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Wednesday, 21 March 2018

Amino Acids Disturbed in Autism? Very Likely


Amino acids in your body are the building blocks for making proteins. There are essential Amino Acids that you must obtain from diet and semi-essential amino acids that in young children are body is still not able to produce and non-essential amino acids that your body can produce. 

There was an earlier post on Amino Acids:- Amino Acids in Autism 



There are also sub-groups, Branch Chained Amino Acids (BCAAs) and aromatic.  The branched chained amino acids (BCAAs) compete with the aromatic amino acids for entry into the brain. Therefore, altering BCAA levels can affect the levels of the neurotransmitters serotonin, dopamine, epinephrine and norepinephrine in the brain. 

Alanine
Arginine (essential)
Asparagine
Aspartic acid
Cysteine
Glutamic acid
Glutamine
Glycine
Histidine (essential) Aromatic
Isoleucine (essential) BCAA
Leucine (essential) BCAA
Lysine (essential)
Methionine (essential)
Phenylalanine (essential)  Aromatic
Proline
Serine
Threonine (essential)
Tryptophan (essential) Aromatic
Tyrosine  Aromatic
Valine
(essential)  BCAA 

Taurine is not an amino acid, but often gets treated as if it was one.

Arginine and its derivatives appear to play a critical role in some types of cognitive impairment including Alzheimer's and other forms of dementia.

I am writing new posts about certain individual amino acids that look interesting. Aspartic acid is next and the post looks like getting rather complex, so I decided to highlight an interesting very simplistic study that I stumbled across, that would otherwise get lost in other complex papers.  
I call it simplistic because it compares a control (NT) group with two groups of children with autism, one group has no intervention and the other group is made up of kids with some intervention, of any kind, under the umbrella of digestive/dietary/enzyme/antifungal. The control group was siblings of the children with autism. So three groups in total.
Nonetheless, this Disney science does show something quite surprising. In most cases it looks like any intervention produced results much closer to the reference range than no intervention. The study did not measure whether the intervention had any effect on the severity of autism, or compare the different interventions.
Since I am currently researching Aspartic acid I was drawn to the fact that Aspartic acid was nearly three times higher for the female controls compared with the males.  This I find notable, given the sex difference in autism, which is the biggest clue nature has left us. 


A total of 63 subjects were recruited, consisting of 34 autistic children with 31 males and three females aged 5–15 years (mean ± SD, 6.9 ± 2.5 years), and 29 controls with 13 males and 16 females also covering a range of 5–15 years (mean ± SD, 8.9 ± 3.3 years). The controls were derived primarily from siblings of the autistic group, where the sex ratio was more reflective of the general population compared to the sex balance of the autistic population which is recognised as approximately 4:1 (male:female).15 Measures were taken to account for the uneven sex-distribution in the interpretation of the results.


Twenty-two of the autistic children were receiving therapeutic treatments related to digestive function and nutritional uptake. These treatments included antifungal medication, to treat confirmed or suspected Candida infection of the digestive tract, probiotics for maintenance of gut microflora, dietary intervention (gluten- and/or casein-free diet), nutritional supplements, or the hormone secretin; this has been shown to be responsible for regulating pH of the duodenum and is, therefore, pertinent to the functioning of digestive enzymes. On this basis, the autism group was further subdivided into two groups for evaluation of urinary metabolites: treated autistic patients (n = 22; range, 5–15 years; mean, 6.9 ± 2.4 years; 91% male) and untreated autistic patients (n = 12; range, 5–12 years; mean, 7.0 ± 2.5 years; 91% male). To account for any sex-associated differences in urinary output, resulting from the disparity in the sex matching of the autistic and control groups, the control population was first subdivided on the basis of gender.

Two compounds emerged as significantly different on a gender basis for the control group: (i) glucose excretion was of a significantly higher mean concentration for the female control group compared with the males (P <0.05); and (ii) aspartic acid was nearly three times higher for the female controls compared with the males (P < 0.05). No other urinary metabolite concentrations proved to be significantly different between the female and male controls. On this basis, the data from the entire control group were compared with the treated and untreated autistic cohorts.




Plasma amino acids vs urinary amino acids 

There are numerous other studies and they do tend to use a blood test rather than a urine sample. Below is a relatively recent study from Egypt. 


Methods
Twenty autistic children were compared to twenty healthy age and sex matched normal children serving as control, where serum amino acids, urea, ammonia and protein electrophoresis were estimated.

Results
As regards essential amino acid levels, autistic children had significant lower plasma levels of leucine, isoleucine, phenylalanine, methionine and cystine than controls (P < 0.05),while there was no statistical difference in the level of tryptophan, valine, threonine, arginine, lysine and histidine (P > 0.05). In non-essential amino acid levels, phosphoserine was significantly raised in autistic children than in controls (P < 0.05). Autistic children had lower level of hydroxyproline, serine and tyrosine than controls (P < 0.05). On the other hand there was no significant difference in levels of taurin, asparagine, alanine, citrulline, GABA, glycine, glutamic acid, and ornithine (P > 0.05).

There was no significant difference between cases and controls as regards the levels of urea, ammonia, total proteins, albumin and globulins (alpha 1, alpha 2, beta and gamma) (P > 0.05).

Conclusions
Autistic children had lower levels of some plasma amino acids except for glycine and glutamic acids and phosphoserine were increased with normal serum levels of urea, ammonia, total proteins, albumin and globulins (alpha 1, alpha 2, beta and gamma). 
In conclusion, autistic children may have dysregulated amino acids metabolism as all amino acids except for glutamic acid, phosphoserine and glycine are decreased in patients than in control; the raised glutamic acid may suggest involvement of an altered glutamate transporter and is consistent with a biochemical basis for autistic disorders. Also, the lower amounts of essential amino acids are correlated with more severe autism.


Conclusion

The fair conclusion is that both excreted and plasma amino acids look to be disturbed in autism. Does this tell you anything actionable? Should you become obsessed by trying to reach the reference ranges?
The answer depends on who you ask and I guess who is paying.

The derivatives of some amino acids may indeed be disturbed as a protective mechanism in which the body is adapting to specific effects of that person's autism. This was suggested in the research as one explanation of why agmatine, a derivative of arginine, is elevated in schizophrenia.  In other words elevated agmatine is a good thing in that person, it may well be a biomarker for schizophrenia, but possibly a "good" biomarker. 
If normalizing amino acids does improve autism, then expect the CM-AT treatment from Curemark to pass its phase 3 trials and become an FDA approved therapy for autism. Interestingly when I looked into the Curemark patents a long time ago, secretin appeared and it made another appearance earlier in this post. Secretin is now viewed as a false hope for autism treatment and those who still use it are seen as quacks. In trials secretin was shown not to help most people with autism, but regular readers will know that this is different from saying nobody responds. 
Irrespective of what finally happens to CM-AT, it looks like individual amino acids do have a place in some personalized autism therapies. This may, in some cases, be irrespective of the reference ranges, in other words in some cases an abnormally high level of one amino acid may be required to get a specific beneficial therapeutic effect.  Staying within the reference range is clearly the safer option.
Now I am back to my complicated post about Aspartate and N-acetylaspartate (NAA), which does look very relevant to autism.







7 comments:

  1. It amazes me how very simple interventions with a lot of research behind it such as supplementing fiber or additional vitamin D as well as other vitamins that are generally better to get from food (but impractical for most people) are discounted or ignored, but you have a lot of people aging far faster than their years proudly discuss all the medications they are taking as if it is some mark of social status just as having rotten teeth was a sign of social status in the Victorian era because it signaled that your family was wealthy enough to afford sugar.

    The same goes with people I actually know who raise alarms about the "supplement industry" and people taking free form amino acids "damaging their liver", yet these people I know have taken a bunch of prescribed drugs that I know are totally unnecessary and this is not including all the psychotropic medication such as SSRI's I may or may not know about. Literally 1/6 of Americans are on some sort of psychotropic medication as confessing your sins to a psychiatrist and then having them absolve you of your guilt with some happy pills seems to be the new secular religion for a lot of people these days which is just sad.

    And a new study covering 30 countries over 27 years comes out showing that increased spending on various dimensions of health care increases health and well-being, except for spending on guess what:

    https://www.sciencedaily.com/releases/2018/03/180321121539.htm

    Yup, increased spending on the pharmaceutical industry actually decreases the health of people, rather than increases the health of people as you would think it should.

    Another recent study here in the United States also showed a strong link between a doctor's income and the number of opioid prescriptions they write. Of course, most doctors are not directly getting a cut from drug companies for writing opioid prescriptions (some are and a few largely symbolic examples have been made in the form of prosecutions), but the point is that people need to keep coming back to their doctor to "treat" them, since the doctor has no incentive to actually cure them or at the very least help them manage their medical needs independently. Just the cost of medical bills for a lot of people will drive a lot of people to an early grave due to the stress from the incessant calls from bill collectors and the need to take second and third jobs after their wages have been garnished and a lean put on their home which leaves little room for sleep or much else. Meanwhile, their doctors are driving home to their gated communities in the Lexus bought and paid for via the patients they have financially taken advantage of.

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  2. Hi Peter and all others,

    As some of you might know I have used memantine in the past for about 4 weeks with mostly positive results regarding the ability to cope with daily stressors. However while on memantine I noticed that it was almost impossible to look forward to future events (such as a planned party), I know the party was going to happen, however in my brain something seems to have disabled (no doubt due to the NMDA blocking), namely the party had absolutely no meaning at all to me. It took a few weeks before it became very clear to me that memantine seemed like a trade off, its either having zero stress and the inability to form memories or the other way around.

    So I decided to stop the memantine, gradually lowered the dose over a couple of days then completely stopped. I must say it has had absolutely no negative effects on stopping for me personally.

    So knowing the fact that NMDA modulation seems to hold alot of promise (just look at the discussions on ketamine for treatment resistant depression for example), I decided to re-try piracetam, in somewhat higher doses 2x 4gram daily and the effect was quite pronounced and dramatic on me, stressfree, carefree and most of all without the memory issues that memantine has had for me.

    Ofcourse piracetam acts on alot of systems such as acetylcholine, nmda and it even protects mitochondria in the brain. Now this seemed something that alot of 'racetams/nootropics' have in common, so I continued searching and decided to try oxiracetam, which again seems to help me alot allthough in a somewhat different way.

    Now there has been alot of debate about the potentiating of NMDA signalling, most people interpreter this as excitotoxicity, while nearly all the research suggest that racetams are actually PROTECTIVE against glutamate induced neurotoxicity (most likely by optimizing the NMDA/glutamate system).

    I suggest you take a deeper look into oxiracetam Peter, it affects everything from N-AA, glutamate/glutamine/glutathione, PKC to optimizing the krebs cycle and mitochondria in the brain.

    Have a look at:

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5577264/
    https://examine.com/supplements/oxiracetam/

    And for those wondering, yes I am still using cordyceps (also affects AMPA signalling like racetams) and yes it is still helping and my urea levels have come down even more :).

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  3. Peter,

    I am really curious about the results of the CM AT phase three trial especially as they have now been directed to conduct a test on autistic kids with normal chymotrypsin levels to see if it helps them too. I feel normal ranges of biochemical parameters probably might not be normal for autistic kids...their normal might be a little less or little more, at least for some kids. We had got done a detailed organic acid test done for my son and he had all values sitting nicely in the middle of the reference range. He has regular healthy motions. His liver and kidney function test result was perfect. Still his belly remains a little distended. Obvviosly, something is off....either dysbiosis or enzymatic insufficiency and hence imperfect digestion. I hope at least a few of these drugs in the final phases of trial are approved soon so that our paeditricians, who really might be wanting to help, have a standardized protocol for at least a few diagnostic tests and drug administration under their supervision.

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  4. Hi Peter and community,

    I'm going to get a requisition over the next week to get an Amino Acids test done, and I believe the results will take 3 weeks or so. I've been wanting to do this for a about a month or so, so your article was perfectly timed Peter,

    And I'm still waiting for the genetic analysis, which may also tell us a lot (depending on if they find anything).

    In the meantime, I found the following recent paper which looks interesting:

    Plasma anandamide concentrations are lower in children with autism spectrum disorder

    https://molecularautism.biomedcentral.com/articles/10.1186/s13229-018-0203-y

    The Conclusion Statement is:

    " In conclusion, this report extends preclinical findings to provide the first empirical evidence that plasma AEA concentrations are lower in individuals with ASD compared to neurotypical control individuals. Future research must now determine the relationship between plasma AEA concentrations and ASD symptom severity, particularly with regard to the core and associated features thought to be related to AEA signaling deficits in patients with ASD (i.e., phenotypic profiles with atypical cognitive and social functioning as measured by gold-standard assessments like the Autism Diagnosis Observational Schedule). In parallel, research is also needed to identify the mechanisms responsible for the lower AEA concentrations observed in ASD patients (e.g., is this reduction related to changes in AEA transporter proteins, synthesizing enzymes, catabolizing enzymes, and/or eCB receptor expression? [8, 25, 26, 30, 31, 32]). Should these follow-up studies implicate a convincing role for AEA in the pathophysiology of ASD, the eCB system may represent a promising target for therapeutic development in ASD."

    So this brings us back to FAAH inhibitors. I know I had looked for these in the past, and found options like Kaempferol, Echinacea, CBD Oil, but most presented issues.

    Hope this is helpful!

    AJ

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    Replies
    1. Hi AJ,

      CB1 receptor function indeed seems impaired/diminished in autism/asd, CB1 has a strong connection with adenosine/ghrelin/leptin/oxytocin (this balance is extremely important and is off in autism/asd/adhd and directly influences adiponectin).

      Here is another example:

      Endocannabinoid signaling mediates oxytocin-driven social reward
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4653148/


      As you might know I have talked about oleoylethanolamide (positive correlation with oxytocin secretion) and Peter has mentioned PEA (influences PPARgamma) aswell. These lipid signalling molecules are overlooked imo, this also includes oleamide (which enhances elevated during sleep deprivation).

      What I have always found striking is that over the years reading on forums is that just soooooooo many people with adhd self medicate with cannabis, this just cant be a coincidence imo and most likely they are self medicating.

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    2. Hi Aspie,

      Yes, based on this paper and others the endocannabinoid system certainly seems involved.

      I want to do a little more research on CBD oil to see if it has any potential.

      I have in fact been using PEA for almost a year now, and no negatives from it (and maybe positives, hard to tell with all the interventions I'm using).

      I also agree with you in terms of people self-medicating. It's like they know that something is off, they find a substance that makes them feel better, and use it to feel better.

      Have a great day Aspie!

      AJ

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  5. I got my daughter's OAT results and it was all normal , MRI reslut is normal, i need to find a clue to improve my 9 year old daughter, mathematical ability , she finds difficulty in understanding multiplying or division , for example simple questions like how many hours in two days , or how many grams are there in one kilogram , also slightly delayed than her mates socially, more naive ,

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