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Showing posts with label Fragile X. Show all posts
Showing posts with label Fragile X. Show all posts

Thursday 12 November 2015

More Support for the use of Statins in some Autism

Monty, aged 12 with ASD, has been taking Atorvastatin for two years, with a clear cognitive improvement from day one.  

This improvement is lost when this therapy is interrupted.

There are several posts in this blog giving the scientific basis why statins might be beneficial in some autism, these included the genes/proteins RAS, PTEN and BCL2.  In addition, statins possess potent anti-inflammatory properties.

Following a flood of visits to this blog to read about statins and autism, I did a quick check and in recent weeks at least three papers have been published suggesting the potential for statins to improve some autism.

I include the word “some” because with 800 currently identified autism genes, and I expect eventually it will be thousands, what works for one person’s “autism” may not help the next person’s “autism” and might even make it worse.

The first paper is the one getting the media coverage, it is from the University of Edinburgh, plus Mark Bear et al from MIT.  Mark Bear’s lab has featured in this blog several times, particularly relating to Fragile-X.  Lovastatin is being already trialed in humans with Fragile-X.

I use Atorvastatin (Lipitor) because it has best side effect profile.  Lovastatin and Simvastatin will have the same effect.  In some countries these drugs are available cheaply OTC.

Their therapeutic effect in autism, based on my sample of one, is from the first pill.


Over to the "experts":-




Intellectual disabilities and autism spectrum disorders could share similar defects although their genetic causes are different, according to Scottish scientists.


A study of two models of intellectual disability in mice by Edinburgh University has found that they share similar disease mechanisms.

Researchers also found that treatment with a statin drug called Lovastatin, which is often used to treat high cholesterol, can correct high levels of protein production in the brain linked to the conditions.


The findings suggest that different types of intellectual disabilities may benefit from common therapeutic approaches, the researchers say.

Professor Peter Kind, Director of the University of Edinburgh’s Patrick Wild Centre for Research into Autism, Fragile X Syndrome and Intellectual Disabilities, said: “Statins, such as lovastatin, are already used widely for treating people, including children, for high cholesterol with minimal side effects.

“Further studies are needed to determine whether these existing medications could also help people with intellectual disabilities.”

The study has been published in the Journal of Neuroscience


The full paper is here:-





Abstract
Previous studies have hypothesized that diverse genetic causes of intellectual disability (ID) and autism spectrum disorders (ASDs) converge on common cellular pathways. Testing this hypothesis requires detailed phenotypic analyses of animal models with genetic mutations that accurately reflect those seen in the human condition (i.e., have structural validity) and which produce phenotypes that mirror ID/ASDs (i.e., have face validity). We show that SynGAP haploinsufficiency, which causes ID with co-occurring ASD in humans, mimics and occludes the synaptic pathophysiology associated with deletion of the Fmr1 gene. Syngap+/− and Fmr1−/y mice show increases in basal protein synthesis and metabotropic glutamate receptor (mGluR)-dependent long-term depression that, unlike in their wild-type controls, is independent of new protein synthesis. Basal levels of phosphorylated ERK1/2 are also elevated in Syngap+/− hippocampal slices. Super-resolution microscopy reveals that Syngap+/− and Fmr1−/y mice show nanoscale alterations in dendritic spine morphology that predict an increase in biochemical compartmentalization. Finally, increased basal protein synthesis is rescued by negative regulators of the mGlu subtype 5 receptor and the Ras–ERK1/2 pathway, indicating that therapeutic interventions for fragile X syndrome may benefit patients with SYNGAP1 haploinsufficiency.
SIGNIFICANCE STATEMENT As the genetics of intellectual disability (ID) and autism spectrum disorders (ASDs) are unraveled, a key issue is whether genetically divergent forms of these disorders converge on common biochemical/cellular pathways and hence may be amenable to common therapeutic interventions. This study compares the pathophysiology associated with the loss of fragile X mental retardation protein (FMRP) and haploinsufficiency of synaptic GTPase-activating protein (SynGAP), two prevalent monogenic forms of ID. We show that Syngap+/− mice phenocopy Fmr1−/y mice in the alterations in mGluR-dependent long-term depression, basal protein synthesis, and dendritic spine morphology. Deficits in basal protein synthesis can be rescued by pharmacological interventions that reduce the mGlu5 receptor–ERK1/2 signaling pathway, which also rescues the same deficit in Fmr1−/y mice. Our findings support the hypothesis that phenotypes associated with genetically diverse forms of ID/ASDs result from alterations in common cellular/biochemical pathways.


The other two papers are from 2015 Society for Neuroscience annual meeting in Chicago.

  

A drug that blocks a cancer-related pathway normalizes neuron number and prevents behavior problems in mice that lack a copy of the autism-linked chromosomal region 16p11.2. Researchers presented the unpublished results yesterday at the 2015 Society for Neuroscience annual meeting in Chicago.
Loss of 16p11.2 results in intellectual disability, enlarged head, obesity and, often, autism. This region spans 27 genes — including one called ERK1, part of a signaling cascade that regulates cell growth. The cascade, called the RAS pathway, is hyperactive in some types of cancer and in four rare autism-linked neurodevelopmental disorders, collectively dubbed ‘RASopathies.’ The proteins encoded by ERK1 and the related ERK2 gene carry out many of the molecular consequences of RAS pathway activation.

Paradoxically, the ERK proteins are hyperactive in mice lacking a copy of 16p11.21. This hyperactivation coincides with a period of intense neuron development in the mouse embryo. The animals also have too few neurons in some parts of the cerebral cortex, the brain’s outer layer, and too many neurons in others.

“Because of this aberrant ERK hyperactivity, we were thinking that we can potentially try to bring the levels down by using a specific ERK inhibitor,” says Joanna Pucilowska, a postdoctoral fellow in Gary Landreth’s lab at Case Western Reserve University in Cleveland, Ohio.

Sniffing clues:

Pucilowska and her colleagues used an experimental drug that blocks activation of the ERK proteins. They injected the drug into pregnant mice to investigate its effects on neuron development in mouse embryos.

Treating mice with the drug prenatally for five days stabilizes ERK activity, the researchers found. It also normalizes neuron numbers in the cerebral cortex.
The treatment has lasting effects on behavior, too. Unlike untreated mice that lack a copy of 16p11.2 — which are underweight, hyperactive and have memory problems — the treated mice resemble those that do not have the chromosomal deletion.
The researchers discovered for the first time that mice lacking 16p11.2 are quicker than those without the deletion to sniff out a hidden snack in their cage, suggesting they have a highly acute sense of smell, like some people missing 16p11.2. Female mice with the deletion are also faster to retrieve pups that stray from the safety of their nest, an innate maternal behavior. The drug treatment normalizes both behaviors.

Pucilowska says she and her colleagues would like to test the drug in cells derived from people missing a copy of 16p11.2. If it works in human cells the same way it does in mice, then it might be possible to treat people with the deletion using cholesterol-lowering drugs called statins, which are also known to block signaling in the RAS pathway. “This can potentially lead to the first treatment for children with 16p11.2 deletion,” Pucilowska says.





Structural changes in the connections between neurons may underlie the enhanced learning and motor skills seen in mice with an extra copy of the autism-linked gene MeCP2. Blocking these changes with a drug blunts the animals’ performance.
The findings, presented yesterday at the 2015 Society for Neuroscience annual meeting in Chicago, point to neural mechanisms underlying the restricted interests and, in some cases, exceptional learning abilities seen in people with autism.
“This could lead to enhanced learning and enhanced performance in constrained behaviors, like in autistic savants,” says Ryan Ash, a graduate student in Stelios Smirnakis’ lab at Baylor College of Medicine in Houston. “Maybe they can’t iteratively refine those kinds of behaviors over time, so they get stuck in a behavior, which can be exceptional in certain cases but then impaired in others.”
People carrying an extra copy of MeCP2 often have autism. Mice with the same duplication have autism-like symptoms, such as avoiding social interactions with other mice.
“But they also have a super-learner phenotype,” Ash says. They perform better than controls do on a test of motor skill learning that involves balancing on a rotating rod. Typical mice fall off the rod as its speed increases, but mice with the duplication learn to coordinate their feet so that they can stay on about 30 seconds longer.
When mice learn a motor task, new synapses, connections between neurons, form in the brain1. The researchers suspected that the superior learning abilities of the mice carrying the extra MeCP2 might stem from alterations in the formation and stability of these neuronal links.
To test this hypothesis, the researchers used microscopy to image neurons in the brain that connect to the spinal cord and control movement. They took pictures of the same neurons before and after the mice practiced the rotating rod test for four days, and again after the animals had four days of rest.
Spine support:
As expected, training spurred neurons in typical mice to form new signal-receiving projections, called dendritic spines. About half of these spines remained after four days of rest, suggesting the formation of stable memories. Mutant mice form more spines than controls do, and more of them stay put after the mice take a break.
The stable spines tend to cluster. Enhanced performance on the rod tracks with a greater number of clustered spines remaining after the rest period.
“We think this is important because spines that are near each other can drive the cell more strongly when they get activated at the same time,” Ash says.
Training stimulates greater activation of a signaling cascade called the RAS pathway in the mutant mice than it does in controls. Activation of this pathway is known to strengthen clustered spines2.
Blocking the activation of this pathway with an experimental drug called SL327 lowers the mutants’ performance on the rotating rod back to the normal range. And the spines in these animals also look more like those of typical mice.
The findings suggest that spine formation and stability underlie the enhanced learning abilities of the mutant mice. Both processes appear to depend on the activation of the RAS pathway.
The drug the researchers used lasts only for a few hours, so it is not likely to help people with autism, Ash says. But cholesterol-lowering drugs called statins block activation of the same pathway by a different mechanism. “Maybe you could do a more chronic treatment with a statin, but we haven’t tried that yet,” he says.
Other mouse models of autism show enhanced performance on the rotating rod test. These include mice with a duplication in chromosomal region 15q11-13 and with mutations in the CNTNAP2, NLGN3 and NRXN1 genes, Ash says.

Interestingly, mice that lack a copy of MeCP2 — the gene mutated in the autism-linked disorder Rett syndrome — have impaired performance on the same test, and show reduced spine stability. “I would hypothesize that all of these things are actually the opposite in the Rett mice,” Ash says.




Friday 16 October 2015

It’s not Autism, it’s Sotos Syndrome – and more about GABA therapies




I recently returned from a 25 year class reunion; of the 200 or so class members about 120 turned up. Of the 200 we know that at least 5 have a son with autism and at least one has a nephew with autism.  So I had my first ever “autism lunch” discussing all those tricky issues we are left to deal with.

What was immediately apparent was how different each child’s “autism” was and that none of them were the autism-lite variants that are now being so widely diagnosed in older children. or even adults .  Of the six, two are non-verbal, one is institutionalized, yet one talks a lot.  Three sets of parents are big ABA fans and one child did not respond to ABA.

You may be wondering about that high incidence of autism.  This was not a gathering of science boffins or mathematicians; this was at a business school.  One thing is obvious, you can correlate some autism incidence with educational level.  You can connect all sorts of measures of IQ to autism, from having a math prodigy in the family, to having professors at Ivy league type Universities, particularly in Mathematics.  It does appear to be true that the so-called clever genes are also associated with some types of autism.

I presume that if my science-only university organized such events the incidence of autism would be even higher.

On the way back home we met an acquaintance at the airport, who was telling us all about his son with Sotos Syndrome.  "It is not autism", we were informed, but then I am not quite sure what is.  When you look it up, many of the symptoms look just like autism.  In fact, it is a single gene dysfunction that leads to gigantism and various elements of autism.

This brings me to the painting above of Peter the Wild Boy; it is not me I should point out.  The above Peter was a German boy who came to live in England in the 18th Century; he was non-verbal and is now thought to have had Pitt Hopkins Syndrome.  Like Sotos, this is another very rare single gene disorder.

We have already come across Rett Syndrome, which for some reason is treated as autism.

Fragile X is thought of as a syndrome where autism can be comorbid.

Timothy Syndrome is fortunately extremely rare, but I have already drawn on it in my own research into autism.

There are also autism related disorders involving multiple genes.

Prader–Willi syndrome  is a rare genetic disorder in which seven genes (or some subset thereof) on chromosome 15 (q 11–13) are deleted or unexpressed (chromosome 15q partial deletion) on the paternal chromosome.  If the maternally derived genetic material from the same region is affected instead, the sister Angelman Syndrome is the result.

The most frequent disorder caused by known multiple gene overexpression is Down Syndrome.  We saw in earlier post that DS is caused by the presence of all or part of a third copy of chromosome 21.  This results in over-expression of some 300 genes.


Why So Many Syndromes

Even before the days of genetic testing, these syndromes had been identified.  How could that be?  Each syndrome is marked by clear physical differences.

These physical differences where used to identify those affected.

Within autism too, sometimes there are physical differences.  Big heads, small heads, slim stature or heavy stature, advanced bone age or retarded bone age.


So many syndromes , but no therapies

Many of the rare syndromes have their own foundations funding research, mainly on the basis that if there is a known genetic dysfunction there should be matching therapy somewhere.

As of today, there are no approved therapies for any of these syndromes.


The Futility of Genetic Research?

A great deal of autism research funding goes into looking for target genes.  The idea goes that once you know which gene is the problem you can work out how to correct it.  There are numerous scientific journal dedicated to this approach.

Since no progress has been made in treating known genetic conditions leading to “autism”, is all this research effort well directed?  Some clever researchers think it is not.

All I can do is make my observations from the side lines.

What do Down Syndrome, Autism and Pitt Hopkins Syndrome all have in common?

In at least some of those affected, they have the identical excitatory-inhibitory imbalance of GABA, that can be corrected by Bumetanide.

If you did whole exome genetic testing on the responders with these three conditions you would not find a common genetic dysfunction; and yet they respond to the same therapy.

I am actually all for continued genetic research, but those involved have got to understand its limitations, as well as its potential.



More on GABA

This post returns to the theme of the dysfunctional GABA neurotransmitter because the research indicates it is present in numerous of the above-mentioned conditions. 



·        Autism
·        Fragile X
·        Rett Syndrome
·        Down Syndrome
·        Neurofibromatosis type 1
·        Tourette syndrome
·        Schizophrenia
·        Tuberous sclerosis complex (TSC)
·        Prader-Willi syndrome
·        Angelman Syndrome


Based on feedback to me, we should add Pitt Hopkins Syndrome to the above list.

The GABA dysfunction is not the same in all the above conditions, but at least in some people, Bumetanide is effective in cases of autism, Down Syndrome and Pitt Hopkins Syndrome.  I suspect that since it works in mice with Fragile-X , it will work in at least some humans.

GABAA has already been covered in some depth in this blog, but I am always on the lookout for more on this subject, since interventions are highly effective.  It is complicated, but for those of you using Bumetanide, Low Dose Clonazepam, Oxytocin and some even Diamox, the paper below will be of interest.



Regular readers will know that in autism high levels of chloride Cl inside the neuron have been shown to make GABA excitatory rather than inhibitory.  This leads to neurons firing too frequently;  this results in effects ranging from anxiety to seizures and with reduced cognitive functioning.  Therapies revolve around reducing chloride levels, this can be done by restricting the flow in ,or by increasing the flow out.  The Na+/K+/Cl cotransporter NKCC1  imports Cl into the neuron.  By blocking this transporter using Bumetanide you can achieve lower Cl within the neuron, but with this drug you also affect NKCC2, an isoform present in the kidney, which is why Bumetanide is a diuretic.  Some experimental drugs are being tested that block NKCC1 without affecting NKCC2 and better cross the blood brain barrier. 

The interesting new approach is to restore Cl balance by increasing KCC2 expression at the plasma membrane.  This means increasing the number of transporters that carry  Cl  out of the neurons.



In the Modulation of GABAergic transmission paper there is no mention of acetazolamide (Diamox) which I suggested in my posts could also reduce Cl, but via the AE3 exchanger.  This would explain why Diamox can reduce seizures in some people.

The paper does mention oxytocin and it does occur to me that babies born via Cesarean/Caesarean section will completely miss this surge of the oxytocin hormone.  This oxytocin surge is suggested to be key to the GABA switch, which should occur soon after birth when GABA switches from excitatory to inhibitory.  In much autism this switch never takes place.

That would suggest that perhaps all babies born via Caesarean section should perhaps receive an artificial dose of oxytocin at birth.  This might then reduce the incidence of GABA dysfunctions in later life, which would include autism and some epilepsy.

Indeed, children born by Caesarean section (CS) are 20% more likely to develop autism.


Conclusions and Relevance  This study confirms previous findings that children born by CS are approximately 20% more likely to be diagnosed as having ASD. However, the association did not persist when using sibling controls, implying that this association is due to familial confounding by genetic and/or environmental factors.

So as not to repeat the vaccine/autism scare, the researchers do not say that Caesarean section leads to more autism, rather that the kinds of people who are born by Caesarean section already had an elevated risk of autism.  This is based on analysing sibling pairs, but I do not entirely buy into that argument.  They do not want to scare people from having a procedure that can be life-saving for mother and baby.

If you look at it rationally, you can see that the oxytocin surge at birth is there for an evolutionary reason.  It is very easy to recreate it with synthetic oxytocin.

Another interesting point is in the conflict of interest statement:-


Laura Cancedda is on the Provisional Application: US 61/919,195, 2013. Modulators of Intracellular Chloride Concentration For Treating An Intellectual Disability


Regular readers will note that in this blog we have known for some time that modifying GABAA leads to improved cognitive function.  I even suggested to Ben-Ari that IQ should be measured in their autism trials for Bumetanide.  IQ is much less subjective than measures of autism.


Conclusion

My conclusion is that while genetic testing has its place, it is more productive to look at identifying and treating the downstream dysfunctions that are shared by many individual genetic dysfunctions.

By focusing on individual genes there is a big risk of just giving up, so if you have Pitt Hopkins Syndrome, like Peter the Wild Boy, it is a single gene cause of “autism” and there is no known therapy.  Well it seems that it shares downstream consequences with many other types of autism, so it is treatable after all.

I also think more people need to consider that cognitive dysfunction (Intellectual Disability/MR) may indeed be treatable, and not just via GABA; so good luck to Laura Cancedda.







Wednesday 13 May 2015

Arbaclofen Given a Second Chance by the Simons Foundation


 Light at the end of the tunnel, for some


I did recently write about autism drugs that target the GABAB receptor.

Western doctors have Baclofen and a few did have experimental use of the more potent version called Arbaclofen, or R-Baclofen.  We saw that Russian doctors have a wider choice.

The rights to use Arbaclofen have been acquired by the Simons Foundation, and they intend to restart autism trials in humans.



  
Arbaclofen was found to be effective in some people with Fragile-X and autism, but it failed its clinical trial and the developer, Seaside Therapeutics, went out of business.

The Simons Foundation, for those who do not know, is probably the best thing to ever happen to people with autism.  The founder of the foundation is an American multi-billionaire, former fund manager and mathematician.  He has a daughter with autism and decided to do something about it.

Having already funded a great deal of research, including by some of the scientists on my Dean’s List, it looks like he is going one step further and taking ownership over the trial drugs themselves.  Being a mathematician he is not averse to funding the most complex areas of research which include genetics and ion channels.  Being a fund manager he understands risk.  Being rich also helps, but you also need to be philanthropic.

Given the poor performance to date of developing practical therapies from the vast wealth of existing autism research, this is a very encouraging development.

There is now a large industry being made out of autism research, but the only coordinated part of it seems to be the Simons Foundation.  Interestingly the Simons Foundation focuses its effort on the very best scientists and not the existing autism researchers.  Apparently they want Nobel Laureates and future Nobel Laureates.  That sounds good to me.

Some people are concerned that by focusing on specific areas like genetics, the Simons Foundation may miss other possibly fruitful avenues.  But it is usually the case that an intelligent person's well thought out strategy is better than no strategy, and, at the end of the day, Simons’ billions are his to spend as he pleases.

Hopefully Simons will do for autism, what Bill and Melinda Gates are doing for polio and malaria.






Wednesday 11 February 2015

Targeted pharmacological treatment of autism spectrum disorders: fragile X and Rett syndrome


Today’s post is to refer the scientists among you to a very thorough paper looking at possible drug therapies for two specific variants of autism, Fragile X and Rett Syndrome.


  
These are single gene autisms and, as such, it is very much easier to study them than classic autism(s) or regressive autism(s).

We have already seen that much can be learnt from Fragile X and Retts.  What helps treat these disorders may give useful pointers to treat other types of autism and some therapies may be directly transferable, in some cases.









Note the use of baclofen, memantine, lovastatin, rapamycin, a PAK inhibitor, two potassium channel drugs, oxytocin, and even lithium.

Ganaxalone is a positive allosteric modulator of the GABAA receptor, probably affects the neurosteroid site.  It does not have the drawbacks of benzodiazepines.  I wonder whether it exhibits interesting effects at tiny doses? 

Tuning GABAa receptors
Treatment of Autism with low dose Phenytoin

Acamprosate appears to be neuro-protective, but the mechanism of action is unknown and controversial.  It is a drug a drug used for treating alcohol and benzodiazepine dependence.  A surprising number of off-label autism drugs are used for to treat substance abuse.

The paper is well worth a read for those who are heavily into the subject.






Thursday 23 October 2014

GERD/Reflux, Autism, Head Banging and mGlu5






This brief post addresses one further issue as to why people with autism can often suffer from various nasty gastrointestinal (GI) problems. 

First a recap.


Mast Cell Activation

We have already seen that some people’s GI problems are caused by mast cell activation/degranulation.  These cells are activated by allergens (certain foods in this case) and then they release histamine and other pro-inflammatory agents like IL-6.  Degranulation of mast cells can itself cause pain, but the main problem is the resulting damage/inflammation caused by the IL-6 and histamine.

The effective therapy is a mast cell stabilizer.  These include Verapamil (better known as a calcium channel blocker), Cromolyn Sodium, Ketotifen, Azelastine and to a lesser extent most anti-histamines like Claritin, Zyrtec etc.  Quercetin, the flavonoid, also has an effect.


Pancreatic Dysfunction

We also saw that L-type calcium channel (Cav1.2) dysfunction in the pancreas may disrupt the production of certain digestive enzymes.  The lack of these enzymes will disrupt the digestive process and likely affects other processes elsewhere in the body.  Verapamil blocks the Cav1.2 channel.


Ulcerative Colitis

We saw that inflammation and colitis, as diagnosed by an endoscopy, is another comorbidity of autism; this may be in part caused by the mast cell degranulation, but it does fit with the broader hypothesis of the over-activated immune system.  We saw how the potassium ion channel Kv1.3 was the mechanism behind some useful immuno-suppressive therapies, including those TSO parasites.  For those who are skeptical, here is another recent study, I just found:-

  

Kv1.3 should then be a target to treat ulcerative colitis and, I believe, autism itself. Some Kv1.3 blockers exist today; one is Verapamil, another is Curcumin, for those who prefer supplements to drugs.




Before I forget to write this down somewhere, it appears that Kv1.3 can also be modulated by PKA and PKC, which decrease its activity. 


We have already come across protein kinase B (PKB) and there will be a post soon of PKA, PKB and PKC.  This all links back to oxidative stress, neuroinflammation and even those dendritic spines.

  
Reflux

Today’s post is about reflux, sometimes known as gastroesophageal reflux disease (GERD) or gastro-oesophageal reflux disease (GORD).  Reflux is when the acid from the stomach rises through the esophagus/oesophagus to the mouth.

Many adults suffer from reflux from time to time and there are many OTC and prescription drug treatments. It can cause pain and discomfort, and would be particularly troubling if you could neither verbalize, nor understand your symptoms.


Why this post?

You may wonder why I have jumped from broccoli (the previous post) to reflux.  There is a reason.

I was recently listening to a conversation between doctors about a head-banging child and then came “it’s not autism; he’s got reflux, that is why he was banging his head.”

That sounded very odd to me.

It turns out many people with autism suffer from reflux, so you could say it is a comorbidity.  But why might that be?


mGlu5 receptors and disease

In an earlier, rather complicated, post I introduced the glutamate receptor, mGlu5.  This receptor is at the centre of research into Fragile X at MIT.  Fragile X is the most common single gene cause of autism.  It has been shown that mGlu5 dysfunction appears in many types of autism and indeed schizophrenia (adult-onset autism).
   
I then chanced upon a recent paper on mGLu5 and came across this section:-

Through contributions to synaptic plasticity, mGlu5 receptors have been implicated in neuronal processes such as learning and memory as well as disorders including Fragile X Syndrome (FXS), tuberous sclerosis, autism, epilepsy, schizophrenia, anxiety, neuropathic pain, addiction, Alzheimer’s disease, Parkinson’s disease, L-DOPA-induced dyskinesias, and gastroesophageal reflux disease


That was quite a surprise, but yet another good lesson of why the comorbidities should all be carefully researched.
 
The full paper, for anyone with time on their hands is:- 



Conclusion

If you have autism, you may have an mGlu5 dysfunction.  This will become treatable once the needed PAMs (Positive Allosteric Modulators) and NAMs (Negative Allosteric Modulators) have been brought to market.  A great deal of research is ongoing.

In the meantime, mGlu5 dysfunction is quite possible elsewhere in the body.  mGlu5 dysfunction is associated with some very rare disorders, but the common ones are diabetes and reflux.

The head-banging boy very possibly had both autism and reflux; he did develop diabetes.

For more on autism and diabetes, a short, thought provoking, but technical, paper:-


Interestingly, we saw earlier that Verapamil seems to offer protection against type 1 and 2 diabetes. This time it is its calcium channel blocking role that is the mechanism.



No big surprise that Verapamil is an ingredient of the autism Polypill.




Verapamil drug may reverse diabetes-related death of pancreatic beta cells