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Saturday, 16 December 2017

Turner Syndrome, Estradiol and Autism-lessons from the X Chromosome

This post is best read if you have reviewed the earlier ones regarding the estradiol/testosterone disturbances in autism and how they govern the RORα “switch” that then triggers a torrent of other dysfunctions. So the hormonal disturbance, if present, is a key point at which to make a potent intervention. 



Beauty is in the eye of the beholder


In the mass media it is now popular to dismiss the fact that autism is far more prevalent on boys than girls. In the scientific literature, fortunately, they stick to the facts and much is written about the sex differences in autism.
As we have seen in earlier posts, females have some natural defences against autism. They have two X chromosomes and of course they have those all-important neuroprotective female hormones (estrogen/estradiol, progesterone etc.). In effect, the more female you are, the more protection you have against idiopathic autism and any X-chromosome linked single gene autism. So a girl with Fragile-X syndrome is likely to be far less affected than her brother with same condition.
Recall that we all have 23 pairs of chromosomes and that the 23rd set contains two Xs in girls and in boys one X and one Y. The girls’ “spare” X chromosome is also what gives them their feminine features.  

It is interesting to look what happens to females who lack part of their second set of X- chromosomes. This diagnosis is called Turner Syndrome. As you might have guessed people with Turner Syndrome have much lower levels of female hormones and a higher incidence of autism, although some people find this controversial. The autism-like characteristics of TS include:-

·      Impairments in social functioning

·      Impairments in face and emotion processing

·      Spatial executive deficits

·      Poor social coping skills and increased immaturity

·      Hyperactivity and impulsivity

Turner syndrome occurs in 50 per 100,000 live-born females. Autism occurs about ten times for frequently, so about 500 per 100,000 live-born females.  Turner syndrome provides the extreme case of what happens when females have too little estrogen/estradiol.
I think you will find a large group of females with idiopathic autism (no identified genetic defects) have/had low levels of estradiol. I think this is the reason that facial recognition studies show that some females with idiopathic autism look different, (as do many boys, of course). We already know that most single gene types of autism produce tell-tale signs, often on the face (big ears, wide face, big/small head etc).

I am not suggesting that there is anything wrong with looking different; rather it may be a useful diagnostic tool and not an expensive or invasive one. Physical variation has long been used to identify genetic syndromes, before genetic testing became widely available.

Physical variation inside your head
We saw in an earlier post that MRI scans of the autistic brains actually do often show subtle differences, particularly when you use software to read them, rather than the naked eye. Traditionally doctors say that MRIs are “normal” in autism and cannot be used to diagnose it. Yet in a recent studies machine reading of MRIs was able to identify 70%-96% of autism cases.  Some of these are scans taken before birth.

This is interesting, because ultimately you might bypass the current very slow and subjective observational diagnosis process.




MRIs show a brain anomaly in nearly 70 percent of babies at high risk of developing the condition who go on to be diagnosed, laying the groundwork for a predictive aid for pediatricians and the search for a potential treatment



Predicting the future with brain imaging

In a new study, Emerson et al. show that brain function in infancy can be used to accurately predict which high-risk infants will later receive an autism diagnosis. Using machine learning techniques that identify patterns in the brain’s functional connections, Emerson and colleagues were able to predict with greater than 96% accuracy whether a 6-month-old infant would develop autism at 24 months of age. These findings must be replicated, but they represent an important step toward the early identification of individuals with autism before its characteristic symptoms develop.


MRI scanners are very widely used, but you do have to keep very still inside when they are in operation. The even harder part is the reading of the data. It is clear that some standardized machine reading (A/I artificial intelligence) process is required to notice every possible variation. You could have a centralized location where you just submit your MRI data, the center gets to keep the data and learn from it; and you get their insight as to what differences there might be.

Facial Differences vs MRI Brain Differences
I like to keep things simple and under my control.  In the short term we have to settle for facial differences, since any well-managed MRI process will be decades away.

Hormonal Variation in Autism
Hormonal differences were one of the key areas I identified years ago in this blog. Big/small heads result from disturbances in pro-growth signalling pathways. We should expect variations in bone-age, early/late onset of puberty and indeed big variations in height and weight.

In Turner Syndrome, the girls tend to be very short and they are often treated with growth hormones, as well as female/feminizing hormones.  
Great caution has to be taken when treating children with any hormones. When children are treated, it is for serious reasons like not achieving puberty, or having a serious growth delay (being very short).

Hormone Therapy During Pregnancy
In some countries hormones are given during pregnancy although I think this would be seen as odd/risky in some advanced countries.

We have already seen that couples who have difficulty producing a child often have a family history that includes autism. It was proposed by one serious fertility expert that what helps prevent miscarriage also helps prevent autism. This did sound odd when I first read about, but when you look in more depth there is a basis for this idea.
That expert has these two websites:-



Progesterone supplements have been recommended for more than 50 years for women struggling with infertility, but research now shows they can also help prevent miscarriage.


Tamoxifen, an estrogen receptor (ER) antagonist, is also used to treat infertility.
Estradiol is sometimes prescribed during pregnancy.
Testosterone is produced naturally during pregnancy.

All this is clearly beyond the scope of this blog, but perhaps altered female/male hormones during pregnancy might be a biomarker of some future autism and female hormones might be a protective therapy in the subgroup of pregnant mothers with low levels of these hormones and/or high levels of testosterone. Recall that human trials in the hospital ER have shown certain substances are highly neuroprotective (progesterone, atorvastatin etc) and when administered immediately after a traumatic brain injury markedly improve the outcome.                                         

Hormone Therapy for Autism
Hormone therapy in people with autism would be controversial, but we saw in an earlier post that via RORα the balance between testosterone and estradiol affects numerous biological relevant to autism.

Many pictures of girls/women with autism, that you can view online, suggest reduced levels of estradiol. Faces look more boy-like. Many males with autism are reported to have physical features of high testosterone and low estradiol. 
One example of many:-


Both faces in the above article show clear indications of autism. Since both young people do have autism, this should not surprise anyone.
My own conclusion is that if you have autism or Asperger’s, a little extra estradiol could therapeutic, particularly if you have physical features that reinforce this.
There are of course many males and females with autism who are physically indistinguishable from the rest of the world. The point of this post is to highlight that visible differences may help to define the sub-type of autism and indicate possibly effective therapies, that exist today.

Obesity and Estradiol
In an earlier post on estradiol, I pointed out that in males estradiol is made in your adipose (fat) tissue. In the US many people with autism are overweight, in part due to side effects from their likely un-needed psychiatric medications; this has the hidden benefit of increasing their estradiol levels, feminizing their behavior slightly and shifting RORalpha in the right direction.
This also means that losing weight should be helpful to obese females with estrogen receptor positive breast cancer.  Research does support this.


Asperger’s and too much Estradiol?
We saw in earlier posts that much autism is associated with reduced expression of estrogen receptor beta and low aromatase, so high testosterone and low estradiol.

We have seen on many occasions that when one extreme exists in autism, so usually does the other; so many big heads, but also some tiny ones, NMDAR hypofunction, but also hyperfunction.

There was a lot of talk a while back in the media about children undergoing therapy to change their gender, and it was highlighted that Asperger’s was much over-represented in this group. One expert got into trouble for suggesting that their autism was causing them to obsess about their identity and so mistakenly convince a boy that he would rather be a girl.  It seems that these days some clinicians are then all too willing to provide drug therapy and then operate on them, to make them female.  I do wonder if perhaps some of these boys with Asperger’s might have the other extreme of aromatise. That would give them too little testosterone and too much Estradiol.
I think measuring these hormones is quite a good idea, as I keep repeating, they go on to affect the critical “switch”  RORα, which then impacts a large number of biological processes implicated in autism.  In other words you can try to normalize a wide range of important autism variables, just be tweaking RORα, via estradiol/testosterone.

A boy with high testosterone, and so low estradiol, will likely exhibit physical signs of this, just like the girl with low estradiol. These are just pieces of the puzzle, in plain view, that can be used to understand each specific case of autism. And no machine reading of an MRI is required.






For those left wanting more:
A very thorough paper on Turner Syndrome:-

Turner syndrome (TS) is a neurogenetic disorder characterized by partial or complete monosomy-X. TS is associated with certain physical and medical features including estrogen deficiency, short stature and increased risk for several diseases with cardiac conditions being among the most serious. Girls with TS are typically treated with growth hormone and estrogen replacement therapies to address short stature and estrogen deficiency. The cognitive-behavioral phenotype associated with TS includes strengths in verbal domains with impairments in visual-spatial, executive function and emotion processing. Genetic analyses have identified the short stature homeobox (SHOX) gene as being a candidate gene for short stature and other skeletal abnormalities associated with TS but currently the gene or genes associated with cognitive impairments remain unknown. However, significant progress has been made in describing neurodevelopmental and neurobiologic factors underlying these impairments and potential interventions are on the horizon

We utilized an ultrasensitive assay to study estradiol levels in 34 girls with TS and 34 normal age-matched prepubertal girls between the ages of 5 and 12 years. The average estradiol level in the girls with TS (6.4 +/- 4.9 pmol/l estradiol equivalents) was significantly lower than in the normal prepubertal girls (12.7 +/- 10.8 pmol/l estradiol equivalents; p < 0.01). Girls with TS were significantly shorter, and weighed less than the normal prepubertal girls, as expected. The estradiol level was not significantly correlated with height, bone age, 








  

51 comments:

  1. Peter,

    What is your view on targetting TRPV and TRPM channels (heat and cold sensors) as an approach for mood and emotional control and even learning.

    Thermal stimulation of vasopressin and oxytocin (VP/OT) release from explants of the hypothalamo-neurohypophyseal system (HNS)
    http://www.fasebj.org/content/26/1_Supplement/900.3.short

    "Maintenance of a constant body temperature is essential in homeotherms. Since evaporative heat loss is necessary for preventing hyperthermia, integration of the mechanisms regulating water and thermal homeostasis is required. We used HNS explants from adult rats to study the impact of increases in temperature on stimulation of VP/OT release. Increasing the temperature from 37 to 39.5°C over 1 hr caused a dramatic increase in VP (850%) and OT (405% of basal) release (both p<0.001). Simultaneously exposing explants to a ramp increase in osmolality (25mOsm/2.6 hrs with mannitol) doubled the response to temperature alone (VP- 1780%; OT-860% of basal). Thermal stimulation of VP/OT release was significantly attenuated by combined exposure to gadolinium (100μM), a non-specific blocker of mechanosensitive channels, and capsazepine (10μM), a selective antagonist of TRPV1 channels, but not by capsazepine alone."

    Crosstalk of Pain and Pleasure: TRPV1 is a Novel Oxytocin Receptor
    http://www.cell.com/biophysj/pdf/S0006-3495(16)33236-2.pdf

    Channels such as TRPV1 even affect LTD and LTP, that alone should be enough for investigation and I find absolutely shocking that they have never been looked at considering the role of temporary 'cure' while some kids have fever.

    Activation of different TRPV channels with their corresponding temperatures taken from:

    Epidermis as the “Third Brain”?
    http://www.sciencedirect.com/science/article/pii/S102781171500049X


    Temperature Agonists Other factors
    TRPV1 >43°C Capsaicin and protons
    TRPV2 >52°C
    TRPV3 ∼30°C Camphor, 2-aminoethoxydiphenyl borate
    TRPV4 ∼30°C 4α-Phorbol 12,13-didecanone Osmotic pressure
    TRPM8 <22°C Menthol
    TRPA1 <17°C Allyl isothiocyanate, cinnamaldehyde Mechanical stimuli?

    "Overall, these results are consistent with the hypothesis that the epidermis plays a significant role in adapting whole-body physiology, and also emotional response, to changing environments."

    Oxytocin modulates nociception as an agonist of pain-sensing TRPV1
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701661/

    "Together our findings suggest the existence of endogenous regulatory pathways that modulate nociception via direct action of oxytocin on TRPV1, implying its analgesic effect via channel desensitization."

    Discrete expression of TRPV2 within the hypothalamo-neurohypophysial system: Implications for regulatory activity within the hypothalamic-pituitary-adrenal axis.
    https://www.ncbi.nlm.nih.gov/pubmed/15156577/

    "Taken together, these data suggest that this channel may play a vital role in mediating physiological activities associated with oxytocin and vasopressin release such as parturition, lactation, and diuresis. These data may also implicate the involvement of TRPV2 in disorders of the hypothalamic-pituitary-adrenal axis, including anxiety, depression, hypertension, and preterm labor."

    Incensole acetate (boswelia/frankencinse), an incense component, elicits psychoactivity by activating TRPV3 channels in the brain
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2493463/

    "Our results imply that TRPV3 channels in the brain may play a role in emotional regulation."

    "Taken together, our data support our original contention, namely that Boswellia resin may affect sensation and emotional states. These observations also indicate that the TRPV3 channel is involved in emotional and behavioral processes in the CNS in addition to its known effects on the perception of warmth (thermosensation). It is possible that IA augments the euphoric feeling produced during religious functions, due to both positive, presumably mild, emotional effects and the sensation of warmth."

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    1. Aspie1983, some people treat autism with raw garlic and report good results. Raw, but not cooked, garlic activates two types of TRPV channel.

      Many people with autism have vascular symptoms, like cold hands. This type of ion channel is very much involved in vasodilation via NO.

      The obvious home remedy would be to crush a clove of raw garlic and eat it. It might not be great for your breath, but if you feel better it might point you in a good direction to explore. There are odorless garlic capsules, but I would start with garlic from the supermarket.

      There is an old post about garlic. Different forms of garlic have different biological properties, for example aged garlic.

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    2. Hi Peter,

      Most of the studies suggest that alot of these channels are indeed highly present in areas of the brain that control learning and emotion.

      From what I understand allicin (garlic) indeed activates TRPA1 receptors (these are cold receptors by the way). With regards to eating raw garlic, I have done this once or twice in the past but I could not get past the foul taste, let alone the stench that it creates for others lol.

      I would assume there is a great seasonal sensitivity in the up and downregulation in particular of the cold receptors such as TRPM8 and TRPA1.
      Such as cold receptor TRPM8 and TRPA1 becoming more active at this time of the year, while they would desentize during the summer.

      From an evolutionairy perspective it also makes sense, maintaining heat is critical for survival and they are probably expressed in areas that control emotion for this reason. This is why people during the winter on average are more careing than for example during summer where people tend to be more arrogant.

      Remember when you recommended me to look into Probenecid a while ago, I just found out that it activates TRPV2 aswell:
      from wikipedia:

      "TRPV2 is activated by high temperatures above 52 °C. Alternatively it can be activated at lower temperatures by chemicals, such as the research tool 2-APB,[9] the plant cannabinoid cannabidiol,[10] and probenecid.[11] It is blocked by ruthenium red and lanthanum.[8]"

      I've ordered some peppermint essential oil by the way and plan on trying it as it activates TRPM8 receptors.
      Im still doing very very good on memantine, Ive nearly always been sceptical about pharma meds, after my somewhat traumatic experience of ssri's and antipsychotics during my childhood.

      All in all I have found it shocking that no research AT ALL has been done on these channels for autism!!! Absolutely shocking in my opinion, there was literally only 1 study on ASD that I could find that very briefly mentions these channels.

      What I found fasicinating is that NMDA antagonists (often also cough supressants) such as memantine and amantadine that have all the amantadane backbone have a camphor like smell:

      Taken from wikipedia:

      "Pure adamantane is a colorless, crystalline solid with a characteristic camphor smell."

      Camphor activates and sensitizes transient receptor potential melastatin 8 (TRPM8) to cooling and icilin.
      https://www.ncbi.nlm.nih.gov/pubmed/23828908

      "In the presence of ruthenium red (a blocker of TRPV1, TRPV3, and TRPA1), the camphor sensitivity of cultured rat dorsal root ganglion neurons was highest in a subpopulation of cold- and icilin-sensitive neurons, strongly suggesting that camphor activates native TRPM8. Camphor has a dual action on TRPM8: it not only activates the channel but also inhibits its response to menthol."

      "The activation and sensitization to cold of mammalian TRPM8 are likely to be responsible for the psychophysical enhancement of innocuous cold and "stinging/burning" cold sensations by camphor."

      Camphor Activates and Strongly Desensitizes the Transient Receptor Potential Vanilloid Subtype 1 Channel in a Vanilloid-Independent Mechanism
      http://www.jneurosci.org/content/25/39/8924

      "The camphor-induced desensitization of TRPV1 and block of TRPA1 may underlie the analgesic effects of camphor."

      Menthol-Induced Ca2+ Release from Presynaptic Ca2+ Stores Potentiates Sensory Synaptic Transmission
      http://www.jneurosci.org/content/24/3/762

      "Menthol and many of its derivatives produce profound sensory and mental effects."

      "Taken together, our results indicate that menthol can act directly on presynaptic Ca2+ stores of sensory neurons to release Ca2+, resulting in a facilitation of glutamate release and a modulation of neuronal transmission at sensory synapses. Expression of TRPM8 receptor on presynaptic Ca2+ stores, a novel localization for this ligand-gated ion channel, is also strongly suggested."

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    3. Menthol enhances phasic and tonic GABAA receptor-mediated currents in midbrain periaqueductal grey neurons
      https://www.researchgate.net/publication/259915627_Menthol_enhances_phasic_and_tonic_GABAA_receptor-mediated_currents_in_midbrain_periaqueductal_grey_neurons

      "These results suggest that menthol positively modulates both synaptic and extrasynaptic populations of GABAA receptors in native PAG neurons. The development of agents that potentiate GABAA-mediated tonic currents and phasic IPSCs in a manner similar to menthol could provide a basis for novel GABAA-related pharmacotherapies"

      Once again im shocked, no research has been done on this with regards to autism, TRPM8 and other channels clearly affect gaba and nmda...

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    4. Aspie1983, garlic has many effects including:-

      Diallyl sulfides in garlic activate both TRPA1 and TRPV1.
      https://www.ncbi.nlm.nih.gov/pubmed/19298793

      You might look into what substances remain in the odourless garlic capsules. Perhaps some of the good parts are still there.

      Our reader Nat did comment a long time ago about the benefit of peppermint. I even bought some capsules. You can even use fresh mint leaves.

      I think you will find that the benefit is marginal, compared to what you find from the "right" drug, which hopefully is Memantine for you.

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  2. Thanks Peter,

    Im well aware that herbs and all wont have much of an effect, was more trying to generate more of an open discussion to a possible new target for drug treatment.

    With regards to memantine it is indeed working very well with the mild negative effect of feeling somewhat 'absent/disassociated' at times.

    That being said, im still convinced that the sigma-1 receptor holds the most promise as a target for my personal problems. Im giving memantine 4 more weeks and I'll be slowly tapering down.
    2-3 weeks after that I'll be trying Afobazole and if it does indeed seem to be very beneficial im pretty sure that it is indeed due to sigma-1 activation.

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    1. Aspie1983, there are numerous interesting Russian drugs like Afobazole, that are completely ignored in Western countries. The same is true with some Japanese drugs.

      Given what we have learned about the potential to repurpose existing safe drugs for other purposes, there is quite a long list of potentially useful drugs.

      I think many people are indeed trying to fix their case of autism with herbs, some go to huge details, but potency is lacking 90% of the time. That is why you need standardized, reliable, safe drugs.

      Delete
  3. Hello Peter,

    I wanted to know from you if kids on the spectrum with classic autism, not aspergers, really grow up emotionally. My son, at almost six now, seems to be acquiring new skill, reading, writing, comprehension, independent navigation on his tab to play games and understand and apply the concepts and rules on his own...just overall cognitive growth..expressive language still being our biggest 'we shall overcome' target. However, rather than speech, I am concerned more about his socio-emotional issues. Like many on the spectrum he seems to be stuck up somewhere between one and a half to two years old developental stage, when it comes to his growth as a 'human' offspring. Curiousity, concern, interest about people with whom he shares his living space is abysmal though he seeks us out all the time.......an infantile primitive need.

    What has been your experience with Monty, who has clearly made remarkable cognitve progress over the years. Is he more like us now or still an indfferent angel (or devil) free from the trappings which make us human? Do your internal worlds 'ever collide'?

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    1. Kritika, we cannot generalize here because people with classic autism are very different. Monty actually shows more empathy than his "normal" elder brother, is is just he uses few words to show it.

      I think cognitive function and speech are the key issues, solve those and everything else will improve.

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    2. Peter,

      We are not at all there when it comes to empathy...Monty is clearly sensitive and soft unlike my rowdy menace. Hope we get there someday, oneday.

      Delete
  4. Hi everyone,

    It's been about 1.5 months since we undertook the following further to my daughter's OAT testing:

    1. Oral Vancomycin (1 week) to address bad GI bugs
    2. Oral Nystatin (4 weeks of increasing doses) to address yeast / fungal issue in GI
    3. Use of S Boulardii daily as a good yeast probiotic (forever)
    4. Use of several good bacterial probiotics daily (forever)
    5. Dramatic reduction in Gluten
    6. Dramatic reduction in Casein
    7. Use of a digestive enzyme when we can't avoid casein and / or gluten

    We have now been off the Nystatin for a few weeks and ... WOW!

    During therapy, we noticed a difference almost immediately. My daughter's speech, cognitive skills, and socialization improved modestly (albeit noticeably). It was clearly due to the interventions due to the sudden impact and timing.

    Examples include an immediate desire to start drawing (and improved drawing, focusing on faces) and writing words. She is already hyperlexic, so can read well, but suddenly her ability to write blossomed. Also, we were getting notes about more play at school with the other kids.

    OK - so let me tell you about the last two days (weeks after ending Nystatin, and no new interventions in the meantime). My daughter was saying something to me yesterday and held my gaze for a prolonged period of time (2 - 3 minutes). And she has been making significantly more eye contact over the last few days (whereas before, she avoided it).

    But here is the kicker - when my wife isn't happy with something my daughter has done (e.g. makes a mess), my wife never reacts negatively and just goes to fix the issue. She is however more focused and less bubbly while she is cleaning the mess, so the difference in my wife's demeanor is there but it is minimally perceptible even to me. Well, as soon as my daughter "reads" this very subtle change, she immediately rushes to my wife, tries to make eye contact, and says "Mommy, be happy". Now, very recently, she in fact has started to vigorously tickle my wife into being happy.

    The eye contact, ability to read extremely subtle changes in mood, the interest in making sure me and wife are happy, and the proactive efforts to make sure my wife and I are happy are so novel, and such a departure from her previous behavior, that this is clearly the impact of our efforts.

    Also, her sense of humour has also blossomed - she is making clever changes to songs she sings to make them silly, just to make us laugh. Previously, a small change to lyrics she knows would have upset her, but now she loves to be creative.

    My understanding is that in ASD, these kids are not very good at reading or even interested in the mood of others (as conveyed by facial expressions or other cues), and this was true of my daughter prior to the above therapy. Since initiating the therapy, we have seen improvements in the three parameters I am hoping to address (cognitive, social, speech), but over the last few weeks, the improvements on the social end (i.e. reading moods, being affected by perceived yet subtle negative moods, and a desperate desire to make people happy) are a complete 180 over historical norms.

    It is not a cure by any stretch, but interestingly, the trajectory of my daughter's regular improvement has changed noticeably for the better due to the above interventions and I hope it continues at this new pace. At this pace, we will be at a far more interesting place a year from now than we otherwise would have been.

    I can't say that my experience is indicative of what anyone else will experience (i.e. your results may vary), but I thought I would share.

    Merry Christmas to all!

    AJ

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  5. Thank you AJ. Merry Christmas. I will pass this information on to a friend. All the best.

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    1. Hi AJ,

      First a big, warm, heartfelt congratulations to you for the strides your daughter has made. She is clearly a special child and so are mum and dad.

      It would be really helpful if you could share the dose for vancomycin and nystatin. Do you think I could pull this off myself without the guidance of a medical doctor or is it too risky. I do not know whether treating GI health will lead to massive improvements in my son as well as he does not have any overt symptoms of GI issues but even a minor deterioration in his digestive health leads to mood and sleep problems. We did get a good response on cefixime but I do not know if it was because of its antimicrobial action or any other effect.

      Best wishes for Christmas and a very happy New Year.







      Delete
    2. Hi Kritika,

      Thank you for the kinds words! I don't recall the dosage for the Vancomycin, and I had to have both that and the Nystatin compounded by a compounding pharmacy so they figured out the dosage of the liquid they made for us and just told us how many MLs to give of the compounded product.

      I'm sure sites like the Mayo clinical will note the standard dosage of oral Vancomycin for kids

      My daughter had virtually no issues at all with either (other than a funny one that lasted about a week after starting the therapy, but I won't go into it), but that doesn't mean others won't. The doctor wrote the script, but did no monitoring - if there were issues I would have gone back to the doctor, but since we did not have any issues, we did not have active monitoring by the doctor.

      One key to success, I believe, is to keep giving the child the probiotics in between dosings, and certainly a few hours after the last dose. I had to give Vancomycin 3X daily and the Nystatin 2 X daily. I did actually also give my daughter a product called Candex to make it easier for the Nystatin to hit the relevant yeast / fungal issues (it eats away at biofilm which makes it easier to get to the bad yeast / fungus (assume its often Candida). If you do go the Nystatin route, check it out. I can't say if it helped (it may have), but it didn't hurt.

      Interestingly enough, my daughter has never had any GI issues, so it was a bit of a surprise when the OAT testing revealed both bad bacteria and yeast.

      In terms of casein, I slowly replaced my daughter's cow milk with Almond milk, by giving her a 90/10 solution for a while, then 80/20, etc etc so that she wouldn't notice the change until we got to 100% Almond milk.

      I also replaced her bread with gluten free bread (many are heavy as lead, but there are some good ones that are virtually indistinguishable from normal bread when toasted) and her snacks with gluten free snacks.

      If you do try to attack and replace the bad bugs / yeast, you may also want to try the gluten / casein thing at the same time to see the impact. That may be helping keep the bad bugs at bay, not to mention the caseomorphin / gluteomorphin issue that the OAT testing identified for us (I know there is some controversy around this, but I'm seeing results, although can't say if any of it is from the casein / gluten aspect)

      Kritika, I genuinely wish the best for you, your son, and your family, and I so look forward to the day when we all can come back to this board once our kids are significantly better, and celebrate.

      Merry Christmas Kritika!

      AJ

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    3. Just to clarify, the caseomorphin / gluteomorphin test we did wasn't part of the OAT testing, it was a separate test we did at the same time using the same urine sample at the same lab.

      AJ

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    4. AJ,

      Thanks for the very helpful response. I am certain we all will come back on board with reasons to celebrate.

      Delete
  6. Hi everyone, I wanted to know if someone tried inulin or what do you think about it, there are different theories about if it feds good and/or bad bacteria at the same time. I would like to try it alone,without probiotics, but Iam not sure. I think that it could be another option to support GI health.
    Merry Christams for all.
    Valentina

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    1. Valentina, does your son show any signs of SIBO (small intestine bacterial overgrowth) - if so, I would stay away from supplementing it. My son developed SIBO many years ago after trying antibiotic approach to treat "infections". At the tme even lots of high fiber foods caused problems.
      Feliz Navidad!

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    2. Tanya, how nice your Christmas greeting in spanish, I did to him the OAT month ago and the result was: No unusual organic acids are detected. I don´t know if this is a guarantee of something. Certainly, the antibiotic approach is not the one for my son also. After a long time chasing parasites and candida, now I realize that from a hig eosinophil marker, in wich are to optons, parasites or allergy, I choose the wrong one. Now I realize that allergy is the key word here, allergy to antibiotics certainly, and fiber foods also.Best wishes for you and your son. Valentina

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    3. Valentina
      We tried inulin for our three and a half year old grandson. He had normal range of short chain fatty acids in his stool test. We started with a pinch and gradually increased dosage. At first there were some improvements like paying more attention to what we say. He also started to pedal the tricycle. But after a few months he developed aggression and mood swings. He would cry and cry for nothing. In a fraction of a second he will launch himself on us and scratch our face. When we stopped inulin both behaviors went away.
      Currently we are giving 2+2 mg of galantamine per day (under Dr.Rossignol’s prescription). Both receptive and expressive language has improved. He pays attention to what we say (almost 70% of the time)and
      answers back to yes or no questions in 4 or 5 word sentences. Like “would you like to go to bed? And he says No I don’t want to go to bed. Before he won’t even pay attention and sometimes will only say no or yes. The side effect is more salivation which he keeps in his mouth and plays noises with it. But the positive effect is worth the side effect.

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    4. Hi salempeacock, galantamine enhances dopaminergic neurotransmission,so as memantine,something that my son needs to stay away.With respect to inulin, we suspended the trial. It is not completly safe. Thankyou for your input and congratulations for your son!
      Valentina

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  7. Peter, what is your current list of medications for your son?

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    Replies
    1. I use what is listed in the Polypill page:-

      https://epiphanyasd.blogspot.com/p/polypill-for-autism.html

      in addition I have been using about 1g of Agmatine for about three months, which I will add to the Polypill.

      I am experimenting with

      - 150ml a day of beetroot juice
      - a small amount of sodium benzoate
      - Svetol/decaffeinated coffee extract as an OAT3 inhibitor

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    2. So, you are using Atorvastatin, Clonazepam, Verapamil, etc every day? What brand of NAC?

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    3. Yes, every day just like it says. It is now 5 years since I started, first with Bumetanide and potassium, and then Atorvastatin and NAC shortly thereafter. I use NAC Sustain mainly, since it is the most potent; but I use effervescent NAC (fluimucil) as the first dose since it also contains some binders that hold the other substances in this 200ml drink together (clonazepam etc).

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    4. Peter,

      Are you sure your son his coq10 levels are still fine? That is one the biggest problems with statins, coq10 depletion.

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    5. Aspie1983, some people on statins develop myopathy, but most do not. There is a lot of conflicting information, but it seems if you have no myopathy, you do not need to worry. My son has no myopathy.

      I also take atorvastatin and after while stopped taking coQ10, since I had no side effects. My brother did get myopathy with statins and just increased coq10 until these side effects disappeared. In trials it seems that the more healthy you are, the less your chance of these side effects.

      This is a good paper on the subject:-

      https://www.sps.nhs.uk/wp-content/uploads/.../Co_enzyme_Q_and_statins-FINAL.doc

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    6. Peter, can you describe the effect from Agmatine. Are there any signs of irritability and aggression from it like you described in your blog?

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    7. One more thing about Agmatine. Excess agmatine release is important in the development of schizophrenia. Rats, when injected with high amounts of agmatine, model schizophrenia: https://www.ncbi.nlm.nih.gov/pubmed/23664672

      Are you concerned about the link between excess of Agmatine and Schizophrenia?

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    8. In my son the effect of Agmatine is very clear, it makes him more energetic. It is like replacing old worn out batteries with new alkaline ones. There are no signs of irritability/aggression. Agamatine is naturally occurring in the body. I have no doubt you can have too much and that not everyone will respond well.

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  8. Just curious Peter,have you ever heard of Potocki-Shaffer Syndrome?
    https://rarediseases.info.nih.gov/diseases/9762/potocki-shaffer-syndrome
    http://www.potockishaffersyndrome.org
    This is a syndrome everybody interested in genetic causes of syndromic autism should know about,even if it is extremely rare.The "our discoveries" page at the second link,has lots more features.I fit what you might call a milder version of this syndrome,with what were learning disabilities,in the US sense of the word,before my folate problems were found,but not classic intellectual disability.I have translocation,without deletion,of all copies of chromosome 11,in addition to the MRE11a mutations.I wonder if I have mutations of the usually deleted genes in PSS,or maybe a microdeletion.The disease is so rare,only about 20 known cases in the world,I don't know if it would be tested for on a WES.I hope to see the doctor at Baylor that discovered the disease.

    I found a few very pages about my gene.This one might interest you.
    https://decipher.sanger.ac.uk/search?q=MRE11#consented-patients/results

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    Replies
    1. Roger, I have not come across that syndrome.

      There are a lot of variants of your gene, each with very specific effects. It is remarkably well documented.

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  9. Hi Peter, my son continues developing allergy,red spots on his body,he is taking quercetin and luteolin, but I would like to add something else.Among the options I can get are: desloratadine, levocetrizine and verapamil, sodium cromolyn but ophtalmic drops.
    Valentina

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  10. I will start with verapamil,due to my son´s profile, 20 mg a day is ok? thankyou Peter.
    Valentina

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    Replies
    1. Valentina, see if it helps. It has a short half life.

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  11. Incidentally, while trying to explain “rapid cycling migraine + PANS flares” in my son and also his recent striking speech increase on memantine, I found an interesting case report on autoimmune encephalitis in Turner Syndrome misdiagnosed as psychiatric disorder:

    “Anti-AMPA-Receptor Encephalitis Presenting as a Rapid-Cycling Bipolar Disorder in a Young Woman with Turner Syndrome”

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4606164/

    “TS is associated (...) with an increased risk of developing a wide repertoire of autoimmune disease.” - this sounds familiar with regard to autism as well.

    The woman described in the paper was doing well until the age of 14 and then developed mood instability and deteriorated cognitively.
    “In the case report we presented, about 8 years have been spent to have the proper diagnosis from the onset of symptoms. This is because these patients are often erroneously diagnosed with refractory primary psychotic disorders, as has happened to our patient, delaying initiation of effective immune therapy or more specific therapy. In fact, the improper use of neuroleptics, antidepressants, and benzodiazepines has helped to worsen the course of the disorder of our patient. In addition, these patients have a particular sensitivity to the neurological side effects of these drugs”.

    Now I wonder if some of those children affected by “second tap”, who “fell over a cliff” in adolescence and other with late regressions can have in fact a well-defined autoimmune encephalitis?

    Memantine was found helpful for that woman. During a very short trial of memantine my son’s speech - all its aspects - improved like never in last few years. If it was due to memantine, it was right from the first dose. Is this something to be expected on memantine? Anyway it all ended up with total insomnia within days, so the trial is over now.

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    Replies
    1. Agnieszka,

      Im currently on Memantine, and I have been experiencing positives right from the very first dose indeed.

      Have been on 5mg for about 2.5 - 3 weeks and literally came back from my psych. today and upping the dose to 10mg.

      Atleast for the high functioning group of ASD memantine looks positive:

      A Prospective Open-Label Trial of Memantine Hydrochloride for the Treatment of Social Deficits in Intellectually Capable Adults With Autism Spectrum Disorder.
      https://www.ncbi.nlm.nih.gov/pubmed/27043118

      Like many believe this is from the NMDA antagonism I do not fully agree, I suspect the sigma-1 receptor plays a HUGE role in its effect as it controls the endoplasmic reticulum and IP3/calcium release.

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  12. Agnieska, this is very interesting. But too bad about the insomnia. Curious if you have ever tried lithium?

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    Replies
    1. Hi Tanya,

      I have never used lithium. Have you tried? Do you think it could be helpful for flares with severe headache/PANS symptoms and mast cell degranulation?

      My son is prone to insomnia, the list of treatments that made him totally stop sleeping is: sulphoraphane/broccoli sprouts, prednisone, MitoQ. In case of memantine at least I can guess why: it's dopamine receptor agonist as well.

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    2. Carefull with lithium it is not something to play around with btw.

      On top of that one of the main reasons it is being used in bipolar is because it slows down IP3/calcium from the endoplasmic reticulum, basically the opposite of what memantine does...

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    3. Yes Agnieszka we are trying it now, under doctor supervision. very Low dose. It is helping! There are many benefits of lithium apparently. I do think I remember reading it can help with cluster headaches..Not sure about mast cell. Interesting thing lately with my son - he hasn't had any allergy/mast cell reactions. I read lithium can lower IL6, but also read some reports it can raise it. nevertheless in our case, his allergies have improved. My son was prone to insomnia too - which I always felt was top priority to get sorted. Does chronic insomnia for those on the spectrum as children mean that once they reach the vulnerable stage of adolescence, there is a risk for mood disorder?
      yes aspie I do agree, however, using anything without a proper diagnosis is not something to play around with. Yes, prescription lithium must be monitored by doctor of course, but probably fine with lithium orotate forms?

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    4. Thanks Tanya and Aspie for sharing and I am glad to hear about your recent positive experiences.

      In my son sleep got back almost to baseline without memantine, the same about speech.

      His episodes of insomnia in the past were drug related and explainable (with the exception of MitoQ, which I can't explain) and I think there is no clear relation with future mood disorder.

      Interesting about IP3 and calcium regulation by memantine. It might well be the pleiotropic effect that makes it so beneficial for some people and just opposite for others.

      Good luck to both of you with your treatments.

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    5. For bipolar disorder they are prescribed up to 1800 mg per day. But for autism many parents give only 500 mcg per day. So no fear of lithium toxicity. Haven’t tried it yet.

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    6. Agnieszka what is your experience with mitoq?

      From what I have read and heard its a more powerfull version of coq10/ubiquinol (which I have had good success with).

      I seem to respond very well to medicines and supplements that lower lactate/urea.

      GPLC, PQQ (this one improved my sleep and there are studies showing it helps a better circadian rythm), COQ10, Ubiquinol and cordyceps, they all helped me tons.

      The thing what I have noticed with too high doses of coq10/ubiquinol is that it seemed to make my emotions more flat so to say.

      I have been thinking of buying these supplements again, currently and taking a small dose of each to get some synergistic effect instead of taking a high dose of just one supplement.

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    7. Aspie, in my son MitoQ improved motor skills and speech. Motor skills improvement was prominent. My son has dyspraxia and this was surprisingly good effect. He is on CoQ10 daily and the effect is not comparable. He is not able to discuss emotional effect of treatments in details, but both MitoQ and Mitospectra (containing CoQ10) use is associated with good mood in him.

      Within a week on MitoQ he developed insomnia in two trials.

      Can you share what is the effect on CoQ10 for you? Can you see the real difference between ubiquinone and ubiqinol? Is there any brand that your can recommend?

      I've learned about GPLC from your comment, did not know about it before. Did you try just l-carinitine or acetyl-l-carnitine also?

      Have you seen Peter's post on MitoQ?
      https://epiphanyasd.blogspot.com/2015/06/mitoe-mitoq-and-melatonin-as-possible.html

      Happy New Year to you and everyone here!

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    8. Hi Agnieszka,

      My experience with coq10 is having more energy and a more positive mood in general (200-300mg/day), I also seem to be able to get more done in a day.

      I have ubiquinol also in my home but I believe it made me fatigued last time i tried it (I know it sounds very odd, but it made me yawn like crazy), i'll try replace my coq10 with ubiquinol soon again once more and try it in the evening at 100mg/day at first and if i dont notice side effects ill see what it does to me.

      Currently Im still on memantine (about 3-4 weeks in now), having lowered the dose from 10mg back to 5mg, 10mg seemed to be too much for me and it felt like a stim.
      Memantine gives me a superior mood stabilizing effect, however I feel as if something is lacking so to speak.

      I have tried L-carnitine, ALCAR, l-carnitine-l-tartrate and GPLC and hands down GPLC is the best for me personally.


      * l-carnitine: helps alot with energy, but it seems to aggrevate my cold hands (no surprise as carntine can raise TSH and lower thyroid hormones! so be aware if your son has hypothyroidisim/subclinical hypothyroidism, which is common in autism btw)

      * ALCAR: felt very dirty to me, it made me very irritable and anxious, had a very hard time looking people into the eyes, the most gaze aversion I have ever had was on ALCAR out of every supplement I have ever taken.

      * l-carnitine-l-tartrate: just gave me headaches as far as I can remember, discontinued after 3-4 days

      * GPLC: this one is a winner for me, studies have shown it lowers lactate, improves mito function, increase NOx levels, however this one is also the most expensive, I take glycocarn, has a very positive emotional effect on me, as in that it makes me want to be around others, very few supplements do this for me. For example even memantine does not do this to me, memantine clearly helps with stress processing and by doing that the brains 'work load' is lowered allowing for normal communication, but it does not improve wanting to be around others.

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    9. I forgot to add, it is critical to take GPLC on an empty stomach, and wait about 45-60mins before eating, this way the effect is very pronounced for me. I have been doing 1500-3000mg

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    10. Aspie, thanks for your comments. I appreciate them very much.

      Let us know how your new trials are going on. I am restarting memantine to see if the effect is replicable.

      I thought you would expect the same effect from ubiquinol that comes from ubiquinone, just with improved bioavailability. Maybe it's not that simple again.

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    11. Peter, while exploring further CoQ10/MitoQ topic, I stumbled upon a longevity blog with comments on MitoQ by Vladimir Skulachev:

      https://joshmitteldorf.scienceblog.com/2014/01/14/mitoq-targeted-coq10/#comment-9834

      "MitoQ can be reduced to MitoQH2 by the initial respiratory chain complexes I and II but MitoQH2 is very slowly oxidized by the next respiratory chain complex III. Moreover, MitoQ cannot be decomposed in a way resulting in CoQ release. This is why MitoQ can hardly help when CoQ level is lowered by aging or statin. As to another function of CoQ as an antioxidant, MitoQ is not the best one since the window between anti- and prooxidant concentrations of MitoQ is as small as several times."

      I considered retrialling MitoQ, now I am confused by this comment. Based on what is known on MitoQ would you say one can use it instead of CoQ10 to improve mitochondrial function and to prevent statin toxicity?

      Delete
    12. Agnieszka, I think we can only apply common sense. MitoQ being electrically charged appears interesting for those with oxidative stress and mitochondrial dysfunction. The OTC dosage is much lower than that used in some clinical trials, which is the only drawback.

      Statin induced myopathy and other side effects looks like they can be caused by the reduction in CoQ10, although studies are far from conclusive. So I would just add back what we know has been lost, ie CoQ10, which is cheap.

      It does indeed look plausible that MitoQ might help with statin side effects. The Russian you quoted says not. On the MitoQ website they suggest that it should work better than regular coQ10 for statin side effects.

      Personally I would use a higher dose of CoQ10 and see if statin side effects disappear. If not try MitoQ.

      Delete
  13. The end of the year is typically a slow time for new papers, but I just came across one that is very interesting that deals with selenium and a postnatal switch from the utilization of sulphur to selenium by an enzyme called GPX4, which if disrupted causes a big die-off of parvalbumin interneurons, a type of neuron at the top of the list of neurological issues and autism, and which is also critically important in processing sensory information.

    Press Release:

    https://www.sciencedaily.com/releases/2017/12/171229095132.htm

    Paper:

    http://www.cell.com/cell/fulltext/S0092-8674(17)31438-1

    Now, I have no idea if low levels of selenium or dysfunction in this enzyme is a cause of any or some autisms, but loss of parvalbumin interneurons will increase the risk of seizures for sure (this was noted in the paper). Without functional GPX4 enzymes utilizing selenium as opposed to cysteine, parvalbumin interneurons are especially vulnerable to peroxide based oxidative stress and rapidly die-off. In another big paper this year utilizing mice, it was shown that maternal inflammation can drive cortical patches of interneuron loss, especially in an area of the somatosensory cortex called S1DZ in the mouse (in humans I think this area is a very small zone between the face and leg area of the primary somatosensory cortex).

    While I don't believe low-selenium levels or their utilization thereof is the cause of autism, perhaps maintaining appropriate levels after birth could mitigate some of this interneuronal loss that may be happening postnatally and offers a realistic way of intervening in the earliest days of life. Perhaps, even for adolescents with autism, selenium deficiency or problems utilizing it for its antioxidant properties may be something to look at here as a practical intervention as well.

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