UA-45667900-1

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.







40 comments:

  1. Hi Peter, 45 days since we started bumetanide, It seems that the excellent effect is fading away.The most striking one was the complete absence of stimming and OCD which are returning little by little.We are on 1 MG. He is also on verapamil, 30 MG.What do you think? Valentina

    ReplyDelete
    Replies
    1. Valentina, you either continue at 1mg or go to 2mg. Note that there may be other things that are affecting him, so his behaviours will not be 100% even and the more you look for changes the more you notice tiny changes.

      Delete
    2. Peter, could be the change of his environment, we are on holidays, another place, another house, another room, and a big swimming pool for him.Did You find that 1 MG was not enough for the full day in normal conditions? Valentina

      Delete
    3. Valentina, for three years we used 1mg and then moved up to 2mg. Best to stay with 1mg and see what happens when you return home.

      Delete
    4. Hi Valentina, have you checked blood potassium level recently?
      My son developed low potassium after a full month on Bumetanide. Low potassium level can affect behaviour. In my opinion potassium issues and dehydration can spoil all good effects of Bumetanide treatment, but both can be effectively managed if diagnosed.

      Delete
    5. Agnieszka, could be, will add banana smoothie. I give his polypill in a smashed avocado, a good source of potassium,with 250 MG potassium citrate.I didn't chek potassium levels.Will do it in 10 days.Do not know if verapamil could be affecting him. Valentina

      Delete
    6. Valentina, how long have you been using verapamil?

      It has short half-life, if you are concerned about adverse effects you can withdraw it for a few days to see if stimming and OCD is verapamil related and then retry.

      Delete
    7. This is what I use for supplementing potassium. It tastes sweet so you can put it in just about anything:

      https://www.amazon.com/NOW-Potassium-Gluconate-Powder-1-Pound/dp/B0015C2ZI2

      Delete
    8. Hi Agnieszka, Peter and Tyler, after making some trials, the first with verapamil and then, citicoline and luteolin for sensory gating, both high dopamine agonists, my son was becoming more anxious,with stimming and ocd.I was taking out these things little by little and now, my son has returned to his normal with bumetanide and BCAAs. I don´t know if it was a bad effect of verapamil and or these dopamine agonists that were increasing his dopamine content. Probably both of them.What do you think of adding Bacopa to bumetanide,as it is a dopamine antagonist?The other chance is adding 125 mg valproate to enhance its effect. Valentina

      Delete
  2. Thank you very much for this post Peter!

    It warms my heart to know that you care to write about such a narrow syndrome. It makes your blog the only place on the Internet where treatment options can be found for parents to SATB2 kids. Also, the SATB2 gene is interesting for many others as it is upstreams of other genetic syndromes like cleidocranial dysplasia (RUNX2) and GRIN2B (loss of function) to mention a few.

    For SATB2 parents finding this page I would recommend checking up the blogposts on sulforaphane and vitamin K, since these treatments seem to have a real connection to bone formation issues in Glass syndrome.

    Also, I suspect that posts on hypofunction of NMDA receptors might be relevant. Hypofunction of NMDArs counterintuitively looks like yet one way to create more excitation in the brain, so there is probably a need to read up on that too.

    The only thing you'd actually don't want to treat is the main feature (83%) "jovial or friendly personality".

    Sending all of you contributing here a very special SATB2 smile composed of the main features "happy demeanor" (in 83%) and dental anomalies (in 100%).

    /Ling

    ReplyDelete
    Replies
    1. Hi Ling, was this found through a WES study? recently? I know you have been contributing to the discussions for a while just wondering if this is a more recent discovery for you.

      Delete
    2. Yes, this is a very recent discovery. We made a micro-array first that did not show anything. So we asked for a WGS. Before we got the appointment, they magnified some suspect DNA and found this. Still, we are screening more genes (WGS) to get the ”whole picture” so to speak.
      /Ling

      Delete
  3. Ford anyone in this knowledgeable community know of a reason for me not to buy and try D-serine? Or think there are side effects or other supplements that should be taken (or not taken) at the same time? For some reason I can’t find many places to get this, and there is probably a good reason. I want to target hypoNMDAr.
    /Ling

    ReplyDelete
    Replies
    1. Ling, it is used for schizophrenia and there are trials to support its use. In the US it is easy to buy, in Europe, as is often the case, it is not so easy. Often you can get supplements shipped from the US for a reasonable charge, but it does vary greatly.

      Delete
  4. Hi everyone,

    An interesting paper about the potential role of NHE9 in ASD - Here is the abstract and the link to the full paper:

    A mouse model of autism implicates endosome pH in the regulation of presynaptic calcium entry

    Psychoactive compounds such as chloroquine and amphetamine act by dissipating the pH gradient across intracellular membranes, but the physiological mechanisms that normally regulate organelle pH remain poorly understood. Interestingly, recent human genetic studies have implicated the endosomal Na+/H+ exchanger NHE9 in both autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD). Plasma membrane NHEs regulate cytosolic pH, but the role of intracellular isoforms has remained unclear. We now find that inactivation of NHE9 in mice reproduces behavioral features of ASD including impaired social interaction, repetitive behaviors, and altered sensory processing. Physiological characterization reveals hyperacidic endosomes, a cell-autonomous defect in glutamate receptor expression and impaired neurotransmitter release due to a defect in presynaptic Ca2+ entry. Acute inhibition of synaptic vesicle acidification rescues release but without affecting the primary defect due to loss of NHE9.

    http://www.nature.com/articles/s41467-017-02716-5

    This is further to the following paper that came out about a year ago:

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555647/

    AJ


    ReplyDelete
  5. The impact of SATB2 on the brain is mediated by a few genes, but together they do a lot of damage. Unfortunately, this is my to-do-list.

    The focus should probably be on the triad of the genes SATB2 (downregulated), CTIP2 (upregulated) and TBR1 (doubly downregulated) which interact with each other.

    "Satb2 mutants also show a nearly complete loss of Tbr1+ neurons in the upper layers"
    According to SFARI, TBR1 has a 99% chance of being a true autism gene. It has numerous implications and is associated with FOXP2 (language impairments) and SOX5 (ID), downregulation of RELN (reelin) and GRIN2B (NMDAr subunit GluN2B) among other things.

    Some of this could be rescued if it was possible to upregulate EphA4 or Unc5c or Semaphorin 7A (progesterone?) or to downregulate DCC or FEZF2.

    SATB2 in itself regulates a lot of miRNAs with well-documented synaptic regulatory functions or which have been directly implicated in learning and memory.
    (miR-125b, miR-132, miR-212, miR-124, miR-132, miR-124)

    Too little SATB2 also affects
    Ghsr (ghrelin receptor) - downregulated,
    Adra2a (an α2 adrenergic receptor) - upregulated
    Penk (Proenkephalin) - upregulated
    Htr5b (5-Hydroxytryptamine (Serotonin) Receptor 5B, Pseudogene) - upregulated

    And: The sympathetic neurotransmitter switch depends on the nuclear matrix protein Satb2.
    (I have no idea what this means)
    https://www.ncbi.nlm.nih.gov/pubmed/21123581

    The above are just the brain effects.
    /Ling

    ReplyDelete
  6. Peter, do you know of anything that could count as an agonist of CaMKII?

    To be honest, I don't really understand what CaMKII does or where it is, but I do know that it upregulates the Tbr1 gene:
    "Although the transcription factor (TF) required for Tbr1 expression is unknown, evidence indicates that CaMKII is involved in Tbr1 upregulation"
    (https://books.google.se/books?id=lf8uDwAAQBAJ&pg=PA166 figure 4, and I suspect that the transcription factor might be SATB2)

    If I could upregulate Tbr1 it would mean a lot to me.

    There was a trial with levodopa for Angelman mentioned here on the blog a year ago that tried to accomplish something similar, but unfortunately it failed.

    /Ling

    ReplyDelete
    Replies
    1. Ling, there are inhibitors of CaMKII, as for agonists read up about Angiotensin 2. This leads to higher blood pressure. So you should see if people with Glass syndrome have low blood pressure, because raising blood pressure would be a strange thing to do. Normally you try to lower Angiotensin 2.

      Delete
    2. As always, thank you for leading me into the (hopefully) right direction! :) I shouldn't be surprised that you already have written about this... The Angiotensin post was actually one of those few I have not read yet.
      /Ling

      Delete
    3. Ling, at some point you might want to contact Yuri Zarate and ask him if any researchers are looking into SATB2 therapies. Perhaps someone is; if nobody is then you could try and change this. This has been done by parents with other rare conditions.

      Yuri Zarate, MD, MBA
      Associate Professor, Section of Genetics and Metabolism
      University of Arkansas for Medical Sciences
      Arkansas Children’s Hospital
      1 Children’s Way Slot 512-22
      Little Rock, AR 72202
      Phone 501-364-1926/ FAX: 501-364-1564
      email yazarate@uams.edu

      Delete
  7. Mutations in the CaV1.2 ion channel (as in Timothy Syndrome) downregulate SATB2:

    "the TS mutation alters SATB2 expression both in vitro and in vivo. () The TS mutation also caused a decrease in neurons expressing SATB2, a marker for callosal projection neurons. This finding is unexpected because Cav1.2 has not been previously linked to the specification of these cells."
    http://europepmc.org/articles/PMC3517299/

    /Ling

    ReplyDelete
    Replies
    1. Ling, there is quite a lot about L-type calcium channels and SATB2. It looks like you might need a Cav1.2 channel opener, so the opposite of what I use. Again this is a blood pressure increasing therapy.

      Delete
  8. I just found out about two SATB2 patients with epilepsy/ESES of which one were treated with Diazepam (valium) and the other with Clobazam with some success. These drugs are both benzodiazepines, and should not work well if GABA was working in reverse - I guess.
    Knowing this, could bumetanide still be beneficial (making GABA work more effectively) or not? Or would low-dose clonazepam be a better bet?

    /Ling

    ReplyDelete
    Replies
    1. Low dose clonazepam is super safe, takes 3 days to show effect (at the right dose) and produces no diuresis, so it is the easier intervention to try first. I would still try both, just to be sure.

      Delete
    2. Actually, is paradoxical benzodiazepine reaction reported in some bumetanide responders enough to assume that bumetanide will not work in a person who previously benefited behaviourally or in other way from BDZs?

      Delete
    3. Is clonazepam the only benzo with this effect in very small doses? At a very quick glance it looks like clobazam and clonazepam are pretty similar, with 20 mg clobazam eqvivalent to 0.5 mg clonazepam.
      I probably need to go back to your old posts on this subject...

      /Ling

      Delete
    4. Ling, it is a very specific effect on the α3 subunit of GABAa receptors. The dose is tiny, I am dividing a 2mg tablet into daily doses of 0.03mg. So no need to worry about the well known side effects of taking 2mg a day.

      Delete
  9. I know that progesterone promotes SATB2 via something called semaphorin 7a, but I really don’t want to induce early puberty in my daughter if there are other options. So, I haven’t been lazy on the researching-other-stuff part.
    Recently I have been digging down into p38 and ERK1/2 since SATB2 happens downstream of these, and probably close to CREB since L-LTP is so badly affected (hello juvenile alzheimers) and near RSK which is implicated in bone formation (hello juvenile osteoporosis). At a quick glance it looked like p38 would be good for the condition while ERK should be inhibited – but, after several hours research I have realized that things in this area are both complicated, and also not researched enough. So, I decided to see this junction as a black box for a while and look further.
    So, I stumbled over something else. I found a paper on colorectal cancer, and how low SATB2 makes this disease even deadlier. SATB2 is even seen as a prognostic marker for the severity of the disease. Yes, I had seen it before but at the time didn’t want to dwell on such depressing facts. But then I thought, so, what are the most effective treatments for this type of cancer? Maybe something that can raise SATB2? Nah, probably something nasty.
    But to my surprise I found out that aspirin of all things has showed very good efficiency in trials for this form of cancer. Now, some of you know that my daughter responded very well to Ponstan, another NSAID. Maybe there was a link? I looked further on the list of protective things. Resveratrol – check (we are having nice results so far at round two with pterostilbene) which also happens to affect COX-2, krill oil/fish oil (think AJs paper on SATB2 and krill oil+MFGM), menopausal hormone replacement therapy (think progesterone and your findings Peter) and other stuff on my list of memory enhancers like berberine (COX-2 again).
    On the list of bad things: diabetes, but probably a co-existing and not a causative factor. Which also fits into the (SATB2) picture. Krill oil is good for diabetes, as are certain ceramides (MFGM?).
    All in all, there actually seemed to be a lot of overlapping treatments and features with my own lists. One tested theory with Celebrex/Celecoxib is that COX-2 inhibition is the key. But at a deeper look it is rather the COX-2 inducing property that is the protective one (aspirin both induces COX-2 expression and then inhibits its action). This might be a fruitful avenue.
    Another thing to explore would be PKC zeta, affected by ceramides (MFGM?) which regulates L-LTP, muscle memory, glucose transport and colorectal cancer.

    /Ling

    ReplyDelete
    Replies
    1. Ling, since you have a precise biological/genetic diagnosis and live in a country with excellent universal healthcare, have you asked to be referred to a paediatric endocrinologist? This might be very useful, since he/she might find your case of interest, even though there are no defined therapies as such. Would targeting ER beta risk early puberty? When I last met our endocrinologist, she was trying to treat a girl with delayed puberty and pregnenolone was what she wanted to use, but it was not available. Many Japanese children have a high estrogen diet, due to all their soy products. I would ask to see an endocrinologist. You have plenty of questions to ask.

      Delete
    2. Well, we actually met one, though at the time we were discussing Verapamil and D-serine. And to sum up what she had to say was this:
      Doctors here are very vary of prescribing _anything_ that can affect brain development of a child. They will listen to parents, and advise them if they use something dangerous (or effective...), but mostly won't interfere. They won't offer any help with bloodwork or other tests to cover for parental ideas of treatments.

      She wasn't rude or anything like that. But it echoes another meeting I attended where doctors here told parents of children with another, extremely rare disease to wait for "a large study" instead of trying a non-toxic, tried-in-newborns supplement with documented treatment success in the same condition.

      There is something very odd with this culture, where doctors are too afraid to even try to treat rare syndromes.

      I will not let these things lessen my own efforts, and whenever possible I'll take the little help that doctors here actually can offer.

      /Ling

      Delete
  10. My concern right now is to get an idea of how many things I can combine with blood-thinning, anti-inflammatory, pro-apoptosis properties without getting in trouble.

    It is also very hard to translate results from studies on cancer (things always seem to work in reverse in cancer in an unpredictable manner from my point of view) but also to know if things that are beneficial for adults or old people are beneficial in developing children.

    /Ling

    ReplyDelete
  11. Time for some reporting!

    My daughter, 3 years and 15 kg, has been on a second round of pterostilbene for 5+ weeks. The dose has been low: 7.5 mg per day and divided into two doses. (According to some sources, 6.5 mg is the lowest dose where pterostilbene has any cognitive effect.)

    The aim was to target PKA via PDE-inhibition with the hope of inducing SATB2 and L-LTP/memory as one important downstream effect.

    Disclaimer: Three weeks before starting pterostilbene we also started vegEPA (fish oil), so this could potentially
    affect the result.

    First three weeks:
    We saw nothing special, only a "good baseline". At the time we were trying to make her learn colours, and for the first time it seemed like she understood what we meant.

    Around day 21:
    There was a sudden cognitive lift, with more presence, happening at the same time as in round 1.

    After 4 weeks:
    She made my jaw fall to the ground one day by throwing a frisbee 4 meters.
    At a couple of occasions she was overhearing and reacting to simple things in our "parental" discussions. Totally unheard of.
    At one evening we were lying in the dark and she pointed and signed what the colours on her blanket where out of memory.
    She discovered her own shadow and has had a lot of fun with it.
    She is opening drawers and doors to check what's behind them.
    At this point I noticed that she had much dryer skin than before (vegEPA effect?).

    Summary after 5 weeks:
    Language comprehension is much better
    Memory is slightly better (very hard to measure but she knows her colours now and maybe even a letter or two)
    More presence - but far from enough
    More exploratory behaviour
    More play and interaction with her sister
    No expressive language gains
    No obvious ongoing cognitive lift after day 21, plateauing?

    All in all - a similar experience to Ponstan/mefenamic acid (but maybe stronger). I guess that I have hit a path where the SATB2 protein is induced, close to CREB.
    Unfortunately this is either not enough or not targeting the place where SATB2 works as a transcription factor, because then I would also see expressive language changes.
    A big question for me is if I should try to work even harder on this pathway (adding Ponstan to pterostilbene) or try another synergistic path like PKC or CamKII.

    /Ling

    ReplyDelete
    Replies
    1. Ling, it is good to see that your efforts are producing results. One thing to consider is making withdrawal trials to double check that positive effects fade when you stop the treatment. You might for example now stop vegEPA and see if anything changes.

      You could try your Ibudilast and see if you get an effect greater than pterostibene.


      If Ponstan did not cause side effects, that is likely a good choice since Knut suggests it has broad ranging benefits.

      Delete
    2. I think I'll stick to pterostilbene for a while as PDE inhibitor, for a couple of reasons. Ibudilast seems more non-selective but also better at targeting neuroinflammation. I wonder if they could be combined, or if that'd be overkill.

      I wish there was a list of the PDEs and their respective targets, some are really interesting for cognition like PDE4 and PDE10 and others are less.

      "PDE11A regulates social behaviors and is a key mechanism by which social experience sculpts the brain."
      https://www.ncbi.nlm.nih.gov/pubmed/27544407

      /Ling

      Delete
  12. Hi all, can someone please recommend (indirectly if need be) an online pharmacy that carries the Ponstan syrup? I have a nearly 3 year old with severe autism, and a 9-month old who is showing signs-including a regression in babbling and language expression. I can only find tabs, which will not work. Even looking at online pharmacies in NZ, etc. It would be much appreciated. I understand this can be sensitive type of info, so even if someone here can point me in a direction. Thanks!

    ReplyDelete
    Replies
    1. It is easy to crush tablets and add to food, drink, jam, apple sauce or similar. This is how many people are giving medicines to small children.

      In some countries (I believe Greece, India etc) Ponstan is widely used by children, since it is extremely effective at lowering temperature during fever, so there will be a syrup. In the Anglo-Saxon world it is mainly used by adult females, hence the tablet form.

      Delete
    2. Capsules (250 mg mefenamic acid prescribed for adults) work very well instead of syrup. You can open one and use, say, a third of the content and then close it again. The powder tastes very little and can be stirred into almost anything. The capsule shell contains colouring stuff, so throw that part away when finished.

      You could google a very bright colour + pharmacy for a certified EU-delivering source with online consultations (probably the only one).

      Delete
    3. Perfect! My son detects very slight changes in his food and water (and will refuse), so the fact that there is not a strong flavor of the powder is very helpful knowledge. Thanks so much, guys!

      Delete
  13. Study showing Icariin increase estrogen receptor beta function in the brain.

    Icariin exerts estrogen-like activity in ameliorating EAE via mediating estrogen receptor β, modulating HPA function and glucocorticoid receptor expression

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4859920/

    "Results: High dose ICA is equally effective in ameliorating neurological signs of EAE as estrogen. Estrogen and ICA has no effects on serum concentrations of IL-17 in EAE. While the CORT levels were decreased by ICA at mid or high doses, the expressions of GR, ERα and ERβ were up-regulated by estrogen or different doses of ICA in a dosedependent manner. Estrogen induced the elevation of ERα more markedly than ICA. In contrast, ICA at mid and high doses promoted ERβ more significantly than estrogen. Conclusion: ICA exerts estrogen-like activity in ameliorating EAE via mediating ERβ, modulating HPA function and up-regulating the expression of GR in cerebral white matter. ICA may be a promising therapeutic option for MS."

    ReplyDelete
  14. Thanks Aspie1983, very interesting!
    at a quick glance it looks as icariin has a _very_ wide range of effects, so a bit hard to predict what to expect from it. I'll look into it.

    /Ling

    ReplyDelete

Post a comment