A subtype of people with classic autism have uric acid
excretion which is elevated (>2 Standard Deviations above the normal mean).
According
to the research these hyperuricosuric autistic individuals may comprise
approximately 20% of the autistic population.
There is nothing new in these
findings and the research goes back 15 years.
At that time nobody looked too deeply as why uric acid was elevated and
the role of the purine
metabolism in behaviour.
Dr Naviaux
at the University of California is the researcher who is developing antipurinergic
therapy. I suspect his research is
really at the root of what is going on and that high uric acid is just a
consequence of an upstream metabolic dysfunction.
It does
seem that in some people doing just that does produce tangible benefits and not
just in autism; there was even a study in bipolar disorder. In bipolar, verapamil can also sometimes be effective.
Uric acid
Uric acid is a
chemical created when the body breaks down substances called purines. Purines
are found in some foods and drinks. These include liver, anchovies, mackerel,
dried beans and peas, and beer.
Most uric acid
dissolves in blood and travels to the kidneys. From there, it passes out in
urine. A high level of uric acid in the
blood is called hyperuricemia, the standard test though is to measure uric acid in urine.
Purine metabolism and autism
To learn about the purine metabolism and autism, I suggest
you read the research by Naviaux, like the study below:
Autism spectrum disorders (ASDs) now affect 1–2% of the children born in the United States. Hundreds of genetic,
metabolic and environmental factors are known to increase the risk of ASD.
Similar factors are known to influence the risk of schizophrenia and bipolar
disorder; however, a unifying mechanistic explanation has remained elusive.
Here we used the maternal immune activation (MIA) mouse model of
neurodevelopmental and neuropsychiatric disorders to study the effects of a
single dose of the antipurinergic drug suramin on the behavior and metabolism of
adult animals. We found that disturbances in social behavior, novelty
preference and metabolism are not permanent but are treatable with
antipurinergic therapy (APT) in this model of ASD and schizophrenia. A single
dose of suramin (20 mg kg−1 intraperitoneally (i.p.)) given to 6-month-old adults
restored normal social behavior, novelty preference and metabolism.
Comprehensive metabolomic analysis identified purine metabolism as the key
regulatory pathway. Correction of purine metabolism normalized 17 of 18 metabolic
pathways that were disturbed in the MIA model. Two days after treatment, the
suramin concentration in the plasma and brainstem was 7.64 μM
pmol μl−1 (±0.50) and 5.15 pmol mg−1 (±0.49), respectively. These data show good uptake of
suramin into the central nervous system at the level of the brainstem. Most of
the improvements associated with APT were lost after 5 weeks of drug washout,
consistent with the 1-week plasma half-life of suramin in mice. Our results show that purine
metabolism is a master regulator of behavior and metabolism in the MIA model,
and that single-dose APT with suramin acutely reverses these abnormalities,
even in adults.
Hyperuricemia
Purine synthesis is increased approximately 4-fold in hyperuricosuric
autistic patients, so they have elevated levels in their blood and also excrete high levels.
Be aware that there is both Hyperuricemia and Hypouricemia.
It looks like things can easily
get mixed up.
Some people have low levels of uric acid in their blood, because the
excrete too much in their urine.
Causes of hyperuricemia can be classified into three functional types:
increased production of uric acid, decreased excretion of uric acid, and mixed
type. Causes of increased production include high levels of purine in the diet
and increased purine metabolism.
In the case study below where
hyperuricosuric autism was successfully
treated, they actually used a therapy which is claimed for Hypouricemia
You will see reference below to this:-
This is very odd and please let
me know if you think of a logical explanation.
It seems that the therapies for
hypouricemia may treat hyperuricemia in autism.
Here is a summary from Wikipedia:-
Treatment
Idiopathic
hypouricemia usually requires no treatment. In some cases, hypouricemia is a medical
sign of an underlying condition that does require treatment. For example, if
hypouricemia reflects high excretion of uric acid into the urine (hyperuricosuria) with its
risk of uric acid nephrolithiasis, the
hyperuricosuria may require treatment.
Drugs and
dietary supplements that may be helpful
Antiuricosurics
Antiuricosuric
drugs raise serum uric acid levels and lower urine uric acid levels. These
drugs include all diuretics, pyrazinoate, pyrazinamide, ethambutol, and aspirin.
Antiuricosuric
drugs are useful for treatment of hypouricemia and perhaps also hyperuricosuria, but are
contraindicated in persons with conditions including hyperuricemia and gout.
Dietary sources of uridine
Some foods that contain uridine in the form
of RNA are listed below. Although claimed that virtually none of the uridine in
this form is bioavailable "since - as shown by Handschumacher's Laboratory
at Yale Medical School in 1981 - it is destroyed in the liver and
gastrointestinal tract, and no food, when consumed, has ever been reliably
shown to elevate blood uridine levels', this is contradicted by Yamamoto et al,
plasma uridine levels rose 3.5 fold 30 minutes after beer ingestion,
suggesting, at the very least, conflicting data. On the other hand, ethanol on
its own (which is present in beer) increases uridine levels, which may explain
the raise of uridine levels in the study by Yamamoto et al. In infants
consuming mother's milk or commercial infant formulas, uridine is present as
its monophosphate, UMP, and this source of uridine is indeed bioavailable and
enters the blood.
·
Sugarcane extract
·
Tomatoes (0.5 to 1.0 g uridine per kilogram
dry weight)
·
Brewer’s yeast (1.7% uridine by dry weight)
·
Beer
·
Broccoli
·
Offal (liver, pancreas, etc.)
Consumption of RNA-rich foods may lead to
high levels of purines (adenosine and
guanosine) in blood. High levels of purines are known to increase uric acid production
and may aggravate or lead to conditions such as gout. Moderate
consumption of yeast, about 5 grams per day, should provide adequate
uridine for improved health with minimal side effects.
Hyperuricemia
Medications most often used to treat hyperuricemia are of two kinds: xanthine oxidase inhibitors
and uricosurics. Xanthine oxidase inhibitors decrease the
production of uric acid, by interfering with xanthine oxidase. Uricosurics increase the excretion of
uric acid, by reducing the reabsorption of uric acid once the kidneys have
filtered it out of the blood. Some of these medications are used as indicated, others are used off-label. Several
other kinds of medications have potential for use in treating hyperuricemia. In
people receiving hemodialysis, sevelamer can significantly reduce serum uric acid,
apparently by adsorbing urate in the gut
Non-medication treatments for hyperuricemia include a low purine diet (see Gout)
and a variety of dietary supplements. Treatment with lithium salts has been used as lithium improves uric
acid solubility.
Decreased
excretion
The principal drugs that contribute to
hyperuricemia by decreased excretion are the primary antiuricosurics.
Other drugs and agents
include diuretics,
salicylates,
pyrazinamide,
ethambutol,
nicotinic
acid, ciclosporin,
2-ethylamino-1,3,4-thiadiazole, and cytotoxic
agents.
A ketogenic
diet impairs the ability of the kidney to excrete uric acid, due to
competition for transport between uric acid and ketones
Hyperuricosuric
Autism
Abstract
A subclass of patients with
classic infantile autism have uric acid excretion which is >2 S.D.s above
the normal mean. These
hyperuricosuric autistic individuals may comprise approx. 20% of the autistic
population. In order to determine the metabolic basis for urate
overexcretion in these patients, de novo purine synthesis was measured in the
cultured skin fibroblasts of these patients by quantification of the
radiolabeled purine compounds produced by incubation with radiolabeled sodium
formate. For comparison, de novo purine synthesis in normal controls, in
normouricosuric autistic patients, and cells from patients with other disorders
in which excessive uric acid excretion is seen was also measured. These experiments showed that de
novo purine synthesis is increased approx. 4-fold in the hyperuricosuric
autistic patients. This increase was less than that found in other
hyperuricosuric disorders. No unusual radiolabeled compounds (such as
adenylosuccinate) were detected in these experiments, and no gross deficiencies
of radiolabeled nucleotides were seen. However, the ratio of adenine to guanine
nucleotides produced by de novo synthesis was found to be lower in the cells of
the hyperuricosuric autistic patients than in the normal controls or the cells
from patients with other disorders. These results indicate that the hyperuricosuric subclass of autistic
patients have increased de novo purine synthesis, and that the increase
is approximately that expected for the degree of urate overexcretion when
compared to other hyperuricosuric disorders. No particular enzyme defect was
suggested by either gross deficiency of a radiolabeled compound or the
appearance of an unusual radiolabeled compound, and no potentially neurotoxic
metabolites were seen. Although
an enzyme defect responsible for the accelerated purine synthesis was not
identified, the abnormal ratio of adenine to guanine nucleotides suggests a
defect in purine nucleotide interconversion.
Here is a case study regarding the successful treatment of
hyperuricosuric autism with uridine supplementation.
Abstract
A single male subject with
hyperuricosuric autism was treated for a period of 2 years with an oral dose of
uridine, which increased from 50 to 500 mg/kg/day. This patient experienced
dramatic social, cognitive, language, and motor improvements. These improvement
decreased within 72 h of the discontinuation of uridine, but reappeared when
uridine supplementation was resumed. Thus, it appears that patients with
hyperuricosuric autism benefit from metabolic therapy with oral uridine therapy
in a manner similar to that seen in other disorders of purine metabolism in
which there is autistic symptomatology.
Uridine as a therapy in Bipolar
Disorder
Here is a
small trial using uridine to treat bipolar disorder in depressed adolescents:-
Abstract
This report is an open-label case series of seven depressed adolescents
with bipolar disorder treated with uridine for 6 weeks. Treatment response was
measured with the Children's Depression Rating Scale-Revised and the Clinical
Global Impressions scale.
Uridine was associated with decreased depressive symptoms, and was well
tolerated by study participants. Further systematic studies of uridine
are warranted.
Conclusion
In people
with autism and high levels of uric acid in urine and blood, there are some
interesting avenues to pursue. Very
confusingly, they appear to be the therapies more commonly suggested for hypouricemia.
Uridine seems
a good choice worth investigating for children with high levels of uric acid.
Beer is
better reserved for adults with Asperger’s.
It may
indeed turn out that high uric acid is a biomarker for people who will respond
to Naviaux’s antipurinergic therapy.
Peter congratulations on your new article!
ReplyDeleteIt looks very promising to a considerable number of autistic population.
It will take quite a long time to be "digested", though.
Peter, as I don't have instant access to uridine supplement and also begged my son to drink a couple of beers but he wouldn't, do you think I should try Suramin for a start?
Petroula
Suramin is an old drug which can have some highly toxic side effects, so it is not available in many countries. There will be a trial in humans with autism, using a single dose. It is considered that a new drug without the side effects is needed, if that trial is positive.
DeleteUniversity of California, San Diego (UCSD) Suramin Treatment Trial for Autism
Deletehttps://clinicaltrials.gov/ct2/show/NCT02508259?term=suramin&rank=6
Do you know if your uric acid needs to be elevated in both blood and/or urine or only one?
ReplyDeleteAll variants are possible, but do not mean the same thing.
DeleteIf you have low uric acid in your blood and high uric acid in urine, it would imply that you are excreting it too fast, rather than producing "too much".
If you had high uric acid in the blood but low uric acid in the urine, it would imply a problem excreting it.
The cluster identified in the research are producing abnormally high amounts of uric acid and then excreting correspondingly abnormally high amounts. So the odd thing is with the production of uric acid.
Anecdotally, I have found supplementing with Inosine (which is metabolized to urate in the body) has shown improvements in my son. It certainly has not made anything worse.
ReplyDeleteParkinsons disease is a neurodegenerative disease which among its symptoms is oxidative stress and researchers found that patients with higher urate levels were more protected from Parkinsons. The mechanism they believe for this is that the urate activated the nrf2 pathway and released glutathione from the surrounding astrocytes.
http://www.sciencedaily.com/releases/2015/09/150901134946.htm
High levels of uric acid may be a symptom of oxidative stress as uric acid is a potent antioxidant whose levels tend to rise with systemic oxidative stress in the body.
http://www.ncbi.nlm.nih.gov/pubmed/16375736
High levels of uric acid obviously cause gout (not something I want for my child), but the evidence I have seen is that exogenously and safely raising uric acid levels with inosine is neuroprotective, rather than the other way around. Here is some other Inosine links you may want to peruse:
http://www.ncbi.nlm.nih.gov/pubmed/12440381
http://brain.oxfordjournals.org/content/130/4/915
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC124418/
http://www.jneurosci.org/content/29/25/8187.full
Most of these studies deal with stroke and regrowing axons after brain injury, but if you see most forms of classic autism as a developmental form of brain damage (that may or may not be repairable) as I do, then you can probably see my point of view here in that long-term positive outcomes depend on favorably remodeling the brain after a developmental insult (which likely happens in utero).
Thanks Tyler for your very comprehensive comment.
DeleteThere is a big research effort to collect the genetic profiles of thousands of people with autism, it might be far more beneficial (in the short term) to collect metabolic profiles instead. Then you could quickly see things like the correlation between oxidative stress markers and high uric acid. When oxidative stress is treated does uric acid go down.
What we normally have in the literature is data on 30 people, if we are lucky. It would not be such a big step to collect data on 10,000 children, even if it cost $500 per child. In the big world of autism research what is $5 million? Without data, everyone is just guessing, or just not bothering at all.
Agreed. I am just reiterating that everything we do as parents right now is a very gray area for those of us who have put in the time to making our best educated guesses as to what will work. There are plenty of blogs/self-proclaimed experts/psychiatrists/quack doctors/etc. who KNOW how to CURE autism because like anybody else they can find one or more correlations in some study and then assume there is a silver bullet approach to fixing the problem. Like diet advice quacks over the years, they all give simple solutions to complex and perhaps impossible to fully understand problems whether it be human metabolism or autism. The more we learn, the more questions are raised.
DeleteAs to what serious researchers are thinking right now with regards to autism at the moment:
https://sfari.org/updates-and-events/sfari-blog/2014/what-we-know/autism-what-we-know-what-is-next
Bumetanide is mentioned there which I also might add I started with my son a few days ago and am seeing some subtle cognitive improvements. Much thanks to you for suggestions on where to source this stuff from.
In many studies, uric acid is used as a marker of antioxidant capacity, a good thing. Though there is a difference between acute, transient hyperuricemia and chronic.
Deletehttp://www.ncbi.nlm.nih.gov/pubmed/17409313
To get a spike in uric acid, some apples should probably do it:
http://www.ncbi.nlm.nih.gov/pubmed/15203196
Hormesis?
http://www.ncbi.nlm.nih.gov/pubmed/17157175
This comment has been removed by the author.
DeleteRG, it is not entirely clear what is going on. The great majority of people with autism have oxidative stress and yet only a minority have high uric acid. It does seem that some people with autism feel better with even more uric acid. Clearly too much uric acid will be bad. So it is another case where some experimentation is needed to get at the answer. Uridine or inositol are among the choices. Inositol is known to help a wide variety of conditions, but, based on very small studies, not autism or schizophrenia. Inositol is very cheap and widely used, whereas uridine is expensive. Based on the above post, we know that at least on person benefited greatly from high dose uridine.
DeleteDoes the role of inositol seem to be clear in the treatment of hyperuricosuric autism? If so, do you think that inositol is needed more or less?
ReplyDeleteThank you
Petroula
Petroula, nothing is totally clear.
DeleteInositol does have some known benefits for certain conditions, including OCD. It also has properties unrelated to hypo/hypouricemia.
"Some preliminary results of studies on high-dose inositol supplements show promising results for people suffering from problems such as bulimia, panic disorder, obsessive-compulsive disorder (OCD), agoraphobia, and unipolar and bipolar depression.[23][24][25]
In a single double-blind study on 13 patients, myo-inositol (18 g daily) was found to reduce the symptoms of OCD significantly, with effectiveness equal to SSRIs and virtually without side effects.[26] In a double-blind, controlled trial, myo-inositol (18 grams daily) was superior to fluvoxamine for decreasing the number of panic attacks and other side effects.[23]
Similarly large doses of inositol have been studied for treatment of depression. A 2004 meta-analysis by randomized controlled trials, with mixed results. The authors concluded the evidence is insufficient to determine whether inositol treatment can reduce depression symptoms, but no evidence of harm or negative side effects is seen.[27]"
Sorry Peter, I must have confused inositol with inosine.
ReplyDeleteNow that I can see Tayler's comment I think I have the answer. Uric acid is high in some autism because it is an antioxidant. Uric acid also causes gout. We don't want the gout but we need the antioxidant properties, so we let inosine to regulate things.
Petroula
Hi Petroula, insitol is interesting. It will increase uric acid and has similar antioxidant effects to NAC. It is very widely used for OCD and especially by women with PCOS (https://en.wikipedia.org/wiki/Polycystic_ovary_syndrome) and now people with type 2 diabetes. If you buy the powder it is quite cheap.
DeleteIf NAC helps, it may be worth trying inositol, regardless of its effect on uric acid. It is not working the same way as NAC, but seems to treat some of the same conditions.
Hello Peter, I am glad you approve inositol for a trial. I also find it interesting and of course it is on the list.
ReplyDeleteMy adult son doesn't like beer, powders, among with so many other things, but he likes tablets!
Speaking of powders,the sulforaphane trial, from which I had mixed results, should be repeated with tablets this time.
Meanwhile, I am expecting Double Wood Uridine from USA. It has been shipped.
Now , as for Nac, we have an excellent base to start with. Nac gives self control together with awareness which leads to cognition. He repeatedly says" I have got rubbish in my mind" and I think that my next step is to address to that .
Uridine is supposed to help make new neuro connections leading to "growth". So my expectation from Uridine is to help him out of the "rubbish".
There is an experiment with a mouse mother who developed antibodies against her embryo and also had IL6 injections. Her offspring adult mouse was found disabled to inhibit thoughts and filter sensory input. This sounds familiar to me.
Thanks for being so helpful
Petroula
Hello Peter, You said that we needed large doses of inositol. Solgar Inositol is 500 mg/tb. How many tablets do you think I could start with? In Omnium there are 75 mg Inositol and 75 mg Choline and maybe they already give benefit, I have to trial and find out.
ReplyDeleteThank you
Petroula
Petroula, people seem to use Inositol powder. It is much cheaper than the tablets and does not taste bad.
Deletehttp://www.swansonvitamins.com/swanson-premium-pure-inositol-powder-8-oz-227-grams-pwdr
As you see the suggested dose given is 6g a day. One scoop of the powder.
There have been many small trials of Inositol in various neurological conditions. Some people it helped and others it did not. The trial in autism was tiny, but did not show a benefit. But given how many sub-types of autism exist, this does not really say a lot. It is simple to try it.
Hi Peter, thank you very much for your quick reply. I had time to cancel my order.
DeletePeter here is a scenario: Broccoli seems to be a "key word" in hyperuricosuric autism, too.
1) Broccoli is supposed to produce uridine.
2) Uric acid activates nrf2 pathway and so does sulforaphane.
But " Is it certain 100% that SFN is the only bebeficial compound produced by eating broccoli?"
In the case of hyperuricosuric autism broccoli may do just fine.
A trial with broccoli extracts gave me some preliminary results.
In twenty minutes time there was a huge laughter. It was relevant and occured from a top comment in a football blog. Then euphoria came. He was very talkative with relevant speech. He had a little stimming, though. Generally he seemed hyper in reciprocation and cognition.
He agreed to add the broccoli in his daily supplementation.
He only had 1500 mg of broccoli extracts, maybe it's too little.
I think 3 days with it would give me a clearer conclusion.
Thank you very much, your question is very inspiring!
Petroula
I think the broccoli powder can really do no harm and it does indeed really help some people. That group are the ones with the laughter about 20-30 minutes after the first doses. I think it is good for long term use.
DeleteThis comment has been removed by a blog administrator.
DeleteSorry Peter, I send my reply twice by mistake. Could you please remove it?
DeleteAlso, trying to figure out why the supersprout SFN activated powder didn't work for us and the broccoli extracts tablets worked, always according to your checklist of expected results, I almost forgot the most important . I have to trial for at least 4 weeks.
Thank you very much for kind reminder.
The tablets we use contain the SFN amount of almost 4,5-5 mg total in three tablets.
Petroula
Petroula, there are substances in broccoli sprouts other than the precursors to SFN. None of these supplements are reliable like prescription drugs, so it is a bit hit and miss and one jar may not contain what is on the label, or be the same as a jar from the previous batch.
DeletePeter, just a few things about Bumetanide.
ReplyDeleteIn the case of hyperuricosuric autism, Bumetanide isn't mentioned among other diuretics. Do you think that it could be as effective as the other diuretics mentioned? Anyway I understand that Bumetanide applies to a greater autism population and the specific label of autism subtype doesn't really matter, so maybe just for the information.
Also Bumetanide should go together with potassium and magnesium, right? I have the magnesium almost 150 mg with vitamin 6 but I can't find the right amount of potassium in Greece. There are pills in the pharmacy containing almost 700 mg per tablet. Is it ok to buy?
One of my problems in my trials is the fact that I don't have instant access to supplements. Ordering them abroad can be a waste of time. For example I ordered Uridine from USA and although the company sent it at once, the parcel has been stuck in the customs for quite a lot of time.
Peter, I don't suppose we could create the Bumetanide effect with something "natural", a herb or anything...couldn't we?
Thanks a lot
Petroula
I think you need the real drug, bumetanide. For the potassium supplement, just break it in half and then you have 2 x 350 mg.
DeleteIf you can check potassium levels before starting, this is best. Then check again 2 weeks after starting when level should have become stable.
I think bumetanide will also have an effect on uric acid.
Bumetanide is a key foundation to my son's therapy. It has a profound impact. Other things do indeed help, but most on a much lessor scale.
Hi Petroula,
ReplyDeleteHave you tried the Uridine yet? What is the dose you are trying?
I bought the Jarrow which is 250mg per capsule, and just realized that I have made a fundamental error in calculating dosage. I missed the /kg part which takes the recommended dosage for autism into the gms. At 150mg/kg, that would be about 7gms for my daughter. There appears to be only source for powder to dose at that level: a website called powder city.com.
I also found this: a patent filing for uridine in autism, and at the very bottom a detailed case study.
http://www.google.com/patents/CA2425593A1?cl=en
Hi RG,
DeleteThanks for asking.
As I have already posted to Peter, yes I've been trying it but for only 4 days now, starting low 300mg, then 600mg and yesterday 900mg. Today hopefully I'll reach 1200 mg.
I use Double Wood Uridine capsules, 300 mg per capsule.
I think I should stop at 1200 mg for a while, maybe the recommended dose is too much? I am not sure yet.
Trials in young adult sons can be difficult to evaluate since my son has to face the music of his unexplained actions. I mean that there are many unpleasant concequences in his life and I have to evaluate his reasonable reaction according to that cotext. Considering that, anger and frustration would be expected but on the whole I can see more of himself.
Thank you very much for the link, I'll have to check it before I go on with Uridine.
We could talk about Uridine trials again when hopefully we have more results.
Thanks Petroula. Here is another report on four children:
Deletehttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC23552/
I would appreciate it if you could keep me informed about your uridine experience, as I am planning on starting only after I find a reliable source for the powder.
I have a daughter with the 16p.11 chromosomal deletion. She's 11 years old and for years we've struggled to get her the help she needs to be successful in school. Can you put us in touch with someone who could give us some idea of we could try the blood pressure meds on her to see if the help? We'd greatly appreciate it.
ReplyDeleteThank you,
Gregory Bonnette
Gbonnette74@gmail.com
Thank you for posting this information. I have a son with asd. I purchased uridine as a supplement for cognitive support. I am hopeful it will be of some benefit. The uric acid dysfunction is very interesting. We have extended family affected by gout issues so it could explain a lot.
ReplyDeleteI just want to add that like Tyler I've seen some positives in my kids while taking inosine - less strange vocalizing and motor tics. We have low function of Adenosine Deaminase (shows as low homocysteine levels) which is why we trialed inosine. It's just very expensive and difficult to get here in Canada do we have not done it recently. All that to say that it is true that some on the spectrum have low uric acid levels.
ReplyDelete