The Hyperuricosuric Subtype of Autism, Uridine and Antipurinergic Therapy

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.

In the meantime, is there any benefit of treating people with autism and hyperuricemia?

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:

Reversal of autism-like behaviors and metabolism in adult mice with single-dose antipurinergic therapy

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:-

Antiuricosuric drugs are useful for treatment of hypouricemia and perhaps also hyperuricosuria

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:-

Hypouricemia

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

·         Inositol

·         Antiuricosurics

                          

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

Purine metabolism abnormalities in a hyperuricosuric subclass of 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.

Metabolic treatment of hyperuricosuric autism.

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:-

Open-Label Uridine for Treatment of Depressed Adolescents with BipolarDisorder

           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.