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 GABA_A 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 GABA_A 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.

Cystathionine beta-synthase is enriched in the brains of Down's patients.

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 To Collaborate With The Fondation Jérôme Lejeune On Down Syndrome (Trisomy 21)

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:

• A family history of homocystinuria
• Flush across the cheeks
• Musculoskeletal
• Tall, thin build resembling Marfanoid habitus
• Long limbs (dolichostenomelia)
• High-arched feet (pes cavus)
• Knock knees (genu valgum)
• Pectus excavatum and Pectus carinatum
• Intellectual disability
• Seizures
• Psychiatric disease

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).

Targeting trisomic treatments: optimizing Dyrk1a inhibition to improve Down syndrome deficits

A chemical with proven clinical safety rescues Down-syndrome-related phenotypes in through DYRK1A inhibition.

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

Epigallocatechin gallate: A useful therapy for cognitive disability in Down syndrome?

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 GABA_A 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.

Long Term Mood Improvement using NAC in Autism

A more recent post on this subject is here:

http://epiphanyasd.blogspot.com/2014/08/nac-for-long-term-use-in-autism.html

NAC (N-Acetyl Cysteine) is an anti-oxidant that is part of the autism therapy I have implemented.  I have now received feedback from other parents who are also surprised by the positive effect it has on their child with autism.  So far, it has had a positive impact in 100% of cases.

In the literature, there are several schools of thought as to why NAC is effective. 

1. As a free radical scavenger in its own right
2. As a precursor to Glutathione (GSH)
3. As a glutamate antagonist
4. Reducing homocysteine

Glutamate is one of the brain's two most important neurotransmitters, the other being GABA.  Glutamate is excitatory and so too much of it would cause you a problem.  NAC can act as an antagonist to glumate.  This is all very nicely explained by Emily Deans, a psychiatrist in Massachusetts who has a very interesting blog of her own.

• Glutathione: We Loves It (NAC and Autism)

In my research into the autism comorbidity asthma, I also came across plenty of talk about oxidative stress and anti-oxidants.  NAC is used, but it seems like they are looking for something stronger.

The main impact is as a precursor to Glutathione (GSH)

I recently learnt that in autism (or at least the one my son is affected by) the reason is without doubt number two.  The other roles (scavenger/antagonist) are irrelevant.

The reason I know this, is that after a few months NAC effectively stopped working.  This coincided with an asthma flare-up.  Now, I initially thought that the asthma attacks had released inflammatory cytokines and that these had stimulated the ever-present neuro-inflammation in the brain.

This is highly plausible and indeed I have literature showing which cytokines are released by asthma attacks.  So I thought that by firmly dealing with the asthma, I would at the same time subdue the autism.  This did not happen.

So after a few days I came up with "plan B", which did prove to be successful.  I hypothesised that the NAC had stopped working because I was not giving enough vitamin B12, which is part of the chemical process in which GSH is synthesised from NAC.  I have no means of knowing how much is needed exactly. In related processes both vitamin B6 and B9 are also involved.

I increased the B vitamins and within hours things began to revert towards the previous behavioural equilibrium.

So it was most likely the failure of NAC to produce GSH, and thus reduce oxidative stress, that had sparked the asthma flare-up. (this is will be covered on my later post of asthma as a comorbidity in autism)

But how much B12 is needed to synthesise GSH?

In your diet you have vitamins B6, B9 and B12, but it is unclear how much is needed to synthesise GSH.  A further complication is that B vitamins are not well absorbed in the gut, and some people absorb them better than others.  Older people are known to absorb B12 poorly.  There are expensive sub lingual B vitamin supplements, but there is no evidence that they actually work better.

There are at least two NAC products targeted at older people to protect them from memory loss and Alzheimer's disease:-

• Betrinac   
• Cerefolin NAC

 Both products combine NAC with vitamins B6, B9 and B12,

                                             Over the counter NAC        Cerefolin NAC        Betrinac


N-acetylcysteine (NAC)              600mg                            600mg                     600mg
Vitamin B9 (folate)                                                          1,000 mcg               800 mcg
Vitamin B6                                                                           25mg                       20mg
Vitamin B12                                                                    1,000mcg                1,000mcg



 Both products are for preventing memory loss, rather than just increasing GSH.


For a comprehensive look into B vitamins including their role in the brain, and how they are (or are not) absorbed, take a look at this link from the US Office of Dietary Supplements.


Reducing homocysteine

Homocysteine is linked with strokes, and particularly in the US there are doctors who use NAC for the purpose of lowering homocysteine.

Dr. Baum, medical director of the Mind/Body Medical Institute, a Harvard affiliate, recommends 1,000 micrograms (mcg) of folate, plus 25 milligrams (mg) of vitamin B6, 1,000 mcg of B12, and 1,800 mg of the amino acid N-acetyl-cysteine (NAC). "With folate, B6, B12, and NAC supplements, almost everyone will have normal homocysteine levels," says Dr. Baum.

There is even a discussion about the role of homocysteine in autism.  A very recent paper from Poland is: A focus on homocysteine in autism

I think think that high homocysteine, just like low GSH, is a marker of oxidative stress.  In some of the literature it is stated that homocysteine cause oxidative stress.

Here is another paper: Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism

 

And yet another one:-

Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders

 

If you read all the papers you will come across various graphics showing biological cycles within the body, like the one below.  This is how I know that the various B vitamins are needed.

Vitamin B12 Therapy

I really just need to know how much B12 is needed and how to give it.  In the end the best resource turned out to be a  bulletin from a US medical insurer, and here it is:-

Clinical Policy Bulletin:  Vitamin B-12 Therapy

The document is very thorough; here are some key parts:-


Background

Vitamin B-12 belongs to the family of cobalamins. It is available in all animal-derived foods, and is absorbed at a rate of 5 mcg per day. After being ingested, vitamin B-12 becomes bound to intrinsic factor, a protein secreted by gastric parietal cells. The vitamin B-12/intrinsic factor complex is absorbed in the terminal ileum by cells with specific receptors for the complex. The absorbed complex is then transported via plasma and stored in the liver. Since the liver stores 2,000 to 5,000 mcg vitamin B-12 (adequate for up to 5 years), dietary deficiency of cobalamin (Cbl) is rare. In most cases, vitamin B-12 deficiency is due to an inability of the intestine to absorb the vitamin, which may result from an autoimmune disease that reduces the production or blocks the action of intrinsic factor, or from other diseases that result in intestinal malabsorption. The most frequent underlying cause of vitamin B-12 deficiency is pernicious anemia, which is associated with decreased production of intrinsic factor.


In a systematic review of randomized trials on vitamin B-6, B-12, and folic acid supplementation and cognitive function, Balk and colleagues (2007) stated that despite their important role in cognitive function, the value of B vitamin supplementation is unknown. A total of 14 trials met selection criteria; most were of low quality and limited applicability. Approximately 50 different cognitive function tests were assessed. Three trials of vitamin B-6 and 6 of vitamin B-12 found no effect overall in a variety of doses, routes of administration, and populations. One of 3 trials of folic acid found a benefit in cognitive function in people with cognitive impairment and low baseline serum folate levels. Six trials of combinations of the B vitamins all concluded that the interventions had no effect on cognitive function. Among 3 trials, those in the placebo arm had greater improvements in a small number of cognitive tests than participants receiving either folic acid or combination B-vitamin supplements. The evidence was limited by a sparsity of studies, small sample size, heterogeneity in outcomes, and a lack of studies that evaluated symptoms or clinical outcomes. The authors concluded that there is insufficient evidence of an effect of vitamin B-6, B-12, or folic acid supplementation, alone or in combination, on cognitive function testing in people with either normal or impaired cognitive function. This is in agreement with Clarke et al (2007) who stated that randomized trials are needed to ascertain the relevance of vitamin B-12 supplementation for the prevention of dementia.

Vitamin B-12 therapy can be administered orally or by injection. Vitamin B12 tablets of up to 5,000 mcg may be obtained over the counter without a prescription.

In a review on vitamin B-12 deficiency, Oh and Brown (2003) noted that, because most clinicians are generally unaware that oral vitamin B-12 therapy is effective, the traditional treatment for B-12 deficiency has been intramuscular injections. The authors cited evidence that demonstrates, however, that oral vitamin B-12 has been shown to have an efficacy equal to that of injections in the treatment of pernicious anemia and other B-12 deficiency states (Elia, 1998; Lederle, 1998; Kuzminski et al, 1998; Lederle, 1991). The authors explained that, although the majority of dietary vitamin B-12 is absorbed in the terminal ileum through a complex with intrinsic factor, there is mounting evidence that approximately 1 % of a large dose of oral vitamin B-12 is absorbed by simple diffusion which is independent of intrinsic factor or even an intact terminal ileum.
Kuzminzki et al (1998) reported on the outcome of 33 patients with vitamin B-12 deficiency who were randomized to receive oral or parenteral vitamin B-12 therapy. Patients in the parenteral therapy group received 1,000 mcg of vitamin B-12 intramuscularly on days 1, 3, 7, 10, 14, 21, 30, 60, and 90, while those in the oral treatment group received 2,000 mcg daily for 120 days. At the end of 120 days, patients who received oral therapy had significantly higher serum vitamin B-12 levels and lower methylmalonic acid levels than those in the parenteral therapy group.

 On treating B12 deficiency :-

Although the daily requirement of vitamin B-12 is approximately 2 mcg, the initial oral replacement dosage consists of a single daily dose of 1,000 to 2,000 mcg (Lederle, 1991; Oh and Brown, 2003). This high dose is required because of the variable absorption of oral vitamin B-12 in doses of 500 mcg or less. This regimen has been shown to be safe, cost-effective, and well tolerated by patients.


CONCLUSION


Long term high dose NAC will require careful supplementation with B vitamins.   If NAC is using up vitamin B12 faster than your child is absorbing it from food and supplements, B12 will be used up from the liver and other vitamin stores in the body.  These stores will eventually be depleted and vitamin B12 deficiency will result, if you continue to give NAC.  This is best avoided.

If money is of no concern, best to buy Cerefolin NAC or Betrinac.  If on a budget, then use the cheap NAC available on-line or in your pharmacy; but be careful to supplement far higher amounts of B6, B9 and B12 than the RDA (recommended daily amount).

Cerefolin NAC and  Betrinac have 400 times the RDA of B12, 4 times the RDA of B9 and 15 times of B6.  But each of these tablets only has 600mg of NAC.  In the autism trials the dose of NAC is 4 times higher.

It is evident that B12 is the key vitamin that acts as a precursor with NAC to form GSH (Glutathione), so this is the one to keep a close eye on should your child's NAC appear "to stop working".

It looks like 1,000 mcg of B12, of which 1% may be absorbed, is a fair place to start.  Such supplements are relatively inexpensive, and widely available.