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. 

A dual function of Bcl11b/Ctip2 in hippocampal neurogenesis.

BCL11B/CTIP2 is highly expressed in GABAergic interneurons of the mouse somatosensory cortex

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

The role of SATB2 in skeletogenesis and human disease

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 

http://satb2gene.com/

http://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.38022/pdf

https://ghr.nlm.nih.gov/condition/satb2-associated-syndrome#synonyms

Some Research Relating to SATB2

Satb2 Regulates Callosal Projection Neuron Identity in the Developing Cerebral Cortex

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.

Ctip2 Controls the Differentiation of Medium Spiny Neurons and the Establishment of the Cellular Architecture of the Striatum

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.

Upregulation of SATB1 Is Associated with Prostate Cancer Aggressiveness and Disease Progression

Genotype and Phenotype in 12 additional individuals withSATB2-Associated Syndrome

SATB2-Associated Syndrome

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:-

Estrogen regulates stemness and senescence of bone marrow stromal cells to prevent osteoporosis via ERβ-SATB2 pathway

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.

A RORα Agonist for Autism?

Today’s post is again about RORα, which was suggested to be a nexus where different biological dysfunctions that lead to autism may converge. I think you can consider RORα like a dimmer switch on your lights, you need to adjust the brightness to give the effect you want.

Fine tuning RORα to tune autism gene expression

I recently came across some research where the scientist clearly has the same idea. He has been working on a synthetic RORα/γ agonist for some years and has investigated its use as both a cancer therapy and an autism therapy.

I have become rather interested in cancer therapies because there are so many overlaps between what can lead to cancer and what exists in autism. The big research money is of course in cancer research.

Tumor suppressor genes/proteins like PTEN and p53 have been shown to be disturbed in autism, as is Bcl-2. The Bcl-2 family of proteins regulate cell death (apoptosis); some members induce cell death and other inhibit it; the balance is important.

Generally it seems that most people with autism might benefit from more PTEN and Bcl-2. 

Therapeutic Effect of a Synthetic RORα/γ Agonist in an Animal Model of Autism  

Autism is a developmental disorder of the nervous system associated with impaired social communication and interactions as well excessive repetitive behaviors. There are no drug therapies that directly target the pathology of this disease. The retinoic acid receptor-related orphan receptor α (RORα) is a nuclear receptor that has been demonstrated to have reduced expression in many individuals with autism spectrum disorder (ASD). Several genes that have been shown to be downregulated in individuals with ASD have also been identified as putative RORα target genes. Utilizing a synthetic RORα/γ agonist, SR1078, that we identified previously, we demonstrate that treatment of BTBR mice (a model of autism) with SR1078 results in reduced repetitive behavior. Furthermore, these mice display increased expression of ASD-associated RORα target genes in both the brains of the BTBR mice and in a human neuroblastoma cell line treated with SR1078. These data suggest that pharmacological activation of RORα may be a method for treatment of autism. 

The RORs have been linked to autism in human in several studies. In 2010, Nguyen and co-workers reported that RORα protein expression was significantly reduced in the brains of autistic patients and this decrease in expression was attributed to epigenetic alterations in the RORA gene.¹⁵ Additional work from this group demonstrated that multiple genes associated with autism spectrum disorder are direct RORα target genes and suggested that reduction of RORα expression results in reduced expression of these genes associated with the disorder leading to the disease.¹⁶ Independently, Devanna and Vernes demonstrated that miR-137, a microRNA implicated in neuropsychiatric disorders, targets a number of genes associated with autism spectrum disorder including RORA.¹⁷ There are also additional links between RORα and autism. Deficiency of Purkinje cells is one of the most consistently identified neuroanatomical abnormalities in brains from autistic individuals^18,19 and RORα is critical in development of the Purkinje cells.²⁰⁻²³ Significant circadian disruptions have also been recognized in autistic patients,²⁴⁻²⁷ and RORs play a critical role in regulation of the circadian rhythm.^7,28 Additionally, the staggerer mouse displays behaviors that are associated with autism including abnormal spatial learning, reduced exploration, limited maze patrolling, and perseverative behavior relative to wt mice.²⁹⁻³³

SR1078 is a relatively low potency compound with limited RORα efficacy (3–5 μM EC₅₀E_max ∼ 40%),⁸ but the efficacy compares favorably to other classes of compounds that have been optimized such as a 38% decrease in the same model induced by the mGluR5 allosteric modulator GRN-529⁴⁹ and a 47% reduction by the mGluR5 antagonist MPEP.⁴⁵ Both of these compounds have been optimized and display high potency (single digit nanomolar range at mGluR5) and strong efficacy.^53,54 Thus, we believe that focused optimization of RORα ligands will provide compounds that will have improved efficacy in this model. It should also be noted that SR1078 has both RORα and RORγ agonist activity⁸ and a RORα selective agonist has not yet been developed. Thus, it is possible that the RORγ activity of this compound may also play a role in its efficacy in this model of autism. In summary, we have demonstrated that a synthetic RORα/γ agonist is able to increase the expression of key genes whose decrease in expression is associated with ASD both in cell culture and in vivo. Furthermore, the agonist decreases repetitive behavior in an animal model of autism suggesting that it is possible that ROR agonists may hold utility in treatment ASD. 

Regulation of p53 Stability and Apoptosis by a ROR Agonist

Activation of p53 function leading to cell-cycle arrest and/or apoptosis is a promising strategy for development of anti-cancer therapeutic agents. Here, we describe a novel mechanism for stabilization of p53 protein expression via activation of the orphan nuclear receptor, RORα. We demonstrate that treatment of cancer cells with a newly described synthetic ROR agonist, SR1078, leads to p53 stabilization and induction of apoptosis. These data suggest that synthetic ROR agonists may hold utility in the treatment of cancer.  

Levels of Bcl-2 and P53 Are Altered in Superior Frontal and Cerebellar Cortices of Autistic Subjects 

Results showed that levels of Bcl-2 decreased by 38% and 36% in autistic superior frontal and cerebellar cortices, respectively when compared to control tissues. By the same token, levels of P53 increased by 67.5% and 38% in the same brain areas in autistic subjects vs. controls respectively. Calculations of ratios of Bcl-2/P53 values also decreased by 75% and 43% in autistic frontal and cerebellar cortices vs. controls respectively. The autistic cerebellar values were significantly reduced (p < 0.08) vs. control only. There were no significant differences in levels of β-actin between the two groups. Additionally, there were no correlations between Bcl-2, P53, and β-actin concentrations vs. age or PMI in either group.

These results confirm and extend previous data that levels of Bcl-2 and P53 are altered in three important brain tissues, i.e. frontal, parietal, and cerebellar cortices of autistic subjects, alluding to deranged apoptotic mechanisms in autism.  

Conclusion

Increasing PTEN and Bcl-2 is already part of my Polypill, via the use of Atorvastatin.

There are of course many other genes miss-expressed in autism and we cannot give a drug for each one. We need to identify a handful of nexus, where multiple anomalies can be resolved with a single intervention.

It is good that Thomas Burris, the lead researcher, has been working on SR1078 for at least 6 years, let’s hope he continues to persevere.

I think it highly likely that some types of autism will need the opposite therapy, a RORα antagonist.

My method of attempting to modulate RORα will be different. I come back to my earlier gross simplification of autism :- 

As we have seen in earlier posts, the hormonal dysfunction, this time the balance between testosterone and estradiol, has a direct effect on RORα (and vice versa).

The schematic illustrates a mechanism through which the observed reduction in RORA in autistic brain may lead to increased testosterone levels through downregulation of aromatase. Through AR, testosterone negatively modulates RORA, whereas estrogen upregulates RORA through ER.

androgen receptor = AR 

estrogen receptor = ER

As you might know, many hormones are interrelated, so what are thought of as male/female sex hormones have much wider effects. They impact growth hormones and play a big role in calcium metabolism. They also affect serotonin.

We know that in most autism aromatase is reduced, estradiol is reduced and that there is reduced expression of estrogen receptor beta.

In the ideal world it might indeed be best to use an agonist or antagonist to fine tune RORα.

We have a chicken and the egg situation. Is RORα out of tune in autism because the hormones are disturbed, or vice versa?

We do know that hormones generally have feedback loops, but we also know that increasing a hormone like estradiol via obesity is not fully matched by a corresponding reduction in aromatase. So it looks highly plausible that you can tune RORα via estradiol, and that this could be a long term strategy, not just a short term strategy.

In the case of people with low T3 thyroid hormone centrally (in the brain), giving exogenous T3 may help initially, but in the long term it does not because feedback loops to the thyroid will reduce production of the pro-hormone T4. In the extreme you will make the thyroid gland shut down, this does happen to people using thyroid hormones for depression and even weight loss. 

T3 is quite commonly prescribed by alternative practitioners in the US for autism and also for depression in older people. In Europe this hormone is rarely even available. 

Many phytoestrogens are used as OTC autism therapies. These are dietary estrogens that are structurally similar to the human hormone estradiol and so produce estrogen-like effects. They include soy products, fenugreek, kudzu, EGCG etc.

Turner Syndrome, Estradiol and Autism-lessons from the X Chromosome

This post is best read if you have reviewed the earlier ones regarding the estradiol/testosterone disturbances in autism and how they govern the RORα “switch” that then triggers a torrent of other dysfunctions. So the hormonal disturbance, if present, is a key point at which to make a potent intervention. 

The Purkinje-RORa-Estradiol-Neuroligin-KCC2 axis in Autism 

Beauty is in the eye of the beholder

In the mass media it is now popular to dismiss the fact that autism is far more prevalent on boys than girls. In the scientific literature, fortunately, they stick to the facts and much is written about the sex differences in autism.

As we have seen in earlier posts, females have some natural defences against autism. They have two X chromosomes and of course they have those all-important neuroprotective female hormones (estrogen/estradiol, progesterone etc.). In effect, the more female you are, the more protection you have against idiopathic autism and any X-chromosome linked single gene autism. So a girl with Fragile-X syndrome is likely to be far less affected than her brother with same condition.
Recall that we all have 23 pairs of chromosomes and that the 23^rd set contains two Xs in girls and in boys one X and one Y. The girls’ “spare” X chromosome is also what gives them their feminine features.  

It is interesting to look what happens to females who lack part of their second set of X- chromosomes. This diagnosis is called Turner Syndrome. As you might have guessed people with Turner Syndrome have much lower levels of female hormones and a higher incidence of autism, although some people find this controversial. The autism-like characteristics of TS include:-

·      Impairments in social functioning

·      Impairments in face and emotion processing

·      Spatial executive deficits

·      Poor social coping skills and increased immaturity

·      Hyperactivity and impulsivity

Turner syndrome occurs in 50 per 100,000 live-born females. Autism occurs about ten times for frequently, so about 500 per 100,000 live-born females.  Turner syndrome provides the extreme case of what happens when females have too little estrogen/estradiol.

I think you will find a large group of females with idiopathic autism (no identified genetic defects) have/had low levels of estradiol. I think this is the reason that facial recognition studies show that some females with idiopathic autism look different, (as do many boys, of course). We already know that most single gene types of autism produce tell-tale signs, often on the face (big ears, wide face, big/small head etc).

I am not suggesting that there is anything wrong with looking different; rather it may be a useful diagnostic tool and not an expensive or invasive one. Physical variation has long been used to identify genetic syndromes, before genetic testing became widely available.

Physical variation inside your head

We saw in an earlier post that MRI scans of the autistic brains actually do often show subtle differences, particularly when you use software to read them, rather than the naked eye. Traditionally doctors say that MRIs are “normal” in autism and cannot be used to diagnose it. Yet in a recent studies machine reading of MRIs was able to identify 70%-96% of autism cases.  Some of these are scans taken before birth.

This is interesting, because ultimately you might bypass the current very slow and subjective observational diagnosis process.

Brain imaging studies seek signs of autism before birth

Infant MRIs show autism linked to increased cerebrospinal fluid

MRIs show a brain anomaly in nearly 70 percent of babies at high risk of developing the condition who go on to be diagnosed, laying the groundwork for a predictive aid for pediatricians and the search for a potential treatment

Functional neuroimaging of high-risk 6-month-old infants predicts a diagnosis of autism at 24 months of age

Predicting the future with brain imaging

In a new study, Emerson et al. show that brain function in infancy can be used to accurately predict which high-risk infants will later receive an autism diagnosis. Using machine learning techniques that identify patterns in the brain’s functional connections, Emerson and colleagues were able to predict with greater than 96% accuracy whether a 6-month-old infant would develop autism at 24 months of age. These findings must be replicated, but they represent an important step toward the early identification of individuals with autism before its characteristic symptoms develop.

A Breakthrough AI Can Now Predict Which Babies Will Develop Autism

MRI scanners are very widely used, but you do have to keep very still inside when they are in operation. The even harder part is the reading of the data. It is clear that some standardized machine reading (A/I artificial intelligence) process is required to notice every possible variation. You could have a centralized location where you just submit your MRI data, the center gets to keep the data and learn from it; and you get their insight as to what differences there might be.

Facial Differences vs MRI Brain Differences

I like to keep things simple and under my control.  In the short term we have to settle for facial differences, since any well-managed MRI process will be decades away.

Hormonal Variation in Autism

Hormonal differences were one of the key areas I identified years ago in this blog. Big/small heads result from disturbances in pro-growth signalling pathways. We should expect variations in bone-age, early/late onset of puberty and indeed big variations in height and weight.

In Turner Syndrome, the girls tend to be very short and they are often treated with growth hormones, as well as female/feminizing hormones.  

Great caution has to be taken when treating children with any hormones. When children are treated, it is for serious reasons like not achieving puberty, or having a serious growth delay (being very short).

Hormone Therapy During Pregnancy

In some countries hormones are given during pregnancy although I think this would be seen as odd/risky in some advanced countries.

We have already seen that couples who have difficulty producing a child often have a family history that includes autism. It was proposed by one serious fertility expert that what helps prevent miscarriage also helps prevent autism. This did sound odd when I first read about, but when you look in more depth there is a basis for this idea.

That expert has these two websites:-

http://www.preventautism.com/

http://www.preventmiscarriage.com/

Progesterone supplements have been recommended for more than 50 years for women struggling with infertility, but research now shows they can also help prevent miscarriage.

Luteal start vaginal micronized progesterone improves pregnancy success in women with recurrent pregnancy loss

Tamoxifen, an estrogen receptor (ER) antagonist, is also used to treat infertility.

Estradiol is sometimes prescribed during pregnancy.

Testosterone is produced naturally during pregnancy.

All this is clearly beyond the scope of this blog, but perhaps altered female/male hormones during pregnancy might be a biomarker of some future autism and female hormones might be a protective therapy in the subgroup of pregnant mothers with low levels of these hormones and/or high levels of testosterone. Recall that human trials in the hospital ER have shown certain substances are highly neuroprotective (progesterone, atorvastatin etc) and when administered immediately after a traumatic brain injury markedly improve the outcome.                                         

Hormone Therapy for Autism

Hormone therapy in people with autism would be controversial, but we saw in an earlier post that via RORα the balance between testosterone and estradiol affects numerous biological relevant to autism.

Many pictures of girls/women with autism, that you can view online, suggest reduced levels of estradiol. Faces look more boy-like. Many males with autism are reported to have physical features of high testosterone and low estradiol. 

One example of many:-

https://www.npr.org/2017/11/28/566788182/navigating-life-on-campus-when-youre-on-the-autism-spectrum

Both faces in the above article show clear indications of autism. Since both young people do have autism, this should not surprise anyone.

My own conclusion is that if you have autism or Asperger’s, a little extra estradiol could therapeutic, particularly if you have physical features that reinforce this.

There are of course many males and females with autism who are physically indistinguishable from the rest of the world. The point of this post is to highlight that visible differences may help to define the sub-type of autism and indicate possibly effective therapies, that exist today.

Obesity and Estradiol

In an earlier post on estradiol, I pointed out that in males estradiol is made in your adipose (fat) tissue. In the US many people with autism are overweight, in part due to side effects from their likely un-needed psychiatric medications; this has the hidden benefit of increasing their estradiol levels, feminizing their behavior slightly and shifting RORalpha in the right direction.

This also means that losing weight should be helpful to obese females with estrogen receptor positive breast cancer.  Research does support this.

Asperger’s and too much Estradiol?

We saw in earlier posts that much autism is associated with reduced expression of estrogen receptor beta and low aromatase, so high testosterone and low estradiol.

We have seen on many occasions that when one extreme exists in autism, so usually does the other; so many big heads, but also some tiny ones, NMDAR hypofunction, but also hyperfunction.

There was a lot of talk a while back in the media about children undergoing therapy to change their gender, and it was highlighted that Asperger’s was much over-represented in this group. One expert got into trouble for suggesting that their autism was causing them to obsess about their identity and so mistakenly convince a boy that he would rather be a girl.  It seems that these days some clinicians are then all too willing to provide drug therapy and then operate on them, to make them female.  I do wonder if perhaps some of these boys with Asperger’s might have the other extreme of aromatise. That would give them too little testosterone and too much Estradiol.

I think measuring these hormones is quite a good idea, as I keep repeating, they go on to affect the critical “switch”  RORα, which then impacts a large number of biological processes implicated in autism.  In other words you can try to normalize a wide range of important autism variables, just be tweaking RORα, via estradiol/testosterone.

A boy with high testosterone, and so low estradiol, will likely exhibit physical signs of this, just like the girl with low estradiol. These are just pieces of the puzzle, in plain view, that can be used to understand each specific case of autism. And no machine reading of an MRI is required.

For those left wanting more:

A very thorough paper on Turner Syndrome:-

Turner Syndrome

Turner syndrome (TS) is a neurogenetic disorder characterized by partial or complete monosomy-X. TS is associated with certain physical and medical features including estrogen deficiency, short stature and increased risk for several diseases with cardiac conditions being among the most serious. Girls with TS are typically treated with growth hormone and estrogen replacement therapies to address short stature and estrogen deficiency. The cognitive-behavioral phenotype associated with TS includes strengths in verbal domains with impairments in visual-spatial, executive function and emotion processing. Genetic analyses have identified the short stature homeobox (SHOX) gene as being a candidate gene for short stature and other skeletal abnormalities associated with TS but currently the gene or genes associated with cognitive impairments remain unknown. However, significant progress has been made in describing neurodevelopmental and neurobiologic factors underlying these impairments and potential interventions are on the horizon

Estradiol levels in girls with Turner's syndrome compared to normal prepubertal girls as determined by an ultrasensitive assay.

We utilized an ultrasensitive assay to study estradiol levels in 34 girls with TS and 34 normal age-matched prepubertal girls between the ages of 5 and 12 years. The average estradiol level in the girls with TS (6.4 +/- 4.9 pmol/l estradiol equivalents) was significantly lower than in the normal prepubertal girls (12.7 +/- 10.8 pmol/l estradiol equivalents; p < 0.01). Girls with TS were significantly shorter, and weighed less than the normal prepubertal girls, as expected. The estradiol level was not significantly correlated with height, bone age, 

Facial features provide clue to autism severity