Autism Biology, Comorbidity, Mortality and Better use of Existing Research

Karolinska Institutet, the Medical University of Stockholm, viewed from garden next door

It is sometimes disappointing how the level of understanding of Autism, even among supposed experts, is so very low.

As readers of this blog are aware there is already a vast wealth of research in autism, highlighting many biological differences and comorbid medical conditions.  Not surprisingly this is reflected in life expectancy.

Autistica, a UK Autism charity, is trying to raise $15 million to fund five years of research into why there is premature death in autism.

This would be a complete waste of money, since the answers already exist in the literature if this “Autism Research” charity employed people who actually could/did read the research.

This subject dates back to a Swedish study from last year that is languishing behind a pay wall, so no open access to it.


The rather skimpy abstract:

Premature mortality in autism spectrum disorder.

  
The rather underwhelming press release from the Karolinska Institute:-

People with autism run a higher risk of premature death

Courtesy of SFARI we have this graphic and highlights.

Large Swedish study ties autism to early death

·        Autistic adults with a learning disability were found to die more than 30 years before non-autistic people.

·        The study found that on average people with autism died over 18 years earlier than non-autistic people.

·        Autistic adults with a learning disability are 40 times more likely to die prematurely due to a neurological condition, with epilepsy the leading cause of death

·        Autistic adults without a learning disability are 9 times more likely to die from suicide

 Autistica did produce a report that is based on the Swedish study:-

Personal tragedies, public crisis - The urgent need for a national response to early death in autism

Is there anything new here?

Epilepsy

People might rather not discuss it, but there are numerous examples of well-known people who had a child with severe autism, MR/ID and epilepsy, and it all ended pretty much as suggested in the Swedish Study.  A fatal seizure (SUDEP), or an accident like drowning following a seizure.

The logical thing to do is to prevent epilepsy developing in the first place, which some readers of this blog are already endeavoring to do.   This is not fantasy, just hard to prove it worked.

Suicide

We have seen that anxiety can be a key problem for people with Asperger’s. 

We heard from a UK pediatrician who found an off-label treatment, Baclofen, which was effective in most cases.  We also were told why he/she did not want to continue prescribing it do to the lack of any clinical trials supporting its use.

We saw how Prozac, the anti-anxiety pill frequently prescribed in autism has the known side effect of increasing suicidal thoughts.

We saw a long time ago in my hypothesis on TRH, that the US military is developing a TRH nasal spray to reduce the suicide rate in soldiers returning from combat.  A homemade version of this nasal spray was used for years by a US doctor/author to treat various neurological disorders.

We do not need to worry about suicide and people with Strict Definition Autism (SDA), but they are highly prone to accidents like drowning, caused by a combination of being allowed to wander off unsupervised and not knowing how to swim confidently.

Medical Comorbidities

Autism has a long list of known medical comorbidities and not surprisingly they will show up as a cause of death.

By accurately treating a person’s autism, you will at the same time be treating some of their comorbid conditions.

For example, if you have a problem with calcium channels (like Cav1.2) in your brain, you should not be surprised to have problems in other parts of the body where they are heavily expressed, so the heart and pancreas for Cav1.2.

The medical comorbidities are indeed a valuable tool to identify the possible biological dysfunctions underlying a person’s autism.  Then you can treat them at the same time, with the same drug.

Bipolar and Schizophrenia

In the case of autism’s adult-onset big brothers, namely bipolar and schizophrenia, there is a reduction in life expectancy of 10-20 years.

By comparison, type 1 diabetes on average reduces life expectancy by 20 years.  But you do not have to be Mr/Ms Average; if you control your condition well and also improve insulin sensitivity (ALA, NAC, Cinnamon, Sulforaphane, Cocoa flavanols etc.) the future can be bright.

People with Bipolar or Schizophrenia have a high suicide risk, in common with Asperger’s, but they also have high levels of substance abuse, starting with smoking and alcohol and going up the scale.

The core biological dysfunctions in both Bipolar and Schizophrenia are studied and some evidence-based therapies exist, lying forgotten in the literature.


Sweden as a Model

The autism mortality statistics in this post are based on Swedish data.  Sweden is not typical.  Sweden is possibly the best country in the world to live in if you have a physical or mental disability.  It is remarkable inclusive and the less able are well looked after.  So if the data existed for other countries, it would very likely look even worse. 

Conclusion

I think quasi-science organizations, like Autistica, are not helping and just add to the public misunderstanding of autism.  It is highly complex, but a great deal is already understood.  

Better use should be made of what is already known. It cannot be adequately explained in tabloid TV, or a few sound bites.

Why don’t researchers/Institutes like the Karolinska Institute, Stockholm, pay up a couple of thousand dollars and make their excellent research open access? 

As we saw when we looked at Down Syndrome, life expectancy is a case of out of sight is out of mind.

What do Autistica think the age at death of someone with autism+MR/ID +epilepsy was in 1960?

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445685/figure/F2/

In the Down Syndrome chart above, you just had to stop locking them up in institutions as babies, for them to have a better prognosis.

Since the 1970s, society no longer locks up toddlers with autism either, so now they live longer.  To live as long as other people, they need some help from science.

If you treat the underlying dysfunctions in people with autism, bingo they will live longer.  You do not need $15 million to figure that out.  You do need an open mind.

Cognitive Impairment in Schizophrenia, Bipolar & Autism

Neurological/neuropsychiatric disorders are often poorly described and poorly treated, but adult-onset conditions have historically been taken much more seriously and so the research is more advanced .  I find myself quite often looking at research on schizophrenia and bipolar; many of the same genes and metabolic dysfunctions common in autism show up in those conditions.

Many people really dislike the term Mental Retardation (MR), which is actually a very accurate descriptive term, meaning that someone is cognitively behind their peers.  Most lay people have no idea what Intellectual Disability (ID) means.

It is interesting that about 90% of people with schizophrenia and 50% of people with bipolar are cognitively behind their peers.  I suspect the figure for autism would also be about 90%, if someone measured it.  Most people with Asperger’s are not top of the class.

Only in extreme cases of being cognitively behind their peers, when their IQ is less than 70, does a person get diagnosed with MR/ID.

So the clinical diagnosis of MR/ID is just an arbitrary cut-off point.  The idea that if IQ is greater than 70 there is no cognitive deficit is entirely flawed.

It seems than in autism, as in schizophrenia and bipolar we should assume that cognitive dysfunction is present; the only question is how much and what to do about it.

Having treated the cognitive dysfunction(s), the person is then in a better place to compensate for the other dysfunctions they might have.

Even though the psychiatrists and psychologists will tell you that autism is all about the triad of impairments, I think they are missing the most important element, which is cognitive dysfunction.

As people with autism age, many find their symptoms associated with the above “triad of impairments” mellow.  The substantial minority who experience untreated flare-ups driven by inflammation caused by things like allergy, GI problems and even juvenile arthritis may not be so lucky.

I imagine that cognitive function in adulthood remains at the level it reached as a teenager.

Cognitive Function as the Therapeutic Target

Since many children with autism do eventually overcome many of their challenges in childhood, perhaps cognitive function really should be given a higher priority in treatment and research.

Many caregivers and educators are mainly focused on minimizing bad/disruptive behaviors (and bruises) rather than the emergence of good behaviors and learning.  This is sad but true.

As the child matures, in many cases these bad/disruptive behaviors may fade without any clever interventions.

So an intervention that stops stereotypy in a toddler, which was blocking learning, may have very much less impact in an adolescent.  Or at least the impact may be much less obvious.

I remember reading about a parent with two children with Fragile-X who was very upset when the Arbaclofen trials were halted, since her kids had responded well.  But two years later in another article it was clear that things were going fine without Arbaclofen.  The son whose violence towards his mother had been controlled by Arbaclofen, was no longer aggressive.  He continued to suffer cognitively, being a male with Fragile-X, the sister was much less affected  (females with fragile X syndrome have two X chromosomes and only one of the chromosomes usually have an abnormal gene, so usually females are less affected).   

The advantage of using cognitive function as a target is that it is much easier to measure than subjective behavioral deficits.  For the majority of people it is likely to be the most important factor in their future success and well-being.

In the substantial minority of cases where there are seizures and/or factors causing autism flare-ups, the behavioral deficits may remain undiminished into adulthood.  These people would also benefit from maximized cognitive function.

Cognitive Deficit in Schizophrenia & Bipolar (BPD)

To most lay people schizophrenia is characterized by abnormal social behavior and failure to recognize what is real. Common symptoms include false beliefs, unclear or confused thinking, hearing voices, reduced social engagement and emotional expression, and a lack of motivation. People often have additional mental health problems such as major depression, anxiety disorders, or substance use disorder. Symptoms typically come on gradually, begin in early adulthood, and last a long time.

Cognitive impairments and psychopathological parameters in patients of the schizophrenic spectrum.

  

Abstract

Cognitive impairment is a core feature of schizophrenia and it is considered by many researchers as one of the dimensional components of the disorder. Cognitive dysfunction occurs in 85% of schizophrenic patients and it is negatively associated with the outcome of the disorder, the psychosocial functioning of the patients, and non-compliance with treatment. Many different cognitive domains are impaired in schizophrenia, such as attention, memory, executive functions and speech. Nowadays, it is argued that apart from clinical heterogeneity of schizophrenia, there is probable heterogeneity in the accompanying neurocognitive dysfunction. Recent studies for cognitive dysfunction in schizophrenia employ computerized assessment batteries of cognitive tests, designed to assess specific cognitive impairments. Computerized cognitive testing permits for more detailed data collection (e.g. precise timing scores of responses), eliminates researcher's measurement errors and bias, assists the manipulation of data collected, and improves reliability of measurements through standardized data collection methods. The aims of the present study are: the comparison of cognitive performance of our sample of patients and that of healthy controls, on different specific cognitive tests, and the testing for possible association between patients' psychopathological symptoms and specific cognitive impairments, using the Cogtest computerized cognitive assessment battery. 71 male inpatients diagnosed with schizophrenia or other psychotic spectrum disorders (mean = 30.23 ± 7.71 years of age), admitted in a psychiatric unit of the First Department of Psychiatry, Athens University Medical School, Eginition Hospital (continuous admissions) were studied. Patients were excluded from the study if they suffered from severe neurological conditions, severe visual or hearing impairment, mental retardation, or if they abused alcohol or drugs.

Bipolar disorder, also known as bipolar affective disorder or manic depression, is a mental disorder characterized by periods of depression and periods of elevated mood. The elevated mood is significant and is known as mania or hypomania depending on the severity or whether symptoms of psychosis are present. During mania an individual feels or acts abnormally happy, energetic, or irritable. They often make poorly thought out decisions with little regard to the consequences. The need for sleep is usually reduced. During periods of depression there may be crying, poor eye contact with others, and a negative outlook on life

It also turns out that cognitive deficit is generally present in bipolar disorder (BPD).

Understanding Cognitive Impairments in Bipolar Disorder and Psychosis

  

“One area that Dr. Burdick is exploring is the frequency of neurocognitive impairment in BPD. Research shows that approximately 90 percent of schizophrenic patients suffer from cognitive deficits compared to only 40 to 60 percent of BPD patients. Understanding why certain patients develop significant cognitive difficulties while others do not is critical in optimizing patients’ quality of life, she says.”

Bipolar is probably not something you would connect with autism.  Being an observational diagnosis you would not tend to look at the biological underpinnings. The biological basis of both bipolar and schizophrenia are far better studied than autism and do significantly overlap with it.

In a recent post I looked at epigenetics and autism, when it comes to schizophrenia and bipolar the role of epigenetics is far more in the mainstream.

There is an approved epigenetic therapy (the HDAC inhibitor Valproate) for Bipolar mania and there is a clinical trial to improve cognitive function in schizophrenia using ather epigenetic therapy (the HDAC inhibitor Sodium Butyrate.)

Butyrate is also showed promise in a mouse model (D-AMPH) of Bipolar.

Sodium Butyrate For Improving Cognitive Function In Schizophrenia

Epigenetic mechanisms in schizophrenia

Effects of sodium butyrate on oxidative stress and behavioral changes induced by administration of D-AMPH

Conclusion

I think people should be more open to discuss cognitive deficits and not hide behind politically correct terminology.

It seems that in both bipolar and schizophrenia cognitive deficits are recognized to be at the core of the disorder, even though 99% will not have an IQ<70 and so not be labelled with MR/ID.

Autism therapies which clearly improve cognitive function, like Bumetanide and low-dose Clonazepam, should be promoted as such.  Clinical trials should measure the cognitive improvement separately from autism measures.  As the person ages I think the benefit will often be more noticeable/measurable cognitively than behaviorally.

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.