Hyperuricemia present in both medicated and unmedicated kids with autism

I was intrigued to read the findings reported by Natchaya Vanwong and colleagues [1] talking about the presence of hyperuricemia - an excess of uric acid in the blood - in their cohort of children and young adults diagnosed with an autism spectrum disorder (ASD). Intrigued not only because the authors discuss how the use of the atypical antipsychotic risperidone might *correlate* with elevations of uric acid but also how: "Hyperuricemia was present in 44.70% of risperidone-naïve patients with ASD."

Uric acid, more readily associated with the condition gout, has been mentioned before on this blog in the context of autism (see here) and other conditions/states (see here) not totally unfamiliar to autism. It's therefore not necessarily new news that elevations of the stuff might have been found again. The Vanwong study looked at uric acid levels in "127 children and adolescents with ASD treated with risperidone and 76 age-matched risperidone-naïve patients with ASD" alongside a few other biological parameters. They concluded that yes, quite a few participants in their cohort presented with hyperuricemia "defined as the level of uric acid concentration in the blood >5.5 mg/dL" bearing in mind no 'not-autism' control group was included for direct study (including those not diagnosed with autism but in receipt of risperidone).

Implications following the Vanwong study? Well, bearing in mind that gout is traditionally seen as a disease of middle-to-older age, the first thing would be to screen for gout in those with high uric acid levels and keep monitoring just in case gout develops. Next up would be to perhaps also look at some of the "rare inherited genetic disorders that cause hyperuricemia" and whether they might 'overlap' with the presentation of autism; y'know in the context that 'autism genes are probably not just genes for autism' and all that. At this point, I'm also minded to remind readers of the important (but often forgotten work) by Mary Coleman and Ted Page [2] on the topic of autism and uric acid, bringing in purine metabolism 'issues' as something potentially important to some autism (uric acid comes about as a consequence of the metabolism of purines). This, in the context of the autisms (plural)...

Insofar as the potential correlation posed between uric acid and risperidone usage, a word of caution is perhaps warranted but big words about 'risperidone causing hyperuricemia' are not required at this point in time without further study. Remember: "Hyperuricemia was present in 44.70% of risperidone-naïve patients with ASD and 57.50% of ASD patients treated with risperidone." I say this mindful that there are biological parameters that do need careful inspection when such antipsychotic therapy is put in place (see here) but the data is not yet so convincing when it comes to uric acid elevations and risperidone use.

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[1] Vanwong N. et al. Hyperuricemia in Children and Adolescents with Autism Spectrum Disorder Treated with Risperidone: The Risk Factors for Metabolic Adverse Effects. Front. Pharmacol. 2017. 5 Jan.

[2] Page T. & Coleman M. Purine metabolism abnormalities in a hyperuricosuric subclass of autism. Biochim Biophys Acta. 2000 Mar 17;1500(3):291-6.

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Vanwong N, Srisawasdi P, Ngamsamut N, Nuntamool N, Puangpetch A, Chamkrachangpada B, Hongkaew Y, Limsila P, Kittitharaphan W, & Sukasem C (2017). Hyperuricemia in Children and Adolescents with Autism Spectrum Disorder Treated with Risperidone: The Risk Factors for Metabolic Adverse Effects. Frontiers in pharmacology, 7 PMID: 28105014

Suramin and the Fragile X (Fmr1 knockout) mouse model (and autism)

Fancy some weekend reading? Well, you could do a lot worse than having a gander through the paper by Jane Naviaux and colleagues [1] (open-access) discussing the results of a whole host of analyses following the use of the antipurinergic agent suramin on a mouse model of Fragile X syndrome.

Overprotective mother, forbidden road trip...

Regular readers might remember some previous discussions about suramin - a pharmaceutic designed to treat African sleeping sickness - and autism which have graced this blog (see here and see here). Following a series of studies which looked at the physiological and behavioural effects of suramin administration on a mouse model trying to recreate conditions of maternal immune activation (MIA (which itself has some autism research history), authors this time turned their attention to a mouse model of Fragile X syndrome, a condition which can in humans manifest with autistic traits (sometimes).

The Naviaux paper is a whopper in terms of data accumulated and results so I'm not going to even try and summarise the findings aside from quoting the authors that their: "results support the novel conclusion that antipurinergic therapy is operating by a mechanism that lies close to the root cause of the core behaviors and development in both the environmental MIA, and the genetic Fragile X models of ASD [autism spectrum disorder]. This mechanism appears to be traceable to mitochondria and regulated by purinergic signaling." Both mitochondrial and purinergic issues have featured in the autism research historical tapestry before (see here and see here respectively).

Just before anyone makes a run on suramin, I might however point out a few things: (a) the current and previous results are based on mouse studies and mice are mice not humans, and (b) suramin, whilst indicated for sleeping sickness, is not without the possibility of some pretty important side-effects (see here).

Still, this latest paper again potentially opens up a number of promising lines of inquiry in need of further investigation. And the added bonus is to see some more metabolomics included in their results!

To close: INXS and Mystify.

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[1] Naviaux JC. et al. Antipurinergic therapy corrects the autism-like features in the fragile X (Fmr1 knockout) mouse model. Molecular Autism 2015, 6:1

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Jane C Naviaux, Lin Wang, Kefeng Li, A Taylor Bright, William A Alaynick, Kenneth R Williams, Susan B Powell, & Robert K Naviaux (2015). Antipurinergic therapy corrects the autism-like features in the fragile X (Fmr1 knockout) mouse model Molecular Autism : 1186/2040-2392-6-1

Uric acid and bipolar disorder

Bipolar disorder appearing again on this blog this week? It's just the way that the papers fall...

With a title like: 'Increased uric acid levels in bipolar disorder subjects during different phases of illness' I was hardly likely to pass up the opportunity to discuss the paper by Umberto Albert and colleagues [1] and their suggestion that there may be a lot more to see when it comes to "a purinergic dysfunction associated with BD [bipolar disorder]".

I lost the defuser gun when I misplaced the invisible car.

Based on the analysis of serum uric acid (UA) levels in 150 participants formally diagnosed with BD compared with "150 age- and gender-matched subjects with MDD [major depressive disorder], OCD [obsessive compulsive disorder], or Schizophrenia", researchers reported that: "Mean serum UA levels (5.06±1.45 vs. 4.17±1.05mg/dL) and rates of hyperuricaemia (30.7% vs. 6.7%) were significantly higher in the bipolar than in the control group." The authors pointed out the limitations of their study: "Our study suffers from the lack of a healthy comparison group; moreover, longitudinal data are missing" so no need for me to say anything further in that respect.

Uric acid, more commonly associated with a condition like gout, has been getting quite a bit of research attention when it comes to behaviour and psychiatry down the years. I've talked previously on this blog about the intriguing work suggestive of a possible connection between levels of uric acid and impulsivity (see here) highlighting a possible biology - trait connection. As per the Albert findings - "No differences were detected between bipolars in different phases of illness, with all three groups (manic, depressive and euthymic bipolars) showing significantly higher UA levels as compared to controls" - other research has hinted that the relationship between uric acid and BD is quite a bit more than just one related to trait [2]. I'm open to accepting that this might however change as more research is done on this topic.

Mechanism of effect for uric acid in BD? A very good question. Unfortunately I don't have a good answer at the moment, aside from reiterating the Albert suggestion "of a purinergic dysfunction associated with BD". Going all the way back to the 1921 book by Emil Kraeplin where the connection between uric acid and "manic symptoms" was discussed, there is quite a long history attached to this area. Even further back, the paper by Sutherland (1892) [3] talked about uric acid diathesis in children exemplified by: "keen precocious minds, and small restless bodies; they are excitable, nervous, bright and amusing at one time, and greatly depressed at another". Lithium salts were the treatment of choice for the 'gouty diseases' [4] and perhaps might offer some further explanation for the mechanism of effect in BD.

Other than that I can say no more, aside from pointing out that if one considers uric acid to be an agent of inflammation [5] and associated with other inflammatory responses [6], one might entertain some possible association between elevated levels of the stuff and other potentially important work in the area of BD...

And to close: White Coats by Foxes.

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[1] Albert U. et al. Increased uric acid levels in bipolar disorder subjects during different phases of illness. J Affect Disord. 2014 Nov 15;173C:170-175.

[2] Kesebir S. et al. Increased uric acid levels in bipolar disorder: is it trait or state? J Biol Regul Homeost Agents. 2013 Oct-Dec;27(4):981-8.

[3] Sutherland GA. On some Symptoms Associated with the Uric Acid Diathesis in Children. Br Med J. 1892 Apr 23;1(1634):856-8.

[4] Amdisen A. & Hildebrandt J. Use of lithium in the medically ill. Psychother Psychosom. 1988;49(2):103-19.

[5] Shi Y. Caught red-handed: uric acid is an agent of inflammation. The Journal of Clinical Investigation 2010;120(6):1809-1811. doi:10.1172/JCI43132.

[6] Lyngdoh T. et al. Elevated serum uric acid is associated with high circulating inflammatory cytokines in the population-based Colaus study. PLoS One. 2011;6(5):e19901.

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Albert U, De Cori D, Aguglia A, Barbaro F, Bogetto F, & Maina G (2014). Increased uric acid levels in bipolar disorder subjects during different phases of illness. Journal of affective disorders, 173C, 170-175 PMID: 25462413

Impulsivity and uric acid

A few years back I posted about an interesting body of research on purine metabolism in relation to the autism spectrum disorders (ASDs) and how some work from the likes of Mary Coleman and Ted Page had reported high levels of uric acid to be coincidentally present in cases of ASD.

The gout @ Wikipedia  

As with other research angles, the initial interest in this finding of hyperuricosuria - elevated urinary uric acid - and autism did not seem to last. Just like the dusty research doll that is sulphation (sulfation) and autism, uric acid came to find itself under the autism research bed listening to the tune of 'when somebody loved me'. Sulphation, I might add with autism in mind, has started to see something of a renaissance recently but only a small one (see here).

Enter then an intriguing paper by Angelina Sutin and colleagues* reporting on an association between elevated levels of uric acid and impulsivity as a trait in both human and mice. As per another recent paper which was discussed on this blog on ADHD and solar intensity, the publishing journal was Biological Psychiatry which is fast becoming a real favourite journal of mine. Reading through Dr Sutin's profile page it is interesting to note that she has some interest in how personality might be associated with physical and mental health. Her latest paper therefore continues this interesting theme.

A few details from the Sutin paper are in order:

• This was a study drawing on both human and mouse model data to ascertain whether the findings of elevated uric acid in behavioural and psychiatric conditions "characterized by high impulsivity" might actually be specifically related to the impulsivity trait.
• Human participants (N=6883) derived from two cohorts - SardiNIA and the Baltimore Longitudinal Study of Aging - completed the Revised NEO Personality Inventory which aims to characterise the Big Five personality traits (openness, conscientiousness, extraversion, agreeableness, neuroticism) via self-report.
• They also provided fasting blood samples which were screened for uric acid both at time of schedule completion and at follow-up (some 3-5 years later).
• A second study was also reported looking at the behaviour of mice "urate oxidase null" = bred to show elevations in uric acid, compared with wild-type controls. 
• Results: lots of them, but a few of the more interesting findings included (i) impulsiveness and excitement seeking individuals were more likely to have higher levels of uric acid (albeit mediated by factors such as BMI and smoking which themselves pose some interesting questions), and (ii) "homozygous urate oxidase-deficient mice" (high uric acid) showed a lot more exploratory and "emotional" behaviour. 
• In short, the two experiments reported "supports the hypothesis that impulsivity is associated with higher levels of uric acid".
• Another quote from the paper sums up where this kind of research could potentially lead: "The identification of biological markers of impulsivity may lead to a better understanding of the physiological mechanisms involved in impulsivity and may suggest potential targets for therapeutic intervention".

Very interesting stuff I'm sure you'll agree. Indeed the participant numbers for the human part of the study are certainly impressive and indeed across the two geographically distinct cohorts too, even more impressive.

But with my science-hat on, lets take a step back and point out some important limitations of this work. First and foremost is the assumption that the personality trait impulsivity measured by only one personality inventory is the only potential correlate here, at least among the human participants. It isn't. And indeed one should always be mindful that just because investigators test for something like a personality trait or a specific cognitive skill or even a specific condition/state/disease does not mean they have excluded all other potentially important variables** (indeed if this is even possible). Next is the assumption that self-report responses on a five-point Likert scale are going to be true and honest. No-one can be totally assured of that, particularly if responses are to some of the more less desirable personality traits that we would all like to put to one side. Finally is the interpretation of a mouse model of high uric acid showing the impulsivity trait based on their novelty-seeking and exploratory behaviours during field tests. I've talked mouse models before with autism in mind and how behavioural animal models are always subject to some degree of interpretation until such time that we can talk to the animals (and they talk back).

Having said all that I do find myself still very interested in the Sutin findings in terms of how the work was done, the results obtained and where it could lead. Without giving anything that looks or sounds like medical or clinical advice, one has to wonder (as the authors have done) whether 'adjusting' levels of uric acid might have a knock-on effect on certain behaviours particularly where uric acid might be seen in more behaviourally or psychiatrically defined conditions. I'm not saying everyone should be taking something like allopurinol or anything like that but perhaps further investigation is at least warranted.

Finally, on a similar note to the Sutin study I also recently came across a study by Soto-Insuga and colleagues*** which reported some very preliminary findings from treating iron deficiency in cases of attention-deficit hyperactivity disorder (ADHD). To quote: "Treatment with iron supplements can be an effective alternative to treat patients with ADHD and iron deficiency, especially the inattentive subtype". By 'treatment' I take it to mean that not only were the authors resolving the iron deficiency but also in specific cases of ADHD identified by that inattentive subtype**** they were talking about the management of behavioural symptoms too.

Example evidence that the psychosomatic or somatopsychological relationship should definitely remain near the top of the research agenda?

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* Sutin AR. et al. Impulsivity is associated with uric acid: evidence from humans and mice. Biol Psychiatry. April 2013.

** Cerecero P. et al. Association between serum uric acid levels and cardiovascular risk among university workers from the State of Mexico: a nested case--control study. BMC Public Health 2013; 13: 415.

*** Soto-Insuga V. et al. Role of iron in the treatment of attention deficit-hyperactivity disorder. An Pediatr (Barc). April 2013.

**** Solanto MV. The predominantly inattentive subtype of attention-deficit/hyperactivity disorder. CNS Spectr. 2000; 5: 45-51.

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Sutin AR, Cutler RG, Camandola S, Uda M, Feldman NH, Cucca F, Zonderman AB, Mattson MP, Ferrucci L, Schlessinger D, & Terracciano A (2013). Impulsivity is Associated with Uric Acid: Evidence from Humans and Mice. Biological psychiatry PMID: 23582268

Gene pathway analysis and autism

"In conclusion, we have developed an accurate diagnostic test for a genetically homogeneous group to aid in early detection of ASD". The big headline to come from this paper by Skafidas and colleagues* (open-access) reporting results based on gene pathway analysis of SNPs previously associated with autism.

This is an interesting paper for quite a few different reasons. Primarily it kinda accepts that looking at SNPs alone as being the key to autism is probably not going to be a great idea. I've talked before about the very messy science of mutation when applied to autism together with the fairly recent news that no one SNP seems to be universally related to autism, all cases of autism. Outside of the growing interest in epigenetics and autism (see here) the current paper looks beyond the SNP alone as being key; instead also looking at the cellular processes behind the SNPs and whether commonalities among ethnically homogeneous groups on the autism spectrum might yield more valuable information.

A quick summary:

• A two-fold study primarily based on the the collected data from the AGRE initiative examining: (i) which groups of SNPs and their cellular processes might be pathogenic or protective for autism spectrum disorder(s) (ASD), and (ii) application of machine learning (artificial intelligence) to categorise SNPs which might be predictive for a diagnosis of autism. Machine learning and autism y'say? Yep.. similar to the ADOS and ADI boiling down papers recently discussed.
• Sample numbers are a bit complicated in that both training and testing sets were used as per the method employed in the five serum metabolites and schizophrenia paper covered a while back; said testing sets derived from other databases including the SFARI database. That and the fact that ethnicity was also a factor which included a Central European cohort (CEU) and a Chinese Han cohort (HAN). We are talking in the high hundreds in terms of participant data used to derive information on which SNPs might be important.
• Results: based on data from nearly a thousand people with an ASD in the CEU, 775 SNPs were identified as being perturbed. Thirteen different pathways were linked to these genes; six pathways crossing both the CEU and HAN. These included pathways tied into quote: "purine metabolism, calcium signaling, phosphatidylinositol signaling, gap junction, long-term potentiation and long-term depression".
• Further analysis pertinent to predicting ASD (ASD vs. not-ASD) suggested that 237 SNPs in 146 genes were really important and "correctly predicted ASD diagnosis in 85.6% of CEU cases". When applied to the tester sets, predictive percentages fell to around 70%.
• Eight SNPs in 3 genes (GRM5, GNAO1 and KCNMB4) were reported to be highly discriminatory in terms of the ASD or not-ASD debate; some protective and others contributory.

And rest.

To continue with the 'its interesting' theme, a few other pointers from this study are apparent. The authors for example make some discussion out of how much overlap there was in the pathways tied to the SNPs between the different ethnic groups. Certainly you would expect that even if the SNPs were in different places, similar functions might be affected which seems to be what is being reported in the current paper.

One particular pathway which cropped up caught my eye relating to purine metabolism; a source of discussion already on this blog as per this post. I don't really want to rehash that post but the watchwords are Coleman and Page, nucleotides, uric acid, uridine. Should I also at this point mention the starting material for BH4 being a nucleotide too? As for the other pathways, interesting but a little beyond my level of competence.

So the final word. Well once again, interesting. If I had to make one suggestion about improving on this work it would focus on bringing together such gene pathway analysis with other sciences such as metabolomics where both genes and functional biochemistry may very well help raise those predictive values to something very much more accurate and reliable.

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* Skafidas E. et al. Predicting the diagnosis of autism spectrum disorder using gene pathway analysis. Molecular Psychiatry. September 2012

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Skafidas E, Testa R, Zantomio D, Chana G, Everall IP, & Pantelis C (2012). Predicting the diagnosis of autism spectrum disorder using gene pathway analysis Molecular Psychiatry DOI: 10.1038/mp.2012.126

Purine metabolism and autism

Autism is replete with different areas of research and investigation. Trends in the various lines of inquiry taken down the years have tended to coincide with the various scientific 'fashions' of the times. Outside of the more psychological themes, there was in the early days up to the mid-1990's, research which seemed to be very heavily biochemistry-focused in autism. Serotonin, dopamine, endorphins and enkephalins and other like-minded compounds took centre stage in the era of biological psychiatry. The brain (and its chemical minions) was King.

Then began the era of genetics which jumped with a loud 'ta-da' onto the autism research stage. The initial mapping of the human genome was the impetus and all and everything was about genes. It initially started with the various population-wide studies of genes, moving in later years to the realisation that autism, like many conditions, is not a 'single gene condition'. Increased interest in the various descriptions of the broader autism phenotype, together with advancing technology, heralded the age of SNPs and CNVs into autism research. Genes were King.

At the current time, I think we are evolving again; currently being in the process of another shift in the research paradigm, with the onset of epigenetics and gene-environment interactions. 'We are all a consequence of our genes and environment' - or so the fashion tells. Certainly the conclusions from many studies seem to be heading in that direction. The brain, genes and environment all sit on the same throne.

For this post I am venturing back a few years to those olden' days of biochemistry and autism, and in particular, research on purine metabolism in relation to autism. Mary Coleman was a main player in purine research in autism. She was no stranger to autism research by any means and credited with some very interesting (and early) observations including the suggestion that about a quarter of people with autism also presented with a co-morbid defined medical disorder.

To the post at hand. What are purines? Stand-by for biochemistry 101. There is quite a complex description of purines here. Basically purines are a class of compound which all share two particular details in their chemical structure called a pyrimidine ring and imidazole ring. Pyrimidines and purines are of some interest to geneticists generally because the nucleotides which form our DNA [(A)denine, (G)uanine, (C)ytosine, (T)hymine] are pyrimidines (C & T) and purines (A & G). Aside from forming the base nucleotides, purines have quite a few other roles to play body-wide, notably in relation to things like ATP as a main energy source for cells.

Purines have been of some interest to autism for a while. The connection between purines and autism seems to have been predominantly due to the excessive excretion of a particular purine, uric acid, reported by some authors (including Coleman). Many people might have heard about uric acid in relation to conditions such as gout (one of the 'many' diseases suggested to be carried by King 'Enry VIII) but there are quite a few other conditions potentially connected to elevated levels of uric acid. Coleman and colleagues estimated that about 20% of people with autism might present with elevated uric acid levels (hyperuricosuria) although whether this is co-morbidity or specifically tied into presented symptoms is unclear. There is a case report by Ted Page (who worked with Coleman) suggesting that treatment with uridine correlated with positive changes to presented autistic symptoms, with regression when treatment was halted. This was followed up by a small trial (n=9) where benefits were noted up to 8 years later. Interestingly, uridine is found in quite a few foods including brewer's yeast (saccharomyces cerevisiae) - a cousin (but not the same as) of our old friend saccharomyces boulardii.

As per my previous disclaimers, I am not suggesting that uridine or brewer's yeast in this context is in any way, shape or form an 'intervention' option for autism or anything else. The Page papers, whilst interesting, reported on only small participant numbers and as far as I can see no-one has yet done anything further on this issue to decide whether raised uric acid levels are a chance finding or if not just epiphenomenal. It is therefore difficult to ascertain proper safety or efficacy data in this area; an area which seems to have gone the same way as the sulphate (sulfate) research.