Under-expression (Haploinsufficiency) of ARID1B in Autism and Corpus Callosum Abnormalities

People keep telling me that my blog is too complicated; compared to the literature it really is not. If your child has a disabling condition you really should be willing to invest all the time needed to learn about it, rather than be a passive bystander.

I think you can investigate even complex sounding genetic disorders without being an expert, which is what happens in today’s post.  

Are there 20,000 types of jeans?

As readers may recall, humans only have about 20,000 genes, far less than originally was thought. Each gene provides the instructions to make one thing, usually a protein.

For the great majority of genes we have two copies, one from Mum and one from Dad. Mitochondrial genes all come from Mum.

These genes are stored on chromosomes (like recipe books).

For 22 of these recipe books you have two copies, so if one page got damaged at least you have an undamaged version from the other book.

The 23rd pair of books is special because while females have two copies, males do not. This is the X chromosome and if a male has a problem on any page in this little book, he has a big problem, while his sister has less of a problem, because she has a spare copy. The male has a Y chromosome in place of a second copy of X. 

Examples of problems on the X chromosome:-

·        The MECP2 gene is on the X chromosome and when there is one working copy and one mutated version you have Rett syndrome and you must be female. If you were male with one mutated version you cannot survive.

·        In Fragile X syndrome a problem with the FMR1 gene means not enough not enough fragile X mental retardation protein (FMRP), which is required for normal development of the connection between neurons. Females would normally have a clean spare copy of the FMR1 gene and so show much less severe symptoms that a male with Fragile X.

Problems on chromosomes 1 to 22:-

If you have a problem in the first 22 chromosomes (recipe books), boys and girls are equal. If one page got damaged you can always look up the recipe in the other book.

In case one gene got mutated but the other copy is fine, things can work out just fine, in which case it is called haplosufficiency. You get to make enough of that protein.

In some cases you really need to use that recipe a lot; that particular protein is in big demand. One copy of that gene just is not enough. This is called  haploinsufficiency.

In most cases when the gene has a problem, it just fails to produce the intended protein. In some cases it actually produces a mutated protein, which can be worse than no protein. 

Pitt Hopkins

In Pitt Hopkins Syndrome there is a problem on chromosome 18, where you find the TCF4 gene. Not enough expression of TCF4 means not enough Transcription Factor 4;  this is an example of haploinsufficiency.

Now the reason why these rare conditions are important to many other people is that they not only affect people who happened to have a random mutation and hence a severe deficit of the protein; moderately reduced transcription of this gene, for any reason, can also result in troubling symptoms.

So in the case of the Pitt Hopkins and the gene TCF4, as was pointed out to me recently, reduced expression is a feature of some MR/ID and indeed schizophrenia. 

The Intellectual Disability and Schizophrenia Associated Transcription Factor TCF4 Is Regulated by Neuronal Activity and Protein Kinase A 

Instead of just a tiny number of people with Pitt Hopkins, you can see that upregulating TCF4 expression could help a lot of people.

It appears that people with Pitt Hopkins have a “clean copy” of TCF4, so it is just a case of making it work a little harder. There are ways being researched to achieve just that.

I suspect people with schizophrenia have two “clean copies” of TCF4, but for some reason have a deficiency of the protein encoded by it.

In the above paper it was shown that Protein Kinase A (PKA) plays a key role in regulating what your TCF4 gene is producing.

We have come across PKA before in this blog and we know that in regressive autism there can be a deficit of PKA. There is also PKB and PKC. All three are very important, but complicated. 

Brain Region–Specific Decrease in the Activity and Expression of Protein Kinase A in the Frontal Cortex of Regressive Autism

Without going into all the details you can see that if someone with Pitt Hopkins has a lack of PKA, like those with regressive autism, then he will struggle to make the most of his good copy of the gene TCF4.

It all gets very complicated, but PKA is controlled by something called cAMP. In turn cAMP is controlled by PDE. PDE4 is known to be disturbed in the brains of some people with autism.

It appears that you can activate PKA with a PDE4 inhibitor. The long established Japanese asthma drug Ibudilast is such a PDE4 inhibitor. At least one reader of this blog uses Ibudilast long term.

PDE4 inhibitor, roflumilast protects cardiomyocytes against NO-induced apoptosis via activation of PKA and Epac dual pathways

PDE4 inhibitors have been explored to treat various neurological conditions like schizophrenia.

PDE4 as a target for cognition enhancement

So logically if you feed a PDE4 inhibitor to a Pitt Hopkins mouse, you might expect something good to happen. There now is such a mouse model.

I think I could keep that mouse quite busy. 

The point being you do not have to figure things out 100%, before starting to see what you have in your drug library might be truly beneficial.  

Some of the things in the drug library are actually in the kitchen cupboard, as we have already seen. 

Protein Kinase A

Protein kinase A (PKA) is something that is both complicated and important.

The effects of PKA activation vary with cell type.

PKA has always been considered important in formation of a memory.  Formation of a normal memory is highly sensitive to PKA levels; too much is bad and too little is bad.

ARID1B in Autism and Corpus Callosum Abnormalities

I don’t think anyone has set up a research foundation for agenesis of the Corpus Callosum (ACC), perhaps they should. 

There was a post on this a while back, prompted by meeting someone whose son has this condition. 

Agenesis of the Corpus Callosum

The Corpus Callosum is just a fancy name for what joins the two sides of the brain together. Agenesis of the Corpus Callosum (ACC) is what they call it when there is a complete or partial absence of the corpus callosum.

ACC is we are told a very rare condition, but clearly smaller corpus callosum variations are a key part of some autism. 

For example, in Pitt Hopkins a small corpus callosum is typical.

An estimated 7 percent of children with autism and macrocephaly (big heads) carry a PTEN mutation. This is associated with an enlarged corpus callosum. 

PTEN is an autism gene, but it is more usually thought of as a tumor suppressor, making it a cancer gene. In older people, losing PTEN appears to be often a first step to developing cancer; up to 70% of men with prostate cancer are estimated to have lost a copy of the PTEN gene at the time of diagnosis  (https://www.ncbi.nlm.nih.gov/pubmed/16079851). 

PTEN is interesting because too little can allow cancer to develop, but too much may eventually result in type 2 diabetes. So, as always, it is a balance. 

PTEN upregulation may explain the development of insulin resistance and type 2 diabetes with high dose statins. 

Evidently from the comments in this blog, regarding tumors/cancers, people with autism are likely shifted towards the direction of lacking tumor suppressing proteins. The exception would be those born very small, or with small heads. 

ARID1B gene

ARID1B is another tumor suppressing gene, like PTEN, and like PTEN it is also an autism gene.

What I found interesting was the link between ARID1B and corpus callosum anomalies. 

ARID1B mutations are the major genetic cause of corpus callosum anomalies in patients with intellectual disability  

Corpus callosum abnormalities, intellectual disability, speech impairment, and autism inpatients with haploinsufficiency of ARID1B

Corpus callosum abnormalities are common brain malformations with a wide clinical spectrum ranging from severe intellectual disability to normal cognitive function. The etiology is expected to be genetic in as much as 30–50% of the cases, but the underlying genetic cause remains unknown in the majority of cases.

Additional functional studies including a systematic search for ARID1B target genes may show how haploinsufficiency of ARID1B predispose to CC defects and to an array of cognitive defects, including severe speech defects

Several readers of this blog have highlighted a recent study:-  

Breakthrough research suggests potential treatment for autism, intellectual disability 

We showed that cognitive and social deficits induced by an Arid1b mutation in mice are reversed by pharmacological treatment with a GABA receptor modulating drug. And, now we have a designer mouse that can be used for future studies." 

The full study:-

Arid1b haploinsufficiency disrupts cortical interneuron development and mouse behavior

Clonazepam also reversed the reduced time spent in the center and reduced moving distance displayed by Arid1b-mutant mice in the open field test (Fig. 7c,d and Supplementary Fig. 14c). However, depression measures, using the forced swim test and the tail suspension test, showed no reversible effect of clonazepam in Arid1b+/− mice compared with controls (Fig. 7e,f). Our results show that clonazepam rescues impaired recognition, social memory, and elevated anxiety in Arid1b+/− mice. 

Our mouse model effectively mirrors the behavioral characteristics of intellectual disability and ASD. Arid1b+/− and Arid1bconditional-knockout mice displayed impaired spatial learning, recognition memory, and reference memory. Open field and social behavior tests also revealed decreased social interaction in the mice. Mice with mutations in genes encoding Smarca2 and Actl6b, other subunits of the BAF complex, have severe defects in social interaction and long-term memory35. Thus, this chromatin remodeling complex may provide a cellular and molecular platform for normal intellectual and social behavior. In addition, Arid1b+/− mice showed heightened levels of anxiety- and depression-related behaviors, which are common symptoms of ASD36. 

For people with intellectual disability, the prevalence of anxiety disorders has likewise been shown to be much higher. This may be due to reduced cognitive function and increased vulnerability to environmental demands. Communication difficulties may also make it more difficult for people with cognitive disabilities to deal with anxiety or fear. ARID1B haploinsufficiency may be responsible for multiple facets of characteristic ASD behaviors. Other isoforms of Arid1b that are not affected by the Arid1b mutation could exist in the mouse line. Additionally, it is possible that the genetic background for the mouse line may impact the effect of Arid1b haploinsufficiency. Thus it is important to consider allele specificity, genetic backgrounds, and knockout strategies for comparing phenotypes of other Arid1bhaploinsufficiency models.  

GABA allosteric modulators, including clonazepam, a benzodiazepine, have been used to treat seizures and anxiety. We found that clonazepam injection rescued deficits in object and social recognition and anxiety in Arid1b+/− mice. These results suggest that treatment with a benzodiazepine could be a potential pharmacological intervention for symptoms of ASD. Furthermore, our results suggest that pharmacological manipulation of GABA signaling is a potential treatment strategy for cognitive and social dysfunctions in ASD- or intellectual disability-associated disorders due to mutations in chromatin remodeling genes.  

ACC Research Foundation

If there actually was an ACC Research Foundation, they could explore whether clonazepam was therapeutic in children who have Arid1b haploinsufficiency.

While they are at it, they might want to look into Hereditary Motor and Sensory Neuropathy with agenesis of the corpus callosum (HMSN/ACC), this is caused by mutations in the potassium-chloride co-transporter 3 (SLC12A6/KCC3) gene. This I stumbled upon a long time ago, when trying to upregulate KCC2, which causes elevated intracellular chloride in many people with autism and likely many with Down Syndrome.

KCC2 is usually associated with neuropathic pain and now we see that so is KCC3. Odd reaction to pain is a well known feature of autism. The rather ill-defined condition of fibromyalgia seems common in female relatives of those with autism and I do not think this is just a coincidence. 

The interesting thing is that the research shows you can potentially upregulate KCC3 with curcumin. 

Transit Defect of Potassium-Chloride Co-transporter 3 Is a Major Pathogenic Mechanism in Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum

HMSN/ACC is a severe and progressive neurodegenerative disease that exhibits an early onset of symptoms. Signs of HMSN/ACC, such as hypotonia and delays in motor development skills, are noticed before 1 year of age. However, the motor abilities of patients progress slowly to 4–6 years of age, and these children are able to stand and walk with some help. This is followed by a motor deterioration that generally renders affected subjects wheelchair-dependent by adolescence. 

Accordingly, we found that curcumin relieved the ER retention of dimerized R207C in mammalian cultured cells. A diet enriched in curcumin may therefore be beneficial for the relief or delay of some of the HMSN/ACC symptoms in patients bearing the R207C mutation, including the Turkish patient described in this study (as patient has not yet reached puberty).

KCC3 defects also cause the very similar Andermann syndrome also known as agenesis of corpus callosum with neuronopathy (ACCPN).

KCC3 defects are associated with epilepsy.

My question was can you have KCC3 under-expression with partial ACC, epilepsy but no peripheral neuropathy? If this was likely, then upregulating KCC3 with curcumin might help.

The gene for KCC3 is located at chromosome 15q14. Based on my “logic of associations”, if you have ACC and epilepsy you should consider KCC3 under-expression.

I did suggest to my former classmate whose son has partial ACC and epilepsy, but no neuropathy, that it might be worth trying some curcumin. Since his son is already on anti-epileptic drugs (AEDs) my suggested effect to look for was improved cognitive function.

6 months later it does indeed, apparently, improve cognitive function.  Of course this does not establish that upregulating KCC3 had anything to do with it. It is nonetheless a nice story and another parent has realized that you can change things for the better, in spite of what neurology currently says. 

The question now is can you have both ARID1B under-expression and KCC3 under-expression, in which case you would add some clonazepam, based on the latest research. At this point you should of course go and talk to your neurologist, rather than read my blog and that was my recommendation. 

Partial agenesis of the corpus callosum in a patient with juvenile myoclonic epilepsy

We describe a patient who presented at our epilepsy-monitoring unit with myoclonic jerks, and was diagnosed with juvenile myoclonic epilepsy (JME). Imaging of his brain revealed partial agenesis of the corpus callosum (ACC). We discuss the known genetic basis of both JME and ACC, as well as the role of the corpus callosum (CC) in primary generalized epilepsy. Both JME and ACC are associated with gene loci on chromosome 15q14. Structural brain abnormalities other than ACC, such as atrophy of the corpus callosum have been reported in patients with JME. ACC has been associated with seizures, suggesting an anti-epileptogenic role of the corpus callosum

Conclusion

If you have a biological diagnosis you are one big step closer to finding a therapy. Even if you have a diagnosis like partial Agenesis of the Corpus Callosum (ACC), you can go one step further and ask why. You have a 50% chance of being able to find out a specific gene that is the cause. If you know with certainty which gene is the originator of the problem, you know a lot.  I think you are then two big steps closer to a therapy.

In the case of Rett Syndrome, a really good website is run by their research foundation (Rett Syndrome Research Trust). They look like they mean business. 

https://reverserett.org/cure/

If you look at the above site you might be left wondering why the much larger and better financed autism organizations look so amateur by comparison.  The big difference is that Rett Syndrome is a biological diagnosis and autism is not. In many ways calling autism a spectrum is not helpful, as the originators of the ASD concept are beginning to realize.  The precise biological dysfunctions are what matter and lumping together hundreds of miscellaneous brain dysfunctions into a pile labelled ASD may not be so clever, in fact I would call it primitive.

Sense, Missense or Nonsense - Interpreting Genetic Research in Autism (TCF4, TSC2 , Shank3 and Wnt)

Some clever autism researchers pin their hopes on genetics, while some equally clever ones are not convinced.

One big problem is that genetic testing is still not very rigorous, it is fine if you know what you are looking for, like a specific single gene defect, but if it is a case of find any possible defect in any of the 700+ autism genes it can be hopeless.

Most of the single gene types of autism can be diagnosed based on known physical differences and then that specific gene can be analyzed to confirm the diagnosis.

Today’s post includes some recent examples from the research, and they highlight what is often lacking - some common sense.

There are numerous known single gene conditions that lead to a cascade of dysfunctions that can result in behaviors people associate with autism.  However in most of these single gene conditions, like Fragile X or Pitt-Hopkins, there is a wide spectrum, from mildly affected to severely affected.

There are various different ways in which a gene can be disturbed and so within a single gene condition there can be a variety of sub-dysfunctions.  A perfect example was recently forwarded to me, a study showing how a partial deletion of the Pitt Hopkins gene (TCF4) produced no physical features of the syndrome, but did unfortunately produce intellectual disability.

The study goes on to suggest that “screening for mutations in TCF4 could be considered in the investigation of NSID (non-syndromic intellectual disability)”

Partial deletion of TCF4 in three generation family with non-syndromic intellectual disability, without features of Pitt-Hopkins syndrome

This all matters because one day when therapies for Pitt Hopkins are available, they would very likely be effective on the cognitive impairment of those with undiagnosed partial-Pitt Hopkins.

Another reader sent me links to the studies showing:-

Rapamycin reverses impaired social interaction in mouse models of tuberous sclerosis complex.

Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis.

But isn’t that Tuberous sclerosis (TSC) extremely rare? like Pitt Hopkins.  Is it really relevant?

Tuberous sclerosis (TSC)  is indeed a rare multisystem genetic disease that causes benign tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. A combination of symptoms may include seizures, intellectual disability, developmental delay, behavioral problems, skin abnormalities, and lung and kidney disease. TSC is caused by a mutation of either of two genes, TSC1 and TSC2, 

About 60% of people with TSC have autism (biased to TSC2 mutations) and many have epilepsy.

How rare is TSC?  According to research between seven and 12 cases per 100,000, with more than half of these cases undetected.  

Call it 0.01%, rare indeed.

How rare is partial TSC?  What is partial TSC?  That is just my name for what happens when you have just a minor missense mutation, you have a mutation in TSC2 but have none of the characteristic traits of tuberous sclerosis, except autism.

In a recent study of children with autism 20% has a missense mutation of TSC2. 

Not so rare after all.

Mutations in tuberous sclerosis gene may be rife in autism

Mutations in TSC2, a gene typically associated with a syndrome called tuberous sclerosis, are found in many children with autism, suggests a genetic analysis presented yesterday at the 2016 International Meeting for Autism Research in Baltimore.

The findings support the theory that autism results from multiple ‘hits’ to the genome.

Tuberous sclerosis is characterized by benign tumors and skin growths called macules. Autism symptoms show up in about half of all people with tuberous sclerosis, perhaps due to abnormal wiring of neurons in the brain. Tuberous sclerosis is thought to result from mutations in either of two genes: TSC1 or TSC2.

The new analysis finds that mutations in TSC2 can also be silent, as far as symptoms of the syndrome go: Researchers found the missense mutations in 18 of 87 people with autism, none of whom have any of the characteristic traits of tuberous sclerosis.

“They had no macules, no seizure history,” says senior researcher Louisa Kalsner, assistant professor of pediatrics and neurology at the University of Connecticut School of Medicine in Farmington, who presented the results. “We were surprised.”

The researchers stumbled across the finding while searching for genetic variants that could account for signs of autism in children with no known cause of the condition. They performed genetic testing on blood samples from 87 children with autism.

Combined risk:

To see whether silent TSC2 mutations are equally prevalent in the general population, the researchers scanned data from 53,599 people in the Exome Aggregation Consortium database. They found the mutation in 10 percent of the individuals.

The researchers looked more closely at the children with autism, comparing the 18 children who have the mutation with the 69 who do not.

Children with TSC2 mutations were diagnosed about 10 months earlier than those without a mutation, suggesting the TSC2 mutations increase the severity of autism features. But in her small sample, Kalsner says, the groups show no differences in autism severity or cognitive skills. The researchers also found that 6 of the 18 children with TSC2 mutations are girls, compared with 12 of 69 children who don’t have the mutation.

TSC2 variants may combine with other genetic variants to increase the risk of autism. “We don’t think TSC is the sole cause of autism in these kids, but there’s a significant chance that it increases their risk,” Kalsner says.

Effects of Combining Rapamycin and Resveratrol on Apoptosis and Growth of TSC2-Deficient Xenograft Tumors

"hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) is a consequence of tuberous sclerosis complex (TSC) 1/2 inactivation."

"the combination of rapamycin and resveratrol may be an effective clinical strategy for treatment of diseases with mTORC1 hyperactivation."

So for the 20% of autism with partial TSC, so-called Rapalogs and other mTOR inhibitors could be helpful, but Rapalogs all have side effects.

One interesting option that arose in my earlier post on Type 3 diabetes and intranasal insulin is Metformin. The common drug used for type 2 diabetes.

 

Metformin regulates mTORC1 signaling (but so does insulin).

'Metformin activates AMPK by inhibiting oxidative phosphorylation, which in turn negatively regulates mTORC1 signaling via activation of TSC2 and inhibitory phosphorylation of raptor. In parallel, metformin inhibits mTORC1 signaling by suppressing the activity of the Rag GTPases and upregulating REDD1."

Source:  Rapalogs and mTOR inhibitors as anti-aging therapeutics

Clearly you could also just use intranasal insulin.  It might be less potent but should have less side effects because it acting only within the CNS (Metfornin would be given orally).

The Shank protein and the Wnt protein family

Mutations in a gene called Shank3 occur in about 0.5 percent of people with autism.  
But what about partial Shank3 dysfunction?

Shank proteins also play a role in synapse formation and dendritic spine maturation.

Mutations in this gene are associated with autism spectrum disorder. This gene is often missing in patients with 22q13.3 deletion syndrome

Researchers at MIT have just shown, for the first time, that loss of Shank3 affects a well-known set of proteins that comprise the Wnt signaling pathway.  Without Shank3, Wnt signaling is impaired and the synapses do not fully mature.

Neuroscientists illuminate role of autism-linked gene

“The finding raises the possibility of treating autism with drugs that promote Wnt signaling, if the same connection is found in humans”

I have news for MIT, people already do use drugs that promote Wnt signaling, FRAX486 and Ivermectin for example.  All without any genetic testing, most likely.

Reactivating Shank3, or just promote Wnt signaling

The study below showed that in mice, aspects of autism were reversible by reactivating the Shank3 gene.  You might expect that in humans with a partial Shank3 dysfunction you might jump forward to the Wnt signaling pathway and intervene there.

Mouse study offers promise of reversing autism symptoms

One reader of this blog finds FRAX486 very helpful and to be without harmful side effects.  FRAX 486 was recently acquired by Roche and is sitting over there on a shelf gathering dust.

Where from here?

I think we should continue to look at the single gene syndromes but realize that very many more people may be partially affected by them.

Today’s genetic testing gives many false negatives, unless people know what they are looking for; so many dysfunctions go unnoticed.

This area of science is far from mature and there may be many things undetected in the 97% of the genome that is usually ignored that affect expression of the 3% that is the exome.

So best not to expect all the answers, just yet, from genetic testing; maybe in another 50 years.

Understanding and treating multiple-hit-autism, which is the majority of all autism, will require more detailed consideration of which signaling pathways have been disturbed by these hits.  There are 700 autism genes but there a far fewer signaling pathways, so it is not a gargantuan task.  For now a few people are figuring this out at home.   Good for them.

I hope someone does trials of metformin and intranasal insulin in autism.  Intranasal insulin looks very interesting and I was surprised to see in those earlier posts is apparently without side effects.

The odd thing is that metformin is indeed being trialed in autism, but not for its effect on autism, but its possible effect in countering the obesity caused by the usual psychiatric drugs widely prescribed in the US to people with autism.

My suggestion would be to ban the use of drugs like Risperdal, Abilify, Seroquel, Zyprexa etc.

Vanderbilt enrolling children with autism in medication-related weight gain study

Here are details of the trial.

Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD) (MET)

Metformin will be dispensed in a liquid suspension of 100 mg/mL. For children 6-9 years of age, metformin will be started at 250 mg at their evening meal for 1 week, followed by the addition of a 250 mg dose at breakfast for 1 week. At the Week 2 visit, if metformin is well-tolerated, the dose will be increased to 500 mg twice daily. For children from 10-17 years of age, metformin will be started at 250 mg at their evening meal for 1 week, followed by the addition of a 250 mg dose at breakfast for 1 week. At the Week 2 visit, if metformin is well-tolerated, the dose will be increased to 500 mg twice daily. At the Week 4 visit, if metformin is well-tolerated, the dose will be increased to 850 mg twice daily.

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

 Peter the wild boy, with Pitt Hopkins Syndrome

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 18^th 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. 

Table 1.  Summary of GABAA signaling alterations in neurodevelopmental disorders (click for the full Table)

·        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.

GABA_A 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.

Modulation of GABAergic transmission indevelopment and neurodevelopmental disorders: investigating physiology andpathology to gain therapeutic perspectives

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.

Chloride extrusion enhancers as novel therapeutics for neurological diseases

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.

Association Between Obstetric Mode of Delivery and Autism Spectrum Disorder - :  A Population-Based Sibling Design Study

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 GABA_A 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.