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Friday, 23 December 2016

Neuroligins, Estradiol and Male Autism


Today’s post looks deeper into the biology of those people who respond to the drug bumetanide, which means a large sub-group of those with autism, likely those with Down Syndrome and likely some with schizophrenia.
It is a rather narrow area of science, but other than bumetanide treatment, there appears to be no research interest in further translating science into therapy.    So it looks like this blog is the only place to develop such ideas.
I did not expect this post would lead to a practical intervention, but perhaps it does. As you will discover, the goal would be to restore a hormone called estradiol to its natural higher level, perhaps by increasing an enzyme called aromatase, which appears to be commonly downregulated in autism.  This should increase expression of neuroligin 2, which should increase expression of the ion transporter KCC2; this will lower intracellular chloride and boost cognition.
It seems that those people using Atorvastatin may have already started this process, since this statin increases IGF-1 and insulin is one of the few things that increases the aromatise enzyme. 

This process is known as the testosterone-estradiol shunt.  In effect, by becoming slightly less male, you may be able to correct one of the key dysfunctions underlying autism. Options would include insulin, IGF-1, estradiol and a promoter of aromatase.




The testosterone – estradiol shunt



It would seem that this sub-group of autism is currently a little bit too male, which might be seen as early puberty and in other features. In this group the balance between testosterone and estradiol is affected not just in the brain, which is actually a good thing.  This should be measurable, if it is not visible.

  

NKCC1, KCC2 and AE3

As we have seen in earlier posts, some people with autism have too little of a transporter called KCC2 that takes chloride out of neurons and too much of NKCC1 that lets chloride in.  The result is an abnormally high level of chloride, which changes the way the GABA neurotransmitter functions.  This reduces cognitive function and increases the chance of seizures.

It is likely that a group may exist that has mis-expression of an ion exchanger called AE3. Potentially some have just an AE3 dysfunction and some may have AE3, KCC2 and NKCC1 mis-expression.  I will come back to this in a later post, but in case I forget, here is the link:


“NKCC1 seems to be responsible for approximately two thirds of the steady-state chloride accumulation, whereas AE3 is responsible for the remaining third”

Genetic dysfunction of AE3 is not surprisingly associated with seizures and should respond to treatment with Diamox/Acetazolamide.

Block NKCC1 with Bumetanide and/or increase KCC2 expression

I was recently updating the Bumetanide researchers about my son’s near four years of therapy with their drug and my ideas to take things further.

My plan is to apply other methods to reduce intracellular chloride levels.  I think that over time, blocking NKCC1 with bumetanide may trigger a feedback loop that leads to a further increase in NKCC1 expression.  So bumetanide continues to work, but the effect is reduced. One way to further reduce intracellular chloride levels is to increase expression of KCC2, the transport that takes chloride out of neurons.

The best way to do this would be to understand why KCC2 is down regulated in the first place. I have touched on this in earlier posts, where I introduced neuroligin 2.

Today’s post will look at neuroligins in autism and how they are connected to the female hormone Estradiol.  We will also look at how estrogen receptor expression may help explain why more males have autism. Taken together this suggests that an  estrogen receptor agonist might be an effective autism therapy in this sub-group.

The difficulty with hormones is that, due to evolution, each one performs numerous different functions in different parts of the body and they react with each other.  So a little extra estradiol/estrogen might indeed increase neuroligin 2 expression and hence increase KCC2 expression in the brain, but it would have other effects elsewhere.  In female hormone replacement therapy care is usually taken to direct estradiol/estrogen to where it is needed, rather than sending it everywhere.

I suspect that in this subgroup of autism the lack of estradiol is body-wide, not just in the brain.  If not you would either need an estrogen receptor agonist that is cleverly developed to be brain specific, or take the much easier route of delivering an existing agonist direct to the brain, which may also be possible.

In the paper below NL2 and neuroligin-2 mean the same thing. 


Background

GABAA receptors are ligand-gated Cl- channels, and the intracellular Cl- concentration governs whether GABA function is excitatory or inhibitory. During early brain development, GABA undergoes functional switch from excitation to inhibition: GABA depolarizes immature neurons but hyperpolarizes mature neurons due to a developmental decrease of intracellular Cl- concentration. This GABA functional switch is mainly mediated by the up-regulation of KCC2, a potassium-chloride cotransporter that pumps Cl- outside neurons. However, the upstream factor that regulates KCC2 expression is unclear.

Results

We report here that KCC2 is unexpectedly regulated by neuroligin-2 (NL2), a cell adhesion molecule specifically localized at GABAergic synapses. The expression of NL2 precedes that of KCC2 in early postnatal development. Upon knockdown of NL2, the expression level of KCC2 is significantly decreased, and GABA functional switch is significantly delayed during early development. Overexpression of shRNA-proof NL2 rescues both KCC2 reduction and delayed GABA functional switch induced by NL2 shRNAs. Moreover, NL2 appears to be required to maintain GABA inhibitory function even in mature neurons, because knockdown NL2 reverses GABA action to excitatory. Gramicidin-perforated patch clamp recordings confirm that NL2 directly regulates the GABA equilibrium potential. We further demonstrate that knockdown of NL2 decreases dendritic spines through down-regulating KCC2.

Conclusions

Our data suggest that in addition to its conventional role as a cell adhesion molecule to regulate GABAergic synaptogenesis, NL2 also regulates KCC2 to modulate GABA functional switch and even glutamatergic synapses. Therefore, NL2 may serve as a master regulator in balancing excitation and inhibition in the brain.

  
Neuroligins and Neurexins

The following paper has an excellent explanation of neuroligins, neurexins and their role in autism.  It does get complicated.





Neurexins (Nrxns) and neuroligins (Nlgns) are arguably the best characterized synaptic cell-adhesion molecules, and the only ones for which a specifically synaptic function was established8,9. In the present review, we will describe the role of Nrxns and Nlgns as synaptic cell-adhesion molecules that act in an heretofore unanticipated fashion. We will show that they are required for synapse function, not synapse formation; that they affect trans-synaptic activation of synaptic transmission, but are not essential for synaptic cohesion of the pre- and postsynaptic specializations; and that their dysfunction impairs the properties of synapses and disrupts neural networks without completely abolishing synaptic transmission as1012. As cell-adhesion molecules, Nrxns and Nlgns probably function by binding to each other and by interacting with intracellular proteins, most prominently PDZ-domain proteins, but the precise mechanisms involved and their relation to synaptic transmission remain unclear. The importance of Nrxns and Nlgns for synaptic function is evident from the dramatic deficits in synaptic transmission in mice lacking Nrxns or Nlgns.

As we will describe, the role of Nrxns and Nlgns in synaptic function almost predestines them for a role in cognitive diseases, such as schizophrenia and autism spectrum disorders (ASDs), that have been resistant to our understanding. One reason for the difficulties in understanding cognitive diseaseas is that they may arise from subtle changes in a subset of synapses in a neural circuit, as opposed to a general impairment of all synapses in all circuits. As a result, the same molecular alteration may produce different circuit changes and neurological symptoms that are then classified as distinct cognitive diseases. Indeed, recent studies have identified mutations in the genes encoding Nrxns and Nlgns as a cause for ASDs, Tourette syndrome, mental retardation, and schizophrenia, sometimes in patients with the same mutation in the same family1327. Viewed as a whole, current results thus identify Nrxns and Nlgns as trans-synaptic cell-adhesion molecules that mediate essential signaling between pre- and postsynaptic specializations, signaling that performs a central role in the brain’s ability to process information and that is a key target in the pathogenesis of cognitive diseases.

Neuroligins and neurexins in autism


ASDs are common and enigmatic diseases. ASDs comprise classical idiopathic autism, Asperger’s syndrome, Rett syndrome, and pervasive developmental disorder not otherwise specified73,74. Moreover, several other genetic disorders, such as Down syndrome, Fragile-X Mental Retardation, and tuberous sclerosis, are frequently associated with autism. Such syndromic forms of autism and Rett syndrome are usually more severe due to the nature of the underlying diseases. The key features of ASDs are difficulties in social interactions and communication, language impairments, a restricted pattern of interests, and/or stereotypic and repetitive behaviors. Mental retardation (~70% of cases) and epilepsy (~30% of cases) are frequently observed; in fact, the observation of epilepsy in patients with ASDs has fueled speculation that autism may be caused by an imbalance of excitatory vs. inhibitory synaptic transmission. In rare instances, idiopathic autism is associated with specialized abilities, for example in music, mathematics, or memory. The relation of ASDs to other cognitive diseases such as schizophrenia and Tourette’s syndrome is unclear. As we will see below with the phenotypes caused by mutations in Nlgns and Nrxns, the boundaries between the various disorders may not be as real as the clinical manifestations suggest.

A key feature of ASDs is that they typically develop before 2–3 years of age73,74. ASDs thus affect brain development relatively late, during the time of human synapse formation and maturation. Consistent with this time course, few anatomical changes are associated with ASDs75. An increase in brain size was repeatedly reported76, but is not generally agreed upon75. Thus, similar to other cognitive diseases, ASDs are not a disorder of brain structure but of brain function. Among cognitive diseases, ASDs are the most heritable (~ 80%), suggesting that they are largely determined by genes and not the environment. ASDs exhibit a male:female ratio of approximately 4:1, indicating that ASDs involve the X-chromosome directly, or that the penetrance of pathogenic genes is facilitated in males73,74.

Mutations in many genes have been associated with familial ASDs. A consistent observation emerging from recent studies is the discovery of mutations in the genes encoding Nrxn1, Nlgn3, and Nlgn4. Specifically, seven point mutations, two distinct translocation events, and four different large-scale deletions in the Nrxn1 gene were detected in autistic patients1318. Ten different mutations in the Nlgn4 gene were observed (2 frameshifts, 5 missense mutations, and 3 internal deletions), and a single mutation in the Nlgn3 gene (the R451C substitution)2124. Besides these mutations, five different larger deletions of X-chromosomal DNA that includes the Nlgn4 locus (referred to as copy-number variations) were detected in autism patients18,2527.

In addition to the Nrxn/Nlgn complex, mutations in the gene encoding Shank3 – an intracellular scaffolding protein that binds indirectly to Nlgns via PSD-95 and GKAP (Fig. 1)66 – may also be a relatively frequent occurrence in ASDs. An astounding 18 point mutations were detected in the Shank3 gene in autistic patients, in addition to several cases containing CNVs that cover the gene18,7782. Indeed, the so-called terminal 22q deletion syndrome is a relatively frequent occurrence that exhibits autistic features, which have been correlated with the absence of the Shank3 gene normally localized to this chromosome section. Shank3 is particularly interesting because it not only indirectly interacts with Nlgns, but also directly binds to CIRL/Latrophilins which in turn constitute α-latrotoxin receptors similar to Nrxns, suggesting a potential functional connection between Shank3 and Nrxns83.

Overall, the description of the various mutations in the Nrxn/Nlgn/Shank3 complex appears to provide overwhelming evidence for a role of this complex in ASDs, given the fact that in total, these mutations account for a significant proportion of autism patients. It should be noted, however, that two issues give rise to skepticism to the role of this complex in ASDs.

First, at least for some of the mutations in this complex, non-symptomatic carriers were detected in the same families in which the patients with the mutations were found. Whereas the Nlgn3 and Nlgn4 mutations appear to be almost always penetrant in males, and even female carriers with these mutations often have a phenotype, the Shank3 point mutations in particular were often observed in non-symptomatic siblings77,78. Thus, these mutations may only increase the chance of autism, but not actually cause autism.

Second, the same mutations can be associated with quite different phenotypes in different people. For example, a microdeletion in Nlgn4 was found to cause severe autism in one brother, but Tourette’s syndrome in the other26. This raises the issue whether the ‘autism’ observed in patients with mutations in these genes is actually autism, an issue that could also be rephrased as the question of whether autism is qualitatively distinct from other cognitive diseases, as opposed to a continuum of cognitive disorders. In support of the latter idea, two different deletions of Nrxn1α have also been observed in families with schizophrenia19,20, indicating that there is a continuum of disorders that involves dysfunctions in synaptic cell adhesion and manifests in different ways. Conversely, very different molecular changes may produce a similar syndrome, as exemplified by the quite different mutations that are associated with ASDs84.

At present, the relation between the Nrxn/Nlgn synaptic cell-adhesion complex and ASDs is tenuous. On one hand, many of the mutations observed in familial ASD are clearly not polymorphisms but deleterious, as evidenced by the effect of these mutations on the structure or expression of the corresponding genes, and by the severe autism-like phenotypes observed in Nlgn3 and Nlgn4 mutant mice8587. On the other hand, the nonlinear genotype/phenotype relationship in humans, evident from the only 70–80% heritability and from the occasional presence of mutations in non-symptomatic individuals, requires explanation. Elucidating the underlying mechanisms for this incomplete genotype/phenotype relationship is a promising avenue to insight into the genesis of autism. Furthermore, in addition to the link of Nrxn1α mutations to schizophrenia19,20, linkage studies have connected Nrxn3 to different types of addiction88,89. It is possible that because of the nature of their function, mutations in genes encoding Nrxns and Nlgns constitute hotspots for human cognitive diseases.

  
As you will have seen from the above paper, whose author seems to be very well informed of the broader picture (a continuum of disorders that involves dysfunctions in synaptic cell adhesion, and even the link to addiction), neuroligins and neurexins are very relevant to autism and other cognitive disease.

Let’s get back on subject and focus on Neuroligin 2 
The very recent paper below mentions sensory processing defects and NLG2 alongside what we already have figured out so far.

Abstract


Neuroligins are post-synaptic, cellular adhesion molecules implicated in synaptic formation and function. NLGN2 is strongly linked to inhibitory, GABAergic signaling and is crucial for maintaining the excitation-inhibition balance in the brain. Disruption of the excitation-inhibition balance is associated with neuropsychiatric disease. In animal models, altered NLGN2 expression causes anxiety, developmental delay, motor discoordination, social impairment, aggression, and sensory processing defects. In humans, mutations in NLGN3 and NLGN4 are linked to autism and schizophrenia; NLGN2 missense variants are implicated in schizophrenia. Copy number variants encompassing NLGN2 on 17p13.1 are associated with autism, intellectual disability, metabolic syndrome, diabetes, and dysmorphic features, but an isolated NLGN2 nonsense variant has not yet been described in humans. Here, we describe a 15-year-old male with severe anxiety, obsessive-compulsive behaviors, developmental delay, autism, obesity, macrocephaly, and some dysmorphic features. Exome sequencing identified a heterozygous, de novo, c.441C>A p.(Tyr147Ter) variant in NLGN2 that is predicted to cause loss of normal protein function. This is the first report of an NLGN2 nonsense variant in humans, adding to the accumulating evidence that links synaptic proteins with a spectrum of neurodevelopmental phenotypes

After some investigation I learned that both estradiol/estrogen and progesterone increase expression of neuroligin 2, at least in rats.
Increasing neuroligin 2/NLGN2/NL2 looks a promising strategy.


In addition, neuroligin 2 mRNA levels were increased by both 17beta-oestradiol (E(2)) and P(4), although P(4) administration upregulated gene expression to a greater extent than injection of E(2). These results indicate that neuroligin 2 gene expression in the rat uterus is under the control of both E(2) and P(4), which are secreted periodically during the oestrous cycle.[1]

So a female steroid-regulated gene is down-regulated in male-dominated autism.  Another example of the protective nature of female hormones?  I think it is.

Estrogens Suppress a Behavioral Phenotype in Zebrafish Mutants of the Autism Risk Gene, CNTNAP2


Highlights


·         Zebrafish mutants of the autism risk gene cntnap2 have GABAergic neuron deficits

·         High-throughput behavioral profiling identifies nighttime hyperactivity in mutants

·         cntnap2 mutants exhibit altered responses to GABAergic and glutamatergic compounds

·         Estrogenic compounds suppress the cntnap2 mutant behavioral phenotype

Summary


Autism spectrum disorders (ASDs) are a group of devastating neurodevelopmental syndromes that affect up to 1 in 68 children. Despite advances in the identification of ASD risk genes, the mechanisms underlying ASDs remain unknown. Homozygous loss-of-function mutations in Contactin Associated Protein-like 2 (CNTNAP2) are strongly linked to ASDs. Here we investigate the function of Cntnap2 and undertake pharmacological screens to identify phenotypic suppressors. We find that zebrafish cntnap2 mutants display GABAergic deficits, particularly in the forebrain, and sensitivity to drug-induced seizures. High-throughput behavioral profiling identifies nighttime hyperactivity in cntnap2 mutants, while pharmacological testing reveals dysregulation of GABAergic and glutamatergic systems. Finally, we find that estrogen receptor agonists elicit a behavioral fingerprint anti-correlative to that of cntnap2 mutants and show that the phytoestrogen biochanin A specifically reverses the mutant behavioral phenotype. These results identify estrogenic compounds as phenotypic suppressors and illuminate novel pharmacological pathways with relevance to autism.


Estrogen is known to help protect premenopausal women from maladies such as stroke and impaired cognition. Exposure to high levels of the male hormone testosterone during early development has been linked to autism, which is five times more common in males than females.

The new findings of reduced expression of estrogen receptor beta as well as that of an enzyme that converts testosterone to estrogen could help explain the high testosterone levels in autistic individuals and higher autism rates in males, Pillai said.
It was the 5-to-1 male-to-female ratio along with the testosterone hypothesis that led Pillai and his colleagues to pursue whether estrogen might help explain the significant gender disparity and possibly point toward a new treatment.

"The testosterone hypothesis is already there, but nobody had investigated whether it had anything to do with the female hormone in the brain," Pillai said. "Estrogen is known to be neuroprotective, but nobody has looked at whether its function is impaired in the brain of individuals with autism. We found that the children with autism didn't have sufficient estrogen receptor beta expression to mediate the protective benefits of estrogen."

Comparing the brains of 13 children with and 13 children without autism spectrum disorder, the researchers found a 35 percent decrease in estrogen receptor beta expression as well as a 38 percent reduction in the amount of aromatase, the enzyme that converts testosterone to estrogen.
Levels of estrogen receptor beta proteins, the active molecules that result from gene expression and enable functions like brain protection, were similarly low. There was no discernable change in expression levels of estrogen receptor alpha, which mediates sexual behavior.



The new findings of reduced expression of estrogen receptor beta as well as that of an enzyme that converts testosterone to estrogen could help explain the high testosterone levels in autistic individuals and higher autism rates in males

They also plan to give an estrogen receptor beta agonist -- which should increase receptor function -- to a mouse with generalized inflammation and signs of autism to see if it mitigates those signs. Inflammation is a factor in many diseases of the brain and body, and estrogen receptor beta agonists already are in clinical trials for schizophrenia.

The following trial was run by a psychiatrist; when I looked at why he thought estrogen might improve schizophrenia, there was no biological explanation.  He is trying to avoid the possible side effects by using of a selective estrogen receptor agonist.  I hope the trial successful.  The question is whether his subjects are starting out as extreme male or just male.



Several lines of investigation have supported the potential therapeutic effects of estrogen for negative and cognitive symptoms in schizophrenia. However, estrogen has had limited therapeutic application for male and premenopausal patients with schizophrenia because of tolerability concerns including uterine cancer liability, and heart disease and feminization effects in men. Selective Estrogen Receptor Beta (ER beta) agonists are a new class of treatments that are relatively free of estrogen's primary side effects and yet have demonstrated estrogen-like effects in brain including improvement in cognitive performance and an association to extremes in social behavior. Thus, these agents may have a therapeutic role for cognitive and negative symptoms in schizophrenia. The primary objectives of this application are to determine if the selective ER beta agonist LY500307 significantly improves negative and cognitive symptoms in patients with schizophrenia. Secondary aims include assessing LY500307 effects on cerebral blood flow during working and episodic memory tasks with fMRI, and electrophysiological indices of auditory sensory processing and working memory. A single seamless phase 1b/2a adaptive design will be used to evaluate two LY500307 doses (25 mg/day and 75 mg/day) in the first stage of the trial (year 1 of the application) to determine which dose should be advanced to stage 2 (years 2and 3 of the application) or if the trial should be discontinued.

More generally:-


Highlights
Steroid hormones exert a considerable influence on several aspect of cognition.

Estrogens and androgens exert positive effects on cognitive functions.

Progesterone and allopregnanolone have variable effects on cognitive functions.

Glucocorticoids act to encode and store information of the emotional events.

Epigenetic modifications are a powerful mechanism of memory regulation.


Conclusion

More female hormones and less male hormones? Seems a good idea.

More of the aromatase enzyme ?  There are numerous drugs to reduce/inhibit aromatase but not specifically to increase it.

Insulin does increase aromatase, as does alcohol and being overweight.
The clever thing to do would be to just correct the reduced level of aromatase, or wait for a selective estrogen receptor beta agonist like LY500307 to come to the market.

In those who are extreme male, a little estradiol might be the simple solution, but not the amount that is currently taken by those that abuse it.  Yes people abuse estradiol – males who want to be females.
Antonio Hardan at Stanford did trial high dose pregnenolone, another hormone mainly found in females, that should increase progesterone.


Brief report: an open-label study of the neurosteroid pregnenolone in adults with autism spectrum disorder.

Overall, pregnenolone was modestly effective and well-tolerated in individuals with ASD.


This steroid should increase the level of progesterone and so might be expected to cause some side effects in males. You would expect it to have an effect on anxiety, but as we saw in an earlier post it should be quite dose specific.




Why Low Doses can work differently, or “Biphasic, U-shaped actions at the GABAa receptor”

So Hardan may have just picked the "wrong dose".

If he would like to trial 0.3mg of oral estradiol in adults with autism, I think he might find a positive response.



 
  


111 comments:

  1. Another way to think of this problem is what substances inhibit aromatase in the body? Well one that I know of is DHT which is a more powerful agonist of testosterone that is both associated with prostate cancer and hair loss (among many other things both good and bad). DHT also is an aromatase inhibitor and also may act as a competitive antagonist of the estrogen receptor itself.

    When bodybuilders do massive amounts of steroids, their gonads stop producing natural testosterone so when they finally come off of steroids, they no longer have any DHT in their system (due to a lack of endogenous testosterone needed as a prohormone for synthesizing DHT) and a rise in unchecked aromatase ensues leading to breast growth. To counter this problem bodybuilders will take natural testosterone boosters like Clomid and/or aromatase inhibitors until they start their next steroid cycle (BTW, I don't do steroids nor have I ever done them, I just happen to know about this stuff).

    So to reduce DHT (and therfore increase aromatase indirectly) there are a class of drugs called 5-Alpha Reductase inhibitors which I believe were first researched for use in male hair loss.

    Now I say all of this with a strong dose of caution because screwing around with hormones and the endocrine system is not something to be done liberally, especially on children whose development is extremely sensitive to proper hormone signaling. Nevertheless, it does not hurt to discuss this because if example there is some research that pops up in the near future that shows perhaps an excess amount of DHT in male autistic youth, then perhaps medically dampening down DHT or some other androgen in the body with one of these types of drugs might help out all the other neurological factors you mentioned in this blog post.

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    1. Tyler, that would suggest finasteride/proscar which is used to shrink the prostate caused by too much DHT. It is again making the person a bit less male. It would be a case of what is the safest therapy. Giving a female hormone or reducing a male one. There clearly is some underlying dysfunction here.

      This is an area where trials on adults would be safer. Trial 5mg of finasteride on some adults with autism?

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    2. Yah that might be worthy of a look. I have never used finasteride myself even though these days it might do my looks some good (-; but I noticed from a quick read up on it:

      https://en.wikipedia.org/wiki/Finasteride

      one thing is mentioned is that it has the potential to dampen GABAa receptor activity via neurosteroid inhibition which would probably not be good for autism.

      I also did a quick look for finasteride and autism and didn't find much other than some informal postings people have made about its potential to reduce aggression in low-functioning males with autism by reducing the androgen receptor stimulation in the body.

      5-Alpha Reductase inhibition is complicated because while it reduces DHT levels, it increases testosterone in the body, but not so-called free testosterone (or that is what I understand at least). How that effects estrogen levels, well I really don't know. I also am pretty weak on my understanding of neurosteroids in general, though I believe you had a past blog posting on allopregnalone if I am not mistaken.

      For hypothetical ideas on a therapy might be to try and modulate aromatase from two sides, namely indirectly with finasteride to reduce DHT and therefore allow aromatase to elevate while at the same time using some insulin related mechanism as you mentioned above to stimulate aromatase production. This of course would be done very mildly on both ends because you would be influencing the push and pull mechanism of aromatase modulation at the same time.

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  2. Peter, as you know my son has moderate NAFLD. He doesn't like the taste of alcohol at all. Although he has been having severe problems with anxiety like issues he has almost never used alcohol to relieve his symptoms.
    As you mention here, alcohol ingestion may promote aromatase activity and affect steroids hormones.
    There are many articles claiming that moderate alcohol consumption lowers risks of NAFLD severity.
    Women at high risk of osteoporosis may also use alcohol for protection.
    Maybe NAFLD can be better handled with modest alcohol consumption particularly when hepatic aromatase activity is low expressed.
    I didn't have time to look at this possibility so I ask your opinion about the connection.
    Of course there are questions about the right amount and the kind of alcoholoc beverages that might work best.
    On my previous comment I told you that his drinking alcohol helped him to become "neurotypical".

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    1. Petra, it appears that lack of autophagy may be the route cause of NAFLD. Many people with autism appear to have unusual liver enzymes ratio ALT/AST, perhaps this reflects a wider problem with autophagy.

      NAFLD is likely directly linked to his Asperger's, so you might want to increase autophagy to treat both issues.

      Function of Autophagy in Nonalcoholic Fatty Liver Disease.
      https://www.ncbi.nlm.nih.gov/pubmed/26725058

      I know your son is not obese, but it does seem that using calcium channel blocker to increase autophagy may help NAFLD.


      Calcium channel blockers as potential therapeutics for obesity-associated autophagy defects and fatty liver pathologies
      http://www.tandfonline.com/doi/pdf/10.4161/15548627.2014.984268?needAccess=true&

      Alcohol probably is not a good idea if you have liver disease, although it may well make people more neurotypical.

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    2. Peter, speaking of autophagy - I read parts of a paper discussiing the antiviral as well as pro viral capabilities of autophagy. I was searching for information on why it seems my son is having cycles of a red rash flare up above upper lip. I was thinking it was due to certain probitioc trials. But haven't done that recently and red rash has appeared again. This has been since starting verapamil. yet I have seen the most improvements of anything we have tried since on verapamil. I am convinced the red rash is not allergy reaction. Do you know anything about potential side effects of stimulating autophagy long term? Do you know about yhe pro viral effects? And if so, do you think for some it might warrant and cyclical or pulse dosing of verap? My son is on a very lose dose. Over all I couldn't be happier about verapamil. I have posted about this a few times here, hoping others reading using verapamil might chime in - but so far, I hear from no one.

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    3. http://www.sciencedirect.com/science/article/pii/S0042682215001828

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    4. Tanya, I do not think many people have tried verapamil. If it works well, you might want to fill in Agnieszka's questionnaire. She needs case studies to show the wide world that it is a useful therapy, otherwise it will remain our secret.

      We also had red lines above the upper lip, but usually connected to probiotics. I think it is an immune reaction. Verapamil caused no negative side effects, I think it is good for continuous use, while probiotics seem not to be.

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    5. For whatever reason I could not dig up a paper I read sometime in the last three months, but in the paper it showed that the reason mice (and likely people) get metabolic syndrome is that their white fat cells are either unable to store fat or else they are filled up to the maximum and cannot store any more. This causes excess fat to accumulate in the blood and eventually deposit as visceral fat. They proved this in an animal model based upon a human disease where people who are super skinny with almost no bodyfat end up with very high cholesterol and type II diabetes. The problem with the people with this disease turned out to be that these people had a problem creating new white fat cells.

      This syndrome is a rather rare syndrome, yet the scientific understanding behind what triggers people to have a pear shape or an apple shape when they gain extra weight is broadly important to many people, especially the people who are so-called "skinny fat" who are some of the most at-risk people for cardiovascular problems, NAFLD, and other diseases associated with metabolic syndrome.

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    6. Another possible reason for NAFLD in some of the autistic population may be due to p53 dysfunction:

      http://www.fasebj.org/content/early/2016/12/05/fj.201600845R.full.pdf+html

      This study looked at what happens in a knockout model of p53 and fasting/starvation. p53 dysfunction is hypothesized in many cases of autism and has many interdependencies with PTEN which also happens to be a top 10 autism candidate gene.

      What they essentially found was that in normal mice, the starvation response (fasting) would cause the mouse metabolism to break down amino acids for sugar (gluconeogenesis) and engage in autophagy while in the p53 mice the starvation response was impaired resulting in hypoglycemia while in the fed state this caused impaired storage of glycogen and raised triglyceride levels in cells (steatosis).

      This suggests (in my opinion) that ketone ester therapy in a ketogenic diet potentially could help in p53 dysfunction (at least for the metabolic issues) because it might help the body to skip gluconeogenesis before ketosis ensues which as the researchers point out seems to be impaired with p53 dysfunction. Since, both the proper storage of glycogen as well as the breakdown of amino acids as and the induction of autophagy via the starvation response is impaired with p53 dysfunction, it would seem like people with p53 dysfunction would definitely want to watch their carbs, probably would benefit from a ketogenic diet, and may benefit even more from ketone esters used as a boost to skip gluconeogenesis which is impaired anyways when entering a fasted state.

      With respect to NAFLD, there of course can be many genetic reasons for it occurring in autism, but this research suggests another avenue of how it might transpire and gives hints as to a type of therapy that might help out a lot.

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    7. Tyler, speaking of P53-SLC2A9 pathway, uric acid/NAFLD and autophagy, I'd like your opinion about the recycling system of uric acid.
      The bad thing is that I don't know my son's uric acid in urine and only know in blood.
      Let's suppose that it is raised both in blood and urine, do you think this would indicate good recycling and autophagy function if we want to keep uric acid as an endogenous antioxidant?
      How do you think Bumetanide complicates things further?

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    8. Peter, yes definitely an immune reaction for my son - in fact since verapamil his immune reaction has shifted - he is less allergic, less reactive to foods. Do you know about drug induced lupus related to calcium channel blocker use? causing lupus-like skin symptoms. Is it possible for a very low daily dose of verapamil to cause this? especially if auto immune disease in family history?

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    9. Tanya, there is drug induced lupus and it goes away when you stop that drug. Calcium channel blockers are not tolerated by everyone, but most people have no problems. Lots of things seem to cause red patches above the upper lip and are not lupus.

      If you stop the verapamil for a week and it goes away you will have the answer.

      We had mild red patches, short term, caused by probiotics, Montelukast and steroids. These are all immune reactions appearing on what is a very sensitive area of the body.

      Delete
    10. Right. I understand. Not saying I think this red line that appears only in cycles since we started vrp in June is lupus. Just commenting on immune sys reaction and this connection with drug induced lupus. Just wanting to understand all the good and even all the bad especially since it is now apparent this has helped tremendously - so I'm now thinking about implications for long term use. I will test the next time the rash appears. I'm still reading about autophagy being antiviral and also pro viral in some cases. as well as some therapies used to block autophagy in treating certain cancers. Since you say vrp stimulates autophagy.... I just want to understand this as best I can - with my very un scientific arts&humanities-degree-in-History-brain. Thanks for your replies

      Delete
    11. I am certainly no expert on uric acid, but chronically high levels are associated with gout and other non-good situations. The levels of any metabolite in blood are usually a better indicator of what is going on in the body while what shows up in urine is simply whatever the kidneys decided to clear. Generally, if there are excess levels of a particular metabolite, it will show up in urine but not always as a particular metabolite could be consumed by some other biological process (depends on the metabolite of course) or excreted as something else entirely.

      But to answer your basic question, I think with respect to uric acid you want the levels to be within normal ranges and for both serious blood and urine screenings, the idea is to take several samples over the course of an entire day or some other longer period of time and then average the results from all of the samples together to see if the levels of a particular metabolite are elevated or depressed. If you have chronically high uric acid levels, ideally you want to figure out what is causing the uric acid levels to rise in the first place, and if not you want to get it lowered via drugs that lower urate levels.

      Last but not least, urea is mostly formed via the liver processing ammonia plus carbon dioxide into urea and water. So high urine levels of uric acid (urea actually as that is what mammals like us excrete while birds when they poop actually dump out straight uric acid which is the white stuff you see on bird poop), can be an indicator of high ammonia levels in the body. Interestingly, one popular intervention for reducing ammonia levels in the body that I came across when researching L-Aspartate was that a combination of L-Orithine and L-Aspartate (often called LOLA) is specifically used to lower ammonia levels in the body during acute liver failure. Ornithine provides extra support for converting ammonia to urea while Aspartate provides support for converting ammonia to glutamine.

      So if you have high ammonia levels in the body, it will show up as high urea levels unless the production of urea is impaired (then you have bigger problems). I would assume more aspartate would increase glutamine levels while also decreasing ammmonia and urea as well. Its best not to think of uric acid, ammonia, and everything else as being good or bad, just that you ideally want them within normal ranges and if they are not, you should not jump to conclusions about whether to try and lower that substance directly, and maybe think about the indirect methods first.

      Delete
    12. Petra, one other option for NAFLD might be trehalose:

      http://stke.sciencemag.org/content/9/416/ra21

      The research suggested that trehalose (you can get it at Swansons) blocks a glucose transporter protein, thereby inducing a state of autophagy in the liver. In effect, you block a sugar (sucrose) with another sugar (trehalose).

      In human beings, things are tricky. I take trehalose daily myself, under the assumption some of it avoids being broken down into glucose via an enzyme in humans called trehalase. How much trehalase can be produced to deal with all of the trehalose you ingest is an open question because almost all of the research on trehalose has been done on animals.

      Delete
    13. Hi Tanya,

      I know the glasses I use to view pharma products are jaded, but I do think drugs have it in them to cause serious side effects, ones we do not know off, especially when used long term and especially in individuals whose systems seem to be wired differently than the population on whom proabably the safety standards apply more appropriately. And yes, auto immune conditions or genetic susceptibility to one might make you react to drugs in strange ways. My late father had all kind of strange and strong reactions to drugs including the red mark around upper lip and later on he came down with a serious auto immune condition. Ironically the steroids that were used to treat him did not do anytjing for his auto immune disorder, most of which are episodic in nature but left him at least twenty years older with wasted muscles, severe thrush and loss of sight in one eye and weakened in the other. And though his idiopathic hrombocytopaenia resolved itself after running its course, when he passed away recently after suffereing a brain haemorrhage, he left his most ambitious book half finished (he was a Professor of sociology) as drug induced dusabilities had really slowed him.down.

      I know we cannot generalize about drug reactions but pulse dosing seems to be an idea I would personally adopt if truly concerned about long term effects of continuous drug use. And remember, the red rash is only a visible symptom of an internal reaction that could be relatively minor too.

      Delete
    14. Tanya,

      If drug induced lupus (or autoimmunity in general) is of concern you can test for relevant autoantibodies eg antinuclear, anti-dsDNA or anithistone anitbodies and in case of positive result retest after verapamil withdrawal and when rash disappears.

      Either positive or negative result could be helpful to make a decision about long-term treatment if you think in a risk vs. benefit analysis way.

      Delete
    15. Hi Kritika, I agree with you and wear those same glasses as well .. So sorry to hear about how your father had to suffer like that. I had really hoped a purely nutrient based approach would help my son all the way - and it has mostly but not enough. Probably a lot of that has to do with not knowing entirely what you are dealing with. One thing is for sure - the verapamil has been a great diagnostic clue. I do like overall how it has helped - but my mother's intuition tells me to pulse dose it. Is it even possible that verapamil could help prime or jump start things and that I can replace it with nutrient calcium channel blockers and that would be just as effective?

      Delete
    16. Agnieszka, thank you! this is very helpful, useful, and wise. Just wanted to clarify that this rash has not been constant - and did not appear immediately after starting. It seems to come about every 3 weeks. Which is why it took me some time to think possibly the verapamil could have caused some kind of shift and therefore the rash. Then i was wondering if it was viral related. we have such little experience with using drugs that I didn't even know about autoimmunity issues. I was thinking by being careful with the cyto p450 enzymes I had the major base covered. Sign of a good group is when you have questions, that might appear to be critical, and you are not bashed by proponents. I learn so much more about what is best for my son when I try to find the answers for why things go wrong. Thanks again! I will contact his ped. about this testing.

      Delete
    17. Tanya, I do not know whether it has a sound scientific basis, but certain drugs jump starting things is something I personally do not find to be just wishful thinking..I think it could be for real. Just like how an acquired gross motor skils paves way for acquiring many other motor skills spontaneously..I hope I am making sense.
      My son, like yours, reacts to chemicals, pharma, homeopathic, supplements and big part of problem is indeed ignorance about what we are dealing with. In autism, we do have a formidable adversary. And it is great that this blog does not cold treat observations contrary to mainstream consensus or what the most insightful members might be proposing..it is the cracks through which light comes in.

      Delete
    18. Kritika, I am really hoping our way of thinking prevails ! I intend to believe in it and try it out . It just feels right. I do think certain medicines can have their place in my son's case - but never for long term use - just to put out a fire and help diagnose things. The other point to consider with long term drug use is nutrient depletion as a result. Even certain nutrient therapies have to be balanced carefully as to not create deficiencies. Such a delicate balance. It is art.

      Delete
  3. Hi Peter,

    Thank god for your confidence..it boosts ours just to read about your unwavering optimism and in this blogs ability to 'develop ideas' for treatment of medical conditions expressed as autistic syndrome. The blog and if I may, its author are truly singular. This particular post (I have finally started understanding a lot of the terminology and principles involved) was a reflection of what makes the posts so special. A background, the theory, a practical takeaway and the most wonderful, plan B. So Peter, nobody leaves here empty handed/headed.

    Here wishing you many more insights in the years to come and long long life for your blog (and the books success as well).

    Warm seasons greetings



    ReplyDelete
  4. So I was searching for an older paper on TRPV2 signaling with respect to obesity and autism I remember reading:

    https://www.sciencedaily.com/releases/2016/03/160311105246.htm

    and happened to come across a short paper from MD discussing both Bumetanide and IGF-1 for treating autism that was posted only 6 days ago:

    http://www.sciencedirect.com/science/article/pii/S0306987716304170

    Strangely, the paper almost seems like some of it has been carbon copied from some of your past posts (-:

    ReplyDelete
  5. Tanya,
    Just wanted to share how my son reacted weirdly to anti allergens. Around a fortnight back, he was prescribed allegra and atarax for a viral rash by his paed. The rash subsided but the antillergens just left his entire sleep cycle so disrupted. He started getting all kind of scares in the night, would keep on waking up and start crying, frustated because he was so tired but could not fall back to sleep. He became all bleary eyed and irritable. Its only now that things are a bit better. I just wanted to illustrate how delicate a balance my sons entire system might have arrived at and how seemingly harmless drugs can throw it off that balance.

    ReplyDelete
    Replies
    1. Kritika, same for my son - he was always so sensitive. Even with certain homeopathic remedies! This is why I spent many hours researching and trying other ways the body heals that does not involve swallowing a medicine or taking a remedy . The things you try to help your kid feel better......

      Delete
  6. Hello everyone,

    I may have posted this before, but I think it's worth re-posting if I have:

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5121959/

    So this study in young children with ASD shows their urinary metabolomic profile, and I find it fascinating. It shows how many pathways may be thrown off in ASD, but it also helps to show what may be happening to these kids.

    I was really focused on the Kynurenine pathway (Tryptophan) because it correlated with other recent studies I read, but I decided to revisit this study tonight and went down the purinergic pathway and found some really interesting things. Many of you will already be familiar with the info, but I'll post them nonetheless as I hadn't seen them.

    So the following is a very interesting paper that Peter had covered at the time:

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334917/

    I wondered what had been done with the info as it looked extremely promising - and I found that a small trial of Suramin has already been conducted on ASD kids with the results having been described as very promising (see the following):

    https://www.gordonmedicalresearch.com/wp-
    content/uploads/2016/03/Suramin-Newletter-April-2016-v8.pdf

    I'm starting to look for natural P2X and P2Y receptor antagonists, but the fact that the UCSD folks are saying the results are very promising and that they're looking at larger trials is exciting to me.

    Just sharing my findings, I know the community here probably already knows this info, but I wanted to share just in case someone hadn't seen it. If anyone has any info or insights on this, would love to hear it.

    Best to all, and a true wish for 2017 that our kids will be significantly better in the coming year.

    AJ

    ReplyDelete
    Replies
    1. Hi AJ Thank you for posting. Have you been able to identify natural P2X and P2Y receptor antagonists.

      Delete
    2. Hi everyone, I'm still working on this, and making some progress. My "raw" download thus far is as follows, but please note that I first find a slew of relevant papers and then go through them in detail, so please consider the following links in that context:

      https://www.ncbi.nlm.nih.gov/pubmed/?term=25096398

      https://www.ncbi.nlm.nih.gov/pubmed/?term=24970925

      https://www.ncbi.nlm.nih.gov/pubmed/?term=24850149

      https://www.ncbi.nlm.nih.gov/pubmed/?term=24671093

      https://www.ncbi.nlm.nih.gov/pubmed/?term=24657446

      https://www.ncbi.nlm.nih.gov/pubmed/?term=24593783

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3817725/

      https://www.ncbi.nlm.nih.gov/pubmed/?term=24191147

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4040168/

      In the meantime, if anyone else can post their research, or insights into what I've posted, it would be much appreciated. As I've said, I'm about 2 months into this journey, so the insights from the many learned folks in this community are always very much appreciated.

      Hope the above is helpful and of interest

      AJ

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    3. And a few more links from my research:

      https://www.ncbi.nlm.nih.gov/pubmed/?term=27154619

      https://www.ncbi.nlm.nih.gov/pubmed/?term=26049028

      https://www.ncbi.nlm.nih.gov/pubmed/?term=25937482

      https://www.ncbi.nlm.nih.gov/pubmed/?term=25730877

      https://www.ncbi.nlm.nih.gov/pubmed/?term=25554221

      Again, not everything will be directly related to the P2X and P2Y receptors in the brain, but I searched for relevant papers for my purposes and sharing in case anyone else is interested.

      AJ

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    4. Hi AJ,

      The suramin study results seem promising but they have not come out with the conclusive results which they were supposed to by end of 2016. Probably will have to wait a little longer.

      Since suramin is a broad antipurinergic drug, targeting both P2X and P2Y receptors, it would be difficult to replicate the effect with natural sources. Also, Dr. Naviaux thinks that the CDR response is more significantly expressed through P2Y aberrant signalling than P2X. Kudzu, magnesium. DHEA, garlic, TMP present in some chinese herbal medicine (dont know if its the same as kudzu) are some p2x receptor antagonist. Kaempferol and tangeritin happen to be P2Y antagonist but which sununits are involved to what effect in purinergic siganalling is still not very clear so that makes things a bit complicated. And sadly, it seems in its present form, suramin can releive autistic symptoms only for six weeks.

      Do continue to share your trials and researches with us.

      Delete
    5. Pyridoxal Phosphate, the active form of vitamin B6, is also a P2Y antagonist.

      Delete
    6. AJ you might want to read this review of P2X7. Both animal and human trials, with various antagonists are covered in great detail http://pharmrev.aspetjournals.org/content/66/3/638

      Both compounds that were trialed for RA were deemed failures but those are some of the of potential safer meds that Naviaux hopes would be taken off the shelf and trialed for autism if their patent holders get encouraged by suramin results.

      Delete
    7. In the paper https://www.gordonmedicalresearch.com/wp-
      content/uploads/2016/03/Suramin-Newletter-April-2016-v8.pdf that AJ posted, they indicate in the first paragraph: " - combined with new observations of a different kind of mitochondrial dysfunction in autism" - how do they quantify this? How do we measure if our child has this mitochondrial dysfunction vs mitochondrial disease (this has been ruled out or us) but I have alway been interested in determinining mitochondrial dysfunction. Would this be important to know before embarking on how to "deactivate" this pathway? I am wondering if there is a way to determine mito dysfunction and if they pre-determined this for the kids enrolled in the study.

      Delete
    8. Hi Kritika, I'm so excited to see the results from UCSD (Naviaux), and yes, they were already supposed to be out so hopefully it'll be out soon. From my perspective, the most important thing is proof of principle that this pathway is very important to ASD (at least in some of the patients). Then, better and better drugs can designed to specifically hit the right targets more effectively, so Suramin could be thought of treatment 1.0 (if it works). It's like the Hep C drugs - a few years ago, it would take a year to cure ~40% of patients, with no oral options and bad side effects - a few years later, we can cure ~99% within a couple of months with oral meds.

      What I don't know, and again, it may be that I haven't read enough due to time constraints (very busy at work) is whether or not the key is broad pruniergic activity or if using Suramin is like killing a fly with a sledgehammer. That is, is it all of the P2X and P2Y receptors that we need to inhibit (or negatively modulate) or is it a few, and Suramin is an imprecise tool.

      If we can get to the same outcome using a few selective inhibitors (e.g. natural compound A blocks one P2X, compound B blocks one P2Y, etc.), then that would be great since we could achieve that now if we knew which P2Xs and P2Ys were relevant.

      I also wonder if we can partial benefits from blocking a few select P2Xs or P2Ys. If my daughter can improve by say 25% via that strategy, until we find something better, I'll take it.

      My fingers are tightly crossed with hope that the Naviaux research will be very important, and that we can find a way to treat our kids via this pathway now using natural sources.

      Have a great day Kritika!

      AJ

      Delete
    9. Hi Nat,

      Thanks for noting P5P is also a P2Y antagonist. I'll have to look that up as one of the papers I listed shows it to be a P2X antagonist. We just recently started P5P so I can't say how its doing yet for my daughter.

      Thanks for the paper on p2X7! It looks like a good one, and I'll definitely add it to my list of papers to read.

      Every time P2X7 pops up in my research the last few days, it seems like its related to brain issues. Check out the following:

      http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0049701

      I'm curious about Paeoniflorin because it was listed in one of papers I listed originally as down-regulating ATP-induced inflammatory cytokine production and P2X7R expression. If P27XR is one of the key P2Xs for our purposes, could Paeoniflorin be a good option? It's one that I'm considering.

      AJ

      Delete
    10. P.S.

      Started to look into Paeonoflorin, and while it looks like it would have a good mechanism of action, It's not as safe for a kid as what I would have hoped. Will keep researching options for P2X and P2y inhibitors / antagonists, but Paeonoflorin doesn't look to be child friendly.

      AJ

      Delete
    11. Hi AJ,

      Your enthusiasm is really infectious..keep it up. I too feel that even 10% improvement, here and there, adding up to 40-50%, in the internal biochemistry that has gone astray will give me something decent to work with, through non drug means. And who knows, in a young child, even a single dose or two of little toxic drug, might jump start things (quoting Tanya), teaching the body to behave..the same way we behaviorally teach an autistic child not what, but how to learn or try hard to do so.

      You have caught up real fast at the theoretical research part while I am still struggling, probably coz 'busy at work' is still less busy than 'busy at home'.

      Wishing you lots of successful trials and a good day as well


      Delete
    12. Hi Kritika and everyone,

      Thanks for kind words Kritika - we will get there, I'm confident in that.

      I'm still so busy at work, barely getting time to do some research but here quickly are some interesting findings:

      1. Naviaux's paper and research:

      Here is a link to Naviaux's Lab's website dealing with ASD, and lots of interesting info on this page such as:

      http://naviauxlab.ucsd.edu/science-item/autism-research/

      I)Results of the study now noted as published by April 2017 ("could be")

      II)With respect to Suramin, the page notes "Another way is to block the release of intracellular ATP through pannexin-P2X7 channels into the extracellular space." - The first way noted is non-selective inhibitor of purinergic signaling, so it's interesting to me that the P2X7-Pannexin channel is one of the two mechanisms of action. What if we could find natural selective P2X7-Pannexin blockers? Are we going to see a mild/partial response at least?

      Interesting page - visit it if you get the chance.

      2. So far, the reasonable natural methods for affecting the purinergic pathway I've found are:

      I) Amentoflavone - seems to have been big with bodybuilders but can't find a good source of it specifically as a supplement - however, it is in Ginkgo Biloba, so I'm going to do some research to see if this is OK for a young girl (small dose of course)

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3817725/

      II) Kudzu - The key is a compound call Puerarin. Again need to check out Kudzu

      Same link as Amentoflavone

      III) Aloe Vera - Seems to affect P2X7, and seems relatively safe. There appear to be two kinds of Aloe Vera, whole leaf and inner fillet. The whole leaf version includes a potentially carcinogenic oompound call Aloin, so I would go inner fillet and hope that whatever works on P2X7 is in the inner fillet

      http://www.sciencedirect.com/science/article/pii/S0161589013001739

      IV) Naringin - Of course, the issue with Naringin is that it can impact metabolism of other compounds taken with it, so I would use this in isolation in terms of time (i.e. no other supplements at the same time)

      http://www.funpecrp.com.br/gmr/year2016/vol15-2/pdf/gmr8649.pdf

      V) Emodin - I've noted this here but likely won't use it as it seems like all the supplements it comes in are problematic for a small child. It's in some resveratrol supplements for those who want to consider it, but given the fact that Resveratrol could act like a hormone (estrogen), I wouldn't
      want to give it to a small child.

      Same link as Amentoflavone

      Now if only Goldfish crackers had all the purinergic blockers in it, I'd have it made in the shade the way my daughter consumes them :-) If Naviaux could only figure out how to get a stubborn kid to drink Aloe Vera juice ...

      If anyone has any thoughts on the above natural antipurinergic options, or any other comments on antipurinergic options please share. We're all in this together

      AJ

      Delete
    13. Hi everyone,

      Looks like we can add berberine to the list of P2X7 blockers:

      https://www.ncbi.nlm.nih.gov/pubmed/27439970

      And it does cross the BBB (Blood Brain Barrier, not Better Business Bureau ;-) ) :

      https://www.researchgate.net/post/Does_Berberine_cross_blood_brain_barrier_If_yes_has_somebody_reported_Berberine_concentrations_in_serum_and_CSF

      Have a great night everyone!

      AJ

      Delete
    14. Hi everyone,

      After an exhaustive search, I think I found something very interesting, and would appreciate any input the learned people of this community have.

      My goal was to find something relatively safe for kids, and unfortunately, it seems like every antipurinergic natural substance has some issues.

      My latest find is this:

      https://eurekamag.com/research/004/463/004463642.php

      It's a research paper that identifies Fenugreek as a P2X (and maybe P2y) receptor antagonist, and they compared it to ... Suramin! and it seemed to match Suramin in the tests they did in terms of antipurinregic capabilities.

      The good news is Fenugreek is widely available, and generally viewed as safe. There is some info that Fenugreek can make some kids pass out, but by starting with a super low dose and titrating up, risks can be mitigated by seeing how a child reacts.

      The funny thing about Fenugreek is that when you take it, apparently you can smell like ... Maple Syrup (bizarre I know).

      The other great option would be Amentoflavone, but it is only used as an ingredient in bodybuilding supplements with lots of things you don't want to give your kid (unless your kid is a bodybuilder) and isn't offered as a standalone product (yet, but should be).

      So, for me, of the list of options, Fenugreek looks like the best one so far. I'll research some more, but does anyone have any thoughts?

      AJ

      Delete
    15. PS note that its the Fenugreek leaves that were identified in the paper, not the seeds

      AJ

      Delete
    16. AJ,

      That is really intersting ..fenugreek! In India, we keep adding fenugreek leaves to pulses and veggies and the leaves but mostly the seeds are considered to be of medicinal value but obviously the amount of fenugreek leaves one has to consume would be lot more for it to confer benefits we are looking for. Any suggestions..I will read up the paper.

      Also, you had started giving your daughter black cumin or were planning to do so. How is that going and how dp you administer it? I gave my five year old a teaspoonful of the oil and he puked it out. He can swallow small pills but he cant do those big capsules. By the way, black seed does seem to be potent, as my husbands grandmother, who suffered from breast cancer, used to keep chewing it through out the day and is said to have benefited. But it is so hard to say for sure.

      Best wishes for your daughter..with a father like you it will all turn out well.

      Delete
    17. Hi Kritika,

      Hope all is well, and thank you for the kind words!

      I have started black cumin oil, but no changes seen with it yet. My daughter doesn't tolerate any unusual tastes, so I dilute it in grape juice. I open the softgel capsule, and mix it with grape juice. I don't think she would have it otherwise.

      As far as the Fenugreek, my plan is to get fresh Fenugreek, dry the leaves, and then make tea out of it. Not sure what the right dosage would be to get any therapeutic impact, but I'm going to try what would look like a reasonable amount if making normal tea and see what happens.

      My biggest challenge won't be making the tea - it'll be getting my very fussy daughter to drink it. I'll have to figure out how to make it sweet enough (I use Agave nectar) or mix it with something else to hide the taste.

      My fingers are tightly crossed on this - based on the research paper, Fenugreek Leaf extract seems to be a P2X inhibitor, so if Naviaux is right, and if I can get the right dosage, and if my daughter will even consume it, I'm hoping to see some impact.

      It'll take a while (buying it, drying it, figuring out how to get my daughter to drink it) but I will certainly keep you and the board updated.

      If anyone else goes this route, please also keep the board updated. We have to figure out how to hit P2x/P2Y using what we have to duplicate Naviaux's study, until we have access to Suramin treatment or even better, a newer drug that hits the right targets more effective and efficiently.

      There were two failed RA (Rheumatoid Arthritis) drugs that hit the purinergic pathway, and I say failed because they didn't improve the RA enough. But since they were in Phase II, and had already passed Phase I safety testing, maybe they can be put through a pivotal Phase II/III study in ASD with a fast track to approval - this is my wish, you never know, but if any condition deserves fast track status, it's ASD.

      Best to you Kritika in 2017, and to all!

      AJ

      P.S. Peter - if you could at some point do one of your great and in-depth blog posts on the Purinergic system / Naviaux's hypothesis it would be much appreciated. What I'm really intrigued about is that it appears to explain the disparate issues seen in ASD (lots of pertubations in various pathways)

      Delete
    18. AJ, since you are interested in Fenugreek you might find this patent from Japan interesting:-

      Autism improving agent and autism improving tea
      http://www.google.com/patents/WO2012160608A1?cl=en

      Delete
    19. Hi AJ,

      I hope I have not committed a faux pa in refering to you as a father..with the medicinal dishes you are creating keeping your daughters delicate taste buds in mind, I think I made a mistake.

      AJ, I am certain we are not going to get dramatic or rapid improvements when we try to substitute for drugs with natural supplements. But I am sure if we consciously try to manage inflammation, oxidative stress, liver function or even purinergic signalling by adopting a nutrition based approach, we might get small incremental gains which might a accumulate over time as our kids are still relatively young. If not anything else, this might make their systems better prepared for a toxic drug assault later. I think Tanya has mentioned somewhere that she is observing lot of improvements in her son after two years of giving black seed oil which in combination with verapamil seems to help her son. I am not at all discounting the potential of natural supplements in imparting huge benefits..just saying if benefits are not really huge but s small, its still worth the effort. And who knows we might hit a jackpot. TCM, traditional chinese medicines seem to use a lot of compounds with potential benefits but its such a mysterious area, I woul d not really trust a practitioner with my son. So for now, keep on trying to give a little more of fenugreek leaves..a little here, a little there. And will try and mix black seed powder in his food. Actually I am more finicky about taste and smell than my son so if I can manage to swallow a spoonfull, he will manage a bowlful.

      Lets keep the faith..in suranim.


      Delete
    20. Hi Peter,

      What do you make of this herbal mix they are patenting? They have given results of the study they did..herbal ingredients which they used, fenugreek, rosemary, celery have been mentioned individually elsewhereand I think rosemary particulary has been the subject of lot of scientific research where a tiny amount and no more has benefits for mental disorders if I remember right.

      So it can be inferred that bioray products which use a lot of herbal inredients (most based on tcm) or even ayurvedic preparations might potentially be useful. But frankly speaking, I am in india but not heard of a many autistic individuals improving dramatically on ayurveda. The herbs, fomentation, oil massages are of course going to help..so will yoga and so will dancing, but how and how much is the big question here.

      Do you think the autism improving agent seems 'promising'?

      Delete
    21. Hi Peter,

      Thanks very much! I just read the patent and will have to delve into the ingredient list of the tea to see what the other ingredients may be doing.

      One thing I don't know is if the fenugreek seeds do the same thing as the leaves - maybe its best to use both.

      My wife went out this morning, and got a big bunch of fresh fenugreek, and I went out and got a food dehydrater as air drying that much fenugreek was going to be difficult. I'm drying some of the fenugreek now in the machine and will then use the method described in the paper I posted (30 minutes of decocting with hot water) to extract the relevant compounds 9which is basically making a tea).

      The fenugreek tea will then be ready to start testing tomorrow - I'll keep everyone apprised. The real challenge is going to be to get my daughter to
      drink the fenugreek tea - we'll see. The agave nectar will be the key.

      My fingers are crossed tightly - there are a lot of variables - IF Naviaux is on the right track, IF the Fenugreek leaves have an effective anti-p2x ingredient, IF I can get enough of it from the leaves, and IF enough of it can be extracted and ingested.

      Have a great day Peter!

      AJ

      Delete
    22. Hi Kritikia,

      No Faux pas, I am the dad :-) ... My daughter is my only child, and she is my whole world, so I am always looking to make things as good for her as possible ... including making her natural treatments as easy to take as possible.

      By the way, you can see from my post earlier, but I have almost finished my first batch of Fenugreek leaves (boy they shrink a lot), and will start my second batch soon. Will start the tea tomorrow, hopefully my daughter will drink it.

      I'll keep everyone posted. If I even get a 10% improvement, I'll be thrilled.

      AJ

      Delete
    23. Hi AJ,

      You may find this interesting:
      http://onlinelibrary.wiley.com/doi/10.1002/ddr.10203/epdf?r3_referer=wol&tracking_action=preview_click&show_checkout=1&purchase_referrer=onlinelibrary.wiley.com&purchase_site_license=LICENSE_DENIED_NO_CUSTOMER

      Sytrinol has been excellent for us.

      Delete
    24. Kritika, I came across that patent a long time ago. I have no idea how effective this mixture is. Many natural products lack bio availability, like curcumin etc.

      Delete
    25. Hi AJ,

      The suramin trial information as posted at their labs website does seem interesting with lot of positive vibes. In fact they have termed the premise on which they are carrying out the research (cdr) as a 'unifying theory behind genesis and treatment of autism'. This might indicate that they have got encouraging prelimnary results. Also, note the variables they have assessed. Quite thorough!

      When my son got his diagnosis two years back, bumetanide and suranim were two drugs, trials related to which, I would keep on lookin up all the time, often visiting and revisting Peters blog too. I was really hopeful about these two. In fact I have been trying to track some parents who have tried suranim on their child and did find one or maybe two but disappintingky they observed no impact.

      However, I am sure something will workout..it has to. Either a unifying theory of cdr behind most autisms or another promising areaea of research where I believe certain key protiens that are quite consistently affected by numerous pathways gone dysfunctionsl in autistic individuals..so instead of targeting each pathway in isolation which at prrsent is quite impodsible or at least tedious to do, if one is able to focus on those protiens, it would make the task easier.

      Do keep posting your findings and experiences and wishing health and happiness to your 'whole world'.

      Delete
    26. Hi RG,

      Wow, is that ever a great paper! Thank you RG! I actually found the following version that provides the full text for free:

      https://www.researchgate.net/publication/230106396_Flavonoids_-_Novel_lead_compounds_for_the_development_of_P2Y2_receptor_antagonists

      And beyond the paper, thank you for identifying Sytrinol relative to the paper, and noting that it has worked for you - that's the real power of a community like this, people like yourself sharing key pieces of info.

      So... My original plan was to "attack" the purinergic system with the safest natural substances I could access, and based on my research, there are several potentially effective compounds, but only 2 that I felt OK giving my daughter - Naringin and my Fenugreek Leaf tea ... until now.

      The missing piece of the puzzle was the P2Y receptors, and your paper seems to offer a great path there. Tangeritin, one of the two main ingredients of Sytrinol (the other being nobiletin) is, according to the paper you posted " The most potent
      compound was tangeretin (25). Further potent com-
      pounds include kaempferol (19), heptamethoxyflavone
      (29), penduletin (22), and the chalcone derivative b-
      oxo-aurentiacin (14). These compounds were more
      potent than the standard antagonist suramin (2) and
      similarly potent as Reactive Blue 2 (3), the most potent P2Y2 antagonist that has been described so far."

      RG - again, really appreciate your input - IF Naviaux is right, and that the purinergic pathway is the cause for at least some cases of ASD, some combination of natural antipurinergic substance may help our ASD kids in the meantime until an effective drug is produced, and based on the science, Sytrinol looks like a good part of a combination.

      Have a great day RG!

      AJ

      Delete
    27. Hi AJ,

      It was actually Peter who wrote about Sytrinol, if you haven't seen it yet, I think you can search for it from the side index. Its obvious that its the purinergic effect that is working well for my daughter since ibuprofen has no effect whatsoever.

      I talked to Dr. Naviaux a few months ago, he did not have all the lab results at that time. The results with the five children who received the Suramin were pretty spectacular. It looks like he funded the first trial privately, and is looking for funding for the next one.

      Delete
    28. AJ, have you seen Peter's post about Knut Wittowski's paper? It is quite brilliant, you can find it under Knut on the side index.

      Delete
    29. Petra, AJ,

      Petra, I think it was you who commented about pain? I have been checking this blog while away, so have missed a bit here and there.

      AJ, you may have seen this already:

      http://www.ucl.ac.uk/ani/GB's%20PDF%20file%20copies/CV1402(proofs).pdf

      Delete
    30. Thank you so much RG.

      It's really interesting. Just hope there are some practical interventions.

      Hope your daughter recovers the soonest possible.

      Delete
  7. Tyler, thank you very much. I don't know many experts who would have explain it better.
    Doctors here, with regular check up, order uric acid/creatinine/urea in blood. If these are between normal means, they don't check in urine. Urate in blood and creatinine are considered sufficient indicators for kidney function, and in my son's case these are between normal means, except uric acid.
    His uric acid is considered a little elevated, so they don't recommend drug therapy.
    As you mention, uric acid could be due to liver dysfunction and I shall have to see if I can find trehalose for autophagy.
    Some experts blame fructose metabolism in NAFLD.
    If you have any comments on fructose metabolism, please let me know.

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    Replies
    1. Tyler, I don't know how much of a coincidence this might be, but ophthalmologist prescribed trehalose eye solution for my son's infection.

      Delete
    2. Probably a coincidence. Trehalose has a lot of interesting properties, but I am not sure why they are used for eye drops other than a quick search suggested trehalose is used to prevent cell death via desiccation (drying out). Waterbears are thought to use trehalose for similar purposes when they go into a hibernation state where they become largely impervious to radiation, extreme heat or cold, very high pH, and even the vacuum of space.

      Delete
  8. Some more new stuff on NRF2 and Parkinson's disease:

    Press Release:

    https://www.sciencedaily.com/releases/2016/12/161226211253.htm

    Paper:

    http://www.pnas.org/content/early/2016/12/23/1522872114

    NRF2 activation via sulphoraphane and broccoli sprout extract with myrosinase has been discussed extensively on this blog as impaired cellular housekeeping in response to oxidative stress has been hypothesized to be a factor in autism symptoms for probably around 5 years now.

    In this study they reprogrammed pluripotent stem cells to overexpress nrf2 while also overexpressing either alpha-synnuclein (the leading protein of interest in Parkinson's disease) and another protein called LRRK2 and concluded that NRF2 activation seemed to be the "most protective thing we have ever found".

    On another note, I have been trialing PomGenex which Peter mentioned a few pages back on this blog. Nothing really to say at this point after less than a week, but if my memory serves me correctly, the results from the small broccoli sprout extract autism study a few years back didn't show significant changes for a month or two (guess I will have to reread it again).

    ReplyDelete
  9. Peter, Agnieszka,Tyler, I realized that tardive diskinesias is what my son is showing since months.Oral,tongue, facial symptoms, eyes rolled up,muscle contraction, dystonia. This is the result of risperidone for 6 years , now he is on 3 drops because don't dare to take it off. But he showed involuntary movements and hyperexitability before risperidone,when he was 3, what means that he could have functional dopaminergic hypersensibility in the receptors and/or uncontrolled increase in noradrenergic neurons, perhaps because of his electrical acitvity. Risperidone made those things worse and TDs appeared. I don't know what was thinking the neurologist, my son clearly was not a candidate for a neuroleptic. Tizanidine is being now my lifejacket for this condition ,that hope is not permament.Verapamil would have been a good option but I can't give it with Tizanidine. Ginkgo Biloba could be another option to add because TDs could be associated with toxic free radical realease.
    Valentina

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    Replies
    1. valentina, have you tried supplementing b6 for the tardive dyskinesia? A nutrient many with autism are low in, also being on certain medications for a length of time can deplete this nutrient and others. Not sure what all nutirents are depleted by risperidol but i know for many drugs the B's especially get depleted.

      Delete
    2. Well receptor antagonists generally upregulate the receptors being antagonized so you need a higher and higher dose to achieve the same result. I am no expert on antipscyhotics, but risperidone's primary method of action as I understand it is as a broad spectrum dopamine receptor antagonist (which makes it one of the dirtiest antipsychotic drugs around). The problem many doctors don't understand or else downplay to their clients is that when you artificially downregulate a receptor type or else upregulate a receptor type, your cells try and produce more or less of the receptor unless somehow you can tinker with the autoreceptors in such a way that you shut off this feedback loop. With excessive antagonism, cells that depend on a type of receptor for stimulation will eventually just die from inactivity.

      So anyways, what are your options? Well, the BCAA blocking therapy I mentioned above was designed for blocking tryptophan and its metabolite kynurenine into the brain, but tyrosine and phenylalanine (both precursors to L-Dopa as tyrosine is metabolized to L-Dopa and phenylalanine is metabolized to tyrosine)) are also blocked by BCAA's which is one reason sugar make you feel good as it allows both tryptophan and tyrosine/phenylalanine into the brain at a greater rate due to insulin spiking which causes BCAA's to be absorbed from the blood stream and into your muscles.

      And apparently my idea I have used for quite a while was not original at all as on Wikipedia I noticed that they explicitly mentioned a BCAA therapy for tardive dyskinesia for the exact same reasons I mentioned using a product called Tarvil:

      http://ajp.psychiatryonline.org/doi/abs/10.1176/appi.ajp.160.6.1117

      So yah the BCAA therapy I have been posting about for a while here apparently has been around for almost 13 years, or at the least the peer-reviewed research has been around since 2003 and I never even realized it. Well, apparently doctors have not realized it either otherwise I would of saved myself the trouble of figuring this out by myself over the course of 3-4 months.

      I guess you learn something new every day (-:

      If I were you this would be worth a shot, at least in the hopes of tapering off the risperidone even more than you already have because you don't want your child on that stuff any longer unless you feel his life is in danger without it.

      Delete
    3. Tyler,it is incredible that there are so many things tried and tested for a long time, floating around, and yet , nobody can put together the pieces of the puzzle, researchers, biologists, neurologists, why is so difficult? I will try BCCA, can get a brand SYLAB 1400 that is L leucine 700 mg, L isoleucine 350mg and L valine 350 mg. Is it ok or should be a more potent compound? and how many capsules? I really appreciate your help.
      Valentina

      Delete
    4. Valentina, there is plenty of older research supporting the use of Baclofen:-

      https://www.ncbi.nlm.nih.gov/pubmed/782159

      There are two studies supporting the use of vitamin B6:-

      https://www.ncbi.nlm.nih.gov/pubmed/11532741

      So along with the BCCAs you have plenty to experiment with.

      Delete
    5. Well, I spent quite a time on figuring out what product of BCAA's to use and getting a version that goes down well is pretty important. Many BCAA products have very high ratios of leucine to valine and isoleucine because pretty much everyone who uses BCAA's does it for sports or bodybuilding and leucine in high amounts is what stimulates mTOR which is what you need to do to get your muscles in an anabolic growth mode. The product you mention has the same ratio as Scivation XTEND (2:1:1 ration with 3500mg leucine, 1750mg valine, 1750mg isoleucine per serving) which also comes in many different flavors and is one of the more price competitive brands around. Also, BCAA's are not typically taken as capsules though I am sure you can find suppliers that do that. Most BCAA powders are terrible tasting (in my experience) and Scivation XTEND for whatever reason has decent tasting flavors. Just my opinion.

      I suppose it probably doesn't matter which brand you use as long as your child though the Scivation XTEND is intended to be used as a drink. I mix in hydrolyzed collagen as well which is largely tasteless and then the nicotanimide riboside (which you need to boost NAD+ levels since tryptophan/kynurenine will be blocked which your brain needs for NAD+ synthesis) you can mix into the drink as well or take separately in capsule form (the ideal manner but if your kid won't do pills like mine then that is just what you have to do).

      Because of school and other things getting in the way, my son gets his drink in the morning and then sometimes twice a day but I had best results early on when I was more diligent by giving him BCAA's three times a day just as they did in the paper under essentially the same regimen (first thing in the morning, then half hour to an hour before other meals).

      Delete
    6. Thank you, BCAA coud be better than expected for my son. It seems that BCAAs supplementation may treat autism with epilepsy according to a team of scientists of the University of California, San Diego and Yale schools of medicine. They identified a form of autism with epilepsy or abnormal electrical activity that may be is treatable with BCAAs. They founded mutations in a treatable metabolic pathway for autism. What would be the right dose for my son?.
      Valentina

      Delete
    7. Valentina,

      A trial of acetazolamide (Diamox) + high dose of vit. B1 for tardive dyskinesia caught my attention a while ago:

      https://www.ncbi.nlm.nih.gov/pubmed/9169964

      Eye rolling is among things I have been tracking in my daily notes. It reduced almost to null on acetazolamide.

      Delete
    8. Agnieszka, apparently there are several options to take into account for this subject. I thank also Tania for her input. I will try with BCCAs. It seems that children with abnormal electrical activity like our sons, or epilepsy, could have a mutation in the gene that regulates BCAAs, this gene is BCKD . If our sons had this mutation would be amazing.
      Valentina

      Delete
    9. Just to be clear again Valentina, the use of BCAA's for the mutation you speak of (which can be tested for and is rare but strongly linked to autism) has nothing to do with the reasons I cited above. Also, there have been multiple hypotheses concerning gut bacteria dysbiosis in the autistic population contributing to improper breakdown of complex proteins into simpler amino acids (these hypotheses are very old). Also, I must add in the obese population (which is correlated with autism) BCAA blood levels tend to run high and are associated with diabetes, but again this is a situation where researchers are unsure if this is something inherently pathological or else the body's response to something else going awry.

      Really, if the BCAA's help for whatever reason then great, but in the case of tardive dyskinesia your goal here I think is to reduce the dopamine receptor blockade while reducing (if possible) the supply of excess dopamine to the brain as a gross imbalance in dopamine to serotonin has been one of the oldest associations with intellectual disability and autism (though the most recent research I have read suggests things are a little more ambiguous).

      Delete
    10. Thanks Tyler,the case of my son is quite rare, he has HFA, not ID, however these movements to which diskynesias are added, not as severe as the cases I saw in Internet, confuse me. If now start with 5 g BCAAs a day without nicotinamide riboside is ok or should wait to give him all together?
      Valentina

      Delete
    11. Valentina, this paper in TD just caught my attention:

      http://www.sciencedirect.com/science/article/pii/S0014488616302795

      in short:

      • Striatal cholinergic activation reduces tardive dyskinesia via nicotinic receptors.
      • Striatal D2 neuron activation decreases tardive dyskinesia via nicotinic receptors.
      • Thus, multiple striatal neurotransmitters systems regulate tardive dyskinesia.
      • Nicotinic receptor drugs may reduce antipsychotic-induced tardive dyskinesia.

      Delete
    12. The Nicotanimide Riboside is due to tryptophan being blocked by the BCAA's (a side-effect in a sense). All cells in the body need NAD+ synethesized because if the NAD+/NADH ration gets too low, then cells die via apoptosis so when they are being challenged by stress (such as an infection) your body upregulates the kynurenine pathway at the expense of the serotonin pathway for tryptophan. Most NAD+ in the body is created via the salvage pathway via an enzyme called NAMPT, but if "recycling" NAD is not enough for the body's needs, it needs to produce new NAD+ and it does this naturally via the kynurenine pathway in converting quinolinic acid to NAD+. Quinolinic acid in excess does some bad things to neurons which is one of many reasons why chronic inflammation is very bad on the brain.

      Now in the last decade or so, another form of vitamin B3 called Nicotanimide Riboside has been shown to directly elevate NAD+ levels via an alternative pathway that has been evolutionarily conserved in mammals for some reason even though we don't produce Nicotanimide Riboside naturally (you can find it in small amounts in cow milk though). The earliest experiments on NR were done on yeast which is obviously quite a bit different than humans, but for whatever reason NR does basically the same stuff in yeast as it does in mammals (elevate the NAD+/NADH ratio in cells).

      So why is NR so expensive if it is naturally found in milk (trace amounts). Well, even though NR is not patented, the patents for efficiently producing it were all scooped up by a company called ChromaDex (the company that makes Niagen) from the Cornell University research group that invented them. So in maybe 8 years when the patent runs out there should be a big price drop, but until then it is a pricey supplement.

      Now, if you are not worried about systemic inflammation issues you can instead add in L-Tryptophan with the BCAA's so that only the aromatic amino acids that produce dopamine (phenylalanine and tyrosine) are blocked. This way some L-Tryptophan will get into the brain, but more importantly for NAD+, more kynurenine will get into the brain as well and if there is no neural inflammation going on, then most of the excess kynurenine will just be drained by the veins and eventually excreted as urine.

      If you can't do NR to replace the lost NAD+ from armoatic amino acid blocking via BCAA supplementation, then adding in L-Tryptophan would be good to try, otherwise chronic use of this therapy runs the risk of pellagra like symptoms in the brain which is what happens when not enough NAD is available to cells.

      Delete
  10. Thank you for the post. I am new here. I just discovered that my autistic son has a homozygous mutation in CNTNAP2 gene, which causes autism. I found that estrogen was used in a study to reduce the autistic symptoms in zebra fish with CNTNAP2 mutation. What else would help to counteract this specific mutation? You mention bumetanide. How exactly does it affect neurexin production?

    ReplyDelete
    Replies
    1. Vladimir, your gene encodes a neurexin which are closely related to neuroligins. It is also closely related to potassium channels, which is itself relevant.

      A common dysfunction in autism is caused by over-expression of an ion channel transporter called NKCC1 and an under-expression of on one called KCC2, leading to so-called immature neurons. The cause of this seems to relate to neuroligins and neuroligins seem to be controled in males by female hormones. So estrogen should increase KCC2 expression.

      Bumetanide blocks NKCC1 and so its effect is to reduce chloride concentration within neurons. Estrogen should increase chloride leaving neurons, so its effect will be similar to bumetanide.

      Bumetanide does not likely affect neurexin production. It corrects a down stream dysfunction caused by neuroligins.

      A neurexin dysfunction quite possibly causes a neuroligin dysfunction, which could lead to KCC2 under-expression and then too high chloride concentration. This causes cognitive loss.

      The conclusion would be that a 4 week trial of the generic drug bumetanide could be well worth your consideration. It is in the process of being approved for autism in Europe, but is an old drug.

      Delete
    2. Thank you. Would adding potassium, which is part of your polypill, be a good idea considering the CNTNAP2 mutation? Also, I am giving my son ionic Magnesium, which has chloride. According to your reply, too much chloride is a problem. Shall I stop the ionic Magnesium?

      Delete
    3. Vladimir, it would be worth seeing the effect of a potassium supplement. The supplement I use has both potassium and magnesium. The level of chloride within neurons is what is most important, you can only measure the level in blood or urine. I have wonder if salt (NaCl) should be avoided, but all I do is ensure it is avoided in excess.

      How old is your child?

      Delete
    4. 7yo son. He has other mutations which are more actionable than CNTNAP2. He has homozygous MTHFR A1298C (very rare), homozygous MAO-A 'Warrior Gene' + homozygous SLC18A1, both leading to high monoamine neurotransmitters, and homozygous GAD1 mutations leading to high glutamate. My son has issues with anger (probably explained by his high monoamines), abnormal EEG (probably from high glutamate), and high blood ammonia (MTHFR + CBS mutations).

      By the way, have you heard of LutiMax? Luteolin is a strong anti-inflammatory and a strong estrogen agonist. My son had very positive reaction to it. Also, check Evening Primrose, which is also anti-inflammatory and pro-estrogen.

      Delete
    5. Vladimir, if your read about the excitatory/inhibitory imbalance you may find this applies to your son. He may have both too much glutamate and GABA working in reverse.

      How is he cognitively?

      In some people the anger issue is resolved with a calcium channel blocker, which is very easy to try since it takes effect in minutes.

      Luteolin has many potential beneficial properties, but does not seem to help mopst people, nor does Neuroprotek. Your son probably reacts so well because of CNTNAP2.

      Does your son improve when on penicillin type antibiotics? If he has excess glutamate he may well. Then all the drugs that help ALS should help him.

      Delete
    6. Very poor cognition. But he can read, speak sentences, do simple math like addition and subtraction. Areas of concern: visual stimming (pinching his fingers in front of his face when excited), poor attention, poor eye contact, not being able to tell in detail what happened, tantrums when is transitioned from a favorite activity, but significantly less than before. We started him on Lamictal (glutamate release blocker) in October to normalize EEG and saw great gains in social behavior and speech, but visual stimmings seem to become worse. The only time we saw his stimmings went away for about 1 month is when we gave him Namenda in 2014, but that didn't last. We also give him Taurine at night to help him with the sleep. It does help with sleep much better than melatonin, which for some reason only effective for the first part of the night. Poor sleep was an issue until 2 years ago, when we discovered Taurine.

      Delete
    7. Vladimir, What testing did you use to determine CNTNAP2 status? Just from 23andme testing I ran my son's data via livewello app, there is a panel for cntnap2 snps and my son has several homozygous snps. This is new information for me. However, we have known for many yrs his mthfr status and he is like your son - homozygous for a1298c and MAOA. Just curious, what is your son's COMT status? Also wanted to mention - since Peter mentioned Verapamil to you - that has greatly helped my son with his fits/rage like behavior. We tried neuroprotek many different times - even the low phenol version - my son did well on it initially then it increased aggression. I was thinking it was due to the quercetin in it - seems at the time I read that quercetin can boost testosterone??

      Delete
    8. Tanya, I used 23&me. My son has two homozyogous mutations in this gene: rs2710102 AA and rs2538976 AA. All his COMT are heterozygous with frequency 40-50%, i.e. almost every second person has them. Nevertheless, homo MAO-A, homo SLC18A1 (rs2270641), and hetero COMT all point to elevated monoamine neurotransmitters, anger issues, possibility of mania and schizophrenia. Thank you for mentioning Verapamil. I will definitely keep it in my arsenal. For now, Trileptal is helping him a lot with the mood. We tried Neuroprotek and didn't see anything, positive or negative. We saw improvements on Luteolin but stooped after a few months, I don't quite remember why. Both Luteolin and Quercetin are MAO-A inhibitors, which is not good in our cases. On the other hand, they have a strong anti-inflammatory action (my son has homozygous mutations elevating his IL-1 beta, IL-4 and IL-6). I attributed improvements in my son to this anti-inflammatory action rather than estrogen agonism.

      Among everything we we tried, the following things helped most:

      - Piracetam. My son lost all his words at 1.5, was diagnosed with autism at 2yo. Starting Piracetam at 3 initiated his communication (first taking our hand and bringing us to an object of his interest and using words within a couple of days). We stopped Piracetam after 9 months when we reached a plateau.

      - HBOT. We started it at age of 6. First course gave impressive results that stuck. We did 2 more courses, each moving our son to the next level. My son was delivered through c-section using a suction cap that left a bruise on half of his head. He also fell at 1.5yo, hit his head and blood came out of his ears. So, there is a possibility of brain damage, and HBOT is the only treatment for that.

      - Trileptal reduced self-injurious behaviors and stabilized EEG. Lamictal gave a great boost in social skills and language.

      - Galantamine gave great improvements in social skills and language, but they lasted only 2-4 weeks after each dose increase. Eventually, I started cycling the smallest dose 1mg 1 month ON, 1 month OFF, and then stopped it completely. My son has a triplication in chromosome 15q13.3 involving gene CHRNA7, which enclodes nicotinic acetylcholine receptors. Duplications in this gene are often seen in schizophrenia and autism. Galantamin potentiates these receptors (so does nicotine).

      - Namenda was great for about 1 month, led to increased communication and language, stopped stimming completely, but eventually led to increased irritability, and we had to stop it. We tried Namenda twice, and both times led to irritability after 1 month of raising the dose.

      - Some supplements (Virustop, Luteolin, Evening Primrose) gave temporary improvements, which lasted only 2-4 weeks. The rest (~70) was totally useless.

      After reading this website and research about Butenamide, I became very interested to try it next. Besides improving cognition through neurotransmitter balancing, this diuretic also suppresses ammonia-induced neurological dysfunction, which is important in my son due to his MTHFR mutation.

      Delete
    9. You may want to try low-dosage clonazepam first (20-25mg). Very easy to get prescribed (in standard dose for anxiety, no need to say its for E/I imbalance (!)) in most countries, far easier than bumetanide and safer.

      Delete
    10. Hi Vladimir,

      First, I think your seven year old is doing great. If he is good at basic numeracy and expressive language (speaking in sentences), I do not understand why you think his cognition is very poor. Kids such as yours do have a good prognosis and lot of studies point to such ptedictive positive outcomes.

      Secondly, you have a used a lot of so called nootropics on your son. Piracetam and galantamine. I would b grateful if you could tell me if

      1. Improvements which you saw, even if for a short period, while on the above drugs, stuck a after discontinuation or got lost. I mean did he regress or plateaued out?

      2. One is supposed to give supportive meds with the above for eg., choline with piracetam and then mg with choline. So there is this whole chain which makes the entire process very complicated. Did you go for the entire package or gave the drugs in isolation?

      My five year old is doing ok but ha s huge issues with language. I was feeling tempted to try these but somthing tells me fiddling with acetylcholine is dangerous.

      Please share your experience.

      Delete
  11. Hi Peter,

    I have been trying real hard to understand why you think probiotics do not seem good for long term use (in your communication to Tanya). If I remember right you had postulated that when used long term certain probiotics could not only preempt allergies and immune issues but also might alleviate autstic traits (research studies support this).

    Do you have apprehensions about continuous probiotic use and its implications for autism?

    ReplyDelete
    Replies
    1. Kritika, it is suggested that very early exposure to certain bacteria somehow calibrates your immune system for later life. Giving the same bacteria later on may not have quite the same effect.

      After several weeks of L.reuteri one reader commented that the good effect was lost. I suggested making a two week break. I found that the anti-allergy effect lasted just long enough, but later on had a reverse effect. The original idea came from our reader Alli, who uses the probiotic three weeks on and then one week off. So she much have found a similar effect.

      Delete
  12. Hi Peter,

    Thank goodness you only implied long term 'continuous' use and not long term use per se, with regards to probiotics. I had just recently ordered a truck load of probiotics (and got penalised b having to pay INR 6000), lysed bacteria and related stuff and intuitively had planned to use these long term, in rotation, but discontinuously until more knowledge accumulates regarding their use.

    Recent researches seem promising (the word 'promising' seems to be used quite indiscriminately nowadays) even in adult subjects and older kids, probiotics impacting behavioral issues and neurological conditions, including spasticity in human adults in a positive manner (Umbrello and Esposito (2016), J. Trans. Med.).

    So when my husband rolls his eyes when making payments for the credit card bills, I tell him its 'rolling in the deep' with Peter and other learned members.

    ReplyDelete
  13. Tyler,found a brand that has 5000 mg in the same ratio, and has no glutamine. For now, I can only get nicotinamide, not riboside, or niacinamide,could it serve?
    Thank you for all.
    Valentina

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    Replies
    1. No, not nicotanimide, niacinimide, or riboside, but nicotanimide riboside (one compound).

      Here are some links to help you:

      https://chromadex.com/niagen/

      https://www.amazon.com/Niagen-Nicotinamide-Riboside-60-capsules/dp/B00L5Q951S

      There are also a bunch of other reseller products that have Niagen NR in it as well (usually more expensive and probably not what you want because they have lots of other stuff added in).

      Delete
  14. Vladimir, thanks for the reply and I hope bumetanide helps your son. We have not tried that - my son's doctor would not prescribe it. Just curious - for the ammonia with the cbs and a1298c snps - did you ever consider kuvan prescription?

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    1. I asked our Dan doctor about Kuvan. He said that he never saw any positive from prescribing Kuvan to his patients. It just increases hyperactivity and that's all. Do you know anyone who benefited from Kuvan? I am using Ornithine and L-Carnitine to reduce ammonia. I don't know if they work or not. Yucca is also recommended to decrease ammonia, but I have read that it irritates stomach and stayed away from it. I think that the twin brother of my autistic son (they are fraternal twins, but the brother is neurotypical) also has this MTHFR mutation and I could smell ammonia in his sweat. In fact, the school once complained that my non-autistic son smelled and we should do something about it. What? Don't let him run and sweat? Anyway, the difference between my two sons is that one sweats and the other doesn't. In other words, my autistic son doesn't excrete ammonia through his natural detox mechanisms likes sweating, which could be due to his poor blood circulation. So, Bumetanide could help excrete ammonia through urine, but long term I need to increase his blood circulation in the brain, which could have been disrupted from the c-section suction cap. By the way, right after birth, my son lost all his hair and was bold for about 2 years. That is why I think HBOT helped him so much (it encouraged capillary growth in his brain).

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    2. Vladimir, sorry for late reply - I remembered I forgot to respond and just found this post.... No, I know of no one who has used kuvan - I've always been curious to know if there were any doctors out there who put credence into the a1298c/low bh4 ammonia issue enough to rx it. Good to know your dr's input. Thank you.... Another question for you: have you tried magnesium and potassium in the aspartate forms to lower ammonia??

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  15. Here is a very interesting paper relating to diet issues and some of the recent discussion on behaviors affected by dopamine, and the areas of the brain affected by dopamine, especially the striatum.

    http://www.sciencedirect.com/science/article/pii/S1550413116305964

    This study is with mice and is related to dopamine signaling in the striatum and obese mice. The researchers hypothesis was that that Parkinsonian like motor symptoms occur in obese people (or at least mice in this study) due to a reduction of D2 receptors in the striatum. This causes reduced signaling in the "indirect pathway" of motor control by the basal ganglia, leading to increased inhibition, due to reduced inhibition from the global pallidus externus on the global pallidus internus which has GABAergic projections to the motor areas of the thalamus. Yes this is complicated and unintuitive, but the basic idea here is a reduction in D2 receptors in the dorsal striatum (caudate/putamen) causes the global pallidus externus neurons to increase their tonic firing rate (inhibitory), resulting in increased inhibition in motor output.

    So in effect, obese people are less likely to exercise and move around not just because of their weight making it harder to move as well as usually being in poor cardiovascular shape, but also because it is mentally harder for them to move their body, just as it is in the more extreme case of hypokinesia in Parkinson's disease.

    So how does this relate to autism? Well, if you have a very hyperactive (hyperkinetic) child who can't control their motor output, a high fat diet might help reduce their D2 signaling in their striatum, thereby causing them to have more normal firing patterns, while if your child is hypokinestic (like in Down Syndrome) and your child moves very slow, then a high fat diet would make things worse (of course the paper mentions in its conclusions that insulin, leptin, and other hunger hormones should not be ignored in this equation so maybe giving your kid a box of captain crunch is not the best idea as it relates to hypokinesia).

    This is all very interesting with regards to broad dietary interventions being selective for the type of dopamine dysfunction a child might have for any particular neurodevelopmental disorder and why one particular dietary intervention might work great for one class of autisms and make things much worse for another class of autisms.

    This study of course was done on mice, but it may give a hint as to parents maybe first trying a diet specific to a child's symptoms as it relates to the research in this paper.

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    1. Very interesting Tyler! Morgan has been on the move ever since he was a baby, although has also failed to reach some motor milestones (eg still can't really hop at age 7). However we have found that when he achieves moderate to deep ketosis on the Modified Atkins Diet, the constant fine & gross movement fiddling almost completely disappears (plus the hip rolling, the pinching our elbows ... & so on). Also, his long muscles seem flatter & more relaxed. I had assumed this might be because he has some kind of glucose/ glycogen utilisation problem: "type 3 diabetes" as discussed in these pages in the past. So you make a good point that dietary interventions really need to be well matched to the type of ASD being treated. Note to self: try not to bang on about ketogenic diets all the time ... Alexandria

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  16. Tyler, my son is taking valproate, Iam concerned about a possible interaction with BCCAs since this in high dosis can increase plasma ammonia hepatotoxicity. Wich would be a high dose? For how long can I give him BCAAs taking valproate? For now I can´t get nicotinamide riboside, but I want to start with 5 or 6 g of BCAAs taking advantage of vacations. Thankyou so much for your help
    Valentina

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    1. Excess BCAA's either don't get absorbed in the digestive tract because your intestines can only produce enough enzymes to absorb them over a given period of time, or else simply excreted through the urine. When people have chronically high amino acid levels, it is usually a homeostatic mechanism gone awry. For me, I just give him one scoop which is 3.5 grams of leucine, 1.75 grams of valine, and 1.75 grams of isoleucine once in the morning and then another when he gets from from school (I would have him do it at school too but they are not people I can work with right now).

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  17. Hi Peter,
    I wanted to ask the readers of the blog if any one had experience with Andrew Cutler Protocol, you use small amounts of ALA and DMSA in it as per the half life.
    We were seeing some benefits with leucovorin, but are interested in the AC protocol.
    Also wanted to know if any one here has used HBOT, our DAN was suggesting it, so researching before renting the machine
    Thanks
    BK

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  18. With respect to this post about neuroligins and neurexins, have you looked at the protein gephyrin before? Dysfunction of this protein as popped up in some studies of autism I have read in causing GABAA receptor dysfunction.

    My interest started from this paper which is actually about diabetes but not directly related, though the drug interaction they talk about relates to gephyrin and a class of compounds called Artemisinins that bind to it and increase GABA signaling:

    http://www.cell.com/cell/fulltext/S0092-8674(16)31531-8

    Another paper mentioned in this paper is specific to gephyrin's impact in neuronal signaling:

    http://www.nature.com/nrn/journal/v15/n3/abs/nrn3670.html

    Though this first paper is about diabetes and the effect of Artemisinins on GABAA signaling in the pancreas, for all I know these compounds might make it past the BBB to some degree and improve GABA signaling in situations where gephryrin is compromised somehow in autism.

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    1. It is also interesting is that increased gephyrin expression seems to upregulate MOCO (Molybdenum Cofactor) which you touched upon two blog posts ago.

      Also, P2rx3, Vamp1, and Nrxn3 were upregulated and intracellular chloride levels were raised significantly.

      All in all, artemether sounds like a very interesting compound for autism even though a quick search for "artemether autism" turned up nothing.

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    2. Artemisinins seem to affect GABAa sub-unit expression, which might have a good or bad effect in autism, depending which subunits it affects and in which direction.

      Low dose clonazepam does this in a good way via α3 upregulation and the Down Syndrome drug RG1662/Basmisanil also aims to do this via a different subunit, it is a selective GABAa α5 Receptor Negative Allosteric Modulator.

      α5 down regulation is also possible with cardiazol/PTZ, used in Italian and India cough medicines.

      Artemisinin did not seem to help in schizophrenia.

      Artemisinin reduces the level of antibodies to gliadin in schizophrenia.
      https://www.ncbi.nlm.nih.gov/pubmed/21546216

      “A total of 57 participants (26 in the artemisinin arm and 31 in the placebo arm) completed the 12 weeks of the trial. The medication was well tolerated and there were no significant side effects associated with the treatment regimen. There was no significant difference in the change of positive, negative, general, or total PANSS symptoms between groups for all of the randomized patients or for just the completers”

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    3. Never knew about the hypothesis about gliadin and schizophrenia (I usually shy away from research talking about gluten this and gluten that).

      Thanks!

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    4. I always thought that artemisinin must have strong antiinflammatory effect as it improved survival in severe malaria and this is in fact inflammatory disease with cytokine storm responsible for many deaths, not the parasite itself. And indeed it has:

      https://www.ncbi.nlm.nih.gov/pubmed/28000518

      "Artemisinin inhibits inflammatory response via regulating NF-κB and MAPK signaling pathways."

      So I also once tried to find out if anyone used it in autism and found only this odd comment in a discussion on a different topic:

      "I was first introduced to Artesunate by a prominent Autism expert at a medical conference who finds it helpful in Autism"

      http://buhnerhealinglyme.com/herbs/artesunate-inhibits-xmrv-retrovirus/

      A prominent autism expert recommends antimalarial?

      Anyway I wouldn't have any idea how to use it in practice (for autism).

      Sorry for the off topic, but the story of Tu Youyou, who discovered artemisinin studying ancient traditional chinese medicine scripts, tried it on herself and colleagues, proved efficacy in malaria and was neglected by the western world for years to finally win the Nobel Prize in 2015 for the first-line antimalarial saving thousands of lives every year now is amazing.

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    5. There are various forms of artemisinins, and for this particular study artemether (which from what I have read is the best orally absorbed form) seemed to have the most effect on gephyrin. It seems to be relatively safe for chronic use, but I thought it would be one of those little interventions like low-dose clonazepam (which also affects GABAA subunits) that could help untangle the logjam in neural protein production at the synapse that seems to cause problems with inhibitory signaling in many cases of autism (the gene that produces gephrin is in the SFARI database). I have no idea how to source artemether, even though it is pretty much used all over the world now (or at least anywhere where malaria is still a problem).

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  19. I just did some more research on artemether (the arteminisin found to be most potent in gephyrin binding) and it does cross the blood brain barrier. It is also though to be neurotoxic in high doses, and the effects of arteminisins seem to be abolished by NAC. Very interesting compound and due to its mechanisms of action, could be a candidate for microdosing (unless you have malaria of course which is its original use even though it is being investigated for cancer as well and its discovery led to a Nobel Prize).

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  20. Peter, a bit over my head, need to read again, but am I correct in thinking if there is a CYP19A mutation would it be wise to be careful with these supplements/nutrients that inhibit cyp19a?? I have no doubt I am looking at this in a simplistic frame of mind. I am just on a liver processing kick right now

    The inhibition of aromatase can cause hypoestrogenism (low estrogen levels). The following natural products have been found to have inhibiting effects on aromatase.

    Apigenin,[20]
    Catechin,[21][22]
    Chalcones,[23]
    Eriodictyol,[20]
    Isoliquiritigenin,[20]
    Mangostin,[20]
    Myosmine,[24]
    Nicotine,[25]
    Resveratrol,[26]
    Vitamin E,[27]
    Zinc,[28]
    Hesperetin.[29]

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  21. My son has autism with regression at 19 months. He found a point mutation in the last exon of the gene nlgn5 ( nlgn4y). How can I help him? There is no information about this mutation. This previously undescribed mutation. I am very upset.

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  22. My son has autism with regression at 19 months. He found a point mutation in the last exon of the gene nlgn5 ( nlgn4y). How can I help him? There is no information about this mutation. This previously undescribed mutation. I am very upset.

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    1. There is quite a lot written about nlgn4y and autism. You need to figure out whether you have under or over expression of this gene. Then you look at exactly what the protein encoded by the gene does. Then you look for strategies that may compensate for variation caused in the amount of the protein.

      The mutation can most likely only do 3 things, increase expression, reduce expression or do nothing. Mutations do not normally produce mutant proteins, rather it is just a question of how much is produced. Neuroligins are well documented and are very important.

      The change in expression will trigger a cascade of other changes, which may well be treatable.

      It is a complex area and most genetic mutations do not have simple fixes. But at least you do have a very precise starting point.

      Read all the literature. There are many links here:-

      https://www.ncbi.nlm.nih.gov/gene/22829

      You have to become your own expert and you may well find useful options.

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    2. Peter, thank you very much

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  23. Found previously undescribed variant (chr Y: 16952920 T >A ) in the hemizygous condition that leads to premature stop codon in the gene NLGN4Y. In the control sample option is not registered. The identified nonsense mutation is located in the last exon of the gene NLGN4Y, which often can affect the function of the protein, but it is within a functional domain, which may significantly affect protein function.

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