Accept Autism or Treat It?

Back in the old days autism was a hidden condition and those affected were usually tucked away in institutions. A trend then slowly developed towards inclusion, with the Individuals with Disabilities Education Act (IDEA) being passed in 1975 in the US.  Other countries have slowly moved in this direction, with France only this year finally following suit.

Having moved on from hiding autism, we then had the new diagnosis of Asperger’s appearing in the 1990s and so autism became a much broader diagnosis. Then followed the idea of awareness and diagnosing adults.

Now we have an ever-growing number of people diagnosed with this “autism” thing, that other people are supposed to be aware of. Is it a disease, a dysfunction, a disability or just a difference?

Most importantly are you supposed to treat it, or just accept it?

I recently watched a BBC documentary where a doctor was the presenter and she was talking about schizophrenia. She said that at medical school she was taught that there are medical problems and there are mental health problems, for some reason she was taught that mental health problems are not just medical problems of the brain. Somehow mental health problems are supposed to be different and not based in biology, where did that idea come from?

The program went on to show that about 8% of schizophrenia appears to be caused by NMDAR antibodies. This is a condition where antibodies attack NMDA receptors in the brain, this causes hallucinations and other symptoms that a psychiatrist would diagnose as schizophrenia.  Rather than treating lifelong with anti-psychotics, the patient needs immunotherapy and can then resume a normal life.

It looks like 30% of modern autism is associated with cognitive impairment leading to a measured IQ of less than 70. This is intellectual disability (ID) to autism parents and mental retardation (MR) to the rest of the world.

The interesting finding in this blog is that some MR/ID is actually treatable. I did suggest to the Bumetanide researchers that they should include measuring IQ in their clinical trials.

I do not see how anyone could object to treating MR/ID, even those parents with Asperger’s who find the idea of treating their child’s severe autism to be repulsive.

Maths, Autism and Hans Asperger

Some people with Asperger’s are brilliant at maths, and I think these are the ones that Hans Asperger was mostly studying in Vienna in the 1940s. Lorna Wing came along in 1981 and then Uta Frith in 1991 and translated into English one of Asperger’s 300 papers, the 1943/4 “Die Autistischen Psychopathen im Kindesalter” and then named autism with no speech delay as Asperger’s Syndrome.

In 1994 the Americans adopted Asperger’s as a diagnosis and then rejected it two decades later in 2013 (DSM5).

In Asperger’s 1943 paper he described Fritz, Harro, Ernst and Hellmuth, who he termed "autistic psychopaths”; all four had high IQs and Asperger called them "little professors" because they could talk about the area of ​​their special interest in detail and often accumulated amazing knowledge.

I think Asperger’s should have been left as the "Little Professor’s Syndrome" (high IQ only).

In 2018 some people have realized that from the mid 1930’s almost all people in high positions in Austria and Germany were implicated in some pretty evil Nazi programs, including killing mentally disabled children. Asperger, being a senior psychiatrist at the University of Vienna, obviously played a role, not wanting to pay a visit to the local Gestapo basement.  He was living in a police state, where people tend to do what they are told.  Unlike most of the University medical faculty he was not a member of the Nazi party.

The particularly evil Austrian psychiatrist was Dr Emil Gelny, who modified an ECT (Electro Convulsive Therapy) device to give his subjects lethal shocks. Having personally killed hundreds of mental patients, after the end of the war he escaped to Baghdad, continued practising as a doctor and lived till he was 71. He was never brought to account and Mossad clearly never paid a visit, so I guess there were no Jewish victims.  His highly publicized use of ECT is one reason why it is little used today, even though it does seem to help certain otherwise untreatable conditions.

What surprised me was that in 1930 (before the rise of Hitler) half of the doctors in Vienna were Jewish and indeed half of the Vienna medical faculty were Jewish. So not so anti-Semitic in 1930.  All these doctors had to leave and so the young Hans Asperger made rapid career progress.

Things were not all rosy elsewhere.

I recently read that in London in the 1950s Jewish doctors struggled to progress within the faculty of medical schools and so some emigrated to the US.

We should also note that the Nazis took their inspiration for eugenics from America, where it backed by well-known names such as the Carnegie Institution and the Rockefeller Foundation. California, which we now might consider very liberal, was the centre for forced sterilization.  Between 1907 and 1963 over 64,000 individuals were forcibly sterilized under eugenic legislation in the United States.

So, I think Asperger deserves a break, he was likely no better or worse than other Austrians, unlike most he did not join the Nazi Party. Wing and Frith (a German) were naïve to name a psychiatric syndrome based on the work of an Austrian written during the Nazi period. I think you would not name a reservation for native Americans after General George Custer. 

Back to Maths

One group of kids with severe autism do have near/distant relatives who have remarkable maths skills but were never diagnosed with anything other than being a bit odd.

Monty, now aged 14 with ASD, had great difficulty with even the most basic maths until the age of 9, so much so that we did not bother to teach it, we focused on literacy.

Five and a half years of drug treatment has produced a boy who is now great at maths, at least in his class of 12 years olds.

Coordinates, no problem; negative numbers, no problem. It still now shocks those who knew him from before.

Today I received a message from Monty’s assistant at school and a photo of his classwork, where he is solving simple equations like
7x - 6 = 15

That is not a complex problem for a typical boy, but at the age of 9, after 5 years of intensive ABA therapy, we were still challenged by the most basic single digit addition.  

Nice neat handwriting

Should you treat autism? 

Pretty obviously I think autism should be treated. I would favour treating all types of genuine disease.

If you can treat it, I’d definitely call it a disease.

I would treat people with Down Syndrome to raise their IQs to improve their quality of life and I would also treat them preventatively to avoid early onset Alzheimer’s, which they are highly likely to develop. By the age of just 40 years old, studies have shown significant levels of amyloid plaques and tau tangles, which will lead to Alzheimer’s type dementia.

If you cannot treat it, then you’re just going to have to accept it.

But how would you know you cannot treat it, if you do not at least try?

Since there are hundreds of types of autism, there is no one-stop treatment shop for autism. For medical advice you should go to see a doctor, but mainstream medicine believes autism is untreatable. Today it is really up to the parents themselves to figure out what, if anything, to do.  Dr Frye might suggest you try Leucovorin, B12 and NAC; some DAN doctor will tell you it is all about candida; another will treat everyone with cod liver oil; another will blame parasites; most will blame vaccines.  One lady will charge you large amounts of money for her genetic tests, baffle you with complicated looking charts and then sell you her supplements by the bucket-load. This blog suggests numerous therapies may be partially effective in specific people, a case for personalized medicine.  My Polypill is what works for my son's autism; it is nice to know it works for some others, but it does not work for all autism, that would never be possible.  

With schizophrenia, you could start by treating that 8% with NMDAR antibodies via a science-based medical therapy; this has got to be a big step forward over psychiatric drugs.

We have gone from aged 9, struggling with: -

5 + 2 =  ?

To aged 14, solving worded maths questions, where you have to create the formula and to neatly solving simple equations like:

7x – 6  =  15                  

In algebra there is no doubt effective treatment wins over acceptance.

There is more to life than algebra, but it looks pretty clear that going through life with an IQ 30+ points less than your potential is a missed opportunity. 

Trivial autism

Many people with mild autism and an IQ much greater than 70 are happy the way they are and do not want treatment. For them autism is not a disability, it is just a difference, so we might call it trivial autism.  Unless years later they commit suicide or hurt other people, then it was not so trivial after all.

Unfortunately, some people with trivial autism will go on to produce children with not so trivial autism.

Then you end up with situation that the adult can block what is in the child’s interest, just like deaf parents who refuse their deaf child to have cochlear implants to gain some sense of hearing. Cochlear implants are only effective when implanted in very young children, so by the time you are old enough to have you own say in the decision, it is too late.  Some deaf parents do not want hearing children – odd but true.

So, I come back to my earlier point better to treat ID/MR, don’t even call it treating autism.

How can the Asperger’s mother then refuse treatment to her son with autism plus MR/ID? She can still be able to celebrate her difference, while he gets a chance to learn to tie his own shoe laces, put his shirt on the right way around and do all kinds of other useful things.

So, focus on the 31% of autism? 

CDC - Community Report on Autism 2018

What was the intellectual ability of the children identified with ASD?

                     
Unfortunately, in the research trials they often exclude severe autism, so they exclude people with epilepsy, people with MR/ID and people will self-injurious behaviour (SIB). The very people who clearly need treatment are excluded from the trials to determine what are effective autism treatments. Rather odd.

Variable Expression of GABRA5 and Activation of α5 - a Modifier of Cognitive Function in Autism?

Today’s post sounds complicated. We actually already know that the gene GABRA5, and hence the alpha 5 sub-unit of GABA_A receptors, can affect cognition, but we do not know for sure in whom it is relevant.

Most readers of this blog are lay people, as such we tend to be predisposed to the idea that autism is somehow “hardwired”, something that just happened and cannot be reversed. Some of autism is indeed “hardwired”, you cannot take an adult with autism and “re-prune” his synapses, to produce a more elegant robust network in his brain. But much can be done, because many things in the brain are changing all the time, they are not fixed at all. Today’s post is good example.

GABA is the most important inhibitory neurotransmitter in the brain. There are two types of GABA receptor, A and B. These receptors are made up of sub-units. There are many different possible combinations of sub-units to make GABA_A receptors. These combinations are not fixed, or “hard-wired”; they vary all the time.

The composition of the GABA_A receptor changes its effect. It can change how you feel (anxiety) and it can change you think/learn.

You can actually measure GABRA5 expression in different regions of the brain in a test subject using a PET-CT (Positron Emission Tomography–Computed Tomography) scan and it has been done in some adults with high functioning autism. This machine looks like a big front-leading washing machine, just a bit cleverer. 

The brain GABA-benzodiazepine receptor alpha-5 subtype in autism spectrum disorder: A pilot [11C]Ro15-4513 positron emission tomography study

our primary hypothesis was that, compared to controls, individuals with ASD have a significant reduction in α5 GABA receptor availability in these areas.

Due to the small sample size, we could not examine possible correlations between GABA_A binding and particular symptoms of ASD, age, IQ, or symptoms of comorbidities frequently associated with ASD, such as anxiety disorders, OCD and depression. We were also unable to address the effects of possible neuroanatomical differences between people with ASD and controls, which might lead to partial volume effects in PET studies. However, the modest magnitude of the volumetric differences seen in most studies of high-functioning ASD suggests that it is unlikely that these could fully explain the present findings.

These preliminary results suggest that potentiation of GABA_A signaling, especially at GABA_A α5-subunit containing receptors, might potentially be a novel therapeutic target for ASD. Unselective GABA_A agonists and positive allosteric modulators, such as benzodiazepines, have undesirable features such as abuse potential and tolerance, but more selective modulators might avoid such limitations. Further research should extend this work in a larger sample of ASD individuals. It would also be interesting to use PET with the ligand [¹¹C]Ro15-4513 to measure GABA_A in disorders of known etiology characterised by ASD symptoms, such as Fragile X and 15q11-13 duplication

In summary, we present preliminary evidence of reduced GABA_A α5 expression in adult males with ASD, consistent with the hypothesis that ASD is characterised by a defect in GABA signaling. 

α5GABAA receptor deficiency causes autism-like behaviors

The prevalence of autism spectrum disorders (ASDs), which affect over 1% of the population, has increased twofold in recent years. Reduced expression of GABA_A receptors has been observed in postmortem brain tissue and neuroimaging of individuals with ASDs. We found that deletion of the gene for the α5 subunit of the GABA_A receptor caused robust autism-like behaviors in mice, including reduced social contacts and vocalizations. Screening of human exome sequencing data from 396 ASD subjects revealed potential missense mutations in GABRA5 and in RDX, the gene for the α5GABA_A receptor-anchoring protein radixin, further supporting a α5GABA_A receptor deficiency in ASDs.

The results from the current study suggest that drugs that act as positive allosteric modulators of α5GABA_A receptors may ameliorate autism-like behaviors 

  

Too many or too few the α5GABA_A receptors or too much/little activity?

Regular readers will know that autism is all about extremes hypo/hyper, macro/micro etc. The same is true with α5GABA_A, too few can cause autistic behaviors, but too many can impede learning. You need just the right amount.

The next variable is how well your α5GABA_A are behaving, because even if you have an appropriate number of these receptors, you may not have optimal activity from them. Over activity from α5GABA_A is likely to have the same effect as having too many of them.

Here it becomes very relevant to many with autism and inflammatory comorbidities, because systemic inflammation has been shown to activate α5GABA_A. It has been shown that increased α5GABA_A receptor activity contributes to inflammation-induced memory deficits and, by my extension, to inflammation-induced cognitive decline.

α5GABAA Receptors Regulate Inflammation-Induced Impairment of Long-Term Potentiation

Systemic inflammation causes learning and memory deficits through mechanisms that remain poorly understood. Here, we studied the pathogenesis of memory loss associated with inflammation and found that we could reverse memory deficits by pharmacologically inhibiting α5-subunit-containing γ-aminobutyric acid type A (α5GABA_A) receptors and deleting the gene associated with the α5 subunit. Acute inflammation reduces long-term potentiation, a synaptic correlate of memory, in hippocampal slices from wild-type mice, and this reduction was reversed by inhibition of α5GABA_A receptor function. A tonic inhibitory current generated by α5GABA_A receptors in hippocampal neurons was increased by the key proinflammatory cytokine interleukin-1β through a p38 mitogen-activated protein kinase signaling pathway. Interleukin-1β also increased the surface expression of α5GABA_A receptors in the hippocampus. Collectively, these results show that α5GABA_A receptor activity increases during inflammation and that this increase is critical for inflammation-induced memory deficits.

We saw in an earlier post that overexpression of GABRA5 is found in slow learners and we know that this is a key target of Down Syndrome research, aimed at raising cognitive function.

What can be modified?

It appears that you can modify the expression of GABRA5, which means you can increase/decrease the number of GABA_A receptors that contain an α5 subunit.

You can also tune the response of those α5 subunits. You can increase it or decrease it.

Activation of the α₅ subunit is thought to be the reason why benzodiazepine drugs  have cognitive (reducing) side effects. By extension, inverse agonists of α₅ are seen as likely to be nootropic.

One such drug is LS-193,268  is a nootropic drug invented in 2004 by a team working for Merck, Sharp and Dohme.

A complication is that you do not want to affect the α₂ subunit, or you will cause anxiety. So you need a highly selective inverse agonist.

The new Down Syndrome drug, Basmisanil, is just such a selective inverse agonist of α₅.

“Basmisanil (developmental code names RG-1662, RO5186582) is a highly selective inverse agonist/negative allosteric modulator of α₅ subunit-containing GABA_A receptors which is under development by Roche for the treatment of cognitive impairment associated with Down syndrome.  As of August 2015, it is in phase II clinical trials for this indication.^“

A contradiction

As is often the case, there is an apparent contradiction, because on the one hand a negative allosteric modulator should be nootropic in NT people and appears to raise cognition in models of Down Syndrome; but on the other hand results from a recent study suggests that drugs that act as positive allosteric modulators of α5GABA_A receptors may ameliorate autism-like behaviors.

So which is it?

Quite likely both are right.

It is exactly as we saw a long while back with NMDAR activity, some people have too much and some have too little. Some respond to an agonist, some to an antagonist and some to neither.

What we can say is that fine-tuning α5GABA_A in man and mouse seems a viable option to enhance cognition in those with learning difficulties.

The clever option is probably the positive/negative allosteric modulator route, the one being pursued by big Pharma for Down Syndrome.

I like Dr Pahan’s strategy from this previous post, for poor learners and those with early dementia

https://epiphanyasd.blogspot.com/2017/10/sodium-benzoate-and-gabra5.html

to use cinnamon/NaB to reduce GABRA5 expression, which has got to consequently reduce α5GABA_A activity.

All of these strategies are crude, because what matters is α5GABA_A activity in each part of the brain. This is why changing GABRA5 expression will inevitably have good effects in one area and negative effects in another area. What matter is the net effect, is it good, bad or negligible?

The fact that systemic inflammation increases α5GABA_A activity may contribute to the cognitive decline some people with autism experience.

We previously saw how inflammation changes KCC2 expression and hence potentially increases intra cellular chloride, shifting GABA towards excitatory.

Ideally you would avoid systemic inflammation, but in fact all you can do is treat it.

Increasing α5GABA_A activity I would see as possible strategy for people with high IQ, but some autistic features.

I think those with learning problems are likely to be the ones wanting less α5GABA_A activity.

The people for whom “bumetanide has stopped working” or “NAC has stopped working” are perhaps the ones who have developed systemic inflammation for some reason.  You might only have to measure C-reactive protein (CRP) to prove this.

More reading for those interested:-

The α-5 subunit-containing GABA-A receptor: a target for the treatment of cognitive defects

The role of α5 GABAA receptor agonists in the treatment of cognitive deficits in schizophrenia

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.

Green Tea Catechin EGCG in Down Syndrome, but Autism? and Cerebrolysin

In a recent comment a reader from Poland highlighted the popularity there of a drug called cerebrolysin to treat autism and Down syndrome.  It turns out that this treatment in also widespread in the former Soviet Union.

Green tea as a source of Epigallocatechin gallate (EGCG)

Cerebrolysin is a mixture of peptides purified from pig brains, including  brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and ciliary neurotrophic factor (CNTF).

While cerebrolysin is used for stroke and vascular dementia, it is used by some as a nootropic. 

There are two Russian studies supporting the use of Cerebrolysin:

The effect of cerebrolysin on cognitive functions in childhood autism and in Asperger syndrome

An effect of long-term cerebrolysin therapyin combination with neuroleptics on behavioral and cognitive disturbances in endogenous childhood autism

 

I was informed that cerebrolysin is prescribed off-label in Poland to treat autism, with some good results.

Three other substances were then mentioned.

MemoProve, an oral OTC product made by the same Austrian company that produces cerebrolysin, and then two research compounds P6 and P21. The P21 research is also part funded by the same Austrians. People in the US are using intranasal P21 as a nootropic.

It does seem that some people with autism do indeed benefit from cerebrolysin. 

As we have seen in previous posts the various growth factors (BDNF, NGF, IGF-1 etc) are disturbed in autism and they play a key role in various signaling cascades. There certainly is logic in using growth factors as autism therapies, but it would be important to use the right ones. In Rett syndrome there is almost no nerve growth factor (NGF), whereas in much autism there are elevated levels. Insulin-like growth factor IGF-1 already is a target autism therapy.

The disadvantage of cerebrolysin is that it is made from pigs’ brains and you need to inject it every day.

Unless you live in Poland, Russia or Romania, I doubt you will be able to try cerebrolysin, even if you want to.

Another therapy I am told is used in Poland is EGCG, which stands for Epigallocatechin gallate, or just green tea. 

Epigallocatechin gallate (EGCG)

EGCG is another natural substance like resveratrol, curcumin and indeed quercetin that has potent properties in lab, but never quite makes it in the human world.

The normal problem is low bioavailability and the lack of funding to do conclusive clinical trials.

In the case of EGCG there are now some serious studies being done in Spain. 

Egcg, a dyrk1a Inhibitor as Therapeutic Tool for Reversing Cognitive Deficits in Down Syndrome Individuals.

There is a mounting evidence of the modulation properties of the major catechin in green tea, epigallocatechin-3-gallate (EGCG), on dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene overexpression in the brains of DS mouse models. The aims are to investigate the clinical benefits and safety of EGCG administration in young adults with DS, to establish short-term EGCG effects (three months) on neurocognitive performance, and to determine the persistency or reversibility of EGCG related effects after three months of discontinued use. 

Epigallocatechin Gallate (EGCG) to Improve Cognitive Performance in Foetal Alcohol Syndrome (FAS) Children (Neuro-SAF)

The flavonoid epigallocatechin gallate (EGCG) is a modulator of neuronal plasticity useful in other neurodevelopmental diseases. A recent study showed that EGCG is a promising tool for cognitive and health related quality of life improvement in Down's syndrome.

The objective is to determine the efficacy of EGCG as a therapeutic candidate for the improvement of cognitive performance in FAS patients  

Using Epigallocatechin Gallate (EGCG) and Cognitive Training to Modulate Cognitive Performance in Patients With Fragile X Syndrome" (TESFX)

Fragile X syndrome (FXS) present alterations in synaptic plasticity that produce intellectual disability. can produce improvement. Estrogens (targeting Estrogen Receptors beta (ER-β) can act as neuroprotective agents, promoting synaptic plasticity and neurite outgrowth, and health benefits derived from flavonoids, as the flavonol epigallocatechin gallate (EGCG), phytoestrogens of natural origin are partially explained by their interaction with membrane ER. Selective ER-β flavonoids are thus good candidates for their therapeutic evaluation in intellectual disabilities. EGCG also targets central intracellular transduction signals altered in FXS and improves memory recognition in a FXS animal model(adenosine triphosphate (ATP)-inhibitor of phosphatidylinositol 3-kinase (PI3K)and mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinase (ERK1/2). This study targets the synaptic plasticity alterations that underlie the learning and memory impairment but also the computational disability in FXS. The hypothesis is that EGCG can act by favoring the physiological processes involved in cognition. 

The Spanish Science.

You might wonder why a hospital in Barcelona is doing all this research into a green tea extract.

EGCG has numerous biological effects and in the three trials they are not claiming the same mode of action.  In the fragile X trial it is the effect on Estrogen receptor beta, while in Down syndrome it is the effect on DYRK1A gene overexpression. 

Trial results

The only trial to have yet published results is the one on Down Syndrome.  Here the results were pretty good, given that this is a cheap supplement and the dose was modest.

The easy reading version:-

Green tea extract 'boosts mental ability' in people with Down's 

What were the basic results?

For most of the tests (21 of 24) there were no differences between the groups.

However, in three tests people who'd taken EGCG did better. This improvement lasted for six months after the study ended.

These were:

·         remembering and recognizing patterns

·         inhibitory control – the ability to override instinct to follow instructions; for example; in this test, to say "cat" when shown a picture of a dog, and vice versa

·         ability to carry out everyday living tasks (adaptive behaviour)   

I am very surprised that the benefit lasted six months after the study ended.  It would be great if they could validate that in their phase 3 trial. 

The full study:- 

Safety and efficacy of cognitive training plus epigallocatechin-3-gallate in young adults with Down's syndrome (TESDAD): a double-blind, randomised, placebo-controlled, phase 2 trial 

We enrolled adults (aged 16–34 years) with Down's syndrome from outpatient settings in Catalonia, Spain, with any of the Down's syndrome genetic variations (trisomy 21, partial trisomy, mosaic, or translocation) in a double-blind, placebo-controlled, phase 2, single centre trial (TESDAD). Participants were randomly assigned at the IMIM-Hospital del Mar Medical Research Institute to receive EGCG (9 mg/kg per day) or placebo and cognitive training for 12 months. We followed up participants for 6 months after treatment discontinuation. We randomly assigned participants using random-number tables and balanced allocation by sex and intellectual quotient. Participants, families, and researchers assessing the participants were masked to treatment allocation. The primary endpoint was cognitive improvement assessed by neuropsychologists with a battery of cognitive tests for episodic memory, executive function, and functional measurements. Analysis was on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01699711.

Findings

The study was done between June 5, 2012, and June 6, 2014. 84 of 87 participants with Down's syndrome were included in the intention-to-treat analysis at 12 months (43 in the EGCG and cognitive training group and 41 in the placebo and cognitive training group). Differences between the groups were not significant on 13 of 15 tests in the TESDAD battery and eight of nine adaptive skills in the Adaptive Behavior Assessment System II (ABAS-II). At 12 months, participants treated with EGCG and cognitive training had significantly higher scores in visual recognition memory (Pattern Recognition Memory test immediate recall, adjusted mean difference: 6·23 percentage points [95% CI 0·31 to 12·14], p=0·039; d 0·4 [0·05 to 0·84]), inhibitory control (Cats and Dogs total score, adjusted mean difference: 0·48 [0·02 to 0·93], p=0·041; d 0·28 [0·19 to 0·74]; Cats and Dogs total response time, adjusted mean difference: −4·58 s [–8·54 to −0·62], p=0·024; d −0·27 [–0·72 to −0·20]), and adaptive behaviour (ABAS-II functional academics score, adjusted mean difference: 5·49 [2·13 to 8·86], p=0·002; d 0·39 [–0·06 to 0·84]). No differences were noted in adverse effects between the two treatment groups.

Interpretation

EGCG and cognitive training for 12 months was significantly more effective than placebo and cognitive training at improving visual recognition memory, inhibitory control, and adaptive behaviour. Phase 3 trials with a larger population of individuals with Down's syndrome will be needed to assess and confirm the long-term efficacy of EGCG and cognitive training.  

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

The science behind EGCG

Green tea catechin, epigallocatechin-3-gallate (EGCG): mechanisms, perspectives and clinical applications 

An expanding body of preclinical evidence suggests EGCG, the major catechin found in green tea (Camellia sinensis), has the potential to impact a variety of human diseases. Apparently, EGCG functions as a powerful antioxidant, preventing oxidative damage in healthy cells, but also as an antiangiogenic and antitumor agent and as a modulator of tumor cell response to chemotherapy. Much of the cancer chemopreventive properties of green tea are mediated by EGCG that induces apoptosis and promotes cell growth arrest by altering the expression of cell cycle regulatory proteins, activating killer caspases, and suppressing oncogenic transcription factors and pluripotency maintain factors. In vitro studies have demonstrated that EGCG blocks carcinogenesis by affecting a wide array of signal transduction pathways including JAK/STAT, MAPK, PI3K/AKT, Wnt and Notch. EGCG stimulates telomere fragmentation through inhibiting telomerase activity. Various clinical studies have revealed that treatment by EGCG inhibits tumor incidence and multiplicity in different organ sites such as liver, stomach, skin, lung, mammary gland and colon. Recent work demonstrated that EGCG reduced DNMTs, proteases, and DHFR activities, which would affect transcription of TSGs and protein synthesis. EGCG has great potential in cancer prevention because of it’s safety, low cost and bioavailability. In this review, we discuss its cancer preventive properties and it’s mechanism of action at numerous points regulating cancer cell growth, survival, angiogenesis and metastasis. Therefore, non-toxic natural agent could be useful either alone or in combination with conventional therapeutics for the prevention of tumor progression and/or treatment of human malignancies.

Mast Cells and EGCG

One interesting effect of EGCG, at least in the lab, is that it can stabilize mast cells. This would mean that it might he helpful in treating allergy and some types of GI problems, if you have enough of it.

Epigallocatechin-3-gallate Reduces Mast Cells Activity TNF-α and NFKB in Colitis by Interrupting an Inflammatory Cascade (MUC2P.827)

Epigallocatechin-3-gallate inhibits mast cell degranulation, leukotriene C4 secretion, and calcium influx via mitochondrial calcium dysfunction.

Conclusion

The green tea extract EGCG is inexpensive and widely available. It is often taken for its antioxidant properties. In most trials so-called phytoestrogens like EGCG have almost no estrogen-like effect in humans, so I doubt this mode of action.

The trials all used a dosage of 9mg/kg of EGCG which is easy to achieve with OTC supplements.

Given the positive results from the small trial in Down Syndrome (DS), it would fall into the “no-brainer” category to make a home trial, if you have a child with DS.

This is quite different to injecting your child with Cerebrolysin from pig’s brains, where there are some drawbacks.

Will EGCG help in Fragile-X or Fetal Alcohol Syndrome? I have no idea; but being having well established antioxidant properties, I expect it is almost guaranteed to help a least marginally.

Will EGCG help in autism? Given its safety profile, price and availability, it really should have a place on your to-do list. It is an antioxidant with numerous other possible effects, some of which hopefully may be evident in humans.  Compared to some exotic antioxidants that people buy, it is cheap.

With no great expectations, I will see if EGCG has any effect. It might help an as antioxidant, it might help stabilize mast cells and, if has enough potency as an estrogen, it would help via RORa. As you can see in the chart above it actually has dozens of potential effects.

Some natural substances like quercetin have undoubted positive effects, but after continued usage can give side effects.  The EGCG trial was 12 months long and they did not find adverse effects compared to the placebo.

The amount of EGCG in green tea varies wildly, making standardized supplements a safer bet.  Apparently, Lipton Green Tea bags contain about 70mg of EGCG per serving. So my son would need to drink 6 cups of green tea a day to match the trial dose.