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Monday, 21 November 2016

Agenesis of the Corpus Callosum


Today’s post is about another supposedly rare cause of autism called Agenesis of the Corpus Callosum (ACC).

As regular readers of this blog will have noted, extremely rare causes of autism, taken as a group are not so rare after all.  In fact it seems that autism is just a very large collection of somewhat rare biological conditions. 
Of the very few "Autism Dads" I have had a face to face conversation with, one has a child with ACC and another has a son with the even rarer Sotos syndrome. Sotos syndrome is characterized by gigantism, mild ID/MR and often autism. Mutations in the NSD1 gene cause Sotos syndrome

ACC is physical malformation of the brain that shows up clearly on MRI scans and potentially shows up on the mother’s regular ultrasound scans. 

The corpus callosum is a wide, flat bundle of fibers about 10 cm long that connects the left and right sides of the brain.  It facilitates communication between the two sides of the brain.
Agenesis of the corpus callosum (ACC) is a birth defect in which there is a complete or partial absence of the corpus callosum.

ACC leads to behaviors compatible with a diagnosis of autism or Asperger’s in about half of cases.

Symptoms of ACC  vary greatly among individuals, as they do in all types of autism.  Seizures are common, some people have poor motor coordination, and some people are non-verbal.

It is suggested by many that a diagnosis of ACC is not compatible with a diagnosis of autism; this just shows a lack of understanding.
Autism is just a description of behaviors, ACC is a biological diagnosis, like Fragile X syndrome or Down Syndrome.  So if a person has autistic behaviors caused by ACC, it is still autism, it is just autism with an explanation of its origin.

The most famous person with ACC was Kim Peek who was the inspiration for the character played by Dustin Hoffman in the well-known film Rain Man.

In addition to having the physical ACC malformation it has been suggested that the cause of ACC in his case was likely FG Syndrome.

Most mutations that cause FG syndrome can be found in the MED12 gene. However, mutations have also been found in FMR1, FLNA, UPF3B, CASK, MECP2, and ATRX genes. Mutations on these different genes lead to the different types of FG syndrome, all with similar characteristics.  Congenital heart defects are common and Peek died of a heart attack aged 58, outlived by his father.  


Agenesis of the Corpus Callosum and broader Autism

Undoubtedly there are people diagnosed with autism, who have undiagnosed ACC, since they never had an MRI scan.  Just like there are many people with autism who have an undiagnosed, but treatable, Chiari “brain hernia”.

It also appears that having a smaller corpus callosum, but falling short of what would be diagnosed as ACC by the MRI scan, is a feature of some people’s autism. You could consider it as partial ACC, like we had partial biotin/biotinidase deficiency.

A very recent paper from the 2016 Society for Neuroscience annual meeting suggested one reason why autism is more prevalent in males.  The study looked at infecting pregnant rats with group B streptococcus to activate the mothers immune system.  Inflammation was then triggered in the fetal side of the placenta, but only in male fetuses.
The males go on to develop brain and behavioral features reminiscent of autism.
Female fetuses were somehow protected and developed normally.  Hopefully Barons Cohen will read this and stop looking for undiagnosed females with autism. There are many good reasons why autism is less prevalent in females, and they are not just “better at hiding it”, as the so-called expert claims. 



What is interesting is that in the male pups with “autism” they had an unusually thin corpus callosum. It turns out that such minor malformations occur in broader human autism. 



The largest of the white matter tracts is known as the corpus callosum, which allows communication between the two hemispheres (halves) of the brain.
"The size of the corpus callosum was smaller in the group with autism, suggesting that inter-regional brain cabling is disrupted in autism," Dr. Just said.

In essence, the extent to which the two key brain areas (prefrontal and parietal) of the autistic participants worked in synchrony was correlated with the size of the corpus callosum. The smaller the corpus callosum, the less likely the two areas were to function in synchrony. In the normal participants, however, the size of the corpus callosum did not appear to be correlated with the ability of the two areas to work in synchrony.

"This finding provides strong evidence that autism is a disorder involving the biological connections and the coordination of processing between brain areas," Dr. Just said.




CONCLUSIONS:

These longitudinal results suggest atypical early childhood development of the corpus callosum microstructure in autism that transitions into sustained group differences in adolescence and adulthood. This pattern of results provides longitudinal evidence consistent with a growing number of published studies and hypotheses regarding abnormal brain connectivity across the life span in autism.




The study suggests that white matter abnormalities manifest early in autism, says Thomas Frazier, director of Center for Autism at the Cleveland Clinic in Ohio. “It also serves as a nice demonstration that brain abnormalities in autism will become clearest and most helpful for pointing to etiology when we look at them developmentally, longitudinally, rather than at a single age," he says.



The findings do not imply that corpus callosum abnormalities cause autism, cautions Ralph-Axel Müller, professor of psychology at San Diego State University, who was not involved with the work. Rather, any irregularities in the corpus callosum may stem from other abnormalities in the brain that have been associated with autism, Müller says.



Still, changes in the corpus callosum may help to explain why autism symptoms worsen in some individuals and improve in others, Travers says. "Is there some aspect of white matter micro-structure occurring early in the developmental pathology that locks in persistent autism across the lifespan? What are the mechanisms? Can they be unlocked?” she says. “These will be important questions for future research.”



  

Conclusion

It is estimated that at one in 4,000 individuals has a disorder of the corpus callosum. I suspect it is more, but you would need to routinely give MRI scans to people diagnosed with autism to find out.

It is clear that milder disorders of the corpus callosum may be a feature of many people’s autism and those changes over time in the corpus callosum may help to explain why autism symptoms worsen in some individuals and improve in others.






39 comments:

  1. Putting aside the shameful and clueless neurodiversity movement,who have hijacked autism,in the name of identity politics,more and more people believe what we diagnose as autism,is only a feature of any number of congenital disorders.Congenital only means present at birth.It could mean gene mutations,or it could mean prenatal exposures,and epigenetic changes.

    I am a big advocate of whole exome and whole genome sequencing for autism.It is one of the easiest ways to tease out which cases are due to rare genetic disorders,which as you say,may make up a significant number of all cases of autism when all grouped together.I have been found to have mutations for one such disorder,but my mutations can be expressed as a few different disorders.It's been a year since my WES,but I think I finally found a doctor willing and able to figure it all out.This means everything else,my FRAs,my folate metabolism stuff is most likely all secondary.

    Before my CFD was treated,I had motor problems just as severe as those described in the Wikipedia entry on Mr.Peek.

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  2. Not on the topic of this post, but I was thinking about the whole "chelation" movement with ALA in particular. Could it be that an intensive period of anti-oxidants could actually result in benefits for a good subset of children with ASD? Not for the reasons that chelators think (mercury toxicity etc), but just like possible with some usage of nystatin for another reason entirely.

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    1. Exactly my thoughts Em, even better are intraveneous antioxidants, they work wonders for problems associated with oxidative stress. Monty's grandfather has IV ALA at the local hospital every few months to avoid diabetic neuropathy, this neuropathy is caused by oxidative stress. It would also benefit Monty, but hard to convince the hospital.

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    2. Peter, would injections do the job as well? If so, this might be a wonderful solution for my daughter. I have both NAC and ALA but haven't used them because of chronic diarrhea. A couple of times a year my parents take a combination shot made up of b12 and a few other b vitamins combined with ALA. I think its a series of 6 shots. They take it because it makes them feel better and my mother is convinced its the reason for them not developing diabetes.

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    3. This is an interesting idea but I am skeptical because unlike an infection where inflammation is upregulated until the infection is cleared, dealing with oxidating stress acutely is really just a bandage that comes off once you stop using antioxidants. On top of that, there is evidence that exogenous antioxidants cause systemic decreases in endogenous antioxidants.

      Nevertheless, a very interesting study I read this week on heart muscle regeneration showed that in mice they could regenerate heart tissue in adult mice (when heart stem cells no longer produce new heart tissue after injury) by lowering the oxygen levels in the air from 21% to 7% over several weeks. Then after several weeks of 7% oxygen exposure, the heart tissue increased in weight which was evidence of heart tissue regeneration.

      The mechanism of action was thought to be that because the heart cells were in a hypoxic state (just like when the baby is in the mother's womb), the heart stem cells are not being exposed to as much oxidative stress from aerobic metabolism.

      How does this relate to autism? Well perhaps reducing oxidative stress to artificially low levels in various tissues does all sorts of interesting regenerative things which only seem to happen in the very young or in animals which have regenerative capabilities.

      I am not saying anyone should go out and give a massive infusion of antioxidants to their child as plenty of autism parents have already done this already with no scientific evidence to back this type of intervention, but this is an interesting idea for research in animal models.

      I mean, who would of thought super mega doses of folinic acid would do anything but bad stuff (certainly not me), but apparently this therapy shows great promise in a subset of those with ASD and appears at this time to be completely safe.

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    4. The ALA infusion is used as a medical therapy in countries using either German-based or Russian-based medicine. It has been used for many years and is combined with oral ALA tablets. The infusion is clearly more potent, but it takes 20 minutes off your day. It is given in cycles, for example 10 days of infusion and then repeat in a few months. It is a mainstream therapy given free in public hospitals, not some private clinic.

      In the US/UK it is not used. In fact the standard therapy for diabetic complications is amputation.

      I doubt the infusion can really be replaced by an injection. But quite possibly the injection is better than a tablet.

      There was a US study confirming the benefit of the infusions, I looked this up several years ago when asked to buy ampules of ALA for my father in law.

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  3. Some new research has found that there are neural stem cells capable of differentiating and localizing into functional neurons in the meninges.

    http://www.sciencedirect.com/science/article/pii/S1934590916303952

    In neurodegenerative disorders (of which many cases of autism likely fall into that category), it has been thought that once brain cells die in the cortex, functionality may be lost forever whereas in a select few subcortical structures such as the hippocampus, new neural stem cells migrating from the dentate gyrus are constantly being added (as others are naturally lost) over the lifetime of the person.

    This I feel is big news for autism as using this natural process of regenerating damaged cortical tissue (from chronic oxidative stress perhaps) and amplifying it with drugs or other therapies could potentially recover lost functions as a result of developmental insults whether they were in utero or post-natal.

    There is also some other big research I read in the last week (don't have the paper's link handy at the moment) that showed that DNA damaged mitochondria is taken out to the trash (so to speak) via mitophagy. Mitophagy is a process where damaged mitochondrial proteins or even mitochondria themselves are encapsulated in an autophagosome and have their parts broken down for reuse or for energy. However, this will do no good if the mitochondrial DNA is bad because the mitochondria will just keep making bad mitochondria and take up space in the cell that could be used by properly functioning mitochondria. This research should give a lot of hope to people and their families who have evidence of mitochondrial disorders as it appears that mitophagy boosting drugs or other therapies could potentially rectify these problems throughout the body, leaving only the least mutated mitochondria with the most functional DNA to replicate and thereby treating many mitochondrial disorders.

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    1. I also think that upregulating autophagy and mitophagy is a good idea in autism and any other cognitive disorder. Verapamil seems the most practical way to do this, until we get new drugs being developed for dementia that may be better.

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    2. Please forgive me, but I have read pretty much everything on your blog on Verapamil and don't recall anything about mitophagy. Could you elaborate or provide a link to a post where you discuss this?

      The best natural way I know of inducing autophagy and mitophagy is of course fasting which is a problematic intervention in children until more research is done which can show a benefit/harm curve (doubt this will ever happen because the idea of fasting children in a study has a low likelihood of being funded for social reasons). Other than that there are the nrf2 pathway and mTOR inhibiting routes which are being studied extensively with respect to autism, but I think the point of this study's "discussion" was that researchers should seek out boosting mitophagy beyond natural methods so as to clean out the junk as fast as possible.

      Is Verapamil a "strong" mitophagy inducer?

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    3. Tyler, I did not publish my autophagy post yet, it is still a work in process. I mentioned autophagy and verapamil in in several comments.

      This table will be interesting for you:-

      http://www.nature.com/cdd/journal/v16/n1/fig_tab/cdd2008110t1.html#figure-title

      Here is what Stanford has to say about Verapamil and autophagy:-

      http://web.stanford.edu/group/hopes/cgi-bin/hopes_test/verapamil/

      Some readers report long term benefit from Verapamil and this might might be associated with increased autophagy. Who can say for sure.

      The good thing is that verapamil is safe, cheap, well tolerated and in some people with autism produces near instant benefits (cessation of aggression and SIB).

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  4. I found several papers connecting epilepsy and body dysmorphic disorder, things seem relevant in our case.
    Some of them also connect chronic sinusitis as part of brain inflammation.

    The Pathophysiology of Body Dysmorphic Disorder
    https://www.ncbi.nlm.nih.gov/pmc/.../PMC3836287/ - Μετάφραση αυτής της σελίδας
    από JD Feusner - ‎2008 -
    Peter, do you know any interventions addressing chronic sinusitis? I need to check if this is relevant.
    I remember back in those days of my childhood, almost every child in Greece was diagnosed with sinusitis and treated aggressively with some kind of huge antibiotic injections, I can still feel the pain of.
    I 'll find an old doctor who knows how to practise this to get details.

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    1. Quercetin helps some people with chronic sinusitis among its other effects. It works very quickly, if it works.

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    2. Petra, chronic sinusitis can be a consequence of GERD - I don't mean the classic 'heartburn' type but also the 'silent reflux' type which can go undiagnosed for years, for precisely this reason.

      Many of the possible symptoms, such as sinusitis, can seem completely unrelated.

      I have been looking into this recently, the possibility that it is involved in many common 'autism' symptoms and recurring problems (repeated ear infections for one! not to mention sleep disturbances etc) is quite large. Definitely worth ruling out. The easiest way would be I guess to try some baking soda, h2 blockers etc and see if they make any difference on bad sinus days.

      There is some evidence that Quercetin is one of the things that can help with GERD.

      Bacterial infections can cause reflux, silent or not, possibly explaining why abx would have helped.

      Here is a good review, including treatments. It doesn't talk about 'silent reflux' but you can find that info separately. http://www.altmedrev.com/publications/16/2/116.pdf

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  5. I used a mixture of antioxidants containing quercetin 125mg with ALA, resveratrol, turmeric and green tea extracts in the past but didn't see much improvement. I am thinking of Sytrinol for a start and then ibuprofen and some corticosteroid nasal spray, Nazonex for instance.
    Then maybe amoxicillin. I know it's too much for liver but at the same time inflammation makes him feel worse.

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    1. I used the cheap 500mg quercetin gelatin capsules and it very quickly resolved sinusitis in my wife's case. I would try that before giving up on occasional use of quercetin. Long term use can have side effects.

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  6. Ok, I'll see if I can get 500mg capsules before rejecting it.
    I think supplementation with potassium gluconate helps in an unknown way.
    Thank you very much.

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    1. Petra, see my long reply above about ruling out silent reflux in sinusitis.

      Potassium-rich foods are touted as being good for chronic gerd. Not sure if that would translate to potassium gluconate supplements... http://www.naturalnews.com/034947_acid_reflux_GERD_foods.html

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  7. Nat, I am most grateful for your help.
    I'll make every possible intervention to see if silent GERD hypothesis stands in our case.
    This might also explain his eating/sleeping disorder and his responsiveness to Gastrus and melatonin.
    There is a simple explanation why potassium supplements would help him in case of GERD. I use a liquid form of potassium disolved in a glass of water, which makes an alkaline drink hepling with acidity.

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    1. Petra, was that you who reported good effects of fasting in your son? Could that be related to this, ie fasting simply reducing GERD?

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    2. Nat, as soon as you told me about GERD and I was looking for interventions, my son declared 24h fasting again.
      I googled fasting and GERD and found out it helps, so I would have had the chance to observe. During fasting rhinitis symptoms almost disappeared and his mood improved, he was quite weak, though.
      I also goggled Gerd and baclofen, to which was a responder, and saw that it strengthens muscle relaxation.
      Some people use calcium channel blockers for Gerd, you can have a look at the mechanism.
      The following morning I substituted the big fresh orange juice with herbal tea with a little honey and lemon. I was very careful with dinner and also raised the head part of the bed 15cm. I think we have had a considerable improvement.
      I added back the melatonin, which was left aside for a while, and supplemented vitamin e 200IU and liquid potassium. For some reason(s) he doesn't seem to react badly on the third day of vitamin e anymore.
      I am also ready to go back to Baclofen. I remember a paper, I had found then, about Baclofen and its GI efficacy.
      Just hope this works.

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    3. Nat, I think you are really on to something here. I have noticed that my daughter's appetite and interest in foods improved after adding the potassium citrate. I assumed that it was because the potassium addressed some sensory issues, but your theory seems more plausible. The mirtazapine took this to a much higher level by widening her interest in foods and flavors. The other day she ate a vietnamese beef dish cooked with mushrooms and onions, along with a big salad of mixed greens and a side of green beans. This was the first time she's voluntarily eaten a salad with a vinaigrette dressing. The best part is also that she is eating around the plate rather than in sequence where she used to finish one dish off before starting on another.

      I have never known if she has GERD or not, and am happy that I have something that could be prophylactic as well. Many thanks.

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    4. Petra, it is very interesting about your son fasting as soon as you read or wrote about it. The same thing happened to us when in 2015 my daughter took up Intermittent Fasting (IF) in 2015. This is where there is a gap of 18 hours between the last meal of the day and the first meal of the following day. There is a range from 14 to 18 hours that is considered acceptable. My daughter did the 18 hours. She kept it up for over a year and lost 75lbs. This was in spite of being both hypothyroid and having PCOS. She had no weakness or loss of energy. Her insulin levels seemed more stable, with no visible signs of hypoglycemia. IF is talked about as being as effective as whole day fasting.

      She gave it up on her own, when she decided to eat a late night supper of eggs every day.

      I have personally tried IF. It worked well when I was eating low carb, high fat. I felt great on it, my labs were excellent, better than they had been in ages. I recently tried IF again, this time around eating a regular diet, not low carb, and from about 14 hours it made me weak. So, I gave it up after a week. It was great for my GERD, which went away during the week and reappeared in a milder way a week after stopping.


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    5. RG have a look at this on mitrazipine and GERD:

      http://www.healingwell.com/community/default.aspx?f=45&m=1401961

      (interesting term 'visceral hypersensitivity')

      Also this report: http://patient.info/forums/discuss/remeron-withdrawal-hell--34786

      Not to say that things are that simple and straightforward, as there are opposite types of reports - of people developing GERD after being on mirtazipine for a while.

      We need to go back and re-read that paper on the treatment trial of mirtazipine for autism with this in mind!



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    6. RG, I also think Nat is really onto something here as our following a loose gerd protocol has been proved promising so far.

      For a start, after fasting, and I can't possibly know how much of a coincidence this would have been, rhinitis subsided.
      In addition, a little while after his last dinner, he said "I have got a pain here" pointing at exactly the spot that gets stressed during gerd. What seemed remarkable was that no tremors, confusion, extreme fear accompanied the pain.

      Peter connects gerd with mGlu5 and says there may be available solutions. I think we should investigate further; how far this could go in one's case?
      Is fasting a quick solution for excessive glutamate? Probably yes-I am not sure if I have got it right here, we are talking about excessive glutamate, aren't we?

      I added Baclofen for LES in specific, not generally for anxiety, and this state of mind might help me to evaluate it.
      Do you have any experience with Baclofen?

      Potassium seems to affect things and trialling different doses and times, before/after meal. I quitted the orange juice and lost almost 750 of dietary potassium which I have to add back and on top of that he was found marginally low.
      How much/how do you administer potassium?

      You said that your daughter is vitamin D marginally low. We are also low, what supplements/foods do you have for this issue?
      How is your daughter's prolactin and uric acid levels?
      For us prolactin now seems ok and uric acid from years stable to 0,8 above normal means dropped to 0,4.

      RG, I apologize for asking you so many things all together, and really would like to thank you for your insightful comments.

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    7. Nat, that's a word, visceral hypersensitivity.

      Its very interesting about mirtazapine and GERD. The withdrawal reports are a bit scary, I hope we never have to face them. It kept me off trying it for quite a while, including the epilepsy connection.

      Its so frustrating that there isn't a benchmark of labs that are used in autism trials, a loss of so much good information and understanding.

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    8. Hi Petra,

      Any relief our children can get is wonderful. Today, my daughter's exercise therapist wanted to work her hard and asked me if she would tell me if she was in pain tomorrow. I said that I am not sure she is ever pain free, so what would be new to report? If suddenly she had no pain at all, then I'm sure she will have something to say!

      My daughter is not HFA or Asperger's, so I haven't tried Baclofen.

      I am going to wax eloquent here, potassium is our little miracle, spreading sunshine and joy...Kritika, this is also for you, I may be capable of some PEE after all. Our standard dose is 400mg once a day with 400mg magnesium taurate. Recently, I have been trying an additional 400mg with Bumetanide and 100mg of magnesium taurate. It has only been a couple of days with the additional dose, but it might be making the mirtazapine more effective for sleep. It also seems to make her calm and deliberate. I will update as I observe more. I remember Peter mentioning in one of his Potassium posts that the supplements are more effective than what is taken in through food.

      I don't do anything for the vitamin D because her serum ferritin is very high and I read that vitamin d can increase it further by its action on hepcidin. It seems to be recommended for anemia. A couple of times when I tried to supplement she reacted negatively, once with a seizure. I am not sure if it was a coincidence or not, I didn't test it long enough. What was very good was Vitamin A per Maja, I saw some very nice things the first day itself. Unfortunately, I made the mistake of adding in the vitamin D on the third day as I was worried about running the D even lower with the addition of the A. With the seizure I stopped both. I really need to try the Vitamin A again.

      Uric acid continues to be high. Prolactin is high, I think because of the verapamil, but the endocrinologist says its ok.

      Please don't apologize Petra, I am so glad for this blog and everybody here, where we are able to learn and share and help our children.

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    9. Hi RG,

      Visceral hypersensitivity..I did not know this word but kind of sums up what I am sure my son and probably most autistics are lashed with, day in and day out. Your daughter probable subjection to chronic pain .. just to think about is hard.


      And it might not really be painful which the word actually means but just a strong can't be missed kind of sensation. I suspect that a lot of autistic kids might be registering changes in internal body mileu like blood pressure or routine digestive processes and responding behaviourally. I just had a nightmarish thought about what if for my son even the sensation of the heart beating becomes so amplified that it becomes a diversion. Thank God, it was just a passing thought.

      RG, between half an hour to one hour after being given the diuretic, my son would start displaying this hypersensitivity. Real odd behaviour, peripheral vision and internal focus..the kind he displays when just about to go potty. And this went on the entire day. Now whether it was sensitivity to the physical component of diuresis or something more sinister like falling blood pressure or electrolyte imbalance, I cannot say.

      RG, could you please suggest if mg citrate could work reasonably well as a source of magnesium and I might add taurine separately. The reason you avoid the citrate form and I prefer it happens to be same. I like the mild laxative effect of citrate might have as in my son, a slightly looser stool equals to 'full evacuaton, mission accomplished'. The same holds true for me so I know, although I am aware most would love to have the well formed kinds my son has sometimes which makes me go 'time for another orange'.

      I did trial magnesium earlier as a mineral combination as well as Epsom salt baths with no effect whatsoever but willing to go for another attempt. If magnesium hepls tolerate potassium better, I could once again repeat a diuretic regime. Again, the stool loosening properties of mg citrate might help as my son stools hardened up a little when on burinex, probably indicative of potassium deficiency as water intake was more than adequate.

      Please suggest. Citrate or the chelated version?

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    10. Hi RG,
      I am so sorry that your daughter is in constant pain.

      There are many papers claiming that vitamin e protects against iron overload and also oregano is considered to inhibit iron absorption. You could check to see if they are relevant and safe for your daughter's high serum ferritin.
      My son seems the type with high ferritin, too, but he sometimes, maybe due to low vitamin d, his complexion is so white that one could believe he has some kind of anemia.

      Perhaps magnesium taurate is a better form, I just used the free form taurine and as I read it can cause nitrogen imbalance to some people.

      Yes, this blog is an excellent means of knowing things better and finding effective solutions to help our children.

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    11. The interesting thing is that my daughter's vitamin E on labs is always high even though she is not being supplemented. I wonder if its her body's reaction, keeping vitamin D low and E high.

      Thanks for the information about oregano, I'll read up on it. Thankfully, she likes it and we use it quite regularly.

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    12. Hi Kritika,

      When I cued you in on the comment, it was my attempt at a feeble joke regarding PEE. I did not mean to advise you on magnesium or taurine. I am actually rather weak on the science, I am an economist by training, and everything I write is merely our experience and should be read like a case report. For analysis and advise, the best people are Peter, Agnieszka, Maja, Alli, Nat, Tyler et al.

      With regards to the magnesium citrate, I like it quite a bit, and would have continued to use it but for its laxative properties. If anything, it seems even more effective than the magnesium taurate.

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    13. RG,

      I got your joke but thought since you are discussing magnesium and taurine I might as well grab this opportunity to ask for your view..see I have a pretty good memory probably because my brain is still not fully occupied with the knowledge most of you seem to be brimming with. So I remember what most of you mention in your passing comments and you had mentioned that mg citrate was good for calming in your daughter but for the laxative effect.

      So the economist in you is avoiding a 'moral hazard', the one based in information Asymmetry by pushing me away. My attempt at a feeble joke!

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  8. Hi RG, thanks for your reply. It's always interesting to read your comments.
    My nephew, from my first cousin, is not diagnosed on the spectrum but epilepsy overlaps with Asperger's.
    His mother (my first cousin) was diagnosed with celiac and Hashimoto disease and his uncle, also my first cousin, was diagnosed with Asperger's later in life. Both conditions could indicate predisposition to ASD.
    I see that your daughter, although she shows visible signs of epilepsy, isn't officially diagnosed with it. This is what I am trying to investigate seriously this time. My son is not supposed to have seizures according to a simple EEG and MRI and these are not enough to have a proper conclusion. A top neurologist, specializing in epilepsy told me that he should be kept in clinic at least two days for testing if we are to investigate this possibility. Then we might have a conclusion.
    In other words, I am saying that if all those autistic meltdowns ans shutdowns are not epilepsy then what are they? We need reasonable explanations.

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    1. Hi Petra,

      My daughter does have an official diagnosis of epilepsy because the first non febrile one was at the school playground and the paramedics were called in who then took her to the ER where they did a full work up.

      I was like you and used to wonder if the meltdowns, staring off into space etc were seizures. During the 5 day video EEG we found that they weren't. At the hospital stay they did a lot of things such as exposing to flickering lights, disco lights, hot temperatures, slight starvation, keeping her awake late into the night when admitting and then attaching all those electrodes, quite painful since they use a glue that has to stay on for the entire stay, past midnight.

      Even two days may not be enough as my daughter did not have any seizures over five days. There was one non epileptic 6 second spike that the neurologist classified as normal. There are very few neurologists who are able to interpret EEGs well, I know none of the ones at Stanford or UCSF can. I have a friend who suspected seizures in her son because of his behaviors and near psychotic outbursts and took him to Dr. Mike Smith in Chicago who was able to interpret the EEGs done by a Stanford neurologist much more accurately and treated him with steroids and Depakote and the boy had a clear EEG in six months.

      Its also a fact that a regular EEG may not catch subclinical seizures. There was a special one called Deep EEG used by Dr. Frank Duffy and Dr. Aditi Shankardas, but three years ago when I was trying to contact them it was impossible. Harvard and Massachusetts General said he was not working there anymore, but recently I see that he is publishing papers again. He seems to be among the best at reading EEGs. Here is one on using EEG to differentiate between Aspergers and HFA:

      http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-11-175

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  9. Thank you very much RG. This account helps me enormously in how to approach things related to epilepsy.

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  10. Peter,

    I wasn’t aware that baclofen is an effective treatment for reflux, and that GABAb receptors are involved in mechanisms of some types of reflux.

    Is it possible, I wonder, that:

    1. because of this GABAb dysfunction people with autism are more prone to reflux, and are suffering not only more ‘heartburn’ and pains but also symptoms and consequences of silent reflux. Silent as in not-involving-heartburn. I am not ignoring things like gut dysbiosis, SIBO, allergies and deficiencies in digestive enzymes, pancreatic juices etc as triggers of GERD, but rather adding GABAb dysfunction to this list. Btw rates of diagnosed GERD are known to be high in autism, and “in people with ID, the incidence of GERD may be as high as 48%” (this percentage comes up when someone bothers to carry out a systemic investigation!)

    2. that the effects of some of the supplements and medications for reducing symptoms and behaviours in autism are at least partially linked to them reducing GERD and its ‘silent’ consequences. Especially since these silent consequences - i.e. Not immediately associated with gerd and so possibly overlooked, can include things like ear infections, sinusitis (brain fog!), headaches/head pressure, ringing in ears, feeding difficulties or food refusal, self-harm/pain/aggression, hypersalivation… Not to mention that reducing reflux would have immediate positive effects on quality of sleep. Internet GERD patient help forums are full of people describing how reflux triggers their brain fog, difficulty concentrating etc. And this is not always linked to length or quality of sleep, the effects seem to be direct ('aspiration of gastric juices' springs to mind!!).


    Apart from PPI’s there is evidence that the following things successfully reduce GERD symptoms:

    — H2 blockers (remember famotidine trial for autism)

    — melatonin

    — low carb diet

    — quercertin, turmeric, ALA (antiinflammatories and antioxidant in general)

    — "… Baclofen offers an option to inhibit both acid and non-acid reflux, and thus an option for treatment of refractory GERD… it has not only been used traditionally as a muscle relaxant for many years, but has also been shown to reduce transient lower oesophageal sphincter relaxations (TLESRs) in both animals and in humans. Clinical studies of its short term or single dose use have demonstrated its effectiveness in reducing the number of TLESRs, and likewise reducing the number of reflux events.

    — gluten free diet, where either celiac or NCGS is the trigger of GERD (https://www.verywell.com/can-gluten-cause-acid-reflex-gerd-563107)


    I have a feeling this is part of the puzzle that has been staring us in the face, one of autism ‘mysteries’ hidden in plain sight.

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    Replies
    1. Nat, one known connection between GERD and autism is mGluR5.

      Here is a paper connecting GABAb, mGluR5 and GERD.

      Treating GERD should also treat autism in some cases, with
      GABAb receptor agonists or an mGluR5 antagonist.


      http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2982.2011.01868.x/pdf

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    2. Peter,

      I was wondering about differentiating between digestive issues arising related to physiology in autism versus those arising out of behavioural or sensory problems. For instance, selective diet or holding back motions, observed in many autistic kids, can cause GI dusturbsnces. It's very difficult to isolate causes from effects in autism and I feel hyper sensitivity to stimulus is a big piece if the puzzle. Sensitivities and behaviour might feed off abnormal gi processes and reverse is also true..in autism.

      My brother, husband and nephew, all very restrictive in their diet choices have digestive issues sans behavioural effects..at least overt ones..who knows about subtle ones?

      In my son, who can be described as having reasonably healthy digestion and diet, even a very minor disturbance creates behavioural and sensory issues. If a flickering light can trigger behaviour what can we say about internal body processes.

      As far as physical GI symptoms are concerned, it would be sensible to assess what percentage of NT population with selective diet has those problems. Then probably we will get a better idea about what is causing what.






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  11. Peter, have a look at the following, relavant to GERD and mGluR5 discussion.

     " Transient lower esophageal sphincter relaxations (TLESRs) are the predominant mechanisms underlying gastro-esophageal reflux. TLESRs are mediated by a vago-vagal reflex, which can be blocked by interaction with metabotropic Glutamate Receptor 5 (mGluR5), γ-aminobutyric acid type B (GABA(B)), γ-aminobutyric acid type A (GABA(A)), and cannabinoid (CB) receptors"

    'Alpha-Tocopheral is considered the main ingredient of vitamin E, and is well known for its anti-oxidant properties and mood elevating abilities. Low levels of alpha-tocopheral in the brain are associated with health issues such as depression and neuronal degradation.

    The authors demonstrated that the actions of vitamin E can be blocked, if the cannabinoid type 1 receptor is blocked by a drug AM251. AM251 can block cannabinoid receptors and prevent them from being activated.

    The authors report that the vitamin E and cannabinoid receptor interactions are occurring in a region of the brain known as the hippocampus, which may help explain the benefits of vitamin E other than its anti-oxidant properties.

    Vitamin E can have profound effects on brain function, and it is widely used as a food additive. Without vitamin E in the diet a number a symptoms can start to appear, such as anxiety or ataxia.

    However, vitamin E does not directly activate cannabinoid receptors, like for example THC, instead alpha-tocopheral modulates the receptor. The receptor modulation from alpha-tocopheral may be an important part of normal cannabinoid receptor function. More research is need to fully understand exactly how alpha-tocopheral obtained from the diet can influence the cannabinoid system."

    This might explain why my son responds to vitamin e supplements.

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