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Tuesday, 17 September 2024

Is it safe to treat autism in very young children? Plus, the impact of impaired autophagy on cognition and treating SIB


This blog is full of clinical trials that use existing drugs that are repurposed to treat autism. One constant issue is whether the trial drug is free from side effects. Generally speaking side effects tend not to be a problem, but there always can be exceptions.

I was recently contacted by the parents of a two year old with a single gene (monogenic) type of autism and they want to treat their child to improve his outcome.  This is the youngest case I have encountered.

With monogenic autisms you often have clear indications from a very early age that something unusual is present. Once you have a diagnosis you quickly discover what issues the child is going to face. You therefore have a good idea of what will happen if you do nothing. Some other two year olds have delayed speech and other signs of autism, but within a couple of years develop normally – it was a case of delayed maturation.

I noted long ago that American autism doctors tend to want to treat younger patients with supplements rather than drugs.

The reality is that the sooner you start to correct a severe biological dysfunction the better the outcome will be. We even see that some treatments are only effective if given to toddlers. This makes perfect sense although it may be uncomfortable to accept.

I was looking for supporting evidence for very early intervention. I found a glowing report of the treatment of a 2 year old with Fragile X syndrome using Metformin. I am amazed Fragile X still remains untreated in most cases.

On examination at age 2 years, typical physical features of FXS were observed, and baseline laboratory findings were normal (see Table Table1).1). He was started on metformin at 25 mg of the liquid form that is 100 mg/ml at dinner, and his dose was gradually increased to 200 mg twice a day (bid) over 1 year (see Table Table1).1). After initiation of metformin, his sleep disturbance resolved, only occasionally awakening once for roughly 30 min. Two weeks after initiation, he went from stacking 3–4 blocks to stacking a tower of 11 or more blocks; within a few more weeks, he began building more complex structures comprised of different size blocks. He showed marked improvement in self‐help and motor activities, including toilet training, clearing the table and loading the dishwasher, brushing his own teeth, dressing independently, and learning how to make toast. His preschool teachers, who were unaware of metformin treatment, told his mother that “it's like something just clicked or he just woke up. He's a whole different kid.”

Source: Metformin treatment in young children with fragile X syndrome


Some drugs including bumetanide are already safely given to babies.

Nonetheless, it is a brave step to start treatment in a two year old. I did connect the parents to a reader of this blog whose child has the same syndrome but is a few years older.

Today’s post was prompted by the news that the child is already showing improvements from the first therapy, which is a small dose of clemastine. In this syndrome there is a mutation in TCF4 and there is impaired myelination and very likely activated microglia (the brain’s immune cells). The near immediate beneficial effect cannot be on myelination, but it could be resetting microglia to the resting state.

Other genes very recently raised have been TRIT1 and PSMB9; neither of these are classed as autism genes, but evidently can cause it. Mutations in TRIT1 cause a problem in the mitochondria and PSMB9 mutations cause the immune system to misbehave.  It looks like both can lead to an autism diagnosis.

A common issue parents encounter is that often the interest shown by researchers and clinicians stops at the point of diagnosis. What really matters is what to do next. Only very rarely will such “experts” suggest what to do next. 

It looks like there nearly always are therapeutic avenues to pursue after such a diagnosis. It should be noted that even in single gene (monogenic) autisms there are varying levels of response to the same therapy. We saw this a while back with the new FDA approved therapy for Rett syndrome – it works for some, but not for others.

 

Treating self injurious behavior (SIB) in idiopathic autism

I recently received feedback from several parents who have had success in treating SIB based on ideas in this blog.

Verapamil came up again as successful.

Pioglitazone, at a low dose of 7.5mg, was the game changer for one child.

Ibuprofen worked in another case, but this cannot be used long term. Celecoxib should be better tolerated and in theory should be as effective. Time will tell.

More people are trying the add-on therapy of a small dose of taurine.

 

Macroautophagy as a cause of impaired cognition

Impaired autophagy came up recently in two people’s genetic testing results. There is a lot in this blog about autophagy and dementia/mild cognitive impairment.

Today we have a paper that links impaired autophagy with impaired cognition.

Twenty years ago severe autism generally also meant impaired cognition. Nowadays it does not; you can have severe autism with normal cognition.

There are various different types of autophagy but in general it is all about collecting bits of cellular garbage that might clog things up. As we get older this intracellular garbage collection process works less well and then diseases like Alzheimer’s follow decades later.

Impaired autophagy may contribute to impaired cognition at any age. Most research concerns dementia treatment, or other conditions affecting older people like Huntington’s disease.

There is little focus on younger populations, even though we know that children with Down syndrome are prone to get early onset Alzheimer’s. Treating young people with Down syndrome to improve autophagy might bring both short and long term benefits. 

Here is the recent paper on this subject. 

Impaired macroautophagy confers substantial risk for intellectual disability in children with autism spectrum disorders

Autism spectrum disorder (ASD) represents a complex of neurological and developmental disabilities characterized by clinical and genetic heterogeneity. While the causes of ASD are still unknown, many ASD risk factors are found to converge on intracellular quality control mechanisms that are essential for cellular homeostasis, including the autophagy-lysosomal degradation pathway. Studies have reported impaired autophagy in ASD human brain and ASD-like synapse pathology and behaviors in mouse models of brain autophagy deficiency, highlighting an essential role for defective autophagy in ASD pathogenesis. To determine whether altered autophagy in the brain may also occur in peripheral cells that might provide useful biomarkers, we assessed activities of autophagy in lymphoblasts from ASD and control subjects. We find that lymphoblast autophagy is compromised in a subset of ASD participants due to impaired autophagy induction. Similar changes in autophagy are detected in postmortem human brains from ASD individuals and in brain and peripheral blood mononuclear cells from syndromic ASD mouse models. Remarkably, we find a strong correlation between impaired autophagy and intellectual disability in ASD participants. By depleting the key autophagy gene Atg7 from different brain cells, we provide further evidence that autophagy deficiency causes cognitive impairment in mice. Together, our findings suggest autophagy dysfunction as a convergent mechanism that can be detected in peripheral blood cells from a subset of autistic individuals, and that lymphoblast autophagy may serve as a biomarker to stratify ASD patients for the development of targeted interventions.

 

There are different types of autophagy and there are some overlaps. 

·      mTOR dependent (Fasting or Rapamycin)

·      AMPK dependent (Spermidine)

·      P53 dependent (no simple therapies)

·      Calcium signalling dependent (Verapamil)

The OTC way to increase autophagy is to use Spermidine, which is made from wheat germ or rice germ. Studies in humans are rather mixed and I think the dose is likely far too low. Supplements tend to contain about 1mg; I suspect you need much more to have an impact. You can indeed grow your own wheat sprouts which are highly nutritious and a rich source of spermidine. You can eat them raw or even in smoothies. 100 g of sprouts contains 10-15mg of spermidine.

The most researched calcium channel drug to induce autophagy is Verapamil, from my son’s original autism Polypill.

My takeaway continues to be to look for convergent mechanisms, like impaired autophagy, myelination, microglial activation etc that commonly occur in severe autism, of any origin. You then try and treat these likely dysfunctions rather than getting overly focused on individual genes.



 



29 comments:

  1. Hi Peter

    23 yr old med chem student with autism

    I went on bumetanide a week ago - using 1.5mg per day to start off with. Keen to see what happens... thank you for all your work here, it seems it is helping a lot of people.

    ReplyDelete
  2. Hello again, I should maybe mention this

    The first few days I took it, I had the expected diuresis. At day 3, the baseline mental and physical tension/"constriction" (best word I can find) I feel almost all the time started to melt away. Not even benzodiazepines or opioids have done that for me. It could still be placebo, don't get me wrong.

    After a few more days, the diuresis ceased, even at 2mg - and the tension started coming back. I became a bit concerned, since a diuretic not working can indicate kidney issues.

    Today, on a hunch, I decided to try taking it under my tongue/sublingually... And lo and behold, the diuresis is back! It seems something is preventing effective oral absorption for me. Very very weird.

    It's lipophilic so one would not expect it to work sublingually, but furosemide (even less water soluble) does work sublingually... It seems to work for me.

    I hope now that I'll get back to where I was and see further benefits.

    ReplyDelete
    Replies
    1. That is interesting. A substantial minority do report that bumetanide causes no diuresis. The follow on question is whether there can be any effect on the brain without diuresis.

      Now we know that such people should follow your example and try sub lingual. Thanks.

      Delete
    2. I'm still testing it out, so not certain of any of this yet, will get back when i have a clearer picture.

      Sublingual does seem to work for me so far, and there might be benefits in certain contexts as you said

      Delete
  3. Hi Peter,

    I really enjoyed reading this article. I think chronic inflammation is one of the hallmarks of ASD. I think you might be on to something with the spermidine. Just waiting on my order...

    Autophagy inducer rapamycin treatment reduces IFN-I–mediated Inflammation and improves anti–HIV-1 T cell response in vivo

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9746825/

    Induction of autophagy by rapamycin or spermidine decreases IFN-I responses in monocytes and macrophages.

    -Stephen

    ReplyDelete
  4. Peter, I got some lab results from Jyonouchi lab I would like to post with group. What's the best way to do this?

    -Stephen

    ReplyDelete
    Replies
    1. Stephen you can either upload the file to Google drive and then share a link to the file in your comment, or if you prefer you can write a guest post on the blog.

      Delete
    2. Hi Peter, here is Leo's cytokine profile. Below I believe is the research report on how to read it. From what I can gather, I think he's in the "higher group."

      https://drive.google.com/file/d/1w190B2pqSM8cuJO30po2Wc7w84wi5Zc5/view?usp=drive_link

      Associations between Monocyte and T Cell Cytokine Profiles in Autism Spectrum Disorders: Effects of Dysregulated Innate Immune Responses on Adaptive Responses to Recall Antigens in a Subset of ASD Children

      https://www.mdpi.com/1422-0067/20/19/4731

      -Stephen

      Delete
    3. Stephen, she has exposed your son's monocyctes to various types of stimulus to measure the level of cytokines produced.

      I think you need more data in order to fully interpret the results and determine whether they tell you much.

      There are huge variations in the non-ASD responses in her paper. I am rather sceptical about what she is trying to do.

      Delete
    4. More pieces to the puzzle. Stephen is one with Profound ASD. Anna is neurotypical. Leo has developmental delay( folate autoantibodies)

      https://drive.google.com/file/d/1huDhYx3YGlGbaUpo3hGiiFUDzr8Fd75f/view?usp=drivesdk

      Stephen il10 is off probably from multiple antibiotics as a baby...

      Delete
  5. Hi peter, i believe you once said with the polypill Monty went from no understanding of expected maths skills for his age to knowing and passing algebra tests in a reasonable time period. Was their any particular maths program you or tutor followed or can recommend for autistic children?

    ReplyDelete
    Replies
    1. There is great online teaching app at www.whizz.com.

      It has a fun teaching approach and you can repeat all the exercises many times, this is the key to learning. Typical kids can go fast through it, but you can repeat each exercise several times. This worked really well.

      Delete
  6. Hi Peter, Online news seems to have gone quiet with Suramin since the successful trials from PaxMedica which was a while back now. Anyone know what's happening there?, ive seen glacias move faster than autism research.

    ReplyDelete
    Replies
    1. You can subscribe to news releases on their website.
      They were recently delisted from NASDAQ.

      Delete
  7. Hello parents! Can anyone please recommend a US physician who offers online consultations? At this point, it is just to be able to get a prescription for Leuco and B12 that we order from the US pharmacy.
    Our current physician is charging USD 700 for a follow up consultation, which I consider to be outrageous, as besides the prescription we do not get any insights from those consultations.

    ReplyDelete
    Replies
    1. Hi madina you can buy folinoral which is the same as leucovorin from France pharmacy for about $15, also unless they are injections b12 is available anywhere even Amazon. You may want to look at if your getting value for money

      Delete
    2. Thanks a lot for the Folinoral! The dosage seems to be appropriate for my DS. Unfortunately, I was not able to find any injectable B12 on Amazon.

      Delete
    3. Thanks a lot for the Folinoral! The dosage seems to be appropriate for my DS. Unfortunately, I was not able to find any injectable B12 on Amazon.

      Delete
  8. 700$ for just prescribing Leucovorin and B12 is a ripoff. If you're in the US a friendly NP, neurologist or psychiatrist should be able to do it for next to nothing.

    ReplyDelete
    Replies
    1. Unfortunately, I am not in the US, I'm in the UAE. Here the "compounding" pharmacies do not prepare either injectable methylcobalamin nor Leucovorin. I have access to the compounding pharmacies in France, but seems like they don't do it either. We always ordered it from the US pharmacy. The problem is that in the US they only accept a prescription from the US lycensed physician. Our current physician is lycensed in the US, but also sees international patients. He is well-known in his field and was mentioned begore, but I am not impressed by the way he manages the little patients at all, to say the least. The price was increased just one day to another from 500 to 700 per hour. Considering that 50% of the online consultation he takes to sloooowly go through lab tests, does not listen, and does not give straightforward answers to my concerns, it is just not worth it.

      Delete
    2. Maybe try this guy, Dr. Huberman. He's based out of NYC and was helpful after my son's clinical trial for Leucovorin.

      https://brainfoundation.org/brain-investigators/brain-pi-harris-huberman/

      Stephen

      Delete
    3. Hi Stephen, thanks a lot! I did not succeed getting in touch with Dr. Huberman: his email is not available online, and what I understood from the hospital operator is that he can only see us in person. In the meantime, I am staying with our current physician just for the sake of the prescription. You guys are so lucky to be in the US, issues with the physicians and the pharmacies seem to be much easier over there!

      Quickly jumping to a previous post and your (valuable) comments, I have a question regarding PQQ: could you please let me know the dosage you use for your kids? In the papers they mention between 0,2mg/kg and 1g/kg per day. Considering that my son is 5 years old and only 17kg (typical MD with muscle waste and inability to gain weight), I am thinking of 5g per day for him. Am I on the right track? Also, I have got LifeExtension PQQ, 10mg. Do you think it is ok to open and split the capsule in two doses?
      Thank you!
      Madina

      Delete
    4. Madina, pqq works but I found better luck with biotin. I would start with 10mg daily to try it out. It needs to be paired with Leucovorin or it will have limited effect.

      I like Seeking heath Pqq.

      Stephen

      Delete
    5. Thank you, Stephen. We are taking higher doses of biotin, along with other Bs for the past 2 years- just as part of a mitococktail. I actually hope that biotin would improve my son's hair, as they are very thin and britle, but no change so far.
      Pairing with folate is what I thought. Also, from what I understood, PPQ creates an additional pathway for folate to get through the ''obstacles''. Thus, I wonder, if taking a regular 5-MTHF with PPQ might also have a beneficial effect, just probably to a bit lesser extent.

      Delete
  9. Hi Madina
    You can get it from pharmashoppi as Lederfoline.Also there is a charity in the us Akhil autism foundation if you pay their yearly membership fees ,they can help you with prescription to get it from Hopewell pharmacy but you need to get a prescription first from another doctor outside the us and they convert it to a US prescription for you .I did this with them about 4 years ago and I was able to get B12 injections and leucovorin

    Hope this helps Apinke

    ReplyDelete
    Replies
    1. Thank you, Apinke. Haven't found the information related to a membership on their website, but sent the email a few days ago to consult with one of their practitioners. If they are affilated with Hopewell it would be perfect, as this is where we get our meds!

      Delete
  10. Hi Peter! You mentioned that there are different types of autophagy. I guess one of the way to identify which type exactly one has is to try one of the pharmaceuticals and see if it has an effect, except sometimes it takes a while to see effect/no effect. I wonder, if there is another way to identify one's specific autophagy?

    Also, after two months of no effect from Bumetanide a year ago, I tried it again with my son last week. Started with 0,5 in the miening (I should be careful with its diuretic effect, as my DS is still struggling with a daytime enuresis and encopresis at school). The effect was rather strange: three incidences of rebellious behavior, when my son had a "theater" attitude at school during group swimming class and a group visit to the library. By the "attitude" I mean being rebellious, swimming away from the teacher, getting on top of the table in the library, laughing at teacher's instructions. Would only stop when it becomes evident for him that the "theater is over" and the spectators are leaving. Also, during his ASA gymnastic class he was running around like a cockroach, to the point that the coach just gave up. This all in typically lethargic boy. I am not sure if this behaviour is related to Bumetanide, it just occurred at the same time. I would also say that the cognition-wise my son seem to be more present, speech is more sensible this week.

    I started Bumetanide together with switching to Tavegyl (from rupatadine), also a week ago.

    ReplyDelete
    Replies
    1. All these types of autophagy are possible in all of us, but it is not so simple to increase this process without making other things happen as well.

      I was recently contacted by another parent whose first trial of bumetanide failed, but second time around the young child is a clear responder. Another parent found it necessary to give 3mg a day to get a positive response, in an adult-sized child.

      Delete

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