responsible for the observed attention deficits. Treatment with methylphenidate (but not with drugs that affect RAS) reversed the attention deficits of these Nf1 OPG mutants, suggesting that defects in brain catecholamine homeostasis contribute to the attention deficits observed. These results suggest that, in addition to drugs that affect RAS/ERK signaling, drugs that manipulate dopaminergic function could also be used to treat the cognitive deficits associated with NF1.

Treatments and future directions

With the availability of genetically engineered mouse models for NF1-associated CNS pathology, it now becomes possible to envision a pipeline in which fundamental basic science discoveries lead to the identification of new cellular and molecular targets for therapeutic drug design, culminating in preclinical evaluation before testing in patients with NF1. First, the success of Nf1 mouse model implementation has already resulted in the clinical evaluation of lovastatin in children with NF1-associated learning deficits and rapamycin analogs for the treatment of glioma. Second, mouse models afford an opportunity to envision specific features of NF1 as distinct diseases defined by the timing of NF1 gene inactivation or the particular cell of origin. Similar to other cancers, the identification of molecular or cellular subtypes of NF1-associated nervous system tumors or learning/behavioral problems may result in more individualized treatments with a higher likelihood of success. Third, as we further exploit these powerful preclinical models, additional cellular and molecular targets may emerge as candidates for future therapeutic drug design. In this regard, one could envision more effective therapies resulting from the combined use of targeted inhibition of multiple growth control pathways regulated by neurofibromin in the neoplastic cell (NF1-deficient neuroglial precursor) or dual targeting of non-neoplastic (microglia) and neoplastic cells within NF1-associated CNS tumors.

RASopathies & Autism

Autism traits in the RASopathies

Higher prevalence and severity of autism traits in RASopathies compared to unaffected siblings suggests that dysregulation of Ras/MAPK signalling during development may be implicated in ASD risk. Evidence for sex bias and potential sibling correlation suggests that autism traits in the RASopathies share characteristics with autism traits in the general population and clinical ASD population and can shed light on idiopathic ASDs.

This systematic study offers empirical support that autism traits are associated with developmental Ras/MAPK pathway dysregulation. It suggests that individuals affected by RASopathies should be evaluated for social communication challenges and offered treatment in these areas. This is the first strong evidence that multiple members of a well-defined biochemical pathway can contribute to autism traits. Future studies could explore potential modifying or epistatic factors contributing to variation within the RASopathies and the role of Ras/MAPK activation in idiopathic ASDs.

RAS/ERK Inhibitors

Inhibition of Ras for cancer treatment: the search continues

Discussion

Despite intensive effort, to date no effective anti-Ras strategies have successfully made it to the clinic. We present an overview of past and ongoing strategies to inhibit oncogenic Ras in cancer.

Conclusions

Since approaches to directly target mutant Ras have not been successful, most efforts have focused on indirect approaches to block Ras membrane association or downstream effector signaling. While inhibitors of effector signaling are currently under clinical evaluation, genome-wide unbiased genetic screens have identified novel directions for future anti-Ras drug discovery.

Conclusion

In some people with “autism” statins are an effective therapy.  Higher doses of statin are associated with side effects.  By knowing the principal mode of action of statins in autism, we might be able to develop a more potent therapy – STATIN PLUS.

On the basis of today’s post, investigating Farnesyltransferase inhibitors, as inhibitors of RAS signalling, looks an interesting option.

Gingerol is available as an inexpensive, supposedly standardized, product.  Ginger itself has been safely used in traditional medicine for thousands of years.

Perhaps Gingerol is the PLUS and for people unwilling to use a statin, perhaps Gingerol could be the statin?

The current medical view on ginger:-

According to the America Cancer Society

Recent preliminary results in animals show some effect in slowing or preventing tumor growth. While these results are not well understood, they deserve further study. Still, it is too early in the research process to say whether ginger will have the same effect in humans.

Anti-Oxidative and Anti-Inflammatory Effects of Ginger in Health and Physical Activity: Review of Current Evidence

  

Note on Intellectual Disability / MR

Regular readers may recall, I have commented that not only are many types of autism partially treatable, but so should be some types of Intellectual Disability / MR.  This same theme about treating cognitive dysfunction is raised in the paper below.

In the days when most readers of this blog were at school, 30-50% of people with an autism diagnosis were also diagnosed with Intellectual Disability / MR.  This is no longer the case; as autism diagnoses have skyrocketed in Western countries, diagnosis of Intellectual Disability / MR has not followed it.

People born today with what used to be called autism, often suffer from epilepsy and impaired cognitive function.  They do now tend to get rather sidelined by the much wider scope of the “autism” diagnosis used today, mainly in Anglo-Saxon countries (where most research is carried out).

The point where this matters is in clinical trials, since many of the milder autisms (now even being called “quirky autism”) may be caused by entirely different dysfunctions.  The observational diagnosis of “autism” is enough to enter most trials, but as we have seen in this blog, autism is not a true diagnosis; it is merely a description of symptoms.  It is like going to the doctor and saying “I think I might have a head ache” and after some questions, the doctors sits back and says “yes, you have a headache”.  You want to know why you have a head ache and how to make it go away.

Understanding Intellectual Disability through RASopathies

A fraction of the cases of intellectual disability is caused by point mutations or deletions in genes that encode for proteins of the RAS/MAP Kinase signaling pathway known as RASopathies. Here we examined the current understanding of the molecular mechanisms involved in this group of

genetic disorders focusing in studies which provide evidence that intellectual disability is potentially treatable and curable. The evidence presented supports the idea that with the appropriate understanding of the molecular mechanisms involved, intellectual disability could be treated pharmacologically and perhaps through specific mechanistic-based teaching strategies.

Allergies, Autism and Cognitive Impairment

Previous posts showed how pollen allergies can lead to summertime flare-ups in autism; most noticeable are violent/aggressive behaviours, but there is actually much more going on.

I established that Verapamil, the calcium channel blocker, and surprisingly also a mast cell stabilizer, can very effectively extinguish the aggression, but without really solving the usual allergy symptoms like itchy eyes.  As a result, you need to use a convention anti-allergy treatment as well.

Asthma/Pollen Hot Spots

Any asthma suffer will be able to tell you about the places that make them feel worse and the places that places that reduce their symptoms.  It seems that pine forests high in the mountains and on certain coastlines are best.

Forested areas around cities are not good for asthma, Berlin being an example. So you can easily check if you live in an asthma hot spot, or in a better place.

Cognitive Impairment

We just spent two weeks under the olive trees beside the sea in Greece, which I would classify as a low pollen location.  Having returned home to a big city and a house directly opposite a forest, we could see the effect of an asthma/pollen hot spot.

Monty, aged 11 with ASD, mild pollen allergy and mild asthma, did change his behaviour almost immediately.

The Verapamil does continue to block aggressive behaviour, but what changed was an immediate return of mild atopic dermatitis (red patches behind knees) and what Monty’s brother Ted, aged 14, described as Monty became “more stupid”.  It is not a nice way to describe it, but when you look closely, it is there.  The allergy has effectively lowered his cognitive function.  It is very easy to check, just ask some simple maths questions or memory questions (what did you have for breakfast?).  It is as if he is very mildly intoxicated (drunk), he is not staggering around, but he is not as sharp as he was in Greece, or at home in the spring.

Faced with an aggressive child, the last thing you would bother about is how good he is at mental maths, and so you would probably never notice it.  But having solved the aggression we are left with the observation that the allergy causes some temporary cognitive impairment.  I say temporary, because if you take away the allergens, everything improves and returns to where it was.

What is going on?

We know that allergens cause mast cell degranulation, which releases histamine, IL-6, and other pro-inflammatory substances in a chain reaction.  We know that these cross the BBB (blood brain barrier) where there are several types of histamine receptor.  The body has at least 4 types: - H1, H2, H3 and H4, and maybe more not yet identified.

Typical anti-histamines only block H1, and the newer ones are specifically designed not to cross the BBB, so as not to make you drowsy.  We later discovered that most H1 anti-histamines have moderate mast cell stabilizing properties, meaning they do reduce the release of histamine itself.

Calcium channel signaling is known to be disturbed in autism and there is excess physical calcium found in the autistic brain.  This did suggest that modifying calcium channel behaviour might be of benefit.  A known genetic variation in autism does affect the L-type calcium channels.  This suggested that blocking the L-channels might be helpful.  This was shown to be true in Timothy syndrome and I showed it to be true in Monty.

Other research has shown that Verapamil is an effective mast cell stabilizer, which did come as a surprise.

Now we come back to the effect of the allergy.  If untreated, it will “dumb down” the child and also lead to extreme behaviours like aggression, but also even odd physical tics, like moving the head forwards and backwards like a pigeon.

Perhaps there is a two stage process going on, which ultimately leads to the aberrant signaling of the L-type calcium channels and aggression.  Or is it just a progression from mild to severe?

Is it a coincidence that a calcium channel blocker can stabilize mast cells?  I think it unlikely.

Autism as an Allergy of the Brain

The idea put forward by Professor Theoharides, that autism is, at least in part, an allergy of the brain, looks more and more valid.  It was the subject of an earlier post.

Is a Subtype of Autism an Allergy of the Brain?

I do wonder how much mental retardation (MR) / cognitive impairment is also caused by the same mechanism.  Depending on how you define “autism” and whose figures you use, between 20% and 50% of people with autism have MR.  MR is defined as an IQ of 70 or less.

·        Mild retardation: Mild retardation: IQ level 50-55 to approximately 70 (85% of people with mental retardation are in this category)
·        Moderate retardation: IQ level 35-40 to 50-55 (10% of people with mental retardation)
·        Severe retardation: IQ level 20-25 to 35-40 (3 - 4% of people with mental retardation)
·        Profound retardation: IQ level below 20 or 25 (1 - 2% of people with mental retardation)

I would suggest that many people with autism might be “cognitively impaired” by allergies, be they caused by pollen, cats, dust, food, detergents, pollution or anything else.  Maybe they just dropped from a potential IQ of 120 to 110, or maybe they dropped from 80 to 35 and are now known as severely retarded.

Verapamil treats more than aggression and SIB

Based on my sample of one, it would be conceivable that Verapamil merely treats aggression and self-injurious behaviour (SIB), and that allergies are a side issue.  But thanks to the feedback on this blog, it is clear that Verapamil is treating the allergy.  One reader gave very extensive feedback showing how Verapamil greatly reduced her child’s GI problems (caused by food intolerance/allergies) and improved behaviour.  So based on a sample of two, Verapamil’s effect does seem to be related to mast cell degranulation and allergies.

Conclusion

I am very happy to have discovered the benefits of Verapamil, but I will continue to look into how further to reduce the “brain allergy effect”.  Perhaps the allergy is somehow affecting the excitatory/inhibitory balance of the Neurotransmitter GABA, I say this because Monty’s behaviour somehow resembles life without Bumetanide.  

Bumetanide’s role in autism is to lower brain Cl^- concentration and to switch GABA to be inhibitory.  A recent comment on one of my Bumetanide posts was from somebody highlighting a paper that questioned whether enough Bumetanide crosses into the brain to switch GABA to be inhibitory.  

Note that a recently published comprehensive review on the use of bumetanide in the treatment of neonatal seizures indicates that theres is no evidence to support the use of this drug in the treatment of central nervous system disorders via the NKCC1-dependent mechanism described above, as at the very low doses that are given to infants and children bumetanide does not reach sufficient levels in the brain.

direct link to the original review:
http://onlinelibrary.wiley.com/doi/10.1111/epi.12620/pdf

It is conceivable that allergies affect the blood brain barrier (BBB), although you might expect allergies to weaken the BBB, rather than strengthen it; but the body does plenty of strange things.  So a second daily dose of Bumetanide just might help.  In France, the autism researchers working with Bumetanide do give it twice a day.

The simplest method to reduce the “brain allergy effect” would be to just avoid the allergen(s).  In the case of Monty, this would be to go and live in a low pollen environment, and perhaps even avoid cats.

Since 30+% of people with autism apparently suffer from asthma, then 30% of people with autism might also find behavioral relief by avoiding pollen.  Those suffering from aggression and SIB would very likely benefit dramatically from Verapamil.

This might also suggest that residential facilities for people with severe autism should be in low pollen areas.

Incidentally, our local special needs school used to be surrounded by a rampant overgrowth of ragweed/ambrosia.  This is one of the most notorious plants for causing allergies in humans.  The current number 1 in the ATP world tennis rankings then gave them some money to tidy up the grounds.  Coincidentally, like many of the “inmates”, he also favors a gluten free diet.

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.

https://files.itslearning.com/data/1512/469/SCHIZO%20PP.pptx

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.

Phenotype of schizophrenia: a review and formulation

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.

Source:  http://pediatrics.aappublications.org/content/early/2011/05/19/peds.2010-2989.full.pdf+html

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

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.

MR

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. 

   

Conclusion

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.