UA-45667900-1

Tuesday, 24 October 2017

Treated ID and CBS/DYRK1A in Autism and Down Syndrome

One of the most interesting concepts I have come across writing this blog is the idea of treating people with mental retardation (MR) / intellectual disability (ID). I do keep using the term MR, because 90% of the world has no idea what ID means. MR is a very precise description, which is increasingly rare these days.
I still recall several years ago going to a French-speaking neighbour’s barbecue. The French are generally very family-oriented, but quite traditional when it comes to parenting, (hence their low rates of ADHD diagnosis). At that time, Monty aged around 8, could act strangely and was rather obsessed with fire, matches and cigarette lighters. Our neighbour introduced us to his French friends and explained Monty with a brief use of the word “retardé”, which did not prompt any comments or requests for clarification. In the English language this might have been regarded as a big faux-pas; it did not bother me.  It seemed to work very well to forewarn people not to over-react to any unexpected behaviours. 
In the English language, autism has become a nice word and seems the new ADHD, with people even wanting to be diagnosed with it.  MR/ID is still something reserved for other people; it is not something most people want to be associated with. I do use the term cognitive dysfunction, which is just as explicit as MR but does not seem to upset people.
Cognitive dysfunction (MR/ID) is an inevitable consequence of more severe autism and it is just a question of degree. It is not a comorbidity, it is all part of the same package.

In Down Syndrome (DS) IQ is usually between 45 and 71 and worsens with age. MR/ID is defined as an IQ less than 70 and accounts for 2.3% of the general population. An IQ of 100 would put you in the middle of the IQ bell curve. People with DS tend to be very happy and contented, without the problematic behaviors that can occur in autism. 
The good news is that cognitive dysfunction (MR/ID) is likely to be treatable, as some readers of this blog have discovered. You just need to figure out how, which in itself is more about your perseverance than your IQ. You do not need to be an Einstein (IQ > 160), rather a marathon runner.
I just had the uncanny experience at school during the parent-teacher meetings, to be told that other class members could learn from my younger son Monty, aged 14 with autism; that he has the neatest handwriting in class, his essay had the best structure and that when his geography teacher told his assistant to skip the final question in the test (using longitude and latitude) because it was hard, the assistant said just let him try it; he was the only one to get it right. 
So from aged 8 to 14 he has gone from “retardé” to being something quite different.  The teachers do love his assistants, who are great; but he has had an assistant from the age of 4 and back then things moved forward extremely slowly. He learnt to read and write the very hard way, with a vast amount of 1:1 instruction and the school was amazed when his then assistant taught him to read; I don’t think they expected it ever to happen. By treating cognitive dysfunction pharmacologically for five years normal learning became possible and remains a big surprise to everyone.  His new English teacher knows him from back in the darker old days and seemed more shocked than surprised, after a month of teaching him. "Is this the same boy?"
For the first time at school I am being told to be proud of my younger son’s academic achievements, rather than how talented my older son is. Big brother certainly did not expect such a day and his response was along the lines of “well the others in his class must be really thick then” (like it or not, this is a typical teenage male comment). Little brother still has autism, but it is much less disabling. Big brother is currently teaching him to fence (sword fighting), which he would not have bothered to try doing until recently, because it would not have ended well. Years ago Monty did learn to ski, play basketball and soccer, but that all took a lot of effort with very patient (mostly female) instruction; he initially had no idea what to do if a ball was rolled towards him.  Last week he happily sat through the new Blade Runner film, which is nearly three hours long with the trailers. 
Perhaps there is no need for further “breakthroughs” with my Polypill therapy.  It may be good enough already.
It just seems a pity that more people with cognitive dysfunctions are not treated. There are some extremely intelligent parents with children who have severe autism, indeed an ironic twist of genetics. Some even write autism research, or indeed fund it. Even these people are not treating it.   Their fear of quackery blinds them. There certainly are quacks and there are also those who straddle the line, some of what they say is nonsense, but other ideas may not be.

Imagine having a conversation with Bill Gates, who is using his billions to use vaccines to save millions of lives in poor countries, about the possibility that in some people vaccines might trigger mitochondrial disease and autism.  Any organization talking about autism in relation to vaccines, chelation, aluminium, heavy metals etc and anyone who associates with them are in effect blacklisted.
Why does the global head of neuroscience at Novartis not attend the Autism One or TACA conferences? He does have a son with severe autism. It would be very difficult for him to apply any therapy promoted by anyone who attends these events.
Why does a Professor of Medicine from the US Ivy League apply ideas from this blog to his son, but never leave a comment? It is very clear to me why.
As our reader Roger has commented, why do some leading autism researchers still go on about vaccines? It does their interests much more harm than good. 
I think Roger could teach Dr Naviaux a thing or two about getting his Suramin research funded.  


Enhancing Cognition
The first area I came across where serious research is underway to treat MR/ID concerns RASopathies, a group of disorders that share disturbed levels of a protein called RAS. It was actually French research.
In Down Syndrome (DS) I highlighted research that aims to increase cognitive function by targeting the alpha 5 subunit of the GABAA receptor. We also saw that the same abnormal level of chloride within in cells that exists in much autism also occurs in Down Syndrome (DS); this is why the Frenchman Ben Ari has patented Bumetanide as a therapy for DS. 
In schizophrenia and bipolar there is also reduced cognitive function, but only in schizophrenia has there been much research and clinical trials to improve it. Histamine receptors were one target of this research. 

Too much or too little CBS (Cystathionine-β-synthase )
One known cause of cognitive dysfunction that has not been mentioned in my posts is CBS and since it was raised in a comment I thought it should be included.
All you need to know if you want to rule out a CBS problem is your level of homocysteine. If it is normal you do not have a problem with CBS. If homocysteine is high you have a case of Hyper-homocystinuria, which may be caused by too little CBS, or for a different reason. If you have very low levels of homocysteine (Hypo-homocystinuria) that may be caused by too much CBS and if you have Down Syndrome elevated CBS is inevitable.
Normalizing CBS is very likely to help cognition.
Cystathionine-β-synthase, also known as CBS, is an enzyme that in humans is encoded by the CBS gene. It catalyzes the first step of the transsulfuration pathway, from homocysteine to cystathionine:

L-serine + L-homocysteine    <------>     L-cystathionine + H2O


Down syndrome is a medical condition characterized by an overexpression of cystathionine beta synthase (CBS) and so a low level of homocysteine in the blood. It has been speculated that cystathionine beta synthase overexpression could be the major culprit in this disease (along with dysfunctioning of GABAA and Dyrk1a). The phenotype of down syndrome is the opposite of Hyperhomocysteinemia (described below). Pharmacological inhibitors of CBS have been patented by the Jerome Lejeune Foundation and trials are planned.


Down's syndrome (DS) or trisomy 21 is the most common genetic cause of mental retardation, and adults with DS develop Alzheimer type of disease (AD). Cystathionine beta-synthase (CBS) is encoded on chromosome 21 and deficiency in its activity causes homocystinuria, the most common inborn error of sulfur amino acid metabolism and characterized by mental retardation and vascular disease. Here, we show that the levels of CBS in DS brains are approximately three times greater than those in the normal individuals. CBS is localized to astrocytes and those surrounding senile plaques in the brains of DS patients with AD. The over-expression of CBS may cause the developmental abnormality in cognition in DS children and that may lead to AD in DS

It is a French foundation that is funding research is develop CBS inhibitors to improve cognition in Down Syndrome.


NovAliX will use its expertise and capabilities in medicinal chemistry and structural biology to develop small molecule lead candidates targeting the cystathionine-beta-synthase (CBS). Indeed inhibition of CBS over-expression has been associated with restoration of cognitive impairment in animal models afflicted with trisomy. 

People with DS have a low incidence of coronary atherosclerotic disease (CAD), which would seem to be linked to their low level of homocysteine (high CBS), but their high level of DYRK1A (see later) may be the cause of their early onset Alzheimer’s. 
Some background on homocystinuria, courtesy of Wikipedia:- 

Classical homocystinuria, also known as cystathionine beta synthase deficiency or CBS deficiency, is an inherited disorder of the metabolism of the amino acid methionine, often involving cystathionine beta synthase.
Homocystinuria represents a group of hereditary metabolic disorders characterized by an accumulation of the amino acid homocysteine in the serum and an increased excretion of homocysteine in the urine.
Signs and symptoms of homocystinuria that may be seen include the following:


The term homocystinuria describes an increased excretion of homocysteine in urine (and incidentally, also an increased concentration in plasma). The source of this increase may be one of many metabolic factors, only one of which is CBS deficiency. Others include the re-methylation defects (cobalamin defects, methionine sythase deficiency, MTHFR) and vitamin deficiencies (cobalamin (vitamin B12) deficiency, folate (vitamin B9) deficiency, riboflavin deficiency (vitamin B2), pyridoxal phosphate deficiency (vitamin B6)). In light of this information, a combined approach to laboratory diagnosis is required to reach a differential diagnosis.  

DYRK1A
You may have noticed that DYRK1A was mentioned as another cause of cognitive loss in Down Syndrome.  DYRK1A is yet another autism gene; it encodes an enzyme that is important in how the brain develops. Too much DYRK1A also leads to reduced levels of homocysteine. 
An OTC DYRK1A inhibitor exists today, epigallocatechin gallate (EGCG).



DYRK1A is important in neuronal development and function, and its excessive activity is considered a significant pathogenic factor in Down syndrome and Alzheimer's disease. Thus, inhibition of DYRK1A has been suggested to be a new strategy to modify the disease. Very few compounds, however, have been reported to act as inhibitors, and their potential clinical uses require further evaluation. Here, we newly identify CX-4945, the safety of which has been already proven in the clinical setting, as a potent inhibitor of DYRK1A that acts in an ATP-competitive manner. The inhibitory potency of CX-4945 on DYRK1A (IC50=6.8 nM) in vitro was higher than that of harmine, INDY or proINDY, which are well-known potent inhibitors of DYRK1A. CX-4945 effectively reverses the aberrant phosphorylation of Tau, amyloid precursor protein (APP) and presenilin 1 (PS1) in mammalian cells. To our surprise, feeding with CX-4945 significantly restored the neurological and phenotypic defects induced by the overexpression of minibrain, an ortholog of human DYRK1A, in the Drosophila model. Moreover, oral administration of CX-4945 acutely suppressed Tau hyperphosphorylation in the hippocampus of DYRK1A-overexpressing mice. Our research results demonstrate that CX-4945 is a potent DYRK1A inhibitor and also suggest that it has therapeutic potential for DYRK1A-associated diseases

Neurodevelopmental alterations and cognitive disability are constant features of Down syndrome (DS), a genetic condition due to triplication of chromosome 21. DYRK1A is one of the triplicated genes that is thought to be strongly involved in brain alterations. Treatment of Dyrk1A transgenic mice with epigallocatechin gallate (EGCG), an inhibitor of DYRK1A, improves cognitive performance, suggesting that EGCG may represent a suitable treatment of DS. Evidence in the Ts65Dn mouse model of DS shows that EGCG restores hippocampal development, although this effect is ephemeral. Other studies, however, show no effects of treatment on hippocampus-dependent memory. On the other hand, a pilot study in young adults with DS shows that EGCG transiently improves some aspects of memory. Interestingly, EGCG plus cognitive training engenders effects that are more prolonged. Studies in various rodent models show a positive impact of EGCG on brain and behavior, but other studies show no effect. In spite of these discrepancies, possibly due to heterogeneity of protocols/timing/species, EGCG seems to exert some beneficial effects on the brain. It is possible that protocols of periodic EGCG administration to individuals with DS (alone or in conjunction with other treatments) may prevent the disappearance of its effects.


Conclusion

Understanding emerging therapies that treat various types of MR/ID, and also the various types of dementia, should unlock interesting avenues to raise cognitive function in many types of autism.
Homocysteine levels are very easy to measure. 
Because the gene miss-expression in Down Syndrome (DS) is fully understood, it makes sense that treatment is more advanced than in autism, which is so heterogenous. There are a lot of people in the world with DS and so there is a big market for drug makers.
The potential drug therapies to improve cognition in Down Syndrome (DS) appear to be:- 

·        Basmisanil, a negative allosteric modulator of α5 subunit-containing GABAA receptors. It appears that sodium benzoate may have a similar effect.

·        Bumetanide, an NKCC1 inhibitor

·        Potassium bromide, Br- displaces Cl- to lower intracellular Cl-

·        CBS inhibitor

·        DYRK1A inhibitor, like Epigallocatechin gallate (EGCG), but a more potent inhibitor like CX-4945 (Silmitasertib) might be better.

There is mouse model research to show that a single dose just after birth of a drug that stimulates the sonic hedgehog signaling pathway results in a "normal" adult brain.

The risk of Down Syndrome (DS), caused by a third copy of chromosome 21 (trisomy 21), rises rapidly with increasing maternal age, nonetheless the number of births is stable to falling in most developed countries, due to increased prenatal testing and termination of pregnancy for fetal anomaly (TOPFA). TOPFA is not practiced in countries like Poland and Ireland. In Denmark screening has long been free and TOPFA has risen to 98%. In the UK two thirds of mothers opt for their free DS screening and 90% of those who test positive, opt for their free TOPFA. The one third letting nature take its course are probably mainly younger mothers.
In Catholic countries you have both extremes - in Cork, Ireland DS is present 30 times per 10,000 births, but in Zagreb Croatia it is just 6 per 10,000. In the US the CDC say it 14, while in the UK it is 10.  In South Africa 20 cases of DS occur per 10,000 births; mothers are younger than in Ireland.
In developed countries, the natural prevalence of DS looks to be 0.3%, which is the same as the incidence of strictly defined autism (SDA), which I estimated in an earlier post to be 0.3%. It is just that in developed countries most people with DS are never born. 

I would have thought CX-4945 should be trialed by some clever Alzheimer's researcher and indeed for any Tauopathy. In the meantime perhaps Grandad should drink a lot of green tea to get his dose of EGCG.







52 comments:

  1. HI Pater,
    How would one determine the dosing of CX-4945 for a trial?
    Thanks
    Nancy

    ReplyDelete
    Replies
    1. Nancy, I do not think you will be able to obtain CX-4945. However, the next best thing for DYRK1A is EGCG, which you can buy OTC. The dosage used in clinical trials is 9/mg/kg per day.

      http://www.thelancet.com/journals/laneur/article/PIIS1474-4422%2816%2930034-5/abstract

      Delete
  2. Hi Peter,
    It appears you can buy it from Santa Cruz Biotechnology.
    https://www.scbt.com/scbt/product/cx-4945-1009820-21-6
    Would one need to be a physician to order? It seemed to allow me to get to the checkout part of the order, though I didn't follow through.
    If I were to use EGCG, do we know the dosing of that? My son is about 170 lbs.
    Thanks very much.
    Nancy

    ReplyDelete
    Replies
    1. Nancy, you would want 700mg a day of EGCG, which is just a couple of supplement pills. I think that the CX-4945 is likely a research product, so I doubt they will sel it to you. I do not know what dose would be required.

      Delete
  3. I see that milligrams of EGCG are separated out from green tea extract.
    Does the 700 mg need to be just the EGCG?
    Should one be concerned with the amount of caffeine in the supplement?
    Nancy

    ReplyDelete
    Replies
    1. Nancy, it is 700mg of EGCG itself. It is a small amount of caffeine. I think you might want to give it a trial for a month, to see if it helps. There are people with autism who seem to respond, while for others it does nothing.

      Delete
  4. Peter,
    It isn't just vaccines,there is far too much time,money,and other resources,spent on proving things that have already been proven,and that one would think should no longer be studied.I'm sure the this is true in so many other areas of medicine.

    I had an autism diagnosis that was "moderately severe",that meant I was verbal,but otherwise low functioning.I had multiple learning disabilities.Language Processing Disorder,dyscalculia,dysgraphia,Non-Verbal Learning Disability,and Visual Motor Deficit,but not intellectual disability/mental retardation.I went on this way until I was well into my forties,at which time I was diagnosed with a combination of Severe MTHFR Deficiency,and high levels of folate receptor autoantibodies.I would go on to get many more diagnoses.Coeliac and other autoimmune diseases,cancer gene mutations and chromosomal rearrangenents,neurocardiac disease,that explained a life of problems.

    My homocysteine and methylmalonic acid were within diagnostic range,but nothing like those with CBS gene mutations.It took a few years of treatment for the folate and homocysteine,but I was able to reverse my autism,and most of the learning disabilities.In the last several months,I have been able to eliminate the betaine,and stick to the leucovorin and B12,that I need for my anemia.My seizures are not gone,but aregreatly reduced in frequency.

    I have the classic Marfanooid build,with long skinny limbs,pectus carinatum,and knock-knees.

    I suspect the higher the homocysteine,the more severe the intellectual disability is.

    Yes,Peter I have been told many times my unique history and unique views would be a great asset,if I could find the right organization or institution to work with.I have tried to both get on the board of Autism Speaks,and to get a seat on the IACC,with no success.

    ReplyDelete
  5. Before going crazy on the EGCG, be mindful there is evidence in liver damage from people taking significant quantities via diet pills. I take EGCG myself but know the risks here and of course engage in interventions that help out the liver to hopefully mitigate those risks.

    This is a question one should always ponder when taking drugs/supplements or other substances that are not easily utilized by the body. So many people in the United States are sickened and eventually killed via liver damage from being excessively medicated from multiple medications often from multiple doctors. Of course on the death certificate liver failure is rarely mentioned, rather cardiac arrest is listed jus as type II diabetes is not mentioned on death certificates.

    EGCG does a lot of interesting things and seems to be a great anti-cancer preventative intervention, but anyone supplementing it themselves or in their children should pay close attention to signs of liver toxicity as not everyone metabolizes EGCG at the same rate, especially children.

    ReplyDelete
  6. Peter,
    I am unable to find an OTC product that contains just EGCG. I see products that have less than 50% ECGC. Can you recommend something online?
    Again, thank you. I definitely want to trial it.
    Nancy

    ReplyDelete
    Replies
    1. Nancy, this one looks a good choice:

      NOW EGCG Green Tea Extract 400 mg

      Each pill has 200mg of EGCG.

      It has other things as well, because it is just concentrated green tea.

      Delete
  7. Hi Peter,
    Are there concerns about dosing of 8-900 mg of EGCG in terms of liver?
    My son, like many on the spectrum, has detoxification issues.
    Should I be giving some kind of liver support?
    Again, thanks for your help.
    Nancy

    ReplyDelete
    Replies
    1. Nancy, the Spanish trial in Down Syndrome lasted 12 months at 9mg/kg/day and they did not detect any negative effects. They did monitor liver markers and EGCG had no effect. It did reduce cholesterol slightly, but in most people that is a good thing.

      Delete
    2. Interesting. I was not trying to be alarmist, especially as I forgot to mention in the study it was a population study and did not control for things like people having liver toxicity because of existing problems with their liver. Also, it is entirely possible a very small number of people can react to EGCG in the same way a rare number of people cannot process phenylalanine properly.

      I have taken significant doses before and too much can cause nausea and a general feeling of being unwell that does not come from the caffeine. Green tea extract sometimes also has copious amounts of fluoride as well which some people can have problems with.

      Delete
    3. Green tea extract will also have a bit of L-Theanine as well which the last time I trialed it would in effect induce super-rage. My 20/20 hindsight on the matter blames mglur1 and mglur5 agonism from L-Theanine.

      Delete
    4. I would add that green tea inhibits folate absortion,so it is out of my list, taking in consideration that Iam MTHFR homozygous.
      Valentina

      Delete
    5. 2.20. Epigallocatechin-3-Gallate (EGCG)
      Epigallocatechin-3-gallate (EGCG) is a phenolic compound present in green tea [72] and is an effective ROS scavenger in vitro and in vivo [73, 74]. EGCG mitigated CSP-induced nephrotoxicity by inducing the expression of Nrf-2 and HO-1 and decreasing that of NFκB and proinflammatory cytokines [72]. Furthermore, EGCG also inhibited endoplasmic reticulum (ER) stress-induced apoptosis through the suppression of phosphorylated (p)-ERK, glucose-regulated protein 78 (GRP78), and the caspase-12 pathway [75]. Furthermore, EGCG inhibited the ligand of death receptor Fas (Fas-L); apoptosis regulator, Bax; and the tumor-suppressor protein, p53, while it increased the expression of Bcl-2 and, thereby, inhibited the extrinsic pathways of renal cell apoptosis [76]. All these studies collectively established the renoprotective actions of EGCG.

      https://www.hindawi.com/journals/omcl/2016/4320374/

      Delete
  8. Peter, this is off topic for this post (btw congrats to Monty -and you - wonderful achievements!) Was wondering if you know anything about this:
    https://www.ncbi.nlm.nih.gov/pubmed/28502607
    It seems not many who comment here are dealing with gut issues in their kids - but thought I'd ask just in case you, or anyone else reading, has any insights

    ReplyDelete
    Replies
    1. Hi Tanya,

      Hope all is well!

      Great find! I just spent a bit of time reading up on Zonulin, and to me, I think this would be relevant to anyone with ASD, whether or not they have gut issues, assuming that ASD symptoms may be caused by the gut/brain axis, whether or not obvious gut issues exist.

      One recent paper on the subject is:

      http://gut.bmj.com/content/early/2017/08/24/gutjnl-2017-314759.long

      I found this article, which seems to indicate that Berberine would be helpful:

      http://jeffreydachmd.com/2015/06/berberine-antidote-for-modern-epidemic/

      Of course, as you may remember, I open capsules and mix in juice to give to my daughter, and my 3 supplements that I have not even attempted to give her are Naringin, Berberine, and TUDCA due to brutal bitterness. Having said that, I think I will have to find a way with Berberine given the Zonulin paper. If you find anything else that can help with Zonulin levels, please share and I will do the same. I have found a few below.

      Colostrum may also help:

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409709/

      And finally Inulin may help:

      https://www.ncbi.nlm.nih.gov/pubmed/23244539

      Also Tanya - I have another major thing to thank you for. As you may recall, you very correctly determined that my daughter may have low Riboflavin due to her getting headaches with P5P, and adding Riboflavin resolved it.

      You then mentioned OAT testing, which I didn't know much about at all at the time, but I looked into it because you had mentioned it. I just got the results and there are some clear issues identified. Getting the OAT testing (through Great Plains Lab) was, one of the best (if not the best) step I've taken, and I sincerely thank you for your suggestion.

      Have a wonderful day Tanya!

      AJ

      Delete
    2. Tanya, zonulin is interesting because it is involved in the blood brain barrier as well as the intestinal barrier. It is also more broadly linked to autoimmune disease, so celiac and type 1 diabetes for example. Alessio Fasano is a very good researcher I have quoted in this blog.

      Butyric acid is the logical intervention here, or Miyairi 588 probiotic that produces it. Some people use sodium butyrate 500mg and some use the probiotic.

      While Monty has no GI issues, I did as a child. In some people verapamil helps with GI problems, I tried it on myself a while back when I has some kind of viral infection and got very sharp stabbing pains. The pains stopped with a very small dose of verapamil, I do not know exactly why. I would certainly use it again if needed.

      I also think cetirizine might help some GI issues, because it is not just an antihistamine. I switched Monty to this as an antihistamine, because you get two effects and it is actually cheaper than the latest H1 antihistamines.

      Delete
    3. When aspie mentioned his response to miyairi, I decided to give it a try and ordered off amazon. Waiting for it to ship here from Japan. And even though I had to stop continuous use of verapamil for my son, I saved a bottle of it thinking if I ever needed to just use it intermittently I would. Thanks for the tip!

      Delete
    4. Hi Tanya, as I had told you, my son has an overactivated immune system, with GI and histamine issues that influence his behavior all the time.The same as yours.For this reason,you need to be very careful with probiotics and Miyarisan is not the exception. Sure you know that. Valentina

      Delete
    5. AJ, you are kind. I mainly have more questions than I do useful contributions to the blog comments, but I am glad something gleaned from my days in the trenches of trial and error helped you!
      Yes - Berberine!! I forgot about the usefulness of this herb - used it many years ago. And I think I remember Dr Theoharides has it in one of his blends for mast cell issues.. yes reading about the sugars like in inulin that help lock out the lectins (which is what we are currently investigating now as gut enemy number 1). Thanks so much for sharing these - helps my tired brain immensely. :)

      Delete
    6. Hi Peter,

      With regards to comparing sodium butyrate vs clostridicum butyricum, I found sodium butyrate to be extremely energizing, while clostridicum butyricum I found more to have a 'GABA' like calm.

      My guess is sodium butyrate spikes butyrate very high above baseline levels after intake, while clostridicum butyricum lets the body create its own butyrate.

      Delete
    7. Hi Valentina, yes indeed, you are right. I have to be extremely careful with trying them - never full capsules and sprinkle little bits spread days apart. For a few years I didn't even try miniscule amounts because of his reactions.
      Aspie, interesting about your experience with butyrate. We used it many years ago for ammonia, but I moved on to something else, i think citrulline. Can't remember why I stopped.

      Delete
  9. Peter,

    Is bumetanide available otc in Germany?

    ReplyDelete
  10. I have an easy question that I am sure many of you can answer.
    I really have trouble finding an antioxidant that can go into our standard regime. It is becoming obvious that histamine is an issue on the rise here, and this seems to eliminate many of the alternatives.
    (Actually histamine intolerance and MCAS depressingly looks like they where designed to prevent most autism treatments)
    So my question is, are there any non-histaminey antioxidants you would recommend? Broccoli powder is hard to give due to the strong taste.
    And yes, I'm getting real nervous of eventual negative reactions to, say, Verapamil and Bumetanide too (sulfonamids?) and any advice on how you handle histamine overload is very welcome.
    /Ling

    ReplyDelete
    Replies
    1. Ling, maybe vitamin E? Besides being antioxidant it should help with histamine, inflamation and mitochondria. Search for "gamma tocopherol" in the blog, Peter already published something.
      Regards,
      Jane.

      Delete
    2. Ling, have you tried Vit E?? It is also good for histamine and stabilizes mast cells.... For my son, at this point what helps with histamine the most is working on inflammation and in the mean time avoiding triggers, esp food triggers. As far as mast cells go, emotional stress is his biggest if not THE ONE trigger for him. the histamine thing, we are still working on. He has always been the allergy/histamine kid - those were his first signs as a baby long before any autism diagnosis : colic as a baby, had to be on allergen free formula, eczema, then asthma, now asthma is gone but mast cells reactions. Things just shift around.. For many years we tried to treat infections as root cause for all of these allergy/histamine problems , then tried "methylation" approaches, treatments for oxidative stress etc., but I really think getting grip on inflammation might be his way. Also hoping the probiotic aspie1983 had luck with helps too (although probiotics have always been tricky for him). So for the immediate fire to put out, we just use antihistamines and avoiding triggers and stress. We also use small dose of B6 to support DAO. we give this with magnesium. Other things alternative would be nigella oil, holy basil, oil of oregano. Many things I have tried could not notice a difference (like turmeric). It is a work in progress.

      Delete
    3. Thanks so much Jane and Tanya for your supportive responses!
      :-)
      No, I had not considered vitamin E before. I'll certainly look into it!
      We have already tried carnitine (got histamine reaction), carnosine (possible histamine reaction) and broccoli won't work due to taste. I shelfed NAC before starting since the leaflet clearly says that it can induce histamine issues with long-term use. ALA seems problematic lowering thyroid hormones too... I do have a bottle with peppermint flavoured olive leaf extract that might work.

      B6 or P5P might be something to add to the magnesium we are giving. I am actually surprised to see that the Mg gives an effect on my youngest daughter but neither on me or on her sister. Tanya, what form of Mg do you use?

      /Ling

      Delete
    4. /Ling, I think you should also consider melatonin as an antioxidant even if your children don't have sleeping disorder. I don't know its relation to histamine, though. When given regularly it could rescue some aggressiveness and promote better behaviour.

      Delete
    5. Tanya, your son is very similar to mine. He seems to suffer from histamine issues, and anything that raises histamine causes irritability and SIB. For instance, B6, zinc, phosphatidylserine, carnosine, and curcumin (DAO inhibitor) are on the list of offenders. Among things that helped to reduce histamine are quercetin.

      V

      Delete
    6. Ah, yes you are probably right petra. We don't have sleeping issues (well, that is not totally true since I am sleeping deprived most of the time, but I blame that on this blog.. ;-)). Melatonin has so many other good properties that it might be worth a try.
      Good, now I have more options to try! Thank you!

      /Ling

      Delete
    7. sorry Ling, looks like my reply to you went to the wrng thread - we are using magnesium taurate at the moment.

      Delete
    8. Valentina, yes our sons do sounds similar.. except a little bit of B6 does seem to help my son - it is a co-factor for DAO. I think I am going to use Peter's recommendation of just butyrate first - give that some time, and then try the probiotic aspie recommended.. I think I have to focus more at the moment on staying away from food autoimmune triggers, working on his gut lining and then probitiocs later.

      Delete
    9. Tanya, Iam not V!, I always sign with my first name,I tell you that a bit of B6 helps my son also. With respect to Peter´s recommendation I think that he is right and just butyrate should be better. Let me know it it works.
      Valentina

      Delete
    10. Thank you Tanya!
      Why have you chosen magnesium taurate? As I am having results with the threonate form I do wonder if there are other (cheaper) forms of magnesium that would be as good or even better. Do you have any visible or measurable effects?
      I just found out that magnesium can activate the Kca1.1 aka BK channel independently from existing Ca2+. This is the channel that works as an emergency break when calcium gets to high inside a cell.
      /Ling

      Delete
    11. Ling,

      Research suggests that magnesium-l-threonate is highly brain specific and this form is like the only form of magnesium that actually reaches the brain, theres been a hot debate over on longecity and other forums to wether it really lives up to its claims, but if true it might be the only form of magnesium that can reach the brain in adequate levels.

      Delete
    12. Magnesium L Threonate doesn't work at all

      Delete
    13. Theres been a fair bit of studies with it proving otherwise.

      Delete
    14. Hi Ling, I experiment with different types of magnesium to see if i notice any difference and I honestly cannot say. Sometimes the only way I can tell something helps is if I stop and re-start a few times. But i haven't completely stopped magnesium in a while because I just consider it as such an important nutrient co-factor (especially for b6) that I am not really looking at magnesium alone to be a magic bullet for anything but keeping it in for general support. I did try threonate a few years ago and didn't notice anything.

      Delete
    15. If we could only believe all studies, especially those sponsored by the makers of a studied drug or supplement (Magnesium L Threonate, Sulphoraphane, etc), our kids would have been recovered by now.

      Delete
    16. Anon, I think you have to start realising a full cure might not be available in a life time worth.
      Show me a paper that magnesium-l-threonate has no potential .

      Delete
    17. Thank you Aspie for the information!
      Anonymous - it does work for my daughter. Staring spells ar much less frequent with it, no placebo effect here. But it doesn't give any noticeable effect on the rest of the family.
      Tanya, I feel the same - magnesium is not a silver bullet, but it is really easy to administer, doesn't taste anything, doesn't have any common adverse effects and, at least theoretically, have a list of very nice effects. And as it is the only thing in my standard repertoir at the moment I am not in the mood for trying something else. I was just wondering if someone else actually saw any effect with another form of magnesium.

      /Ling

      Delete
    18. Tanya, sorry to hear about your sons hardships. I wish I could help, but I am some years behind you into autism research and experience.

      Do I remember it right that you have been dealing with both DAO snps and HNMT snps?
      How did you try to address these dysfunctions in histamine degradation, and what did work/not work?
      I am looking at supplements with SAMe and DAO enzyme at the moment, but would be very thankful for insights from previous travellers on this path.
      I also saw that you tried Verapamil but had to stop - was it the DAO inhibiting effect that made this?

      Best wishes to you and your son,
      /Ling
      If so, how do you deal with histamine issues

      Delete
    19. Going back to blogposts very long ago, I find the mention of whey protein as a precursor/building block to glutathione. Is this an alternative that I should consider at all? Hair pulling is becoming an issue here, and NAC is as I mentioned not an option.
      Or does undenatured whey have a too weak effect? Surely someone here must have tried it...

      Tanya, Petra, Jane and others - thanks for input, now that I've read more it really looks you have covered all the best antioxidants!
      :-)

      /Ling

      Delete
    20. Ling, cysteine is the rate-limiting amino acid for synthesis of glutathione (GSH). Bovine whey proteins are rich in cystine, the disulfide form of the amino acid cysteine. The research shows that it does indeed increase GSH.

      Delete
  11. Hi everyone,

    For those of you that are looking to hit IDO (to address high quinolinic acid), I have found a great new option!

    I have been using Apigenin thanks to Tyler's recommendation, and now we can add Tart Cherry to the list:

    https://www.ncbi.nlm.nih.gov/pubmed/?term=28901958

    AJ

    ReplyDelete
  12. HI,
    As I ponder the EGCG that arrived today, I looked again at our Yasko genetic results. My son is COMT heterozygous. My understanding is that I should stay away from flavenoids. Yet, quercitin (small doses) and another luteolin/rutin/quercitin supplement have been quite positive for him over the years, along with NAC which I started when I began reading Peter's blog. There clearly is a histamine issue as when I trialed L-histamined, then cromlyn sodium, both at Peter's suggestion, my son's skin began to clear for the first time in years.
    As cognition, suddenly regressing after 2 years of ABA around age 5, is such a goal for us, I would love to try toe EGCG. According to Yasko, I would stay away from it due to the COMT +/- but flavenoids have only resulted in positive outcomes.
    I am really lost as to how to sort this out. I would appreciate anyone's help.
    Thank you so much.
    Nancy

    ReplyDelete
    Replies
    1. Nancy, Yasko has a right to her opinions, but she is not a medical doctor or a researcher published in scientific journals. I would pay no more attention to what she says than anyone else. Some of what she says has been shown to be totally false, at which point I personally pay no further attention.

      Delete
  13. Right now we are using magnesium taurate

    ReplyDelete
  14. Here is an interesting study with a tangential angle to autism that deals with caloric restriction:

    Press Release:

    https://www.sciencedaily.com/releases/2017/10/171030112223.htm

    Paper:

    http://www.sciencedirect.com/science/article/pii/S0891584917306469?via%3Dihub

    As calcium channels have been discussed extensively as well as calcium channel blockers being suggested as a useful therapy for some autisms, I thought this study was especially relevant.

    In summary, the researchers first did a standard calorie restriction experiment on mice and found increased angiogenesis in the skin of calorie restricted mice, which suggests an increased ability to pump warm blood to the extremities. They also found increased fur density in calorie restricted mice. This makes sense as a calorie restricted animal has less fat to insulate themselves from cold exposure. In general due to the increased angiogenesis in the skin seemed to contribute to better skin health, i.e. younger looking skin.

    In the next experiment which is more relevant to autism, the research group showed that in calorie restricted mice, liver damage via ischemia (stopping arterial blood flow as happens in a heart attack) was significantly reduced in calorie restricted mice relative to control mice. They hypothesized that it might be due to excessive calcium influx into cells as ischemia can cause tissue absorption of excess calcium and then did further tests and found that calorie restricted mice has mitochondria that were better able to absorb more calcium and use it to produce more ATP (good) relative to the control mice whereby calcium overflow happened at a lower threshold.

    So obviously calcium poisoning of cells, including brain cells is a bad thing that has been known for a long time and is associated with many diseases, including aging itself as mitochondria become less efficient over time. Calorie restriction seems to help keep mitochondria quality high so that when they are challenged with excess calcium, they are able to actually utilize it efficiently for respiration and produce more energy (ATP) as a result.

    With respect to autism, simply blocking calcium channels to prevent excessive calcium influx into cells could help throughout the body if mitochondria are of poor quality. What this research may also suggest is that double downing on improving mitochondrial quality/efficiency for cellular respiration may also improve calcium problems indirectly as well. Finally, this research suggests fasting could be a legitimate intervention for autism, though obviously this should be validated in animal models and should be relatively straightforward for researchers to test, especially with regards to autism model mice challenged in the same manner in the aforementioned experiments to see if the same calcium poisoning side effects from ischemia to the liver and perhaps other tissues are ameliorated via fasting or caloric restriction in autism model mice and whether or not unchallenged autism model mice improve mitochondrial calcium absorption and ATP output significantly more with these types of interventions.

    ReplyDelete

Post a comment