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Wednesday 10 December 2014

Biotin/Biotinidase Deficiency in Autism and perhaps Autistic Partial Biotin Deficiency (APBD)?








Crete, as seen from the International Space Station
By ISS Expedition 28 crew (NASA Earth Observatory) [Public domain], via Wikimedia Commons

In this blog there is a tab at the top called “Disorders leading to Autism”.  This includes a long list of, supposedly rare, known conditions that lead to the development of autism.

In that list is Biotin deficiency and I even put the name of the gene that is thought to be dysfunctional.  The BTD gene encodes an enzyme called Biotinidase, that in turn allows the body to use and recycle biotin.

Biotin deficiency is a known cause of autism, but it seems that the assumption is made that the cause is Biotinidase deficiency.  The usual test done is for Biotinidase deficiency.

In good hospitals they routinely test for many of these dysfunctions when a child is originally diagnosed with autism.  When I say good hospitals, I mean big US hospitals attached to a university.  In other countries such testing rarely takes place, nor is it even mentioned.

We will see later that even these good hospitals may be getting the result wrong.  They are likely testing for the wrong defect, and so getting a "false negative" in some cases.

The take home message is that Biotin Deficiency may not be rare in autism, only Biotinidase Deficiency is rare.  Both are treatable.


How rare is Biotin Deficiency?

Biotin deficiency is supposed to be extremely rare.

One of this blog’s readers made reference to a recent Greek study.  They checked 187 children in Crete, diagnosed with autism, for various metabolic dysfunctions.

Evidence for treatable inborn errors of metabolism in a cohort of 187 Greek patients with autism spectrum disorder (ASD)



As the reader pointed out, the results are very odd.

The researchers identified 13 children whose results suggested something strange was going on with biotin.  When they did the further tests for biotin deficiency, which is usually caused by deficiency in  biotinidase, they could find nothing unusual.

Nonetheless, they implemented the standard therapy for biotin/biotinidase deficiency.  This involved large doses of oral biotin, which is very cheap and seemingly harmless.

The researchers found that 7 of the 13 made clear advances.  This indicates that they suffered from a biotin deficiency, but not a biotinidase deficiency. Biotinidase is used by the body to recycle its biotin.

Biochemical abnormalities suggestive of IEM

For 12/187 (7%) of patients, urinary 3-hydroxyisovaleric acid (3-OH-IVA) was elevated and sera methylcitrate and lactate levels were also elevated in two of these patients. Despite these biochemical abnormalities, defects in biotinidase, or holocarboxylase synthetase could not be demonstrated in either sera or fibroblasts. Of interest, none of these 12 patients was undergoing valproate intervention, the latter a potential source of 3-OH-IVA elevation in urine. Despite an absence of confirmatory enzyme deficiencies in these 12 patients, we nonetheless opted to treat empirically with biotin for 3 weeks, 2 × 10 mg and then for 6 months at 2 × 5 mg, which led to a clear therapeutic benefit in 7/13 consisting of improvement in the Childhood Autism Rating Scale (CARS; Table Table2).2). For those benefiting from biotin intervention, the most impressive outcome centered on a 42 month-old boy whose severe ASD was completely ameliorated following biotin intervention. This patient was subsequently followed for 5 years, and cessation of biotin intervention (or placebo replacement) resulted in the rapid return of ASD-like symptomatology. This patient currently attends public school without any clinical sequelae and remains on biotin at 20 mg/d.

In the following table are the results showing the effect on the CARS rating scale, before and after treatment with biotin.








Patient #1

Just look at what happened to the first patient in the above table.

For those benefiting from biotin intervention, the most impressive outcome centered on a 42 month-old boy whose severe ASD was completely ameliorated following biotin intervention. This patient was subsequently followed for 5 years, and cessation of biotin intervention (or placebo replacement) resulted in the rapid return of ASD-like symptomatology. This patient currently attends public school without any clinical sequelae and remains on biotin at 20 mg/d.

He went from severe autism to no autism.  (and back, when he stops the biotin)

Yet, if he was tested for the standard biotin(idase) disorder, even at the best center for autism in the world, nothing would show up


  
Biotin Deficiency

Genetic disorders such as Biotinidase deficiency, Multiple carboxylase deficiency, and Holocarboxylase synthetase deficiency can also lead to inborn or late-onset forms of biotin deficiency. In all cases – dietary, genetic, or otherwise – supplementation with biotin is the primary method of treatment.



Implications

Of 187 children, 13 were identified for biotin treatment and 7 responded .  None of these children would have been noticed by the normal diagnostic procedures of even the best laboratory, which look for biotinidase deficiency.

Also of interest is the effect of partial biotin deficiency.

·        profound biotinidase deficiency (<10% of mean normal serum activity)
·        partial biotinidase deficiency (10%–30% of mean normal serum activity).

Children with partial biotinidase deficiency and who are not treated with biotin do not usually exhibit symptoms unless they are stressed (i.e., prolonged infection)

Partial biotinidase deficiency isusually due to the D444H mutation in the biotinidase gene



Profound biotin deficiency would hopefully be noticed

Mild symptoms linked to biotin deficiency:-


  •        Loss of hair colour
  •         Loss of hair
  •         Fine and brittle hair




Background

The results of clinical studies have provided evidence that marginal biotin deficiency is more common than was previously thought. A previous study of 10 subjects showed that the urinary excretion of biotin and 3-hydroxyisovaleric acid (3HIA) are early and sensitive indicators of marginal biotin deficiency.


It does seem that biotin deficiency is usually caused by things that lead to biotinidase deficiency, so let’s look at the data on frequency (Epidemiology)


Biotin Deficiency – Epidemiology
Based on the results of worldwide screening of biotinidase deficiency in 1991, the incidence of the disorder is: 5 in 137,401 for profound biotinidase deficiency

·         One in 109,921 for partial biotinidase deficiency
·         One in 61,067 for the combined incidence of profound and partial biotinidase deficiency
·         Carrier frequency in the general population is approximately one in 120.

Both parents need to carry the genetic defect, for a child to inherit it.

So something odd is going on (in Greece).

In 61,067 people we would expect 600 people with autism.

It seems that in 600 Greek children with autism there may be 22 with a biotin dysfunction.  This is vastly higher than we would expect.

Not everyone with biotin dysfunction has autism and even if they did, in Greece there would be 22x greater incidence than elsewhere.


Implications

I think we (and the Greeks) have likely discovered some new phenomenon “autistic partial biotin deficiency”, APBD, which is not caused by the usual lack of biotinidase.  Somehow the dietary biotin is insufficient in these people, even though biotinidase is present.

APBD does not seem to cause all the severe symptoms of biotin deficiency, just the neurological ones and so remains undiagnosed.

Perhaps one of the other odd metabolic disorders in autism is affecting the biotin metabolism?  Remember that Harvard study suggesting the oxidative stress in the autistic brain reduces the activity of a key enzyme D2, that is needed to convert the thyroid pro-hormone T4 into the active hormone T3.  This would mean that despite a “normal” set of thyroid lab results from your doctor, you might well be hypothyroid inside the brain (low on T3).

Those with access to a good laboratory might consider sending a urine sample to measure 3-hydroxyisovaleric acid (3HIA).

Those without these options might have to settle with the option of trying 10-20 mg of Biotin for a short period and see if it has any effect.

Biotin appears to be one of those vitamins, like B12, where even huge doses may have no ill effect; they are just excreted.  The supplement companies are selling 10 mg pills of biotin;  the RDA for a 10 year old is 0.03 mg which is 333 times less.

Based on the Greek study, you would expect about 4% of autistic people to show a clear benefit, without first doing the 3HIA urine test.

A small chance of success per child, but a chance nonetheless.



Note on the study
  
I have referred to this Greek study once before. On that occasion I was talking about the ketogenic diet and modified Atkins diet.

It is widely accepted that the ketogenic diet can greatly reduce epileptic seizures, so it is not really surprising that it can also help some people with autism (but which ones?).

In the Greek study, via laboratory tests, they identified 9 % children who might benefit from this diet.  Just over a third of these identified children did indeed improve on the diet.

16/30 patients manifested increased sera beta hydroxybutyrate (b-OH-b) production and 18/30 had a paradoxical increase of sera lactate. Six patients with elevated b-OH-b in sera showed improved autistic features following implementation of a ketogenic diet (KD).

This remarkable study was published one year ago.

It has been cited just one time in subsequent literature (although twice now in this blog); this really tells us a lot. (nobody is interested)

Changing diet can require a great deal of effort and, if a fussy eater is involved, it can be even more difficult.  If biomarkers exist to narrow down who would benefit from a modified diet, this is really very significant.

You can easily try biotin pills for a couple of weeks, trying a ketogenic diet just on the "off chance", requires much more bother.   









31 comments:

  1. Thanks for this very interesting interpretation. When I read this study I couldn’t find any information about the inclusion criteria, so I sometimes wonder if the numbers of kids affected by metabolic abnormalities described here is really what is to be expected in general. Anyway, as you wrote, the trial with biotin is easy and risk free.

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  2. Hello Peter,
    Having my son on Nac for almost a month and on SFN for almost a week, I thought I should try Biotin to see any possible additional benefit.
    So yesterday morning I trialed Biotin 800 μg 1 tablet daily.
    It certainly had an effect. In the evening he stopped stimming completely and became seriously normal. The same effect was when he woke up in the morning.
    I am overwhelmed but I try to keep calm and watch his progression objectively.
    Peter, do you think that the dose mentioned would be efficient for a young adult?
    Is there anything else I should be aware of APBD and Biotin supplementation?
    Thank you very much
    Petroula

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    Replies
    1. It appears high levels of biotin are harmless, it just gets excreted.

      I tried the 5mg biotin. There are even cheap time release 10mg biotin tablets.

      I would try 5 or 10 mg for a few days then stop. Was there an improvement and did it disappear?

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  3. Hi Peter,
    My son has been on biotin supplementation for almost 2 weeks now and so far so good.
    As I have already mentioned my son has elevated uric acid for no obvious reason and he is also suspected of autistic biotin partial deficiency. I was wondering if you happen to know the connection between biotin/uridine in the metabolic function/dysfunction.
    Also, is mitochondrial disease considered as a metabolic dysfunction?
    As for the Nac sustain, how can I use it? My son gets almost 3.000 mg of normal Nac daily. He gets it divided into equal doses of 600 mg every 3-4 hours approximately. If I needed to combine Nac sustain with normal Nac how do you think I could do it?
    Thank you very much and Happy New Year to you and the readers of your blog.

    ReplyDelete
    Replies
    1. Mitochondrial disease is considered genetic, but there are many possible genes involved. It can be inherited, but does not have to be. If you give NAC every three hours you probably do not need NAC sustained release. I doubt that biotin and uridine dysfunctions are related. I did read somewhere that the unusual uridine levels in autism seem to be transitory and as the person gets older, they become normal. The early research on uridine seems to have been abandoned.

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    2. I would think the reason might be - Biotin is involved in the citrulline metabolism which is involved in Uric Acid metabolism - when citrulline availability increases the body can then detoxify from Ammoniac, leading to increased uric acid.

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    3. Biotinidase is a thiol enzyme and is experimentally inactivated with mercurials.

      Also of note is that biotin is absorbed by the same intestinal transporter as B1, B5, and lipoic acid. ALA chelation, in me, induces biotin deficient rashes on my face, just like the babies have. So watch out for that if you're on Team Cutler.

      Delete
  4. The Autism Oxalate Project at the Autism Research Institute has been using high dose biotin as a way to work around the effects of the staggeringly high levels of oxalate seen in children with autism. Our project was responsible for initiating and helping complete a study in Poland that finally gave us numbers on how many children with autism are high in oxalate. Please read our study published in the European Journal of Paediatric Neurology and you can read it here: http://usautism.org/content/PDF_files_newsletters/oxalate_and_autism.pdf. Oxalate inserts itself in biotin-dependent carboxylases, and this problem can be overcome with high dose biotin as has been confirmed in animal studies. That is why our project at has always advocated higher doses of biotin for children with autism in its eleven years, after we were convinced of biotin's safety at higher doses. Recently, a pharmaceutical company began doing clinical trials with biotin at adult doses of 600 mg/day for ALS and multiple sclerosis, so they and the FDA were comfortable with that dose. There is other science at play here that we have been working on for at least fifteen years, but if you have a child with autism and have been missing an understanding of the role of oxalate condition, then you may also haven't given yourself the the opportunity to understand a primary biochemical lesion that drives a lot of the issues in autism. For more info, please see our site (aimed at the general public and not just autism) at www.lowoxalate.info. We have gained experience now with more than 22,000 people in reducing oxalate, and we've also learned that reducing the amount of oxalate in the diet MUST be done slowly, or it can produce very difficult symptoms. These symptoms occur as the body takes the opportunity to clear this toxic compound. Even before our project began,we anticipated this clearance might occur because it happens in primary hyperoxaluria after people with that genetic condition reduce their primary source of oxalate by getting a combined kidney/liver transplant. For children with autism, the source of this elevated oxalate can vary. In some, it is a biochemical issue with the body making its own oxalate because of problems with vitamin B6 or thiamine. In others, it is from dietary choices. In most, it is a combination of oxalate coming from both sources, but high dose biotin can definitely help this issue with oxalate by at least helping to restore carboxylase activity. If anyone has any questions, please ask. We have an autism tab at our site under "conditions and research" which will tell you a little more about the link to autism, but it has not been updated for years.

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    Replies
    1. Susan,if iam not mistaken, biotin suppresses the growth of yeast,and this is related to oxalates,but high dose biotin should be taken with the rest of b vitamins,in at least a low dose?Valentina

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  5. After reading this article, I tried a biotin supplement and it worked. He has begun to be more verbal, active and understand us when we talk to him. It's been only one week, but the progress is so visible. Thank you very much. We tried with 150 mcg and little by little we will give him more.

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  6. Hello,
    Thank you for all the great information. Please let me know if I can start my 5 year old on biotin- he is on methyl B12 spray and omega 3. He weighs around 48 lbs. I would like to continue with the supplements he is on, and add biotin.
    Thank you.

    ReplyDelete
    Replies
    1. It should not be harmful to try biotin. A small percentage of people with autism do benefit from specific B vitamins. Most have no reaction and some have a negative reaction.

      Very high doses of one B vitamin can disturb the other B vitamins. It is best to only supplement what gives a long term positive effect. This varies depending on what is causing the autism.

      Delete
  7. Thank you for the reply.
    I am planning to add folinic acid as well to my supplements.
    I have NAC capsules, planning to mix it with some juice, but it's verma challenge to give anything that has some odor to it. Had tried NAC in tab form, but my son could not tolerate the sulfur, I got the idea of buying capsules from your blog.

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  8. An interesting article (although not related to autism) which shows high dose of biotin can help myelin synthesis and this may also beneficial to autism.

    http://www.clinicaleducation.org/news/biotin-multiple-sclerosis-a-brief-review/

    http://www.sciencedirect.com/science/article/pii/S2211034815000061

    The only question is the what dose level is effective, not sure is 300mg/day is too much for kids.

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    Replies
    1. Yes this is interesting. Well worth forwarding to anyone you know with multiple sclerosis (MS). MS is not so rare.

      I think in severe regressive autism re-myelination may also be impaired. This was suggested by Dr Kelley as a reason why some people improve and others do not.

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  9. Peter what do you think about oxalates? It seems according to some studies that autist people have very high values. They talk about a low oxalate diet. Example:

    https://www.greatplainslaboratory.com/articles-1/2015/11/13/oxalates-control-is-a-major-new-factor-in-autism-therapy

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    Replies
    1. un tio, oxalates are elevated in both the blood and urine of most people with autism, but they do not seem more prone to kidney stones than anyone else.

      It is not clear that the high level of oxalate is harmful, it may just be a consequence of the altered metabolism in autism. Perhaps oxidative stress results in higher levels of oxalate, see the paper below:-


      Reactive oxygen species, inflammation and calcium oxalate nephrolithiasis
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4220551/

      Delete
    2. Many thanks. One thing, you brought "calcium oxalate" study. I think you are of those with the theory that the guilty is the calcium, in plain words. Perhaps it could be a relation through it.

      Regards

      Delete
    3. un tio, calcium seems to be "in the wrong place" in autism, as is chloride and quite possibly zinc. This gets highly complex, but I doubt oxalate is the root cause.

      Delete
    4. Of course I didn't mean oxalate was root cause, but perhaps they point oxalate and who knows if they are right or if it is the calcium in it.

      I guess you probably have seen this page about calcium and autism:

      http://www.autismcalciumchannelopathy.com

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    5. That site is by an "Autism Mum" in England, who had a bad experience giving her son a calcium supplement, that triggered a big regression.

      IP3R appears to be dysfunctional in much autism and may explain much of what is wrong with calcium levels within cells. There are posts in this blog about it.

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    6. Hello Peter,

      What do you think about the link between autism and growth hormone? Autist kids grow faster. Perhaps is mainly here the problem? Their brain grew too fast?

      This is known even as old as 2007:

      https://www.nih.gov/news-events/news-releases/boys-autism-related-disorders-have-high-levels-growth-hormones

      Regards

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    7. un tio, growth factors are disturbed in autism, but there are many of them other than GH, there is BDNF, NGF etc and many are implicated.

      IGF-1 is a proposed therapy for autism.

      There are highly complex signalling pathways that control your body, there are pro-growth signalling pathways and these are hyperactive in most autism, but hypoactive in a minority. Some autism is characterized by big heads, while some is characterised by small heads.

      The tendency towards growth is why there is a higher incidence of cancer in autism, except for those with tiny heads.

      Girls with Rett syndrome have very little nerve growth factor (NGF) in their brains and you might expect NGF eye drops to have a positive effect.

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    8. What would be the best for the ones with big growth and big heads?

      On the other hand, changing the subject, have you studied this meds?

      The calcium channel blockers:

      "verapamil and diltiazem were effective in preventing early calcification that occurs in aortic valves after transplantation."

      I guess they could help against calcification.

      Last, have you tried betablockers? They say propanolol could work but I think even others such as bisoprolol would. You can try on your self and see the effects, which may be wonderful for autistic children.

      Regards

      Delete
    9. un tio, there is a vast amount in this blog about calcium channels and on Verapamil in particular. Verapamil is part of my son's polypill.

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

      Propranalol was covered in 2016.

      https://epiphanyasd.blogspot.com/2016/02/propranolol-autism-and-sodium-ion.html

      Delete
    10. Lol I should have thought it. Thanks.

      Anyway, did you try propanolol? Why or why not?

      I have taken bisoprolol and I confirm you it got down the anxiety.

      What if the main problem of autistic children is not a channelopaty, but simply a high and strong heat beat rate?

      I say this because of my own experience, having had arrhythmia with tachicardy and after that some pain in the chest and "bad sensation" which disappeared with bisoprolol.

      Delete
    11. un tio, there are many hundreds of different types of autism ranging from severely disabling to trivial.

      Anxiety is a common problem in autism, but it has many different causes. Anxiety was never a core issue for my son, but it is for some people and a small number of those do use propranolol.

      The problem is you cannot take too many things that lower your blood pressure. Many autism therapies also happen to lower blood pressure, but high blood pressure is not a driver of most people's autism. It is just that most drugs that lower blood pressure have other modes of action and some of those are beneficial to some people with autism.

      Delete
    12. Hello,

      Of course it depends on the type of autism but if only we could find a common cause for 40%, that would be very much. By curiosity, did you measure the heart beat rate and/or pressure of your child?

      In the case of my child is high the rate, but it is supposed to be "in range" as for little children the top is high.

      Regards

      Delete
    13. An in this case as the rate is high I think would be no problem lowering it.


      I have some personal experiences related to heart and pain issues which I ask to myself if a little child could have it and can t tell it or understand it.

      One problem to find the answer is that little child can t speak nor know what is normal and what is not.

      Regards

      Delete
  10. Hi Peter Lloyd Thomas!
    As always, thank you for your blog, research and community.

    I have been supplementing with biotin (working up to 20,00) together with other B vitamins (B1, B2, B5, B9, B12 - all at lower doses. The other Bs, I cannot do).

    I had my plasma amino acids tested again, with supplementation. Quite a few things improved. My lysine levels doubled and is now high. Asparagine tripled and borderline high.

    Have you heard of this happening to anyone?

    Thank you -

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  11. High‐dose biotin restored redox homeostasis driven by NRF‐2, mitochondria biogenesis and ATP levels, and reversed axonal demise and locomotor impairment.

    High‐dose biotin restores redox balance, energy and lipid homeostasis, and axonal health in a model of adrenoleukodystrophy

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018149/

    ReplyDelete

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