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Friday, 11 December 2015

Treatable ID and Some Autism







Vancouver is one of the most attractive cities I have visited.  It is home to BC Children’s Hospital and Dr Sylvia Stöckler-Ipsiroglu and Dr Clara van Karnebeek. Together they have produced a remarkably thorough website called Treatable-ID, which sets out information on 82 treatable forms of Intellectual Disability (ID), formerly known as Mental Retardation (MR).
  
This excellent resource was recently brought to my attention by a reader of this blog from Down Under, another place well worth visiting.  Thanks, Alexandria.



ID/MR and Autism

ID/MR is defined as having an IQ less than 70; this means the cognitively weakest 2.2% of the population.

Classic Autism, Autistic Disorder or what we might now also call Strict Definition Autism affects about 0.3% of the population.  It is likely that about half of this group would score <70 in an IQ test.  I do not suggest they take one.

It is clear that an overlap might exist between the causes of MR/ID and the cause of some Strict Definition Autism.

In earlier posts I have referred to improving cognitive function in autism using Bumetanide.  We even saw that it should also improve cognitive function in Down Syndrome.

I suggested that Diamox/ Acetazolamide, another diuretic, could also have a similar effect (via the AE3 cotransporter).  One reader of this blog, Agnieszka, has been sharing her use of Acetazolamide, in the comments on the previous post.

People with RASopathies often have autism and MR/ID.  There are potential RAS therapies, one of which is a cheap statin drug.

We saw how dendritic spine morphology could be modulated and how that could affect cognitive function.  PAK inhibitors can, in theory, achieve this.

So I am already sold on the idea of some cognitive dysfunction being treatable, but I thought I was in a minority of a few dozen. Apparently not.

A friend recently highlighted my suggested autism therapies to a leading Spanish Neurologist, who clearly thinks I am just dreaming.  What would he make of Sylvia and Clara, the BC Duo?  Too much medicinal marijuana, perhaps? 

Science is all about remaining open-minded.  This should also be true for Medicine, but very often it is not. Combine this with the reality that kids with ID/MR/autism are bottom of the list of most people's priorities and you will see why things do not change, unless YOU make the changes, for your n=1 at home. 




81 inborn errors of metabolism related to Intellectual Disability and amenable to therapy

The BC Duo have collated the data on 81 treatable forms of ID/MR.

Not surprisingly some of these 81 also lead to “autism”, so they must also be treatable.  Roger, one this blog’s followers, has at least one of these 81.

So I suggest that anyone interested in a type of autism with some degree of cognitive impairment takes a good look at their site.













These are the 81 inborn errors:-







Not to confuse Sylvia and Clara with the other dynamic duo, your kids may know, from DC, rather than BC.

With so many treatable forms of MR/ID/Autism out there, is it not a little strange that thorough metabolic testing and Whole Exome Sequencing (WES) are not standard procedures after diagnosis?

By the way, WES is only as good as its interpretation.  Even world leading centres can be very weak in this respect. Insist on receiving the extended report and check all the possibly dysfunctional genes yourself.  It is not so hard.







67 comments:

  1. I have known about the Treatable-ID web site,and Tide-BC for a while now.They are a very good resource.

    As I have said here before,I have Severe MTHFR Deficiency and Homocystinuria,high folate receptor autoantibodies,and a unique form of a very rare primary immune deficiency,among other diagnoses.My PID has been my most recent diagnosis.It was diagnosed a few months ago through a whole exome sequencing.I'll get to that.

    My original autism diagnosis was one of being verbal but otherwise low functioning.I had serious learning,but not intellectual,disabilities.As well as cognitive dysfunction similar to Alzheimer's or dementia.I was originally diagnosed as a child,long before any of this stuff was known in relation to autism.But when my autism was rediagnosed,as an adult,in 2008,the first thing that the developmental psychologist that performed the evaluation did was present my mother with papers to put me in a residential treatment facility.I was considered hopeless,and a danger to myself.

    I think a big part of the problem is that we have psychologists and psychiatrists that perform autism evaluations,not neurologists and medical doctors.The majority of psychologists and psychiatrists are not thinking of underlying medical causes for autism and DD/ID/LD.Many may not be trained to look out for diseases such as inborn errors of metabolism.Many doctors are told,in medical school,that IEMs are so rare that they may likely never see one,which is of course a big lie.IEMs are more common than thought,especially in those with developmental and intellectual disabilities.Inborn errors of metabolism,once identified,can be treated at any age.My Severe MTHFR Deficiency and Homocystinuria and FRAs were found after I was rediagnosed,and went to what was then called a DAN! doctor who was not quite sure how to interpret the tests.I have since seen other prominent specialists like Richard Frye.Next.I am going to see one of the few specialists in the world in my type of PID,at UCLA,who is collecting a worldwide database of mutations.He also works with an autism neurologist.

    I had my whole exome sequencing done through a company called GeneDx.They send specimens to the lab at Baylor University in Texas.GeneDx has a very good program for low income families and individuals.They will do the testing either at no cost,or at very low cost,depending on your income.I would highly recommend them to anybody in the USA.

    As you say,nobody is going to help you,or your child,get a medical diagnosis beyond autism and ID.It is up to families and individuals to want to work for these diagnoses.And keep working every step of the way until you get all your answers.In a complicated case,like mine,it can take a few years,six for me,and going to multiple doctors,some of which may be more help than others.

    ReplyDelete
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    1. Roger/Peter.
      After looking at the websites of GeneDx and Illumina, it appears there are various testing platforms and test groupings. How would one know which is right to choose? Does a geneticist need to be involved to make that determination and order the testing?
      Thanks
      Nancy

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    2. Nancy, you need Whole Exome Sequencing, like Roger had done and somebody to explain the results.

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    3. Hi Roger/ Peter,
      Can you suggest any geneticist who can interpret "whole exome sequencing" results in USA?...thanks

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    4. Hi Bhuvaneswari, this appears to be the weak link. I recently saw the test results from one of the top US labs, and they classed as not relevant a whole series of mutations that are known autism risk genes. They were not in the results given to the patient/clinician, you had to ask for the wider results, deemed by the lab not to be relevant. I was not impressed.

      The metabolic testing for known dysfunctions seems much less problematic. Go to a childrens' hospital attached to a leading University, like Boston Children's Hospital.

      Roger may likely suggest you go and see:-

      http://www.archildrens.org/Physician-Directory/F/Richard-E-Frye-M-D-Ph-D-.aspx

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  2. Hi Peter,
    link: http://www.cnbc.com/2015/12/10/unlocking-my-genome-was-it-worth-it.html
    Cnbc in the US posted an article saying a co called Illumina does genome sequencing for around less than 3000$,
    I know my sons geneticist applied to insurance for approval for chromosome mapping,
    I was wondering how is genome sequencing different from chromosome mapping, I will probably print this and show this to the genetics doc on my next visit to see if it helps
    Thanks
    BK

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    Replies
    1. There are two types of genetic testing in common use.

      Chromosone microarray analsis
      Whole exome sequencing

      They are different and are complementary. Whole exome sequencing costs a few hundred dollars and if you can only have one, would be my choice.

      Genome sequencing is exome sequencing plus the other 95%. This would be even better if data existed to compare your results against. It does not.

      Ask the genetics doctor.

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  3. I recall 23andme is supposed to be offering whole genome sequencing for $1000 (I read this a while ago and have not checked lately).

    Nevertheless, I don't think autism can be reversed by just treating a genetic defect here and there unless you catch it while in the womb either from genetic malprogramming either endogenous to the fetus that leads to abnormal development, environmental insults (maternal diabetes, toxins, pollutants, etc.) that epigenetically dysregulate development in the womb, or both.

    By the time you know your child has autism, much of the damage is already done developmentally. Now, if I believed that damage was irreversible, then I wouldn't be here and I would just droop my head like so many other parents in our situation do but the approach I have taken instead is to first figure out how to:

    ReplyDelete
  4. (1) Deal with systemic problems that make autism worse over time and essentially cause further brain damage and developmental abnormalities that will be more difficult to address as the child gets older. Most of the discussions here center around these topics.

    (2) In the short-term make sure you can provide your child with an environment that gives them a crutch so that they do not become overstressed by their environment. In the long-term you need to remove the crutches that may cause long-term harm and address each individual problem head on. For example, the school teacher for my oldest son demanded that my son wear noise cancelling headphones (which I thought was strange because there was little ambient noise in the classroom which is what noise cancelling headphones block out). What I later found out is that she wanted him wearing these earmuffs that essentially muffle all sounds. On the surface you can see how this suggestion would logically make sense, but unfortunately what makes sense is often not the truth as in this circumstance depriving the ears and all the neurons that connect to them of sensory stimulation actually leads hyperacusis, tinnitus, and eventually permanent hearing loss. The problem with sound sensitivity with autism needs to be addressed in the auditory cortex itself (NAC coincidentally has shown promise for some people in this area as has Nicotanimide Riboside), not by depriving the upstream processing areas of sensory input which actually makes things much worse over time. In other words, sensory deprivation is bad for the brain.

    (3) Since children with autism are way behind developmentally by the time a parent or medical professional or anyone else can get a hold on what to do since autism is very complex and the only treatment available now that is standard now are early intervention treatments which don't seem to alter the long-term developmental trajectory of autism much except for a small subset of very high functioning individuals, you need to figure out a way to cheat when it comes to learning.

    There is a lot of promise in this regard as a healthy human brain is pretty much optimized for information transfer and while interventions to make smart people even smarter do little, nothing, or actually make things worse as is the case with smart drugs like Adderrall, in people with ID, interventions to better normalize the brain actually can boost IQ significantly in some cases. There are improving technologies for dampening activity in hyperactive areas of the brain and boosting activity in hypoactive areas of the brain now and I personally have been working on a novel technology for not only doing that, but also boosting functional connectivity between various networks that seem to be dysfunctional in most autisms. Not long ago this was thought to be impossible but we now know various disease states (which can be replicated via drugs) that worsen connections between different brain areas (areas you may want to decrease) and technologies and drugs that can improve connections between different brain areas (most of these drugs have nothing to do with autism but are more in the sphere of Alzheimer's and especially Multiple Sclerosis).

    Anyways, I imagine many people here kind of are on the same approach, but I believe many people don't stress the third point here in that at the moment I feel that desirable outcomes for classic autism involve artificial rewiring of the brain both at a local level as well as at a long range functional level. There are many different vectors that various research groups around the world are pursuing to achieve this feat using TMS, Neurofeedback, tCDS, Deep Brain Stimulation, drugs, to name a few and optimal treatments may involve a variety of these interventions to give low-functioning people with autism the agency to pursue their own dreams independently.

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  5. Today I came across an article in "The New Yorker" about the life of a cancer researcher who has put out a book about his frustrations with the conservatism of cancer researchers (i.e. don't try anything that can get you sued) as well as the FDA in impeding progress.

    http://www.newyorker.com/magazine/2015/12/14/tough-medicine?mbid=social_facebook

    What is relevant here to this discussion is his main premise that there may be plenty of existing drugs and research in treating cancer, just that everything works at a snails pace because of the inertia of getting doctors who are economically entrenched in the system, to make real efforts at treating their patients, rather than simply making them "feel better" and then billing their insurance company.

    My experience with autism parallels this article in that there may be existing drugs and treatments that can make a world of difference in the lives of people with autism, but that physicians and researchers are too scared to fail, meanwhile the standard recommendations for young children with autism are "early intervention" services that have long-term studies that show they do little or nothing to improve the outcomes of the vast majority of people with autism once they reach adulthood. Instead of treating autism as a medical disease that will ruin the life of a person, conventional wisdom suggests that if you just beat a child's brain to mush with ABA, then they will eventually "outgrow" it.

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    Replies
    1. That New Yorker article tells a story that sounds all too familar.

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  6. Tyler,I am living proof that autism due to an underlying metabolic cause can be reversed.I do realize this does go against much of the conventional wisdom.Much of this conventional wisdom,being based on scientific ignorance.Autism or intellectual disability due to inborn errors of metabolism,is not the same as either ABA or simply outgrowing the autism.It means a medical condition that requires treatment for the rest of a person's life.Stop treatment,and the person will regress.It's that simple.

    The older a person is,and the more severe their neurological deficits,the longer it takes to reverse.As an adult,with very serious problems,it took me about three and a half years before I fully became what you could call neurotypical,but there were cognitive and behavioural improvements about six weeks into treatment.


    23andme charges $100.For all their hype,their testing is more or less worthless.Especially for many diseases that are considered "rare",like most inborn errors of metabolism are.I did the 23andme test,twice.Both times there were zero results on me.

    Tyler,there are many different forms of autism.The type that you describe,caused by environmental damage in the womb,is only one of these.

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    1. Dear Roger,

      Thank you so much for your comments. Do you think Dr. Frye is a good person to go to for testing metabolic disorders. Does he have a massive wait for appointments? Would you mind contacting me in private, so I could discuss a bit more about this with you?

      Many thanks,

      RG

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    2. Roger, I was not referring to the 100 dollar test. I could be wrong, but they were or are offering full exome sequencing for $1000. The point I was trying to make is that full sequencing is economical enough now for individuals who want to make this leap and feel they can do something useful with the knowledge of a full genetics screening.

      Also, I perhaps should of been more specific in that the evidence as I understand it suggests the vast majority of idiopathic autism happens in the womb and is not due to single genetic hits (such as inborn metabolism issues) that are systemic and more importantly are reversible. If you felt offended, I apologize.

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  7. Peter, as ever, thank you very much. I am feeling both horrible and optimistic at the same time. I ran an amino acid profile on my daughter a year ago, many were off, tried to find information online and through doctors, nothing. The only things I found were that the low tyrosine could contribute to her hypothyroidism and the low citrulline could be impairing nitric oxide production. She also has low creatinine.

    Looking at the Treating ID website, I have begun looking at various conditions, and PKU specifically. It seems that first pass diagnostics looks at the ratio of phenylalanine to tyrosine. Her phe is normal, but that I think is because for years now, she has inadvertently been on a low phe diet. There are other signs such as reddish brown urine with a very strong musty odor. Apparently, one of the types of PKU is tied to BH4 which synthesized from guanosine. In hyperuricosuria, there is increased breakdown of purines, even though adenosine seems to breakdown more than guanosine. I wonder if it could all be in reverse for my daughter, going back from hyperuricosuria to inadequate bh4 to pku symptoms.

    Adenosine is also strongly inhibitory and plays a role in seizure prevention and neuroprotection and this may explain uridine's success in treating epilepsy. Here is a good write up, though other than the ketogenic diet and a mention of deoxyglucose, it does not discuss other ways of stimulating extracellular adenosine. http://www.ncbi.nlm.nih,gov/pmc/articles/PMC2769009



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  8. Replies
    1. Gordon, you have to find a helpful doctor.

      The genetic testing labs do not want to deal with patients direct. So you need a doctor to order the tests, though you way for them. The US seems to be the best place for genetic testing and they accept samples sent from other countries.

      Many of the above tests are not genetic, rather more standard lab tests that any big hospital can do.

      The idea of treatable-ID website is to be a resource for doctors. You just need a doctor who is interested to help you. Either that, or take the next plane to Vancouver.

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  9. RG and Gordon,I see no contact information for you,so I will post the reply here.

    Dr. Frye and Dr. Kahler are probably the best doctors in the USA as far as metabolic disorders related to autism are concerned.I would say if I lived in Europe,or outside North America,I would go see Vincent Ramaekers in Liege,Belgium.This is the man who discovered cerebral folate deficiency in the early 2000s.I know a woman,through Facebook,whose son who has purely immune based CFD and autism,no metabolic problems,who traveled from Singapore to see Dr. Ramaekers.

    I was seen at ACH in September of 2014.At that time I was the first ever autistic adult and second only adult patient ever seen at the Autism Multispecialty Clinic.The first was another woman I know through Facebook,who is the mother of one of the autistic children seen by Dr. Frye.This woman has mitochondrial disease but not autism,and was only seen there because of her child.

    As the first autistic adult seen there,I had to provide a good bit of documentation.Especially metabolic test results.This would probably be the case for anybody else.The wait for new patients is at least a year and a half,but there is a cancellation list,and you can move up this list very fast.

    If you are just starting out,I suggest you see Dr. Frye's research partner,Daniel Rossignol,either in Melbourne,Florida or Irvine,California.I see Dr. Rossignol too.It is a lot easier to see him.

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  10. Hi Roger,

    Thank you for replying. I have heard of Dr. Rossignol, but have stayed away because he seemed to be a typical DAN doctor recommending chelation, hbot etc. Until I read about your experience, I had assumed that Dr. Frye was the same as well, though he did have a good paper along with Rossignol on various AEDs in autism.

    I am really looking for a doctor who can test for metabolic disorders and treat them. Something like this: http://www.merckmanuals.com/professional/pediatrics/inherited-disorders-of-metabolism/approach-to-the-patient-with-a-suspected-inherited-disorder-of-metabolism

    Is it possible for you to get my email from Peter? Peter, is this possible? Sorry for the trouble.

    Thank you.

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    1. RG, you raise a key point for parents. Where are the lines between proven science, valid experimentation and quackery/pseudoscience?

      When I reviewed HBOT, a long time ago on this blog, I dismissed it. At that time I was researching autism, not 1000 autisms. I now think people whose autism is associated with either mild hypoxia, or reduced cerebral blood flow might very well improve with HBOT, but you would need to continue it. Maybe a few percent benefit, but we know that the majority do not. But in which category is your n=1 ?

      Those DAN doctors seem to give vitamin B12 injections to all their patients. There is data indicating that about 15% do actually benefit from B12, also some of those 82 treatable-ID dysfunctions are treated by B12. But in responders you would need to continue B12 for life, not just a few months.

      We saw in a Greek study that about 5% of kids with ASD responded to another B vitamin, biotin. Biotin appears more than once on the treatments for those 82 inborn metabolic errors.

      Your example case study of Uridine, showed that one person made remarkable improvements, but that patent lapsed and has been forgotten. Other people might also benefit, it might be 1 in 500 or 1 in 50,000.

      All these “rare” cases should be studied, documented and biomarkers identified.

      As Tyler pointed out, what sane mainstream doctor is going start giving advice about treating all this, given the complexity and uncertainty?

      Delete
    2. Hi Peter,

      If the rare cases were documented, they might make up a significant percentage of all autism.

      I have a fundamental difference with the DAN doctors, they believe that heavy metal toxicity underlies all autism. I also don't subscribe to their approach of throwing everything at everybody. Some things help some people, for some they do nothing, and there is another category in whom they have severe negative effects. I think it was Dr. Chez, a long time ago, who said that it is important to do a SPECT scan before hbot as there could be existing hyper perfusion in which case it would be contraindicated. Usually, negative reactions are passed off as 'yeast' or 'die off' by the DAN doctors.

      I did try the B12 injections, but at a much higher dose than prescribed by the DAN protocol. I did this after reading on the fibromyalgia/ME forums where the smaller doses have no effect. So, with the non responders one cannot quite know.

      Peter, I originally found your blog when I was looking at TRH. I was amazed that you had found taltirelin and were trialling it with your son. At that time I was with a doctor, not a DAN, but somewhat similar 'functional medicine' one, who had been willing to try progesterone. My daughter had failed the oral and the high dose cream was not preventing the new, allergy provoked seizures, so I took the research on TRH and your experience to her. What I got from her was a lecture to stop with all the experimentation and get to work on the root cause which was heavy metal toxicity. Her recommendation was that we start chelation asap. The irony of it.

      Delete
    3. On Uridine, it appears that the researchers most interested in purine metabolism and autism, namely Ted Page and Mary Coleman have not been around since 2002 or so. The company Repligen which was also a patent applicant, licensed it from University of California San Diego, and was granted the patent in 2004. It appears that there were some legal troubles and better funding for bipolar research. So, I guess it is up to Dr. Naviaux now.

      There even seems to have been a Purine Research Society in the 80s, established by parents of children with autism. It appears to be defunct.
      http://www.purineresearchsociety.org/

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    4. It seems that Dr. Barshop is the Medical director of the UCSD Genetics and Biochemical lab. He is also practicing. He is listed on the Advisory Board of the Purine Research Society. I looked at the tests offered by the lab and it is extensive and appears quite comprehensive. I would think they would be able to catch many of the rare disorders and hopefully treat them.

      I am going to try to get an appointment, will keep you posted.

      Delete
  11. Roger and RG,
    If both of you send a comment to this blog with your email address, which will not be published, I will email each of you with the email address of the other.

    ReplyDelete
  12. Dr. Frye and Dr. Rossignol have cowritten a number of articles.Look at this one.

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4073259/

    Dr. Rossignol's name appears on many of Dr. Frye's other articles.

    Like this one about folate receptor antibodies,which I have.

    http://www.nature.com/mp/journal/v18/n3/full/mp2011175a.html

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    1. Does it make sense to go see one of these doctors with testing results (genetic at least) in hand or to wait and see and what they suggest?

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    2. Nancy, you probably will need the doctor in order to access genetic testing. I think you need realistic expectations from any doctor. The subject is highly complex and nobody understands all of it.

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  13. HI Peter, iam thinking of the possibility that my son could have cerebral folate deficency ,since i have the very serious mutation MTHFRhomocygous and his autism includes dyskinesias, hypotonia, clumsiness , electrical activity, not epilepsy, and mitochondrial dysfunction. I would like to know what Roger thinks too , should i give him methylfolate or folinic acid or both? I have tried almost all and nothing seems to make the difference, specially with dyskinesias. could be CFD? Valentina

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    Replies
    1. Roger is the one to answer your question.

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    2. ok, I hope that Roger can read my post, as far as clonazepam, I will make a trial because we finish valproat wthdrawal in december. and i must choose a replacement, should i start with 25 mcg a day or 40 mcg? regards and merry christmas!Valentina

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    3. I would start with 25 for a week and if nothing changes increase it to 40. If there is no effect, then he is not a responder.

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    4. Valentina,

      I have many of the same problems your son does but they are more severe.Mitochondrial dysfunction,MTHFR mutations,dyskinesia,and abnormal electrical activity are all very common with cerebral folate deficiency.Here is a good introduction.

      http://www.generationrescue.org/assets/Published-Science/frye-autism-folate-receptor-autoantibodies-simplified-2011.pdf

      Note this article is four years old.This testing should be routine by now for everyone with autism.

      There are three different ways to diagnose cerebral folate deficiency,The Folate Receptor Antibody test,the FOLR gene mutation test,and a spinal tap.There are currently only two places in the world that I know of that do the Folate Receptor Antibody test.One is Iliad Neurosciences in Pennsylvania.

      http://iliadneuro.com/lab_tests

      The other is Dr. Ramaeker's clinic at Centre Hospitalier Universitaire de Liège in Belgium.

      http://www.chu.ulg.ac.be/jcms/c_11119/centre-de-ressources-autisme-liege

      What you need to do,is find a MAPS doctor that can order these tests for your son.Here is the worldwide list.

      http://www.medmaps.org/clinician-directory/

      In the USA you cannot buy folinic acid or 5-MTHF in doses that will be effective without a prescription.These are the only forms of folate that reverse CFD.

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    5. Hi Roger, thankyou so much for the information, are you taking leucovorin? becuase in my country can find it as calcium folinate 15 mg. I would like to know for how long my son should take it to reverse the CFD . Before I decide to do the test , I would like to know if can expect a complete recovery or improvment, or not necessarily. Valentina

      Delete
  14. Hello Peter,
    I've managed to make an appointment with Dr. Athanasios Evangeliou, neurologist and specialist in metabolic diseases in Thessaloniki, Greece.
    It'll be today at 8 o'clock in the evening in St. Lukas Hospital in private. He seemed interested in my case.
    He told me that we are going to need a huge amount of tests which are going to be held in the university clinics free of charge.
    I don't know how many of your readers or yourself have gone through this procedure but it seems hopeful and horrible at the same time.
    And another thing about Ponstan. I am quite sure that it affects my son's behaviour towards normality, he wants to stim but he can't. Deprived of the stimming tool, he says "I don't feel well" and he doesn't look happy. Then he overcomes it, I just can't explain it.

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    Replies
    1. Petra, that is great. Regardless of the result, you will have ruled out missing things that you could have treated. So it is win, win whatever happens.

      Delete
    2. Hi Petra,

      It is great to hear that you and your son have such an opportunity. I want to reassure you that my son had some extended neurometabolic testing and it was not that horrible. What was needed was a blood draw or two and we had to collect his urine at some points of the day and bring it frozen to the hospital. They did a number of tests from these samples, but it was not really disturbing for my son. I had to pay for some and nothing tested positive but at least I can rest assured that we didn't miss a few important things.

      Actually this kind of testing is not usually offered for autism here and in our case it's quite unusual history. This doctor found some old documents of my son on the table in the neurologic department and linked the papers with the story she heard from her friend living elsewere: about a family who visits them often with an autistic boy with strange symptoms when they have appointments in the capital. Incidentally it happened to be about us. This doctor found my number and called me asking if we would like to have the tests done.

      Before in a tertiary hospital we were advised to better think more of therapy than medicine in autism.

      I always think that if we stayed at the hotel and not at my cousin, we wouldn't have those metabolic tests done... One question I have on my mind is if it would be possible to develop reasonable recommendations what tests for inborn errors of metabolism should be done in autism with or without other co-morbidity?

      Good luck Petra with your appointment!

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    3. Hello Peter,

      Peter, Agnieszka, thank you for being with me.

      I also think it's win, which started almost by chance with melatonin supplements, then your blog enlighted me and helped systemising my effords and hopefully Dr. Evangeliou would help things further with genetic tests.

      Dr. Evangeliou seems a very friendly and easy-going qualified doctor. He is motivated when it comes to autism.

      My son's case is probably inherited and my problematic pregnancy together with other environmental factors must have triggered it.

      We are going to have genetic tests in the near future. He established that there are treatable metabolic diseases but some of them are not.

      He asked me to make a list of all supplements/drugs we used and mark them 0-10. First trial is biotin 20 mg devided twice a day, in the morning and in the afternoon (not late in the evening) for 5 days. So biotin is his priority.

      He also asked me the name of the doctor who advised me on melatonin and other supplements and told him that no doctor ever advised me on them. It was a hit and then followed an Englishman's blog who helped me with other successful supplements. He said that he really likes English people and worked with their children when he was in Liverpool.

      Peter, when I send him my e-mail with the stuff he wants I'll write him the name of your blog to have it in mind.

      Hope it works and let you know.

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    4. Petra, that is excellent and shows again that experts are often very helpful. The more you can inform yourself, the more likely it is that others will help you. Quite often it costs you nothing, as you have found with your tests.

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    5. Hi Roger,
      I have been following your posts on Peter's site with great interest and then tried to email on your blog.
      Can one supplement without the testing and just see if there is a positive response?
      My son, 22, has the MTHFR hetero mutation (according to Yasko genetic testing ) but not the A1298C mutation.
      His vision appears to be normal. He has had tons of movement issues (muscle tensing in his jaw and upper body) since he was little. He appeared to be doing great with ABA starting at 3 then had a regressive crash around age 5 with a severe brain fog/short term memory issue pretty much halting his learning. HIs gait seems fine (enough). He bikes, skis...very little language. Diagnosed with an intellectual disability but we never would have said that before the crash around age 5.
      Does any of this rule out CFD in your opinion?
      I am happy to take him for testing in PA and/or do whole exome genetic testing (he has done testing through Courtagen a few years back --Next generation sequencing for mitochondrial. Is that important testing?)
      Thanks so much.
      Nancy

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    6. Hi

      Petra, it’s great to hear about your appointment, I think this is very good news for your son!

      Can you share in the future what Dr Evangeliou considers worth testing in a person with ASD? Especially among those treatable diseases?

      I talked once more to the doctor I mentioned before and she says that all persons with autism should have creatine metabolism deficiency syndromes (called GAMT/AGAT) checked - they are treatable. If autism is accompanied by other issues then it gets more complicated.

      Also she told me about a condition called GLUT1-deficiency syndrome, in which glucose transportation across the blood-brain barrier is impaired. The classic, severe type does not look like autism, but there have been atypical and milder cases diagnosed recently. Here is an example of autism as a feature of GLUT1-DS:
      https://www.genedx.com/wp-content/uploads/2012/09/91150_SLC2A1_Case_Study1.pdf

      For this doctor, abnormal eye movements (paroxysmal upgaze) and epileptiform sleep EEG without seizures were enough to have my son tested now.
      There are children with autism and movement disorders/abnormal EEG, some of their parents I was even lucky to meet thanks to this blog. The common symptom in GLUT1-DS is also deterioration after fasting and improvement after meal.

      We also found a paper which states:
      “It is important to consider that GLUT1-DS and other channelopathies, such as EA2 caused by mutations of the CACNA1A gene, share chronic and intermittent clinical features and responsiveness to acetazolamide. It is possible that chronic neuroglycopenia may lead to developmental alternations in channel expression or function, causing abnormal neuronal excitability in GLUT1-DS. Responsiveness to acetazolamide may be a key component in the diagnosis of GLUT1-DS”
      http://www.ncbi.nlm.nih.gov/pubmed/24200040

      GLUT1-DS is treatable with ketogenic diet and there is a trial with triheptanoin aka C7 oil, which – in short – some call a “ketogenic diet in a pill”.
      Triheptanoin was found effective in mice model of Rett syndrome: http://www.ncbi.nlm.nih.gov/pubmed/?term=triheptanoin+autism

      The company which is doing this trial offers free genetic testing for those suspected of GLUT1-DS and call doctors to order a free test kit. The test requires a blood draw. All details are on their webpage:
      http://www.glut1study.com/sites/all/themes/ultragenyx/assets/pdfs/Genetic%20Testing%20Ad%20Download%20Version%5B1%5D.pdf

      Perhaps most doctors are not aware of this, but I am sure that it would not be a problem to find one who will order the test.

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    7. Hi Agnieszka, once again we meet in Peter´s blog linked by the same thing!, do you think that my son is suspected of GLUT1.DS? We were right a few months ago when we decided a ketogenic diet or at least the light version!,you can e mail me, and i have a question for Peter,perhaps he can answear me from his point of view, he knows my son´s case. the fact that he is HFA , means that probably has no CFD? Valentina

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    8. Hi Valentina,

      I planned to send you this information, but you've been the first!
      I don't know if your son may have GLUT1-DS. It has usually been diagnosed in people with severe symptoms, but not only. I guess that not many children with autism have been tested, so one cannot say much about the prevalence. There are big gaps in what is known about neurometabolic diseases in ASD I think. This doctor I met said once: "they shouldn't be called rare inborn errors of metabolism, but rather rarely diagnosed ones". Who knows if there can be CFD or GLUT1-DS in HFA if no-one checks? I was lucky to be offered the test as this doctor rembered my son's upgaze recordings, but otherwise I would print the stuff from this company website and bring it to any neurologist to discuss the testing, this seems pretty easy.

      Delete
    9. Valentina, all conditions like CFD are rare, but very many exist on a spectrum from mild to severe. So it is possible. Petra's son also has HFA but the specialist is testing for these rare dysfunctions. It probably is easier to diagnose the severe cases. I think it very good that Petra has found such a helpful specialist. It is important not to get obessessed with all these possible dysfunctions, most people will not have any of them. But if you do have a treatable dysfunction, it would be a pity not to treat it.

      Delete
    10. thanks Peter for your advice, in order to keep the course, i think that the main thing to prevent or to worry in my son´s case is electrical activity, , because for the time being,we can´t prove all this rare dysfunctions, and an abnormal electrical activity can spoil all you have achieved in a second, because it deteriorates all mental processes. I have a consult in b.a with my neurologist in 20 days. we are out of valproate , the question is which would be a better substitute, it seems like he will need more support with electrical activity. Valentina

      Delete

  15. Hello Mr.Peter,

    I'm new to your blog. I don't have a great science background but I'm trying to understand what's going on with my daughter. When she was 2 years old, she could read almost anything in English even though our first language is not English, creative and seemed to have high IQ but did not have any meaningful conversation. She was diagnosed with mild ASD and put on ABA therapy. Now she just turned 7 and her conversation skill is like a 3 year old. Few months back as her milk teeth started falling she developed sudden OCD, panic and anxiety disorder. ( I can't remember whether she had any infections at that time). She is making funny facial gimmicks and wants me to do that along with her. She also seems to be irritable and struggles to focus which is very unlike her.

    I'm going to take all the genetic testing and other blood work you recommend to find what's going on biologically inside her. Mean while do you have any suggestions for me?

    Thank you.

    ReplyDelete
    Replies
    1. There are thousands of individual conditions that lead to autsim:-

      http://epiphanyasd.blogspot.com/2015/12/one-of-thousands-autism.html

      but there are certain common pathways affected. So it is quite likely that you will find some widely used interventions that help your daughter.

      I would suggest you try antioxidants like NAC, which do seem to help 70+% of people with ASD.

      Milk teeth eruption increases inflammatory signaling and it is quite likely that simple OTC Ibuprofen will improve her behavior. If you live in a country where Ponstan is widely used, that would be another choice.

      A great deal of research implicates a key neurotransmitter working as excitatory, instead of inhibitory. If that is the case for your daughter, then both bumetanide and low dose clonazepam might help her. These are prescription drugs used "off-label".

      OCD and tics are different to classic autism and more like Tourette's Syndrome. My son does not have this and so I am no expert on it. There are many ideas about treating OCD/Tics.

      Genetic and metabolic testing is a good idea, because you can then rule out known treatable disorders.

      Delete
  16. Hi Peter, what are your thoughts on Organic Metabolic test and then based on that it can be decided whether NAC and other supplements are necessary or not..

    ReplyDelete
    Replies
    1. You can measure oxidative stress. The best way seems to be to measure the GSH:GSSG ratio. If you have no oxidative stress, do not take NAC. The great majority of people in every study in autism show oxidative stress.

      NAC was the subject of a clinical trial at Stanford. It is very widely used for other conditions that feature oxidative stress. Clearly giving antioxidants to people that have no need of them may cause problems. Also, do not give NAC to people having chemotherapy.

      https://med.stanford.edu/news/all-news/2012/05/antioxidant-shows-promise-as-treatment-for-certain-features-of-autism-study-finds.html

      One doctor, Jill James, who works with Dr Frye, (from my last reply to your other message) published a paper showing how much better people with autism are when oxidative stress is corrected.

      In typical people NAC has no behavioral impact, but in people with autism and oxidative stress the impact is the same day.

      If you live in the US, best go and see Richard Frye/Jill James.

      Delete
  17. Peter, what are your thoughts on zyflamend instead of ibuprofen ?

    ReplyDelete
    Replies
    1. People spend a fortune on supplements, this is huge industry.

      Ibuprofen has certain known effects, but is not for long term use, however if it helps it would point you in the direction of what is going on in your specific case. If you take a herbal mixture of 10 products, how do you know which one(s) where helpful?

      Delete
  18. Hi Peter, I'm trying to get an appointment with Dr. Richard frye in Arkansas childrens hospital. I'm trying to reach other doctors that you and Roger mentioned just in case dr.frye is too busy. It's Christmas vacation and no one is available. After holy days I will start with EEG....GSH:GSSG ratio..If possible I will go ahead with neurometabolic testing.....whole genome sequencing. I have a friendly pediatrician who I think I will be able to convince now thanks to your blog. I had already tested her for MTHFR mutation and she A1298C positive.. So she is taking a supplement called CERENITY which is like you said a mixture of 12 products with folate in it. But the ingredients looked complementary and comprehensive to me. But I don't think Inositol in it is helping her OCD. I'm just trying to educate myself through your blog. It's better than most of the books I read on this subject. She has struggled to gain reasonable height and weight even though she eats healthy. Her cholesterol is high. What does that mean to you?

    ReplyDelete
    Replies
    1. Growth hormones are affected in autism. She is small now, but at birth what percentile was she height/weight and head circumference (if you have it)?

      Cholesterol is high in one large group of autism. The body makes its own cholesterol and sometimes this is a response to inflammation (as in heart disease in older people).

      The side effect of many drugs that seem to help autism is that they lower cholesterol. I do not think this is a coincidence.

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  19. She was healthy. Her weight, apgar score, head circumference..everything was good. She met all her milestones earlier than usual till 14 to 16 months of age..then everything changed after she weaned off..
    ..but if cholesterol is body's repair mechanism then why reduce it using statin drugs?
    Do you think statins are helping in some other way?

    ReplyDelete
    Replies
    1. Statins have many effects, in heart disease they target the inflammation itself and while they do reduce cholesterol, experts think there real benefit is reducing the inflammation that triggered the cholesterol to be produced.

      Cholesterol is is a protective coating, but it gets thicker and thicker and then blocks your arteries. Better to reduce the inflammation in the fist place.

      Some people with classic autism start out as very big babies with perfect apgar, then after a year or two they slip back and become smaller than their peers. This is the progression of the underlying disease. Growth factors are disturbed and so is growth.

      Statins affect RAS and PTEN which are very much involved in autism. They even support remyelination, so there are numerous reasons why some people with autism might benefit, my son certainly does.

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  20. Hi Peter, I want to put my daughter on Astaxanthin. What do you think about that. She has GI issues and could react to NAC.There seems to be lots of research proving astaxanthin's benefit for reducing neuro inflammation. All the studies are done on mice and I can't figure out the appropriate dosage for little people. My daughter weighs 40 pounds. Prior to that I will start her on miyarisan probiotics and brocolli sprout powder. she eats brocolli sprouts in her juice and salad. So I never thought of giving her the supplemental form. From now on I will stick with appropriate dosage and careful/ rational observation.thank you

    ReplyDelete
    Replies
    1. All antioxidants are likely to have a positive effect in someone with autism. I think that NAC and ALA (alpha lipoic acid) are among the best and are well studied.

      As you found, there is a trial showing Astaxanthin to have such an effect.

      Astaxanthin improves behavioral disorder and oxidative stress in prenatal valproic acid-induced mice model of autism.
      http://www.ncbi.nlm.nih.gov/pubmed/25732953

      You would have to experiment to find the dosage. Personally I would use NAC/ALA.

      Delete
  21. Also for your information my daughter drinks a green juice every morning with cranberries and brocolli sprouts in it. She talks a lot after drinking it for a short period. Now I know from reading your blog that probably cranberries acted as 'diuretic' and together with sulforaphane resulted in the improvement.

    ReplyDelete
  22. Hi peter, I started my daughter on 2 doses of NAC six hours apart (500mg each that I dissolve in water) and 2 doses of broccoli sprout extract 500mg each that I powder and dissolve in water. Can I continue to give her CERENITY (from ortho molecular products) for her mthfr ac1298 homozygous mutation? Are there any supplements or medication that should not be given with NAC?

    ReplyDelete
    Replies
    1. NAC seems well tolerated. It is also available as a prescription drug, so you should be able to check online to see if there are drugs that interact with it.

      Delete
    2. I have read that NAC should be given apart from magnesium, don't know why.

      Delete
  23. Hi Peter,

    I was using NAC a year ago, and it was quite effective initially. Later, it appeared to stop working with the allergies and other stresses. I decided to restart and got the Jarrow Sustain. I opened the bottle and there is a rotten egg smell, opened some of the capsules, they are all off. Is this what you are using, and have your bottles been ok?

    ReplyDelete
    Replies
    1. Quality control is not good in supplements. So far the NAC sustain has been good, but the gelatine capsules of NAC often smell bad, but they do work. So some degree of smell does not seem to matter. The effervescent tablets (Pharmanac/fluimucil) are made by a drug firm and are better made, but you pay much more.

      Delete
  24. Nandini seems to have become little bit more hyper after NAC and Broc sprouts extract. Is that normal?

    ReplyDelete
    Replies
    1. The broccoli does have that effect, NAC in most people stops stimming and OCD. In some people NAC stops self injury.

      Delete
  25. Hi Peter,
    Wishing you a happy new year and to Monty.
    Also, My son is currently on NAC (2*900)& ALA 500mg, bumex 5 ml, cloezapam - 0.02 mg, and I got the broccoli sprouts from australia and have been using 2.5 ml for about 10 days.(although he refused 2 times)
    Question is: He continues to run all the time if we leave him alone, and some times makes clenched jaw or a curls his hand and takes them to his mouth (probably all stimming). His therapist said when he is off NAC, he pays less attention and we saw improvement with Bumex. Is there any thing else that will work for his constant running(funny thing is he stops running if I work on a game with him on the ipad- mostly).
    Also, I have seen a little more smiling, but not much else from super sprouts.
    Thanks
    BK

    ReplyDelete
    Replies
    1. One of the first goals of ABA should be get your son to sit still at a table and pay attention to the therapist. While pills can help, there is also a great deal of value in behavioral therapy. Even if he is hyperactive, he can be taught to sit still at work time and run/jump to his heart's desire at break time. If you do not have a trampoline, buy one and use it as a reward for not running around.

      If the broccoli has no clear benefit, I would not bother with it, it may be adding to his hyperactivity.

      Delete
    2. Hi BK,

      My daughter used to be that way when she was younger. A few things helped calm her. The very first was a program we started at home, we set aside a room for her that was very simple, just table and chairs and shelves, and a small trampoline. We also engaged her in various ways, early learning such as sorting, counting, puzzles, music, etc. She had exercise every day, plus an outing in the car to a park, playground etc. Also, got her a theraball/medicine ball for her to sit on, she loved it, even used to eat while sitting on it. I think exercise is key, vigorous and plenty: bicycling, roller skates, skateboarding, snowboarding etc. My daughter also loved her riding lessons, she was taking regular dressage. Challenge him, I think too little is expected and asked of our kids, and they do get bored. He will surprise you.

      It is also interesting what you write about your son being able to focus at work. I have been reading recently about adenosine which is inhibitory, and it seems that intellectual stimulation promotes production of it. It also explains why my daughter asks me for class late at night when she is not able to fall asleep.

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