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.

More Support for the use of Statins in some Autism

Monty, aged 12 with ASD, has been taking Atorvastatin for two years, with a clear cognitive improvement from day one.  

This improvement is lost when this therapy is interrupted.

There are several posts in this blog giving the scientific basis why statins might be beneficial in some autism, these included the genes/proteins RAS, PTEN and BCL2.  In addition, statins possess potent anti-inflammatory properties.

Following a flood of visits to this blog to read about statins and autism, I did a quick check and in recent weeks at least three papers have been published suggesting the potential for statins to improve some autism.

I include the word “some” because with 800 currently identified autism genes, and I expect eventually it will be thousands, what works for one person’s “autism” may not help the next person’s “autism” and might even make it worse.

The first paper is the one getting the media coverage, it is from the University of Edinburgh, plus Mark Bear et al from MIT.  Mark Bear’s lab has featured in this blog several times, particularly relating to Fragile-X.  Lovastatin is being already trialed in humans with Fragile-X.

I use Atorvastatin (Lipitor) because it has best side effect profile.  Lovastatin and Simvastatin will have the same effect.  In some countries these drugs are available cheaply OTC.

Their therapeutic effect in autism, based on my sample of one, is from the first pill.

Over to the "experts":-

Cholesterol drug could aid autism sufferers

Intellectual disabilities and autism spectrum disorders could share similar defects although their genetic causes are different, according to Scottish scientists.

A study of two models of intellectual disability in mice by Edinburgh University has found that they share similar disease mechanisms.

Researchers also found that treatment with a statin drug called Lovastatin, which is often used to treat high cholesterol, can correct high levels of protein production in the brain linked to the conditions.

The findings suggest that different types of intellectual disabilities may benefit from common therapeutic approaches, the researchers say.

Professor Peter Kind, Director of the University of Edinburgh’s Patrick Wild Centre for Research into Autism, Fragile X Syndrome and Intellectual Disabilities, said: “Statins, such as lovastatin, are already used widely for treating people, including children, for high cholesterol with minimal side effects.

“Further studies are needed to determine whether these existing medications could also help people with intellectual disabilities.”

The study has been published in the Journal of Neuroscience

The full paper is here:-

Convergence of Hippocampal Pathophysiology in Syngap+/− and Fmr1−/y Mice

Abstract

Previous studies have hypothesized that diverse genetic causes of intellectual disability (ID) and autism spectrum disorders (ASDs) converge on common cellular pathways. Testing this hypothesis requires detailed phenotypic analyses of animal models with genetic mutations that accurately reflect those seen in the human condition (i.e., have structural validity) and which produce phenotypes that mirror ID/ASDs (i.e., have face validity). We show that SynGAP haploinsufficiency, which causes ID with co-occurring ASD in humans, mimics and occludes the synaptic pathophysiology associated with deletion of the Fmr1 gene. Syngap^+/− and Fmr1^−/y mice show increases in basal protein synthesis and metabotropic glutamate receptor (mGluR)-dependent long-term depression that, unlike in their wild-type controls, is independent of new protein synthesis. Basal levels of phosphorylated ERK1/2 are also elevated in Syngap^+/− hippocampal slices. Super-resolution microscopy reveals that Syngap^+/− and Fmr1^−/y mice show nanoscale alterations in dendritic spine morphology that predict an increase in biochemical compartmentalization. Finally, increased basal protein synthesis is rescued by negative regulators of the mGlu subtype 5 receptor and the Ras–ERK1/2 pathway, indicating that therapeutic interventions for fragile X syndrome may benefit patients with SYNGAP1 haploinsufficiency.

SIGNIFICANCE STATEMENT As the genetics of intellectual disability (ID) and autism spectrum disorders (ASDs) are unraveled, a key issue is whether genetically divergent forms of these disorders converge on common biochemical/cellular pathways and hence may be amenable to common therapeutic interventions. This study compares the pathophysiology associated with the loss of fragile X mental retardation protein (FMRP) and haploinsufficiency of synaptic GTPase-activating protein (SynGAP), two prevalent monogenic forms of ID. We show that Syngap^+/− mice phenocopy Fmr1^−/y mice in the alterations in mGluR-dependent long-term depression, basal protein synthesis, and dendritic spine morphology. Deficits in basal protein synthesis can be rescued by pharmacological interventions that reduce the mGlu₅ receptor–ERK1/2 signaling pathway, which also rescues the same deficit in Fmr1^−/y mice. Our findings support the hypothesis that phenotypes associated with genetically diverse forms of ID/ASDs result from alterations in common cellular/biochemical pathways.

The other two papers are from 2015 Society for Neuroscience annual meeting in Chicago.

  

Experimental cancer drug eases autism symptoms in mice

A drug that blocks a cancer-related pathway normalizes neuron number and prevents behavior problems in mice that lack a copy of the autism-linked chromosomal region 16p11.2. Researchers presented the unpublished results yesterday at the 2015 Society for Neuroscience annual meeting in Chicago.

Loss of 16p11.2 results in intellectual disability, enlarged head, obesity and, often, autism. This region spans 27 genes — including one called ERK1, part of a signaling cascade that regulates cell growth. The cascade, called the RAS pathway, is hyperactive in some types of cancer and in four rare autism-linked neurodevelopmental disorders, collectively dubbed ‘RASopathies.’ The proteins encoded by ERK1 and the related ERK2 gene carry out many of the molecular consequences of RAS pathway activation.

Paradoxically, the ERK proteins are hyperactive in mice lacking a copy of 16p11.2¹. This hyperactivation coincides with a period of intense neuron development in the mouse embryo. The animals also have too few neurons in some parts of the cerebral cortex, the brain’s outer layer, and too many neurons in others.

“Because of this aberrant ERK hyperactivity, we were thinking that we can potentially try to bring the levels down by using a specific ERK inhibitor,” says Joanna Pucilowska, a postdoctoral fellow in Gary Landreth’s lab at Case Western Reserve University in Cleveland, Ohio.

Sniffing clues:

Pucilowska and her colleagues used an experimental drug that blocks activation of the ERK proteins. They injected the drug into pregnant mice to investigate its effects on neuron development in mouse embryos.

Treating mice with the drug prenatally for five days stabilizes ERK activity, the researchers found. It also normalizes neuron numbers in the cerebral cortex.

The treatment has lasting effects on behavior, too. Unlike untreated mice that lack a copy of 16p11.2 — which are underweight, hyperactive and have memory problems — the treated mice resemble those that do not have the chromosomal deletion.

The researchers discovered for the first time that mice lacking 16p11.2 are quicker than those without the deletion to sniff out a hidden snack in their cage, suggesting they have a highly acute sense of smell, like some people missing 16p11.2. Female mice with the deletion are also faster to retrieve pups that stray from the safety of their nest, an innate maternal behavior. The drug treatment normalizes both behaviors.

Pucilowska says she and her colleagues would like to test the drug in cells derived from people missing a copy of 16p11.2. If it works in human cells the same way it does in mice, then it might be possible to treat people with the deletion using cholesterol-lowering drugs called statins, which are also known to block signaling in the RAS pathway. “This can potentially lead to the first treatment for children with 16p11.2 deletion,” Pucilowska says.

Autism model reveals brain processes behind ‘super’ skills

Structural changes in the connections between neurons may underlie the enhanced learning and motor skills seen in mice with an extra copy of the autism-linked gene MeCP2. Blocking these changes with a drug blunts the animals’ performance.

The findings, presented yesterday at the 2015 Society for Neuroscience annual meeting in Chicago, point to neural mechanisms underlying the restricted interests and, in some cases, exceptional learning abilities seen in people with autism.

“This could lead to enhanced learning and enhanced performance in constrained behaviors, like in autistic savants,” says Ryan Ash, a graduate student in Stelios Smirnakis’ lab at Baylor College of Medicine in Houston. “Maybe they can’t iteratively refine those kinds of behaviors over time, so they get stuck in a behavior, which can be exceptional in certain cases but then impaired in others.”

People carrying an extra copy of MeCP2 often have autism. Mice with the same duplication have autism-like symptoms, such as avoiding social interactions with other mice.

“But they also have a super-learner phenotype,” Ash says. They perform better than controls do on a test of motor skill learning that involves balancing on a rotating rod. Typical mice fall off the rod as its speed increases, but mice with the duplication learn to coordinate their feet so that they can stay on about 30 seconds longer.

When mice learn a motor task, new synapses, connections between neurons, form in the brain¹. The researchers suspected that the superior learning abilities of the mice carrying the extra MeCP2 might stem from alterations in the formation and stability of these neuronal links.

To test this hypothesis, the researchers used microscopy to image neurons in the brain that connect to the spinal cord and control movement. They took pictures of the same neurons before and after the mice practiced the rotating rod test for four days, and again after the animals had four days of rest.

Spine support:

As expected, training spurred neurons in typical mice to form new signal-receiving projections, called dendritic spines. About half of these spines remained after four days of rest, suggesting the formation of stable memories. Mutant mice form more spines than controls do, and more of them stay put after the mice take a break.

The stable spines tend to cluster. Enhanced performance on the rod tracks with a greater number of clustered spines remaining after the rest period.

“We think this is important because spines that are near each other can drive the cell more strongly when they get activated at the same time,” Ash says.

Training stimulates greater activation of a signaling cascade called the RAS pathway in the mutant mice than it does in controls. Activation of this pathway is known to strengthen clustered spines².

Blocking the activation of this pathway with an experimental drug called SL327 lowers the mutants’ performance on the rotating rod back to the normal range. And the spines in these animals also look more like those of typical mice.

The findings suggest that spine formation and stability underlie the enhanced learning abilities of the mutant mice. Both processes appear to depend on the activation of the RAS pathway.

The drug the researchers used lasts only for a few hours, so it is not likely to help people with autism, Ash says. But cholesterol-lowering drugs called statins block activation of the same pathway by a different mechanism. “Maybe you could do a more chronic treatment with a statin, but we haven’t tried that yet,” he says.

Other mouse models of autism show enhanced performance on the rotating rod test. These include mice with a duplication in chromosomal region 15q11-13 and with mutations in the CNTNAP2, NLGN3 and NRXN1 genes, Ash says.

Interestingly, mice that lack a copy of MeCP2 — the gene mutated in the autism-linked disorder Rett syndrome — have impaired performance on the same test, and show reduced spine stability. “I would hypothesize that all of these things are actually the opposite in the Rett mice,” Ash says.

The Brain is Hypothermic in Mitochondrial Disease, but is it in Autism?

Having noted in the previous post something as simple, and measurable, as reduced blood flow in the brain exists in autism, I decided to dig a little deeper.

Not only can you measure blood flow in specific regions of the brain, but using Magnetic Resonance Spectroscopy you can measure the temperature of the brain.

Intense heat production is an essential feature of normal brain energetics; most of the energy used for brain functioning is eventually released as heat.  In the brain, heat is produced mostly by mitochondrial oxidative chemical reactions. Most of the energy required for brain activity is generated from the net chemical reaction of oxygen and glucose; some of this energy (33%) is immediately dissipated into heat, and the rest (67%) is used to synthesize ATP. The final ATP hydrolysis releases part of the energy back to the system as heat.

Note that your core temperature is not the same as your brain temperature.

Brain temperature T_br should be near constant

Increases in Cerebral Blood Flow reduce T_br and increases in brain metabolism increase T_br.

Neuronal activity is temperature dependent, with neuronal firing increasing with increased temperature.  Many other functions in the brain are temperature dependent.

When your brain gets too hot febrile seizures can be the result, caused by excessive neuronal firing.

Mitochondrial Disease

Since heat in the brain is produced mostly by mitochondrial oxidative chemical reactions, when mitochondrial disease is present, it would be expected that there would be less heat and therefore a lower Brain temperature T_br.  This time biology is indeed logical and this is the case.  People with mitochondrial disease have measurably colder brains.

The brain is hypothermic in patients with mitochondrial diseases

We sought to study brain temperature in patients with mitochondrial diseases in different functional states compared with healthy participants. Brain temperature and mitochondrial function were monitored in the visual cortex and the centrum semiovale at rest and during and after visual stimulation in seven individuals with mitochondrial diseases (n=5 with mitochondrial DNA mutations and n=2 with nuclear DNA mutations) and in 14 age- and sex-matched healthy control participants using a combined approach of visual stimulation, proton magnetic resonance spectroscopy (MRS), and phosphorus MRS. Brain temperature in control participants exhibited small changes during visual stimulation and a consistent increase, together with an increase in high-energy phosphate content, after visual stimulation. Brain temperature was persistently lower in individuals with mitochondrial diseases than in healthy participants at rest, during activation, and during recovery, without significant changes from one state to another and with a decrease in the high-energy phosphate content. The lowest brain temperature was observed in the patient with the most deranged mitochondrial function. In patients with mitochondrial diseases, the brain is hypothermic because of malfunctioning oxidative phosphorylation. Neuronal activity is reduced at rest, during physiologic brain stimulation, and after stimulation.

The question is whether this lower brain temperature, in itself, leads to changes in brain function/performance and hence mood, behaviours and cognition.

Mitochondrial Disease in Autism

There are various types of mitochondrial disorder in autism and, confusingly, different terminology is used for similar biological conditions.  Regressive autism triggered by a viral illness, fever, or in some cases a reaction to a vaccine is likely mitochondria-related.

I have covered Dr Kelley from Johns Hopkins ideas on this subject, but there are others.  Here are some other perspectives:-

Has Your Child with Autistic Symptoms Been Properly Screened for a Subset of  Mitochondrial Disease Known as OXPHOS?

Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis

Fever Effect in Autism

It is well documented that in many people with autism their symptoms subside when they are sick and have a fever.  This is the so-called “fever effect”.  It only applies to some people with autism and in a small number the effect can be dramatic.

There are numerous unproven theories.

A Study of Behaviors Associated with Fever in Children with Autism/PDD

Hyperthermia and the amelioration of autism symptoms 

  

Hyperthermia and the Improvement of Autism Spectrum Disorder (ASD) Symptoms

Background:  The observation that some ASD patients manifest clinical improvement in response to fever suggests that symptoms may be modulated by immune-inflammatory factors.  The febrile hypothesis of ASD stems from this observation, and could be due to (1) the direct effect of temperature; (2) a resulting change in the immune inflammatory system function associated with the infection of fever; and/or (3) an increase in the functionality of a previously dysfunctional locus coeruleus-noradrenergic (LC-NA) system.  

Objectives:  To assess the effect of hyperthermia on ASD symptoms.

Methods:  We completed a double blind crossover study of 15 children with ASD (5 to 17 years) using two treatment conditions, hyperthermia condition (102°F) and control condition (98°F) in a HydroWorx aquatic therapy pool.  Five children with ASD without fever response acted as controls, completing only the hyperthermia condition, to ensure safety and feasibility.  Safety measures and Social Responsiveness Scale (SRS) were collected.  Ten patients with ASD and history of fever response were enrolled and received both treatment conditions.  Vital signs, temperature monitoring and clinical observations were completed throughout their time in the pool.  Parents completed the SRS and RBS-R.  Pupillometry biomarker and buccal swabs for DNA and RNA extraction were collected pre and post pool entry. 

Results:  Ten subjects with ASD and a history of fever response were enrolled and completed the hyperthermia condition (102°F) and control condition (98°F) at the aquatic therapy pool.  Improvement during the hyperthermia condition (102°F) was observed in social cognition, using the Social Responsiveness Scale (SRS) total raw score (p = 0.0430) and the SRS Social Behavior subscale raw scores (p = 0.0750); repetitive behaviors, using the Repetitive Behavior Scale-Revised (RBS; p =0.0603) and the SRS Restricted and Repetitive Behavior subscale (p = 0.0146); and on global improvement, using the Clinical Global Impression Scale-Improvement (CGI-I; p=0.0070). 

Conclusions:  This study demonstrates the feasibility of observing the direct effect of temperature in children with ASD, both with and without a history of febrile response, and provides preliminary data on the relationship between body temperature and changes in social and behavioral measures. It explores the direct effects of temperature on ASD symptoms, and offers a window into understanding mechanisms involved in improvement in ASD symptoms during fever episodes.  Behavior changes observed for each child were similar to those observed by parents during febrile episodes, including increased cooperation, communication and social reciprocity and decreased hyperactivity and inappropriate vocalizations. This study is important for the development of translational models on the mechanism of symptom improvement and the identification of novel targets for therapeutic development.

Why not measure Brain temperature T_br in a large number of people with Autism?

The above study at the “Albert Einstein” medical school involved putting people in hot tubs to warm them up and then measuring their autistic symptoms. You would have thought it would have occurred to them to quickly pop upstairs to the MRI to measure brain temperature T_br.  I do not think you need to be an Einstein to think of that.

Perhaps the people that exhibit the fever effect are the ones with low brain temperature T_br ?  That would seem well worth checking.

It also is logical to just warm up the part of the body that will affect behaviour.

Hypothermia in Mouse Models

If you look up hypothermia and autism you again encounter Robert Naviaux, from University of California San Diego, and not much else.  Naviaux is a very clever researcher, but more importantly he just does not give up.  He is doggedly pursuing his antipurinergic therapy for autism.

It turns out that hypothermia is a feature of the maternal immune activation (MIA) mouse model of autism that he is using in his research.

Indeed his antipurinergic therapy corrects this hypothermia.

From:-

Antipurinergic therapy corrects the autism-like features in the poly(IC) mouse model.

Relative hypothermia is a long-term feature of the Poly(IC) MIA Model. This is the lower line (PICSAL), when treated with Suramin, you get the yellow line PICSUR, with a higher body temperature similar to that of the regular mice (blue lines)  When they gave Suramin to regular mice (dark blue line) the was no overall change in body temperature.

So we know that in at least one major mouse model of autism, hypothermia is known feature.  Did anyone measure it in the others?

Conclusion

If raising T_br improves autism symptoms so much, in some people, then why not just figure out a clever way to increase it?

Raising blood flow apparently should lower T_br.

There are likely numerous options like increasing the oxygen level in the blood, which might be expected to increase heat production, for example using Diamox (Acetazolamid). 

Reducing heat loss by wearing a wooly hat, should marginally raise brain temperature, unless the brain then compensates for this.

Since the illicit drug MDMA, or ecstasy, is already known to raise brain temperature, there probably are ways to develop a safe drug therapy to achieve a small increase in brain temperature.  

  

Hopefully Naviaux will find a safe antipurinergic therapy, which might also be used in people with low T_br, as well as broader autism.