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Showing posts with label Agenesis of the Corpus Callosum. Show all posts
Showing posts with label Agenesis of the Corpus Callosum. Show all posts

Thursday, 15 August 2019

Wandering, Water, Sense of Danger and Accidents


We were recently at the seaside in Greece, where Monty was enjoying swimming in the sea. He is now a very competent swimmer and behaves in the water just like any other confident swimmer. Together with Mum he actually rescued a Russian swimmer in distress.  Monty does not get crazy ideas to swim to islands in the distance, or anything like that. Not so far, at least. 

Water is behind a shocking number of wanderings and deaths.

In the North American media, you can see that on a very regular basis children with autism and/or ID/MR (Intellectual Disability/Mental Retardation) wander off and get lost. Very often they are found in or beside water.

In Europe you hear much less frequently about children wandering. A high-profile case recently was an Irish teenage girl with MR/ID who disappeared while on holiday at a tiny jungle resort in Malaysia.  She left behind an open ground floor window and was found 10 days later beside a stream in a ravine a mile away. 

She had holoprosencephaly, which is an umbrella term for conditions relating to when the forebrain of the embryo fails to develop into two separate hemispheres, it includes Agenesis of the Corpus Callosum (ACC) when the part of the brain that is supposed to connect the two hemispheres fails to develop. Partial ACC and the exact opposite are features appearing in some severe autism.

People with MR/ID have no sense of danger and are usually enchanted by water. Wandering is far more likely than abduction.

Another case recently was an American teenager on a cruise arranged by his residential care home, it appears that he jumped over the deck railing at night to go for a swim in the ocean.

Even a bath tub can be dangerous, a young man with autism and epilepsy was left unattended in a bath at a UK care facility. He had a seizure and drowned.

I do think much more could be done to prevent wandering and water-related accidents. Firstly, people (parents) should be made more aware of who is at risk; anyone with a low IQ and unable to travel independently is at risk.

People with ID/MR often live in a world of cartoons, where all kinds of crazy things are possible, like jumping off a cruise ship and nobody ever gets hurt.  Going to a jungle retreat, like you are living in the Jungle Book cartoon, why wouldn’t you sneak downstairs in the night and enter your private jungle world?

Just because you have never been able to wander before does not mean you never will. 

The shortened life expectancy of people with severe autism is in large part down to preventable accidents, seizures and poor basic healthcare.

I do think that treating MR/ID would be much more socially acceptable than treating autism. Understanding the danger of crossing a road, or falling into a lake is more important than being able to tie your shoe laces.  If you can improve cognition with a pill, who could possibly object to that? 

It is no surprise that we have www.Treatable-ID.org but no www.Treatable-ASD.org 

In reality you will struggle to have treating ID taken seriously, although for many people it is possible.




Friday, 19 January 2018

Glass Syndrome / SATB2-associated syndrome – Osteoporosis and ERβ


The world’s longest glass bridge is in China.

Today’s post is about Glass Syndrome / SATB2-associated syndrome, it occurs when something goes wrong with a gene called SATB2; there are several variants because different mutations in this gene are possible.

Glass Syndrome / SATB2-associated syndrome is another of those single gene types of autism, so you can think of SATB2 as another autism gene.  As we will see in today’s post SATB2 is involved in much more than autism and is very relevant to osteoporosis and some types of cancer.

While autism caused by SATB2 is very rare, diseases in old age quite often involve the SATB2 gene being either over expressed or under expressed. As a result there is much more research on SATB2 than I expected.

The current research into Glass Syndrome / SATB2-associated syndrome is mainly collecting data on those affected, rather than investigating therapies. There are some links later in this post, for those who are interested.

The research into SATB2, unrelated to childhood developmental disorders, is much more science heavy and already contains some interesting findings.   

I have only made a shallow study, but it seems that you can reduce SATB2 expression with a drug called Phenytoin and potentially increase expression via an estrogen receptor beta agonist. We saw in earlier posts that an estrogen receptor beta agonist might well be helpful in broader autism.

As with other single gene types of autism, it will be important to look at all the downstream effects caused by a lack of SATB2, some of which will very likely overlap with what occurs in some idiopathic autism or with other single gene autisms.

In Johns Hopkins’ simplification of autism into either hyper-active pro growth signaling, or hypo-active, SATB2 fits into the latter. It is associated with small heads and a small corpus callosum; that is the part that joins the left side of the brain to right side.

I think it is fair to say that SATB2 is associated with partial agenesis of the corpus callosum (ACC), a subject that has been covered in earlier posts.

I have mentioned two therapies recently that seem to help in certain variants of  ACC. The reason SATB2 causes partial agenesis of the corpus callosum (ACC) is well understood.  SATB2 needs to be expressed in the neurons that extend axons across the corpus callosum, in effect you need to build a bridge across from one side of the brain to the other and all the connections across that bridge need to match up and not be jumbled up. In some people with SATB2 they have an apparently normal corpus callosum (the bridge) but it does not work properly (the connections do not function).

SATB2 is also associated with a cleft palette, this occurs because the roof of the mouth (another bridge) does not join correctly left to right. You end up with an unwanted opening into the nose.

Building bridges is never an easy business. The Chinese have found this with their recent glass bridges, as in this post’s photo above. It looks like SATB2 is the “bridging” protein for humans, if the SATB2 gene is mutated you do not make enough of the SATB2 protein. The less SATB2 expression the more consequences there will be.

The other extreme also exists, too much SATB2 expression. That will lead to too much growth which makes it another cancer gene. In cases of aggressive prostate cancer SATB2 is over-expressed. So a therapy to slow this cancer would be to reduce SATB2 expression. For Glass Syndrome we would want the opposite. 

There is SATB2 associated syndrome research, but it is still at the stage of collecting data on people who are affected and investigating what particular mutation is present.

The logical next stage is to see more precisely the role SATB2 plays in different parts of the brain. By seeing how SATB2 interacts with the world around it, it may be possible to correct for the lack of it.  For example there is an interaction with Ctip2, a transcription factor that is necessary and sufficient for the extension of subcortical projections by cortical neurons. This look very relevant to building bridges.

Confusingly, Ctip2 is also called B-cell lymphoma/leukemia 11B encoded by the BCL11B gene. 






The research relating your bones looks the most advanced and already suggests possible therapies to both increase and reduce SATB2 expression.



The above paper (the full version is not public)  is very detailed and shows how important SATB2 may be in bone diseases and therefore be of wide clinical relevance.  It also suggests that it could be treated by gene therapy.






Molecular Regulation of SATB2 by Cytokines and Growth Factors

It appears that the anti-epileptic drug (AED) Phenytoin reduces SATB2 expression, which is the opposite of what we want, but shows that modification is possible.

Osteoporosis,  SATB2, Estrogen and ERβ
There already is much in this blog about estrogen/estradiol and estrogen receptor beta. There are was a phase in this blog when there were many comments about disturbed calcium metabolism in family members.
It appears they may be connected via SATB2.
Older people lack estrogen, particularly females, and this is associated with osteoporosis.
Very recent research shows that there is an ERβ-SATB2 pathway (ERβ = estrogen receptor beta, which is activated by estrogen). So a reduction in estrogen during aging reduces signaling along the ERβ-SATB2 pathway (making less SATB2).
We know from earlier posts that people with autism tend to have a reduced number of ERβ receptors and also a lower level of estrogen/estradiol. This might explain some of the problems readers reported with bones in their family members.
This raises the question of what happens to SATB2 expression when you add a little extra estrogen/estradiol. The implication from the Chinese study highlighted later is that this may well be one way to make more SATB2 from the non-mutated copy that you have (you likely have one mutated copy and one clean copy of this gene). This is something that should be investigated.


How to treat Glass Syndrome/SATB2?
Ideally you would use gene therapy to treat Glass Syndrome/SATB2; this will in future decades very likely be possible.  In the meantime the more old-fashioned options must be relied upon.
We know that people with partial agenesis of the corpus callosum (ACC) face challenges, some of which match those faced  with Glass Syndrome/SATB2. We know certain types of ACC do respond to treatment, based on research, so it would seem highly likely that treatment for  Glass Syndrome/SATB2 should be possible.
Very likely some of the myriad of treatments researched for autism may be helpful. But which ones?
The treatment proposed by Knut Wittkowski for very early intervention in idiopathic autism to alter the trajectory from severe autism towards Asperger’s looks interesting and particularly because our reader Ling finds it helpful for her daughter with SATB2. Knut’s research identified Ponstan (mefenamic acid) as a target drug to minimize the cascade of damaging events that occurs as autism progresses in early childhood.
Here you would hope that some researcher would create a mouse model of Glass Syndrome/SATB2 and then see if Ponstan (mefenamic acid) has any effect, not to mention estradiol.


Websites with Information on Glass Syndrome/ SATB2 associated syndrome 






Some Research Relating to SATB2


Satb2 is a DNA-binding protein that regulates chromatin organization and gene expression. In the developing brain, Satb2 is expressed in cortical neurons that extend axons across the corpus callosum. To assess the role of Satb2 in neurons, we analyzed mice in which the Satb2 locus was disrupted by insertion of a LacZ gene. In mutant mice, β-galactosidase-labeled axons are absent from the corpus callosum and instead descend along the corticospinal tract. Satb2 mutant neurons acquire expression of Ctip2, a transcription factor that is necessary and sufficient for the extension of subcortical projections by cortical neurons. Conversely, ectopic expression of Satb2 in neural stem cells markedly decreases Ctip2 expression. Finally, we find that Satb2 binds directly to regulatory regions of Ctip2 and induces changes in chromatin structure. These data suggest that Satb2 functions as a repressor of Ctip2 and regulatory determinant of corticocortical connections in the developing cerebral cortex.


Striatal medium spiny neurons (MSN) are critically involved in motor control, and their degeneration is a principal component of Huntington's disease. We find that the transcription factor Ctip2 (also known as Bcl11b) is central to MSN differentiation and striatal development. Within the striatum, it is expressed by all MSN, although it is excluded from essentially all striatal interneurons. In the absence of Ctip2, MSN do not fully differentiate, as demonstrated by dramatically reduced expression of a large number of MSN markers, including DARPP-32, FOXP1, Chrm4, Reelin, MOR1 (μ-opioid receptor 1), glutamate receptor 1, and Plexin-D1. Furthermore, MSN fail to aggregate into patches, resulting in severely disrupted patch-matrix organization within the striatum. Finally, heterotopic cellular aggregates invade the Ctip2−/− striatum, suggesting a failure by MSN to repel these cells in the absence of Ctip2. This is associated with abnormal dopaminergic innervation of the mutant striatum and dramatic changes in gene expression, including dysregulation of molecules involved in cellular repulsion. Together, these data indicate that Ctip2 is a critical regulator of MSN differentiation, striatal patch development, and the establishment of the cellular architecture of the striatum.







Neuroimaging. Brain abnormalities, documented in half of affected individuals who underwent head MRI, include nonspecific findings such as enlarged ventricles (12%), agenesis of the corpus callosum (5%), and prominent perivascular spaces (5%). Of interest, abnormal myelination for age and/or non-progressive white matter abnormalities appear to be particularly common (26%) in those with pathogenic nonsense, frameshift, and missense variants [Zarate & Fish 2017, Zarate et al 2017a]. Note that these findings are not sufficiently distinct to specifically suggest the diagnosis of SAS.

Other neurologic manifestations

·         Hypotonia, particularly during infancy (42%)
·         Clinical seizures (14%)
·         EEG abnormalities without clinically recognizable seizures [Zarate et al 2017a]
·         Less common neurologic issues include gait abnormalities/ataxia (17%), hypertonicity and/or spasticity (4%), and hyperreflexia (3%).



Growth restriction. Pre- and postnatal growth restriction, sometimes with associated microcephaly, can be found in individuals with SAS, particularly in those with large deletions involving SATB2 and adjacent genes (71%).

This is likely to be the most relevant paper, even though the tittle might not suggest it:-


Decline of pluripotency in bone marrow stromal cells (BMSCs) associated with estrogen deficiency leads to a bone formation defect in osteoporosis. Special AT-rich sequence binding protein 2 (SATB2) is crucial for maintaining stemness and osteogenic differentiation of BMSCs. However, whether SATB2 is involved in estrogen-deficiency associated-osteoporosis is largely unknown. In this study, we found that estrogen mediated pluripotency and senescence of BMSCs, primarily through estrogen receptor beta (ERβ). BMSCs from the OVX rats displayed increased senescence and weaker SATB2 expression, stemness, and osteogenic differentiation, while estrogen could rescue these phenotypes. Inhibition of ERβ or ERα confirmed that SATB2 was associated with ERβ in estrogen-mediated pluripotency and senescence of BMSCs. Furthermore, estrogen mediated the upregulation of SATB2 through the induction of ERβ binding to estrogen response elements (ERE) located at -488 of the SATB2 gene. SATB2 overexpression alleviated senescence and enhanced stemness and osteogenic differentiation of OVX-BMSCs. SATB2-modified BMSCs transplantation could prevent trabecular bone loss in an ovariectomized rat model. Collectively, our study revealed the role of SATB2 in stemness, senescence and osteogenesis of OVX-BMSCs. Collectively, these results indicate that estrogen prevents osteoporosis by promoting stemness and osteogenesis and inhibiting senescence of BMSCs through an ERβ-SATB2 pathway.

Therefore, SATB2 is a novel anti-osteoporosis target gene.

3.2 Estrogen enhanced SATB2 levels, pluripotency and alleviated senescence of OVX-BMSCs.

Estrogen has been shown to promote bone formation and proliferation both in vivo and in vitro (Wang, J. et al., 2014; Du, Z. et al., 2015; Kim, R. Y. et al., 2015), so we asked whether estrogen affected SATB2 expression, stemness and osteogenic differentiation of BMSCs. We found that both Sham-BMSCs and OVX-BMSCs treated with 10-8M estrogen (Matsumoto, Y. et al., 2013) regained the colony forming capacity as compared to the control (Fig. 2A). Higher expression levels of SATB2, Nanog, Sox2 and Oct4, were observed in BMSCs treated with estrogen relative to the control group (Fig. 2B, C). These results were further confirmed by human BMSCs (Fig. 2D). The role of estrogen on anti-senescence was verified by the decreased SA-β-gal positive cells and alleviated expression of senescence markers (Fig. 2E, F). After osteogenic induction, the expression of osteogenic markers, Runx2 and OCN, significantly increased (Fig. 2G and H). Consistently, estrogen significantly enhanced the mineralized node formation (Fig. 2I). Interestingly, the expression of osteoclast-related activator, RANKL, and inhibitor, OPG, significantly changed in OVX-BMSCs treated with estrogen (Fig. 2J).

Together, these results suggest that estrogen rescued pluripotency and alleviated senescence of OVX-BMSCs accompanied by a higher expression of SATB2.



3.4 SATB2 is a confirmed target of ERβ.  
Estrogen is known to regulate gene expression by binding to ERs, which subsequently binds to EREs present in promoters (Klinge, C. M. 2001). Analysis of 2 kb upstream and 50bp downstream of SATB2, using Promo 3.0 software, showed the presence of three putative EREs that had (achieved through site-directed mutagenesis at the ERβ binding site in the SATB2 promoter). As anticipated, ERβ overexpression induced by estrogen increased luciferase activity in wild-type but not mutant promoter region A (Fig. 4C, D). 
 Further, to check dynamic recruitment of ERβ to the EREs following estrogen treatment, we used chromatin immunoprecipitation (CHIP). CHIP analysis was conducted in OVX-BMSCs with or without estrogen treatment using antibodies specific to ERβ or IgG control. This revealed that following estrogen treatment, various putative EREs facilitated dynamic recruitment of ERβ. Furthermore, the binding of ERβ was considerably more robust in region A than other regions (Fig. 4E). Thus, the induction of SATB2 by estrogen is mediated by the binding of ERβ to various EREs present in the SATB2 promoter.

Discussion


Although it is well-known that osteoporosis due to estrogen deficiency is associated with bone loss, the detailed mechanisms underlying this are not fully understood (Liao, L. et al., 2013; Villa, A. et al., 2015; Wang, J. et al., 2016). We recently found that the expression of SATB2 was associated with ERs, especially ERβ, after estrogen treatment of BMSCs (Fig. 3A). In this study, we successfully established an ovariectomized rat model of postmenopausal osteoporosis and showed that STAB2 was associated with estrogen-ERβ complex in OVX-BMSCs. Moreover, our data demonstrated that SATB2 was a downstream effector of ERβ. The induction of SATB2 by estrogen was mediated by binding of ERβ to various EREs present upstream of SATB2. Our study suggested the central role of SATB2 in the etiology of postmenopausal osteoporosis, suggesting it as a candidate target of osteoporosis prevention and treatment.



                                                                                                                                 


Conclusion
Our reader Ling is busy researching this syndrome and this is a good place to post comments with her findings, so others can find them later.







Thursday, 23 November 2017

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. 


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. 


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

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. 

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. 


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 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:-  


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:-


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. 

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. 


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. 


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.









Tuesday, 5 September 2017

Autism MRI



Source: Brain MR Imaging Findings and Associated Outcomes in Carriers of the Reciprocal Copy Number Variation at 16p11.2


In the early days of this blog, one medical reader told me that in cases of autism an MRI scan of the brain should appear normal.
This also fits with the idea that once you have a biological diagnosis, you no longer have a case of “autism”. It is only Autism, when it is of unknown origin.  
People who have a single gene type of autism actually can have significant variations in brain structure that appear clearly on an MRI.  This was the subject of a recent study and the source of the MRI in this post.




Many people with autism have abnormalities at a specific site on the 16th chromosome known as 16p11.2. Deletion or duplication of a small piece of chromosome at this site is one of the most common genetic causes of autism spectrum disorder.
People with deletions tend to have brain overgrowth, developmental delays and a higher risk of obesity.
Those with duplications are born with smaller brains and tend to have lower body weight, but also developmental delays. 
For regular readers of this blog there are some interesting points to note.

Agenesis of the Corpus Callosum

The corpus callosum is a wide, flat bundle of fibers about 10 cm long that connects the left and right sides of the brain.  It facilitates communication between the two sides of the brain.
Agenesis of the corpus callosum (ACC) is a birth defect in which there is a complete or partial absence of the corpus callosum.
ACC leads to behaviors compatible with a diagnosis of autism or Asperger’s in about half of cases.
Symptoms of ACC vary greatly among individuals, as they do in all types of autism.  Seizures are common, some people have poor motor coordination, and some people are non-verbal.  My original post on the subject:-


Agenesis of the Corpus Callosum (ACC)                                                                                 
You may recall that in the film Rain Man, Dustin Hoffman’s character was inspired by a man with ACC called Kim Peak.  It is now thought that Peak had FG Syndrome and this is what caused his ACC. It appears that his brain adapted and made unusual connections leading to his remarkable memory.
The Corpus Callosum is clearly visible on an MRI.
In 16p11.2. deletion you end up with an overgrown (thick) corpus callosum, while in 16p11.2. duplication you end up with a thin corpus callosum, which equates to a partial Agenesis of the Corpus Callosum.                                
At least one reader of this blog has a case of partial Agenesis of the Corpus Callosum and as he told me, it is not autism it is ACC.


Chiari 1 “brain hernia”
Another point of interest on the above MRI has been highlighted as Cerebellar Ectopia. Now if they had called it a Chiari malformation, you might have linked it to an old post on this blog.


In people with brain overgrowth and/or a small skull, what happens when there is no space left for a growing brain? Well it appears that pressure builds up and you get a kind of hernia with the brain expanding downwards into the spine.
This is called a Chiari 1 malformation and it seems to be quite common in the types of autism associated with over active pro-growth signalling pathways.
Since 16p11.2 deletion is associated with too much growth (thick corpus callosum, brain overgrowth and obesity) we should not be surprised that they often present with Chiari 1 “brain hernia”, which is treatable and this should improve symptoms. 

Conclusion

An MRI can sometimes tell you a lot, when you know what to look for and clearly should be carried out on anyone diagnosed with disabling autism.
Undoubtedly there are other areas of the brain where important variances occur.
This would provide useful data to assign individuals with autism into subgroups and hence improve the chance of finding effective therapy.  What works for Peter may help Paul, but what works for Zach probably will not help Amber.