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Regressive Autism


This blog is mainly about classic early-onset autism and the biology underlying it.

There are many other disorders that also result in autistic behaviours, some of which are much better understood than classic autism.  Today’s post is about Mitochondrial Disease which appears to be the precursor to most cases of regressive autism, according to Dr Richard Kelley, at Johns Hopkins and the Kennedy Krieger Institute.

In well-resourced centers for autism, by which I mean large teaching hospitals in the US, cases of autism are often fully investigated.  First they rule out mitochondrial disease and common known single gene causes like Fragile X.  Next comes the chromosome microarray. The microarray (often referred to as CMA) may identify a genetic cause in 15-20% of individuals with an ASD. 

In the rest of the world no such testing takes place, unless you are very lucky.

If the supplement Carnitine makes you feel better, read on, because you quite likely have some mitochondrial dysfunction and have Asperger’s secondary to Mitochondrial Disease.

If you are interested in regressive autism and particularly if you live outside the US, this post could be very relevant.

In short, medical testing can establish whether mitochondrial disease is present.  If it is present, it may be the underlying cause of the regressive autism, or perhaps just an aggravating factor.  If steps are taken quickly, further damage can be limited and the final outcome much improved.

Some of the therapies are the same as for classic autism, like anti-oxidants but some are the opposite.

Certain common drugs should be avoided like types of painkiller (Tylenol/ acetaminophen/paracetamol and aspirin), statins, steroids, valproic acid, risperidone (Risperdal), haloperidol, and some SSRIs; all are inhibitors of complex I / toxic to mitochondria.

There is at least one emerging drug therapy to treat the mitochondria, as opposed to just limit further damage.

The following extensive extracts are all from a paper by Dr Richard Kelley, at the Kennedy Krieger Institute and the neighboring Johns Hopkins Hospital.  I suggest reading the full original paper.  It is the most useful paper related to autism that I have come across, and that is thousands of papers.


Autism secondary to Mitochondrial Disease (AMD)



Most children with autism secondary to mitochondrial disease (“AMD”) experience a single episode of injury, while a few suffer two or more periods of regression during a characteristic window of vulnerability between 12 and 30 months. The subsequent natural history of AMD is typical for regressive autism, with most children showing partial recovery between 3 and 10 years. The principal clinical differences between AMD and non-regressive autism are, variably, a mild myopathy, abnormal fatigue, and, occasionally, minor motor seizures in the years following the first episode of injury. Others with biochemically defined AMD experience a period of only developmental stagnation lasting several months or more between ages 12 and 30 months and show overall better recovery than those who experience a severe autistic regression during this period of neurological fragility. More noteworthy, but uncommonly identified, are sibs of AMD individuals who have all the biochemical features of AMD with no or only minimal developmental or behavioral abnormalities, such as ADHD or obsessive-compulsive disorder.

While permanent developmental losses in AMD can be substantial, especially in the few individuals who suffer more than one episode of regression, recovery can be almost complete in some children when treatment is started early after the first episode of regression, and a partial response to metabolic therapy remains possible indefinitely. Treatment of AMD includes augmentation of residual complex I activity with carnitine, thiamine, nicotinamide, and antothenate, and protection against free radical injury with several antioxidants, including vitamin C, vitamin E, alpha-lipoic acid, and coenzyme Q10 (CoQ10).

Although a deficiency of mitochondrial complex I may be the most common identifiable cause of regressive autism, the relatively mild biochemical abnormalities often are missed by “routine” metabolic testing. In some cases, all test results are in the normal range for the laboratory, but abnormal ratios of metabolites offer clues to the diagnosis.

The identification of patients with AMD has now become routine Kennedy Krieger Institute, in part because of its specialization in both ASD and metabolic diseases and in part because of the availability of onsite biochemical testing.

Natural History of Autism with Mitochondrial Disease. The natural history of AMD and the events surrounding the period of regression are as important as the biochemical abnormalities in establishing the diagnosis. Before regression, all affected children have had normal or even advanced language and cognitive development and no neurological abnormalities apart from mildly delayed gross motor milestones and hypotonia in a few. Regression often can be dated to a specific event, most often a simple childhood illness, such as otitis media, streptococcal pharyngitis, or viral syndrome, or, rarely, an immunization, most often the MMR vaccine or the former DPT. The common feature of all identified precipitants is inflammation. Regression occurs either acutely during the illness or within 14 days of immunization with the MMR attenuated virus vaccine. Regression is otherwise typical for autism and includes acute or subacute loss of language, onset of perseverative behaviors, and loss of eye contact and other social skills. Although neurological regression in many mitochondrial diseases and other metabolic disorders often occurs because of illness-associated fasting, most children with AMD continue to eat normally during the crisis. Moreover, regression during an illness can occur whether or not there is fever. The nature of the regression and its timing suggest that mitochondrial failure is caused by immune-mediated destabilization of mitochondria as part of a TNF-alpha/caspase-mediated apoptosis cascade [5]. Because “steady state” loading of complex I in brain is close to 50% [6,7], if a child had a 50% reduction in complex I activity due to  aplo insufficiency for a complex I null mutation, just a 5 or 10% further reduction in mitochondrial activity could cause neurons to cross the threshold for energy failure and cell death. 

The well-defined role of nutritional factors in modulating the inflammatory response and the shift from animal fats to vegetable-derived fats in western diets are important factors to consider in the cause and treatment of AMD. The increase in the consumption of pro-inflammatory omega-6 fatty acids in infancy and early childhood over the last generation has been particularly striking. The established role of inflammation in causing mitochondrial destabilization [8,9] could explain an increasing incidence of regressive autism in individuals who have otherwise asymptomatic variants of complex I deficiency, which may have specific adaptive function in host defense and cognitive development [10]. In this respect, AMD, which in our experience is the cause of most regressive autism, could be another inflammatory disorder among several that have seen a markedly increased incidence over the last 20 to 30 years: asthma, inflammatory bowel disease, atopic dermatitis, eosinophilic gastroenteritis, and type I diabetes [11]. The recognition of inflammation as an apparently common cause of regression in AMD recommends the use of anti-inflammatory agents, including ibuprofen and leukotriene receptor inhibitors (i.e. montelukast, zafirlukast), to prevent further injury in children with AMD. For example, the recently reported increased risk for post-MMR autistic regression in children given pro-oxidant acetaminophen [12] could also be interpreted as an increased risk for developmental regression in those who were not given ibuprofen. Moreover, the effect of the gradual elimination of aspirin use in children between the 1980s and 1990s following the Reye syndrome epidemic 6 may have contributed to the rise in the incidence of autism, although, epidemiologically, aspirin elimination alone is not likely to be a major factor in the rising incidence of regressive autism.
  
Although most patients with AMD have a discrete episode of acute or subacute language loss and social regression, some will manifest only relative stagnation of development for a period of several months to a year or more. At least 90% of such events––developmental regression or stagnation––occur in a window of vulnerability between 12 and 30 months.

  
The goals for treatment of AMD due to complex I deficiency are:

1)    Augment residual complex I activity

2)    Enhance natural systems for protection of mitochondria from reactive oxygen species

3) Avoid conditions known to impair mitochondrial function or increase energy demands, such as prolonged fasting, inflammation, and the use of drugs that inhibit complex I.


Combining the first and second parts of the treatment plan, the following is a typical prescription for treating AMD:

L-Carnitine 50 mg/kg/d                Alpha Lipoic acid 10 mg/kg/d
Coenzyme Q10 10 mg/kg/d       Pantothenate 10 mg/kg/d
Vitamin C 30 mg/kg/d                  Nicotinamide 7.5 mg/kg/d (optional)
Vitamin E 25 IU/kg/d                    Thiamine 15 mg/kg/d (optional)



Immediate behavioral improvement with carnitine treatment in a child with regressive autism makes complex I deficiency the most likely cause

Another important clinical observation is that many children with mitochondrial diseases are more symptomatic (irritability, weakness, abnormal lethargy) in the morning until they have had breakfast, although this phenomenon is not as common in AMD as it is in other mitochondrial diseases.

When early morning signs of disease are observed or suspected, giving uncooked cornstarch (1 g/kg; 1 tbsp = 10g) at bedtime effectively shortens the overnight fasting period. Uncooked cornstarch, usually given in cold water, juice (other than orange juice), yogurt, or pudding, provides a slowly digested source of carbohydrate that, in effect, shortens overnight fasting by 4 to 5 hours. 

the MMR vaccine has been temporally associated, if rarely, with regression in AMD and other mitochondrial diseases when given in the second year. Doubtless some of these regressions are coincidental, since the usual age for giving the MMR falls within the typical window of vulnerability for AMD regression. In some children, however, MMR-suspected regression has coincided with the peak inflammatory response on days 8 to 10 post-immunization, as measured by IL-10 levels [28]. Unfortunately, the falling rates of immunization with MMR in the United States and other countries all but guarantees that major outbreaks of measles, mumps, and rubella will occur in the near future


Nutritional Factors Diet is another variable to consider in the treatment of AMD. Vegetable oils that are “pro-inflammatory” due to low levels of omega-3 (n-3) fatty acids and increased amounts of linoleic acid and other omega-6 (n-6) fatty acids today predominate in infant formulas and most prepared foods, largely because 13 of nutritional recommendations to avoid animal fats containing saturated fatty acids and cholesterol. The serious consequences of this trend are now being felt. A study in 2000 [29] showed that two- to four-month old breast-fed infants had more than twice the level of docosahexaenoic acid (C22:6n-3) and higher levels of most other n-3 fatty acids compared to formula-fed infants, although immunological consequences of the difference could not be demonstrated using limited immunological assays in that particular study. While the average child may suffer no obvious ill effects from diets deficient in n-3 fatty acids, the possible proinflammatory effect of these diets could be a contributing factor to infection-induced regressive autism in a child who has a metastable mitochondrial disorder. Moreover, in view of a recent study that associated decreased synthesis of cholesterol with rare cases of non-regressive autism [30], the early termination of breast-feeding and the major shift in infant diets toward low-cholesterol vegetable fats could be contributing factors to the apparent rise in the incidence of both regressive and non-regressive autism. Indeed, studies over the last two decades have shown that absence or early termination of breast-feeding is associated with higher rates of autism [31]. The simplest way to assure a adequate amount of C22:6n-3 and related fatty acids for children on typical vegetable-oil enriched diets is to provide an oil supplement, such as flaxseed oil, which is enriched in the precursors for C20 and C22 n-3 fatty acids, or salmon oils, which contain substantial amounts of DHA and EPA and a relatively low mercury content compared to many other fish species. C. Medications Certain behavior medications used in the treatment of ASD are inhibitors of complex I and, therefore, warrant consideration in treating children with AMD. Although these medications appear to have little effect on overall energy metabolism in individuals with normal mitochondria, clinically significant compromise of mitochondrial function can occur when complex I is impaired and relatively high doses of the more inhibitory drugs are prescribed. The complex I-inhibiting drugs most likely to be used in the treatment of ASD include both typical and atypical neuroleptics, such as risperidone (Risperdal), haloperidol, and some SSRIs. Although these medications are used most often in older children who are beyond the vulnerable period for autistic regression, this theoretical risk should be considered when prescribing older generation neuroleptics, such as haloperidol and related drugs, with a higher risk for development of tardive dyskinesias.

These older neuroleptics have been shown to inhibit complex I activity in direct proportion to their propensity to cause tardive dyskinesia [32]. However, there is no evidence that the newer “atypical” neuroleptics, such as risperidone and quetiapine, which have a low risk for extrapyramidal damage, are contraindicated in children with AMD and other mitochondrial diseases. Indeed one of the commonly used atypical neuroleptics, risperidone, has been shown to possibly against mitochondrial injury via modulation of damaging stress induced calcium influxes into mitochondria [33].



Novel Mitochondrial Drugs

Edison Pharmaceuticals is developing treatments for mitochondrial disease.

EPI - 743
  
EPI-743 is a drug candidate in clinical development primarily focused on inherited mitochondrial diseases. EPI-743 is administered orally, passes into the brain, and works by regulating key enzymes involved in the synthesis and regulation of energy metabolism.
Through expanded access protocols and prospective clinical trials, EPI-743 has been dosed for more than a cumulative 130,000 patient dosing days (as of November, 2013), and has recorded a favorable human safety profile. Subjects with over 15 discrete diseases have been treated. 



Genetic Dysfunctions

The prevalence of mitochondrial disorders (excluding autism) is estimated to be about 1:8500


and yet it is estimated that 1 in 200 people have a defective gene linked to a mitochondrial disorder. 


This implies a multiple hit mechanism, like we saw with cancer in an earlier post.  It also shows the potential to be misled by genetic information.  Just because the defect is there does not mean it will actually cause anything to happen, further rare events may also be needed to trigger it.

Alternatively, maybe there are far more people with a mitochondrial disease than the above studies suggest.  They are not including people with regressive autism, for one.  Something like 1 in 200 people have regressive autism.

  
What happened to Dr Richard Kelley?

If you have read the full paper by Dr Kelley you are probably wondering what else he has to say about autism.  He is an extremely rare mainstream clinician who actually does know about the subject.

You might also be wondering how come such a doctor can write about vaccination triggering mitochondrial disease and then autism, albeit in rare cases.

Perhaps this is why he does not write further about autism?

Dr.Kelley's research has focused on the elucidation of the biochemical basis of genetic disorders. Through the application of various techniques of biochemical analysis but especially mass spectrometry, Dr. Kelley has discovered the biochemical cause, and thereby the genetic etiology, of more than a dozen different diseases.

People do write about autism and mitochondrial disease, but some of these researchers are from the fringe and are not taken very seriously by the mainstream.






31 comments:

  1. excellent article Peter - as always very interesting

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  2. I wish I had known this stuff 20 years ago.

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    1. I wish they had known about this stuff 50-60 years ago.Just a few addendums to what you say.

      There are more severe forms,like I have,where you have nearly all the features of classic autism,but no problems with speech or language.These more severe forms include serious learning disability,but not classic intellectual disability,much as more acute mitochondrial disease can include learning disabilities.

      The initial regressions can occur much earlier,like 6-12 months,if there is an acute infection during this time,as there was with me.

      You really need to include Richard Frye and Vincent Ramaekers in your "Deans List".Both have made important advances in discovering treatable causes of autism.Dr. Frye has discovered that mitochondrial disease in autism,often includes treatable inherited disorders of folate,redox,or tetrahydrobiopterin metabolism,the severity of which corresponds to the severity of the autism.I have the folate stuff.Here is a summary from last year.Dr. Frye has newer research to be published,maybe with other metabolic disorders.
      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4073259/

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  3. Hi Peter,
    Have you heard about Mitospectra developed by Mitomedical, this is the cocktail for regressive autism you mention above. The product seems to be based on Dr.Richard Kellys research.
    From what I have read, it seems like using ALA, carnitine and others mentioned in the cocktail are the only medicine to help with regressive autism, so was wondering why then go through all the chromosal tests like microarray etc.. instead of just using this medicine - just like the trial and error for symptoms of classic autism.
    Thanks
    BK, I have ordered mitospectra, will post once i see how it works
    Thanks

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    1. Dr Kelley seems to believe that regressive autism is always caused by mitochondrial disease. Nothing is black and white in autism, usually it is a shade of grey.

      You can establish mitochondrial disease via metabolic testing at a good hospital lab, it is not so expensive. You only do the genetic testing if you want to know why there is mitochondrial disease.

      I have heard about Mitospectra and the big advantage is its simplicity of use. Because it is a powerful mixture of antioxidants it would improve the symptoms of almost all people with any type of autism. The difference is that in someone with mitochondrial disease it would likely take a few weeks or even months to show effect, whereas in classic autism antioxidants will be effective almost immediately. So if Mitospectra has an immediate effect on your child, it might not be mitochondrial disease.

      Even the term regressive autism is highly subjective. I think all autism is slightly regressive.

      Dr Kelley's mito-cocktail aims to halt the deterioration caused by mitochondrial disease, it does not undo the damage that has been caused; that is case of hoping for self-repair, which seems to vary wildly.

      It is also clear that there can be mitochondrial dysfunction which is a lesser problem than mitochondrial disease. This is claimed to be quite common. If you respond well and quickly to carnitine, it is suggested that mitochondrial dysfunction is likely.

      Dr Richard Frye (University of Arkansas) is another researcher active in the area of autism and mitochondria. He has his owns ideas.

      Both Kelley and Frye see patients. If you live in the US you can always try to see one or both.

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  4. Hi Peter! I am a mother of a 22 year old aspergers from Greece. Things got really worse for my son for the last 3 years, with self injurous behaviours, social withdrawal,gave up his studies at university and generally lots of suffering. He is completely stuck and there is a terminology for this it is called perseveration. he is doing the same repetitive behaviour over and over which finally leads to meltdowns. Do you have any ideas how I can help him?

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    1. I think that perseveration is the Asperger's word for stereotypy. The cure for stereotypy in greater than 50% of people with autism is the antioxidant NAC (N-acetyl cysteine); it is available cheaply in Europe from the big American supplement companies on Amazon. You may find it easier to buy online than in a pharmacy, they all ship within the EU. For his age I would suggest 600mg x 4. For example 1200mg at breakfast, then 600mg after lunch and 600mg in the evening. If it is going to be effective it will change things within 2 or 3 days. If it has no effect then stop. You could even use 600mg x 5.

      Stereotypy is usually caused by oxidative stress and NAC increases the bodies main antioxidant called GSH.

      It was shown to be effective in a clinical trial at Stanford, 3 or so years ago.

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    2. Hi Peter! Thanks for your immediate and so hopeful reply.

      I very much suspect myself that lots of his" burden" is due to oxidative stress. He has recently had an operation and his sleeping disorder got worse. No drugs could help him go to sleep apart from melatonin 3 mg Health Aid. Melatonin doesn't always get him to bed but somehow it gives him a much better mood. Melatonin is an antioxidant and we saw direct stress relief. Then I added spirullina 1-2 tablets a day and saw little more benefit. As I was trying to order brocolli sprouts from Australia and knew it will take time I added Solgar Omnium 2 tablets which has sulforaphane without knowing if it's active. Then again I noticed a great relief after almost 20 minutes. It lasts for about 7 hours. Stereotypy hasn't gone but it seems a little bit better. Now I have my brocolli sprouts delivered, and I should order Nac. I prefer Solgar because I trust this brand. I am a little confused for my next steps. Could you advice me on my priorities?
      Thanks for your concern.
      Petroula

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    3. Hi Petroula, the important thing is to try one intervention at a time; that way you know which ones work, or not.

      The broccoli sprout powder (sulforaphane) will either have an effect within one hour of the first dose, or your son is not a responder. So you can try this one straight away.

      Then order NAC and use it for a few days to see the result.

      As I put in a recent post on melatonin, there are some trials in France looking at higher doses of melatonin. At double the sleep inducing dose, the antioxidant properties become greater. Melatonin has a specific effect on oxidative stress in mitochondria.

      So my suggestion is :-

      1. Try the broccoli powder and if no effect after 3 days just stop.

      2. Try NAC, maybe gradually build up to 4 x 600mg over a few days and hopefully see a good result.

      3. Later on, try a double dose of Melatonin and see the effect

      4. If the double dose of melatonin helps look at other things that help mitochondria, like carnitine and co enzyme Q10 (all Dr Kelley from Kennedy Krieger's ideas for regressive autism)


      Solgar Omnium has numerous useful ingredients including NAC itself. Tumeric is also helpful in oxidative stress. It has flavonoids plus B vitamins etc. In large amounts, Tumeric can be very effective, but it is poorly absorbed, which will be looked at in a new post shortly.

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    4. Great! As for the dose, shall I try half a teaspoon, he is quite big, young adult.

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    5. You can try a whole teaspoon (5ml) since he is big. If he responds you can always reduce the dose to see if it keeps its effect.

      These doses are all lower than the dose suggested on the packaging.

      I give 2.5ml at breakfast and then 1.25ml in the evening.

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    6. Hello Peter!
      You don't mess up with an asperger, I mean he was fine tuned with the interventions I've mentioned before, however I needed desperately to see if sulforaphane works as I wanted the real "himself" effect.
      First day in the morning half teaspoon sulforaphane, twenty minutes later "I'm fine", looked normal. It lasted 2,5 hours and then he started "I'm not OK.Literally or unknown feeling detected as a threat? He wanted more time alone to process. After more' I'm not OK' and as a last resort, though I should have kept one intrevention at a time, I gave him an omnium tablet. then balanced, no mood swings, stereotypy, melatonin at night, some agitation but no further escalation.
      I thought, whenever he had a fever he seemed normal, why doesn't sulforaphane work, he must be a responder.
      Next morning 5mg and ok for less than 4 hours. Then the "I'm not ok" thing. Cognition raised dramatically, solved really difficult maths for fun. He seemed arrogant, irritability,mood swings, wanted to be left alone from times to times,stereotypy decreased. He had an omnium and a spirulina just in case... but so far no escalation... He messed me up. What do you make out of it , is he a responder?

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    7. I think you just need to try various interventions and judge the effect. Since there are so many types of autism, different things help different people. So try the NAC by itself and later add the broccoli and see if the effect is different.

      In typical people the broccoli has no behavioural effect at all. In most people with ASD it improves mood, in most of the rest there is no effect, but in a small number it makes them "worse".

      Your son is a responder, but you are the one to judge if it is positive or negative.

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    8. Hello Peter! This is Petroula.
      Thank you very much for being exceptionally considerate to other people's challenges. Your dedication to autism research in order to help your son Monty, seems to go together with your motivation to share with affected families worldwide.
      The sulforaphane trial ends after day 3 with 7,5 mg. It brought some kind of "normality" and gave my son high cognition but it did not bring good mood.
      He seems a negative responder.
      It is not that I underestimate cognition, which is absolutely important, especially for people who are not equipped with specific brain functions, but if you are not in a good mood you can never be happy and vice versa.
      I start NAC the soonest possible. I raised melatonin dose to 6 mg with good results.
      Peter, my son was diagnosed with Asperger's at 19. My nephew from my younger sister was diagnosed at 10 a few weeks ago and also my younger sister at 40. Now I suspect everyone including myself. It looks as if it runs in the family.
      I'll let you know whenever I have results.

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  5. Hi Peter, i have been trying nac since nearly 3 days and the behaviour improvement is very noticeable, more than any else we have tryed. The sense of wellbeing is so noticeable for my son that he calls it the magic pill. But, like a fairy tale, i call it cinderella effect because it lasts 3 hours more or less. I also must tell you that stereotypies are still there, specially when are sensory triggered. Do I have to increase the dose? Is nac safe in the long run? thanks, Valentina

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    1. NAC has a short half-life. There is a product called NAC SUSTAIN, which is delayed release. I also find that after 3 to 4 hours the effect is lost. It does seem to be safe, we have used it every day for two and a half years. The effect does vary from person to person. In some people it is the key to preventing self injury. I think you need to adjust the size and frequency of the dose to maximize the effect. I use both the regular NAC and the delayed release pills.

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    2. he is 9 , how would you adjust the dose? he is taking 600 mg 3 times daily, regards and thanks

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    3. You can use up to 3000 mg, but if you can find NAC Sustain or split the 600mg in two you can make a more stable level throughout the day. There is also Fluimucil available in many countries, which is NAC as an effervescent tablet, which can be split into two. For our son the morning and early afternoon is the critical period, giving NAC after 6pm has no purpose. So I start the day with 900mg and then give 300mg, or 600mg NAC Sustain about 3 hours later at school. Then at 2pm he has 600mg and again at 6pm.

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  6. Hello Peter, this is Petroula,

    First day with NAC trial, in the morning a tablet of 600 mg and felt OK for about 2,5 hours. Then there was something wrong - anyway he didn't have enough sleep last night so this might also cause him an annoyance. Then another nac tablet and still there was something wrong, as if we had mixed results.
    After I had had a look at your post about nac failure to produce GSH and that it sometimes needs to be combined with B vitamins I gave him an omnium which has B6 25mg, B12 50 mg and B9 200 mg and things got a lot better. He had energy, good mood, seemed normal and focused.
    Now do you think that 2500-3000 mg of nac would be too much for him? Is it ok if I combine it with the omnium?- we can't risk a meltdown. If you have any comments on that please let me know. Thank you

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    1. Hello Petroula, after about 3 hours NAC has lost its effect. NAC does need vitamin B12, but most people have plenty. About 15% of people with autism have a problem with B12 and respond well to large doses of it.

      Maybe your son does not respond to NAC? Some people only respond to a larger amount. The positive response is normally very obvious.

      A small number of people respond badly to all antioxidants,as if they have no oxidative stress. I am sure you can combine it with omnium, but if it does not make him feel better, NAC is not a good idea.

      You can also increase GSH using tumeric/curcumin. I have never done this, but there are numerous supplements claiming to increase bioavailability. There is a special one from Solgar, I think. If NAC does not help, this might be worth a try.

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    2. Hello Peter, it's Petroula.

      Day 2 with NAC trial and things changed dramatically in terms of the "himself" effect I was looking for.

      My initial condition is to try NAC for 3 days. Having "failed" on day 1 and not knowing what to do with NAC, I did it the other way round. I gave him first OMNIUM and after an hour NAC. He was fine.

      Then he started a conversation with my husband about international politics. My husband had shallow arguments but also seemed very confident about his views. My son had a burst out- not a meltdown- and told him that he could either conclude that he was being nonsense or he was trying to manipulate him. He said that being autistic doesn't mean he can't understand things and expects others to give him preoccupied knowledge. He needs to find the truth for himself and also needs respect because he is a grown-up. After I had explained that people sometimes lack the skills to see their contradiction in their reasoning because of several other factors in between, he calmed down nece and easy and went on talking about interesting things.

      Yesterday NAC gave him back some of his lost executive functions. Proper and positive mood according to the context, self control, clarity of mind, awareness,self expression, communication skills and so on.

      Total quantity: NAC 1800 mg every almost 3 hours
      Omnium 2 tbs every almost 7 hours
      Melatonin 6 mg late at night

      The most important thing is to see if NAC has a "permanent" effect and also experiment with the dosage- lasting time and a balanced combination among supplements in 24 h basis.

      Any comments would be more than welcome. Let you know my results. Thank you

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  7. Hi Peter,
    I recently learned something you may already know.Mitochondrial disease is not the only cause of regressive autism.

    I finally got the results of my Whole Exome Sequence last week,and I have been telling everyone I can about it,because it's so unusual.Also in the hopes someone might be able to give me some more information.

    I was expecting the test to say I had genetic mitochondrial disease,because this was what my clinical picture looked like.Instead the test came back with MRE11A mutations and a diagnosis of a de novo type of Ataxia-telangiectasia-like disorder.This was a big shock to me.I had no idea what this was.I have done a lot of digging on the web,and I can only find one case of autism with ATLD.This is a teenage boy who is far more disabled than I am.I found another case,in Italy,that was very similar to mine,except this boy had deletions rather than mutations,and the article did not say if he had an autism diagnosis,but autism was described in great detail.I can post a link if you want.

    Of course there is no known case of Ataxia-telangiectasia-like disorder and cerebral folate deficiency either.I would be the first.

    So now the next step is to try to be seen at Kennedy-Krieger.

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    1. Hi Roger

      Whole Exome Sequencing (WES) is not the wonder diagnostic tool many imagine. You can have a proven metabolic disorder without there being a dysfunction in your exome. More confusingly, you can have dysfunctions found on your exome that are not (currently) being expressed in your body and so may be seen as irrelevant.

      In the case of cerebral folate deficiency:


      Brief Report: Autistic Symptoms, Developmental Regression, Mental Retardation, Epilepsy, and Dyskinesias in CNS Folate Deficiency

      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4131536/


      "No mutations were found in the exons and intron/exon boundaries of genes encoding proteins involved in folate transport (RFC, FRα, FRβ, PCFT), methylenetetrahydrofolate reductase (MTHFR), dihydrofolate reductase (DHFR), and formiminotransferase cyclodeaminase (FTCD)."

      So in those test subjects there was folate deficiency, but the genes were just fine.

      Remember that the exome is just 5% of the genome and in the remaining 95%, where enhancers and silencers are found, there might be something relevant. Also, epigenetic changes will not show up in WES.

      The same is true with mitochondrial disease. Metabolic testing can indicate mitochondrial disease, the patient responds to treatment, but genetic testing finds nothing relevant.

      The main thing is that you have found effective therapies.

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  8. Good evening Peter,
    I am about to order uridine supplement and I need some information.
    Do you know if uridine causes any problems to bones during osteogenesis?
    This might sound irrelevant to autism, but my son is recovering from an Ilizarov limp operation...let's call it an accident... due to severe persevaration and destructive meltdowns.
    We have been lucky with Nac and melatonin because there is evidence that both help during osteogenesis.
    Also according to his blood checking, which was two years ago, he was found 8 in uric acid with maximum 7, but my mum's lab gives maximum 6. What is your knowledge of the maximum level?
    I found Jarrow formulas uridine 250 mg / 60 capsules and thought I should buy it. What is your opinion on the dose? Should I expect a direct response?
    Thanks a lot
    Petroula

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    1. Hi Peter, Petroula,

      Peter, many thanks for the links, big relief to see that something can be done about it. It is sad though, that Ted Page the lead author, has not published much since the early noughts.

      I did find this page: http://www.greatplainslaboratory.com/home/eng/book/ch9.asp

      Wondering if it might be worth testing for the succinylpurines. Also, the urine uric acid. Have you tested for this?

      Peter, do you have access to the full paper? It would be good to see the age/weight of the individual and the basis for the dose increase.

      Again, many thanks.

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    2. Hi RG, I do not have the full paper. I just wrote a post on this subject. You would have to test both blood and urine for uric acid. Both are elevated in the 20% autism subtype with hyperuricemia.

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    3. RG, note my recent post that:

      "A ketogenic diet impairs the ability of the kidney to excrete uric acid, due to competition for transport between uric acid and ketones"

      So this may be relevant in your case.

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  9. Petroula, a small trial in people with bipolar used 500mg twice a day. It was well tolerated. People using it as a nootropic use a similar dose. I would expect to see an effect quite soon. I do not know about the osteogenesis. I think the case study I gave a link for previously used a much higher dose. Trying 500mg twice a day would seem to be the safer option.

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    1. Hi Peter and Hi to you RG,
      Peter, uridine is not available in Greece and just because there are capital controls here I can't order uridine from Amazon. Amazon is not marked as a pharmacy. I tried Double Wood supplement company, they have a prime product of 300mg uridine, and still waiting for my order to proceed.
      Although I am in an emergency, I shall have to wait.
      Petroula

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  10. Hi Peter, I think vitamin E may play an important role in my son's regressive autism.
    About a month ago you advised me on trialling vitamin E as a potent antioxidant and ordered some. The day before yesterday, in the evening, I used 200IU and I had no results during the first 4-5 hours. Then things changed for the better particularly in promptness and skills. His general function seemed excellent, very close to the "himself effect" I am looking for.
    I hope this is not going to loop. If it's vitamin E deficiency in relation with his low LDL, I have to check damage immediately. There may be problems with his GI system, liver, pancreas, retina and other neurological damage.
    Could you possibly advise me on priorities?

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    1. Petra, I would direct the medical questions to your doctor. I doubt he is deficient in vitamin E, you are just seeing the effect of extra vitamin E.

      If you have oxidative stress, all antioxidants should help, but some more than others. Also, oxidative stress is another "umbrella" term, so it depends just where is the oxidative stress and what is the source. It remains a guessing game. If mitochondria is the target, then that special vitamin E is supposed to help, but so is melatonin. Melatonin is cheap and is very potent at reducing oxidative stress affecting mitochondria. Since it will make you sleep, it should be taken just before bedtime. I would compare the effect of the vitamin E to 3mg of melatonin.

      The other thing is to wait and see the effect over time. I found biotin helpful but after too long at a high dose the effect turned negative.

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