BH4 for autism?

I've talked about tetrahydrobiopterin (sapropterin or BH4) a few times on this blog with reference to autism (see here and here) and also some interesting suggestions about it being a potential intervention for the archetypal 'diet can affect behaviour' condition, PKU (see here).

The Nubian Giraffe @ Wikipedia 

A quick recap: BH4 is a hold-my-hand cofactor involved in some pretty important biochemical reactions; notably quite a few utilising those interesting aromatic amino acids (see here) and their neurotransmitter relations. Deficiency of BH4 has a few consequences as one might imagine; one of the important ones being a build up of the amino acid phenylalanine, which as seen in PKU and perhaps other conditions, is not necessarily a great position to be in.

Going back to the autism connection, the paper by Cheryl Klaiman and colleagues* caught my eye, as they reported on the results of a gold-standard double-blind, placebo-controlled trial of BH4 in young children (3-7 years old) diagnosed with an autism spectrum disorder (ASD). Actually, you can see a little bit more about their trial from their entry in the ClinicalTrials.gov database (see here) with the requirement for the study authors to update their study details!! (as of July 2013).

Anyhow, in their fairly small participant group they looked at children taking BH4 - 20mg/Kg body weight per day - compared with those taking a placebo for 16 weeks and examined various autism and related behaviours. They reported no statistically significant difference on their primary outcome measure (the CGI-I and CGI-S) but..... there were a number of significant improvements noted on some of the secondary measures used including behaviours related to social awareness, hyperactivity and aspects of language. Importantly too, reported side-effects from BH4 were minimal and on a par with those reported by the placebo group. They conclude: "These results indicate that BH4 offers promise in reducing symptoms of ASD".

These are interesting results both insofar as what is reported and the speculations about what BH4 might be doing. Unfortunately, this study did not report on any specific biochemical measures so it's slightly difficult to add anything further even though just some simple measures of things like blood phenylalanine levels** or even nitric oxide (NO) metabolites*** would, I dare say, have been quite revealing.

I'm not going quibble however about this paper because it adds to the already interesting evidence base on BH4 for at least some cases of autism. That and the quite impressive record on few and far between side-effects of BH4 makes for another interesting potential therapeutic agent (and its targets) should anyone wish to take up the research gauntlet further.

----------

* Klaiman C. et al. Tetrahydrobiopterin as a treatment for autism spectrum disorders: a double-blind, placebo-controlled trial. J Child Adolesc Psychopharmacol. 2013 Jun;23(5):320-8. doi: 10.1089/cap.2012.0127.

** Burton BK. et al. Sapropterin therapy increases stability of blood phenylalanine levels in patients with BH4-responsive phenylketonuria (PKU). Mol Genet Metab. 2010 Oct-Nov;101(2-3):110-4. doi: 10.1016/j.ymgme.2010.06.015.

*** Frye RE. et al. Metabolic effects of sapropterin treatment in autism spectrum disorder: a preliminary study. Transl Psychiatry. 2013 Mar 5;3:e237. doi: 10.1038/tp.2013.14.

----------

Klaiman C, Huffman L, Masaki L, & Elliott GR (2013). Tetrahydrobiopterin as a treatment for autism spectrum disorders: a double-blind, placebo-controlled trial. Journal of child and adolescent psychopharmacology, 23 (5), 320-8 PMID: 23782126

Just say NO to sapropterin for autism

Actually the title of this post is a bit of a misnomer.

I'm not really asking readers to say 'no' to sapropterin, otherwise known as tetrahydrobiopterin or BH4, for autism as if it were some kind of Zammo-esque drugs in the toilet scenario (note: for anyone born post-Grange Hill golden era or for my non-UK readers, you might want to follow this link to see what I'm going on about). But neither am I saying yes, as per my prime directive on this blog: no medical or clinical advice given or intended (resistance is futile... and all that).

Mr Bronson / Admiral Ozzel @ BBC News

The 'no' actually refers to NO - nitric oxide - and in particular the findings reported by Richard Frye and colleagues* (including Jill James yet again) on the potential involvement of NO metabolism in the behavioural changes noted when BH4 was introduced to a small cohort of children diagnosed with autism. I think we might have seen shadows of this study presented at IMFAR 2012.

OK, a quick description might be in order first. I've covered BH4 previously on this blog (see here) and some of the various roles that it plays; not least in its co-factor duties for the metabolism of some important aromatic amino acids eventually into things like neurotransmitters. Also not forgetting the potential role for BH4 in relation to managing conditions like PKU also (see here). Similarly, NO has also appeared on this blog before (see here). The Frye paper stresses the important role that BH4 has in the production of NO.

A few details from the Frye paper bearing in mind it is open-access:

• Starting with 10 participants (aged 2-6 years) diagnosed with an autism spectrum disorder (ASD) whose parents agreed "to not change any traditional or alternative medical or behavioral therapy during the study", various measures of behaviour and language function were charted over the course of a 16-week open-trial of BH4 (Kuvan).
• Alongside the behavioural and psychometric measures used (which included the VABS and PLS), CSF samples were collected via lumbar puncture (not normally recommended because of its invasiveness) and blood samples used to measure for various marker compounds including BH4, the amino acids L-arginine and L-citrulline and everyone's favourite redox coverboy/covergirl, glutathione.
• Results: bearing in mind that this was an open-trial and that no control group or placebo arm was used, the authors report some interesting changes to various parameters. So language (receptive at least) showed a significant improvement across the group across the testing periods (baseline, 8 weeks, 16 weeks). Some of the VABS subscales also indicated some positive changes (albeit one of them, VABS personal daily living, presented with a p-value of 0.061, I assume to denote Nick Berry style 'we nearly made it').
• The biological stuff: well there was an increase in the reduced-to-oxidised glutathione ratio (good thing) and a decrease in levels of 3-Chlorotyrosine (3CT) (also a good thing) over the course of intervention, positive in terms of oxidative stress (redox status) and the presence of "reactive nitrogen species" respectively (see below).
• Findings also pointed to "a fundamental change in pterin metabolism" coinciding with BH4 supplementation. I won't pretend to know all the ins-and-outs but it all has to do with supplementation modifying the reduced-to-oxidised pterin ratio and degradation of BH4 onwards to the appearance of something called peroxynitrite which is not particularly a good thing. I think this article** (open-access) might explain it a little better than I could.
• The authors also reported that despite no significant change in NO metabolism markers (arginine and citrulline, and their ratio), it did appear that baseline levels of these compounds were allied to behavioural outcomes. Specifically improvements on the behavioural parameters "were related to higher baseline arginine and arginine-to-citrulline ratio".
• Importantly, BH4 supplementation was generally well tolerated with "only one patient discontinuing the medication because of mild adverse effects".

Yes, this was a very small trial, and yes again, there was no control group, no placebo and no blinding. It is preliminary work, of that there is no doubt. I find it a little unusual that the authors also chose HPLC with electrochemical detection when it came to the measurement of important metabolites like CSF levels of BH4. A little bit '80s' if you'll forgive me, given the startlingly increased precision offered by mass spec and NMR techniques as exemplified by papers like this one. Indeed even more odd that LC-MS was used for the analysis of amino acids: why not all metabolites? It should also be noted that Dr Frye is listed as having a potential conflict of interest in this paper via receipt of funding from the producers of Kuvan for this trial; not that this should or did influence the findings in any way, shape or form.

Nevertheless there are a number of interesting observations which might require some follow-up from this paper. That for example, a higher baseline level of arginine seemed to quite strongly correlate (r=0.91) with the PLS total raw score (language) as a result of BH4 supplementation is a point worth following up, particularly in these days emphasising the identification of best- and non-responders to various interventions for the autisms. The implication being that "only some of the participants were able to significantly change their NO metabolism with the dose of Kuvan used in this study" potentially as a result of this correlate - or at least this studied and known about correlate. An endophenotype eh? Or even a biomarker for intervention response?

Given the body of work already published on BH4 supplementation and autism and how BH4 levels might tie into lots of different areas outside of just being a co-factor (see this paper*** open-access) I'd like to see quite a bit more done on this compound and its relations. That it might also overlap with other conditions too - schizophrenia for example**** and other diagnoses***** - is also an important point given the genetic common ground being postulated between quite a few conditions (see here). One also wonders whether that recent vitamin B12-folate supplementation for schizophrenia paper****** by Roffman and colleagues (open-access) might also hint at some involvement of BH4 (more on that paper to come).

To finish, the old Grange Hill intro, including that sausage. Alongside due respect to actor Michael Sheard who played the unfortunate Kendal Ozzel ("he is as clumsy as he is stupid"). Steady on Darth.

----------

* Frye RE. et al. Metabolic effects of sapropterin treatment in autism spectrum disorder: a preliminary study. Transl Psychiatry. 2013; 3: e237.

** Pacher P. et al. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. 2007; 87: 315-424.

*** Frye RE. et al. Central tetrahydrobiopterin concentration in neurodevelopmental disorders. Front Neurosci. 2010; 4: 52.

**** Richardson MA. et al. Evidence for a tetrahydrobiopterin deficit in schizophrenia. Neuropsychobiology. 2005; 52: 190-201.

***** Coppen A. et al. Depression and tetrahydrobiopterin: the folate connection. J Affect Disord. 1989; 16: 103-107.

****** Roffman JL. et al. Randomized multicenter investigation of folate plus vitamin B12 supplementation in schizophrenia. JAMA Psychiatry. March 2013.

----------

Frye RE, Delatorre R, Taylor HB, Slattery J, Melnyk S, Chowdhury N, & James SJ (2013). Metabolic effects of sapropterin treatment in autism spectrum disorder: a preliminary study. Translational psychiatry, 3 PMID: 23462988

Brain glutathione redox status, Brussels sprouts and autism?

Sprouts, sprouts, sprouts @ Wikipedia

Glutathione in relation to autism spectrum conditions is a bit of a favourite topic of mine. I've talked about glutathione a few times on this blog (here and here) and how the various reports on a reduced level of functioning of this fantastic part of our antioxidant system seem to show more than a passing connection to cases of autism. That and the fact that consumption of a favourite foodstuff of mine, the Brussels sprout, might have quite a positive influence on some of the inner workings of the glutathione system (see Nijhoff and colleagues*) makes it a compound of some interest.

Up until this point, the collected research looking at glutathione in relation to autism had however tended to be focused on circulating levels of glutathione in its various forms alongside the enzymes supporting its important tasks. Enter then a paper published by Rose and colleagues* (full-text) on glutathione, the brain and autism previously described at IMFAR 2012 (here). You may have spotted a few familiar names on the authorship panel of this paper including Jill James (hypomethylation and autism) and Richard Frye (folate receptor autoantibodies).

Aside from a couple of forays into the world of brain research and the autism spectrum (see here for example), I have tended to keep away from discussing such investigations in too much detail on this blog. My reasoning: adhering to the phrase 'a cobbler should stick to his last', coupled with a view that the various research focused on the brain and autism just seemed so darned complicated. Suffice to say that it all brings back blurred memories of my undergraduate days where I admit to being more than a little confused about what brain region was supposed to do what.

In this post I am going to include some discussion on the findings reported by Rose et al albeit with the caveat that my brain may not be up to exploring all the avenues of potential interest related to these findings and what they mean.

Since I am discussing glutathione, I also want to bring to your attention some slightly more 'preliminary' findings reported in this poster by Cruikshank and Wood** on urinary glutathione in relation to autism. The caveat here being that this is not a peer-reviewed piece of research and hence still requires quite a lot more work before being taken as Gospel (despite the recent media interest).

Back to Dr Rose's paper:

• This was a study of post-mortem brain specimens. In light of the recent news of a freezer malfunction linked to the destruction of a number of stored brain tissue samples from people with autism, there is a degree of poignancy to this study reiterating how valuable these types of tissue are to furthering autism research.
• Samples from two areas of the brain - the cerebellum and Brodmann area 22 (BA22) (part of the superior temporal gyrus) - were studied, comparing samples from people with autism (n=15 & n=12 for the two areas) with control specimens. These brain areas have been talked about before with autism in mind (here and here) as the name Eric Courchesne drifts into my consciousness.
• Levels of various compounds were examined in samples including: reduced glutathione (GSH), oxidised glutathione disulfide (GSSG), 3-nitrotyrosine (3-NT) and 3-chlorotyrosine (3-CT); calculating glutathione redox/antioxidant capacity (GSH/GSSG), oxidative protein damage and oxidative DNA damage (8-oxo-deoxyguanosine; 8-oxo-dG). Aconitase activity was also measured.
• The results: in both brain regions, all studied compounds were altered at a group level in cases of autism compared to controls. So, levels of glutathione (GSH) were decreased in both brain areas compared to control samples (43% and 32% reductions in cerebellum and BA22 respectively). Levels of oxidised glutathione disulfide (GSSG) were elevated in autism vs. controls in both brain areas (18% vs. 19% elevations respectively) and overall glutathione redox/antioxidant capacity (GSH/GSSG) was significantly different in autism vs. controls. These findings are roughly in line with what has been reported in studies of other tissues in cases of autism.
• Oxidative stress and oxidative protein damage markers were also significantly elevated in the autism group vs. controls in both brain areas. Aconitase activity was significantly lower in the autism group in the cerebellum but escaped significance in relation to BA22. 
• The authors note: "decreased glutathione-mediated redox/antioxidant capacity previously observed in plasma and immune cells from children with autism is also significantly decreased in two brain regions previously shown to be affected in autism, the cerebellum and BA22".

There is quite a bit of information to take in from this study and as a result, several important things which will require some external replication with suitable age and sex matched controls. Oxidative stress / damage is something that tends to get banded around quite a lot in these days of the free radical. Rose and colleagues have now provided some very important preliminary flesh on the bones to this story, suggesting "functional consequences" on specific brain areas previously linked to autism following their results. Their findings also pretty much confirm what quite a few others have been saying about glutathione in relation to cases of autism: whether causative or epiphenomenal, there's something amiss with the whole oxidative stress / antioxidant balance in at least a proportion of cases of autism and it may well extend beyond just a casual relationship. 


I note also their findings with regards to glutathione redox/antioxidant capacity (GSH/GSSG) and 8-oxo-dG in the cerebellum. Combining autism cases and control data, the authors report on an important relationship between how well the GSH/GSSH capacity performs and the amount of oxidative DNA damage potentially present. Similar things have been reported in other studies so no real surprises there.


I'm not going to get too far into the findings with regards to decreased aconitase activity in the autism cases and its link to mitochondrial oxidative stress. If you really want some reading on the subject, this paper by Cantu and colleagues**** (full-text) should keep you going for a while. Suffice to say that mitochondrial aconitase inactivation might have some pretty negative implications as per this article by Vasquez-Vivar and colleagues***** (full-text).


Just a couple of more things to add then I'm done. The suggestion of "a chronic neuroinflammatory state" at the brain sites under investigation has to be included in any synopsis. Neuroinflammation in autism is a topic that has cropped up quite a few times in the research literature. To pick out one study that springs to mind, the findings from Vargas and colleagues****** and their introduction of microglia into the mix is a case in point. Microglia is another area not readily touched upon this blog so in this case I will perhaps refer you to a nice blog post by Paul Patterson on the topic of hungry microglia potentially eating synapses in autism. I'm not necessarily saying that this is an essential part of the Rose findings but it could be a potentially important tie-in.


The link between elevated levels of 3-NT and elevated nitric oxide (NO) production described in the Rose paper is a final point. The mechanism for this relationship is explained pretty well here. I've covered some of the work on elevated NO metabolites and autism in a previous post. The net results seeming to indicate that levels of NO metabolites are elevated quite consistently in cases of autism. And then there is the inflammation link which has been covered quite a bit before.


OK that's enough for now. You might have realised that I am fairly interested in this paper by Rose and colleagues despite the preliminary nature of their study and the limitations of my knowledge in the area of the brain in autism. Yet another good reason why glutathione in relation to autism deserves a lot more research interest alongside tentative suggestions on whether we might actually be able to do something about it (see previous post). 


To finish, how very dare they make this song which implies a world without Brussels sprouts. You will eat your phenylthiocarbamide and like it...

----------

* Nijhoff WA. et al. Effects of consumption of Brussels sprouts on intestinal and lymphocytic glutathione S-transferases in humans. Carcinogenesis. 1995; 16: 2125-2128.

** Rose S. et al. Evidence of oxidative damage and inflammation associated with low glutathione redox status in the autism brain. Translational Psychiatry. July 2012.
DOI: 10.1038/tp.2012.61

*** Cruikshank C. & Wood T. Quantitation of glutathione as a urinary autism biomarker (poster).

**** Cantu D. et al. Oxidative inactivation of mitochondrial aconitase results in iron and H2O2-mediated neurotoxicity in rat primary mesencephalic cultures. PLoS ONE. 2009; 4: e7095.

***** Vasquez-Vivar J. et al. Mitochondrial aconitase is a source of hydroxyl radical. The Journal of Biological Chemistry. 2000; 275: 14046-14069.

****** Vargas DL. et al. Neuroglial activation and neuroinflammation in the brain of patients with autism. Annals of Neurology. 2005; 57: 67-81.

----------

Rose S, Melnyk S, Pavliv O, Bai S, Nick TG, Frye RE, & James SJ (2012). Evidence of oxidative damage and inflammation associated with low glutathione redox status in the autism brain. Translational Psychiatry, 2 PMID: 22781167

Autism said NO

Another play on words form the title of this post. Whilst no means no (or even NoMeansNo if you are partial to a little punk rock), NO in this case actually refers to nitric oxide and a few snippets of research potentially relevant to autism and a few other conditions.

A recent paper in bipolar disorder research brought me to this post. The paper by Bielau and colleagues* suggested evidence of issues with NO signalling might be a facet of bipolar disorder. When I read the words "influences the balance of monoaminergic and glutamatergic neurotransmission" I thought to myself that it was about time to look at NO with autism in mind, given the quite interesting links being suggested around glutamate and autism for example.

Indeed, it was perhaps inevitable that I would arrive at NO at some point on this blog given the numerous references to inflammation and oxidative stress seemingly present in some cases of autism spectrum conditions as exemplified by the post on glutathione and autism. The more general connection between NO and inflammation is a complicated one but nevertheless an important one. I might add that I will be coming back to inflammation and autism in future posts.

A brief history of NO and autism.

This paper by Zoroglu and colleagues, whilst built on a small participant group, paved the way for several subsequent studies of NO metabolites in plasma and urine. Zoroglu is a name that comes up quite a bit in NO research. Findings of elevated levels of NO metabolites are pretty consistent in the autism studies so far as evidenced by this paper and this paper. Even research which did not find any group connection between elevated NO and autism, implied that the onward problems following a Clostridial infection in a case of autism might show elevated NO values (Clostridia difficile toxins can do some pretty nasty things to the gut).

More recent publications continue the theme. So this paper by Essa and colleagues** added to the melting pot of research. Based on the analysis of a small group of children with autism living in the Sultanate of Oman, a significant elevation among several markers of oxidative stress were found including plasma levels of NO. An even more recent study published by Tostes and colleagues*** also reported elevations in NO alongside quite a few other issues such as elevations in interferon-gamma (IFN-γ) and some other very interesting peptide findings (e.g. VIP). Again based on quite a small participant group.What this might imply is that elevated NO levels in cases of autism may represent cases of autism with some kind of 'inflammatory' process attached.

Not yet convinced about a possible role for NO in some cases of autism?

Even the father of the minicolumn hypothesis Prof. Manuel Casanova might be swayed by the potential for a link. What to do about NO is altogether another matter and indeed it might not just be a case of trying to reduce levels or somehow reduce the source of the inflammation. A positive effect from NO in relation to cardiac function has been pretty well documented as evidence by papers such as this one. NO might also happen to be quite a good antioxidant; with a little seemingly going a long way.

The question is whether there might be a tipping point; a point where too much of a good thing causes problems and whether what has been seen in cases of autism and in other conditions, represents too much?

* Bielau H. et al. Immunohistochemical evidence for impaired nitric oxide signaling of the locus coeruleus in bipolar disorder. Brain Research. 2012; 1459: 91-99

** Essa MM. et al. Increased markers of oxidative stress in autistic children of the Sultanate of Oman. Biological Trace Element Research. November 2011.

*** Tostes MH. et al. Altered neurotrophin, neuropeptide, cytokines and nitric oxide levels in autism. Pharmacopsychiatry. March 2012.

The glutamate:glutamine ratio and autism

There they go again.

An Athenian butterfly @ Paul Whiteley

That Saudi Arabian autism research group who figured so heavily on this blog in 2011 have yet another publication out in this one by Abu Shmais and colleagues* (full-text) examining nitrogen-related parameters and autism. I'll admit that I'm a fan of this group; not only for the quantity of research that they are producing but the fact that there is clear evidence of 'blue-sky' thinking in their research material. These chaps are quietly contributing to some really interesting avenues in some cases of autism spectrum conditions, albeit at the moment based on quite small participant numbers.

Their latest offering asks a few interesting questions but before summarising some of them, I just want to run a sentence by you from the paper's introduction: "A recent epidemiological study in Saudi Arabia established the autism prevalence at 6:1000 (Talat; unpublished data, personal communication)". Bearing in mind that there are some important differences between personal communications about unpublished data and the public communication of the peer-reviewed variety, lots and lots of questions immediately start to appear in my mind about how this figure was arrived at, what criteria for autism used and if accurate, why the slight discrepancy with the [less than] 1 in 100 figure usually cited for the UK, US, Canada, etc. (or 1 in 38 if you believe the SK study last year). Answers on a postcard please addressed to...

Back to the paper:

• The analysis of nitrogen containing compounds and their metabolism makes up the main reason for this paper so inevitably compounds such as ammonia (NH3) get a mention. More specifically how the the body harvests nitrogen from lots of different sources (including those funny amino acids which I seem to been talking a lot about recently) and consequently disposes of it. 
• In terms of nitrogen metabolism, and concepts like the nitrogen balance, some familiar names crop up noted previously in autism research including glutamate and glutamine and how these compounds are involved in the removal of ammonia from the brain in the absence of important urea cycle enzymes.
• Fasting blood samples were collected from 20 participants with autism and compared with 20 controls. There is a bit of typo in the methods section which states that controls were all male and in the next breath, 16 males and 4 females(!) 
• Based on analyses looking at enzyme activity (5'-nucleotidase, adenosine deaminase and glutamate dehydrogenase), ammonia, urea, creatine, nitric oxide (NO), GABA, glutamate and glutamine - catch my breath - there were a few interesting results.
• Mean plasma levels of creatine, glutamate and GABA were elevated in autism compared to control means. By contrast plasma glutamine levels were lower. Looking at the values and standard deviations, these differences seemed pretty pronounced particularly across the glutamate:glutamine ratio. The results coincided with significant increases in 5'-nucleotidase and a marginal mean decrease in adenosine deaminase activity (p=0.048).
• A little bit of statistical wizardry (ROC) applied to the results suggested that the glutamate:glutamine ratio was the best measure of determining autism samples from controls based on a ratio cut-off value of 0.906. 

So what does all this tell us? Well, lots of things; some perhaps more important than others bearing in mind the small participant numbers. I'm going to focus specifically on the glutamate - glutamine findings as per the title of the post because the results are cumulatively most significant, as once again amino acid chemistry red flags are raised. I should also point out that plasma levels of glutamate and glutamine might not necessarily be the same as 'brain levels' as per the blood-brain barrier (BBB) and its amino acids transporters [note: I have a post scheduled soon on P-glycoprotein and BBB transport].

Not for the first time have elevated levels of glutamate and lower levels of glutamine been reported in autism research. The paper by Shimmura and colleagues** (open-access) found similar results in their analysis and once again pointed to the potential discriminatory power of this finding in cases of autism independent of learning disability from asymptomatic controls. Even Jim Adams and colleagues have reported similar trends (at least with regards to glutamate) on top of other group findings. As for searching the brain, well there is some evidence of issues there too at least in certain areas of the brain.

Fine, the result is pretty consistent but what does it mean?

Most commentary on glutamate reverts back to it being an excitatory neurotransmitter with reference to the hyperglutaminergic hypothesis of autism. I don't really want to go to heavily into the details of the hypothesis in this post but alongside elevated levels of glutamate, there is a corresponding decrease in activity of enzymes linked to glutamate metabolism (GAD65 & 67) and increased gliosis. Only a few days ago, a new paper*** was discussing the presence of autoantibodies to GAD65 in a subgroup of children with autism (and ADHD) which is probably not good news either.

The glutamine findings are also quite interesting. Abu Shmais and colleagues talk about how glutamine is an essential part of the process removing ammonia from the brain via processes such as glutamine synthetase. Low levels of glutamine may potentially reflect issues with this process. Outside of this however, other potential roles for glutamine need to be highlighted seemingly independent of the brain, in the liver and gut for example. The evidence for a connection between glutamine and glutathione (GSH) is also at the back of my mind bearing in mind the evidence so far on GSH in relation to autism.

A post on a sister blog discussed the issue of glutamine and its relationship to some gastrointestinal findings with its simplified role as the 'food of the gut' in terms of things like its effect on gut barrier function. It is therefore conceivable that low plasma levels of glutamine are probably not going to be particularly good for maintaining a healthy gut barrier; even outside of other confounding issues such as sulphation, etc. It might seem like a peripheral finding but more and more there is a realisation that physiology and psychology are linked as per the recent constipation - language impairment findings in autism.

So, another finding which requires large scale replication and another possible 'marker' for autism research is discussed. As time goes on, I am really starting to appreciate just how important amino acid chemistry is to lots of different functions and states outside of the classsic phenylalanine and PKU direction.

To finish something a little bit different as I ask the question: are you a man or a muppet (or perhaps neither)?

----------

* Abu Shmais GA. et al. Mechanism of nitrogen metabolism-related parameters and enzyme activities in the pathophysiology of autism. Journal of Neurodevelopmental disorders. February 2012.
DOI: 10.1186/1866-1955-4-4

** Shimmura C. et al. Alteration of plasma glutamate and glutamine levels in children with high-functioning autism. PLoS ONE. October 2011.
DOI: 10.1371/journal.pone.0025340

*** Rout UK. et al. Presence of GAD65 autoantibodies in the serum of children with autism or ADHD. European Child & Adolescent Psychiatry. February 2012

----------

Abu Shmais GA, Al-Ayadhi LY, Al-Dbass AM, & El-Ansary AK (2012). Mechanism of nitrogen metabolism-related parameters and enzyme activities in the pathophysiology of autism. Journal of neurodevelopmental disorders, 4 (1) PMID: 22958401