Methionine synthase and autism

The paper by Christina Muratore and colleagues* (open-access) including Dick Deth and Antonio Persico in the authorship line-up, is the source of today's post. Concerned with quite an important enzyme, methionine synthase (MS), and in particular MS mRNA status in post-mortem frontal cortex samples, the authors report lower levels of MS mRNA in cases of autism. I should add that quite a good overview of this paper can also be found here.

Recycle @ Wikipedia  

OK, let's start from the beginning here. Methionine synthase (MS) is an important enzyme concerned with the regeneration of methionine from homocysteine.

Homocysteine or the 'big H' has been mentioned on more than one occasion on this blog with autism in mind (see here and quite recently here). Indeed, the relationship between methionine and homocysteine intersects a number of other important cycles including those related to folate metabolism and the important methyl-giving properties of SAMe (see this post to see what I'm talking about) and further down the line, that all-important glutathione link (see this post). Oh and it's vitamin B12 dependent.

Anyhow...

• In this study, levels of messenger RNA (mRNA) - an important part of the translation of DNA to proteins - for MS were studied in post-mortem brain samples from deceased person who were diagnosed with autism (n=10) and control, not-autism persons (n=41). Ages at death ranged from 4-30 years for the autism group and 28 weeks - 83 years for the control group.
• Based on the application of qRT-PCR, MS mRNA status across the lifespan of samples included suggested a "striking age-dependent decrease in mRNA levels". In other words, the older the person at time of their death, the less MS mRNA levels were detected in the frontal cortex samples. That being said, they didn't observe corresponding alterations to the level of MS protein despite this age-related change. 
• With the autism group specifically in mind and depending on the primers used to detect specific domains of MS, mRNA levels were reduced compared to controls. The caveat being that again, levels of MS protein were not different when comparing autism vs. controls. That and the suggestion of a lack of an age-dependent decrease in MS mRNA in autism compared to that observed across control samples. 
• Oh and the fact that addition of the pro-inflammatory cytokine TNF-α also seemed to affect levels of MS mRNA.
• There were also some additional findings reported which warrant further attention. So when looking at some of the main players related to that methionine cycle (including methionine, homocysteine, glutathione, etc) in frontal cortex samples (via HPLC) in autism (n=10) and control (n=8) samples, only two parameters came up different: lower, yes lower, homocysteine levels in the autism group alongside lower cystathione levels. Immediately I'm taken back to the recent paper by Jill James discussed quite recently (see here) and their cautions on the use of peripheral markers to denote what might be happening in the brain, albeit with the caveat that the Muratone group was quite a small group.

There are some other details included in this paper regarding "alternative splicing of MS mRNA" but I wouldn't pretend to know all the ins-and-outs of these findings. Suffice to say that there is a suggestion that oxidative stress might have some role to play in what happens to MS both over the course of normal ageing and potentially also in cases of autism.

There's not a great deal more to add about this paper. Yes, again research with a reliance on post-mortem brain samples and all the caveats that go alongside their use (cause of death, comorbidity, etc.). Again however we are presented with some tantalising data about the processes around an important enzyme which has quite a bit of research around it with autism in mind. That alongside some interesting differences found between measures in brain compared with other peripheral tissues which starts to ask some interesting questions about the application of such secondary measures.

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* Muratore CR. et al. Age-dependent decrease and alternative splicing of methionine synthase mRNA in human cerebral cortex and an accelerated decrease in autism. PLoS ONE. 2013; 8: e56927.

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Muratore, C., Hodgson, N., Trivedi, M., Abdolmaleky, H., Persico, A., Lintas, C., De La Monte, S., & Deth, R. (2013). Age-Dependent Decrease and Alternative Splicing of Methionine Synthase mRNA in Human Cerebral Cortex and an Accelerated Decrease in Autism PLoS ONE, 8 (2) DOI: 10.1371/journal.pone.0056927

Epigenetics, EN-2 and the 'autism brain'

A paper by Jill James and colleagues* (open-access) caught my eye recently. Centred on Engrailed-2 (EN-2), a gene with more than a passing relationship to cases of autism (see here), James et al report results based on analysis of a small number of post-mortem cerebellar samples with a particular focus on an epigenetic evaluation.

Cerebellum @ Wikipedia  

What is epigenetics? Well, I've written before about some of the basic concepts involved (see here) and how despite not everyone being enamoured with the rise and rise of the science, the discipline of epigenomics adds quite a distinctive layer to the functioning of a persons genome.

The basic tenet: your DNA might not necessarily be your destiny and that subtle changes to the epigenome can influence the expression of certain genes or not. Certainly in areas such as cancer medicine, epigenetics is starting to make some real waves (see here).

With autism in mind, epigenetics is also starting to make an impact on the scientific literature and promises so much more. I'm taken for example, back to some previous work looking at prefrontal cortex neurons** with autism in mind which concluded that there might be more to see in this area at least for some cases of autism.

Anyhow....

• James and colleagues focused on cerebellar samples because (a) the cerebellum has been a real area of interest to autism research, and (b) EN-2 is "highly expressed in Purkinje cells"; reaffirming some interesting observations noted about Purkinje cells in the cerebellum of people with autism***.
• They analysed 26 samples from 13 people with autism and 13 asymptomatic controls. Details of how participants died and other details are provided in the paper, bearing in mind the various discussions on how post-mortem brain samples from those deceased who had autism are subject to various confounders including how they died and the role of any comorbidity. Incidentally, some of the autism samples originated from the same place which had that very unfortunate freezer malfunction last year (see here).
• Various methods and techniques were used to assess the details of epigenetic functions focused on methylation. I can't and won't pretend to understand all of them but interestingly as well as looking at EN-2 promoter region methylation, global methylation and "the methylation status of histones H3K27 (associated with gene silencing) and histone H3 lysine 4 (H3K4; associated with gene activation)" was also included (see here), part of the histone code.
• Results: some interesting ones such as the finding of hypermethylation of DNA extracted from autism cerebellum samples, which contrasts sharply with the DNA hypomethylation of immune cells noted by some of the authorship group on another occasion****. The authors speculate that this could be indicative of "tissue-specific" DNA methylation in autism; also noting that short of looking at brain samples - which is neither desirable or feasible for the living - we can't conclude too much from "peripheral cell DNA methylation patterns". This should make for some interesting future discussions I reckon.
• Alongside this global hypermethylation, James reports hypermethylation of the EN-2 promoter region. This, alongside sustained gene expression of EN-2 and greater levels of EN-2 protein in the autism samples. Similarly when looking at the methylation of histones (H3K27 and H3K4), the histone H3K27 which is linked to gene suppression was decreased and the histone H3K4 linked to gene activation, was increased (albeit not significantly).
• Assuming that I've understood this all correctly, the suggestion is that epigenetic issues with the histones involved in gene suppression or gene activation (via methylation) were congruent with a pattern of "sustained EN-2" gene over-expression which might tie into the loss of Purkinje cells***** noted in the cerebellum of some people with autism. At least I think so.

It all makes for some really rather interesting findings. That for example, the modification of histones ties into the levels of gene expression and importantly gene protein levels is really exciting and perhaps a valuable addition to the notion that mutation in the form of SNPs are the only influencing variable on gene function. Indeed that an epigenetic process might affect the timing of gene activation/suppression at critical periods of development is also an important point bearing in mind that we don't all walk around with all our genes permanently stuck in the 'on' position.

One also starts to wonder about not just the availability of methyl groups in this process but also the functioning of things like the DNA methyltransferase enzyme family (adding methyl groups) and indeed the demethylase enzymes (removing methyl groups) and the circumstances of their control at certain periods of development. Indeed methylation is only one facet of histone modification, as per the acetlyation and deacteylation of histone which potentially brings us back to things like the valproate connection being made to cases of autism (see here). It's all quite complicated.

Perhaps just as important are the implications of hypermethylation and those histone modifications to other genes tied into things like neuronal development and immune function in conditions like autism. Noting for example the Saxena paper (covered here) and their linking quite a few of the autism-related genes to things like immune function, James and colleagues make mention of one demethylase, JMJD3 (see here) and its potential link to the "IL-6 gene promoter" with regards to processes such as neuroinflammation. Certainly one has to ponder how deep the rabbit hole goes.

OK, coming back down to earth, caution is required in that this was a relatively small scale study which is again, always going to be confounded by the use of post-mortem brain samples and factors such as cause of death and the important point that autism is a behavioural label and that link of possible heightened comorbidity. Added to the fact that the focus was on one particular gene - one of quite a few - with some apparent connection to autism, the results should be viewed as preliminary at best.

That being said, we have a template now for expanding this area of work to cover other candidate genes in different tissues, to start working on those all-important rodent models. Then, with some degree of caution and assuming a strong connection is made, looking at the various factors which might potentially influence and moderate such epigenetic issues - including sex differences****** (open-access) - bearing mind the golden concept of phenotypes.

This could be something quite big...

Speaking of big (famous), they don't come much bigger than this lady....

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* James SJ. et al. Complex epigenetic regulation of Engrailed-2 (EN-2) homeobox gene in the autism cerebellum. Translational Psychiatry. 2013: 3; e232.

** Shulha HP. et al. Epigenetic signatures of autism: trimethylated H3K4 landscapes in prefrontal neurons. Arch Gen Psychiatry. 2012; 69: 314-324.

*** Fatemi SH. et al. Purkinje cell size is reduced in cerebellum of patients with autism. Cell Mol Neurobiol. 2002; 22: 171-175.

**** Melnyk S. et al. Metabolic imbalance associated with methylation dysregulation and oxidative damage in children with autism. J Autism Dev Disord. 2012; 42: 367-377.

***** Baader SL. et al. Ectopic overexpression of engrailed-2 in cerebellar Purkinje cells causes restricted cell loss and retarded external germinal layer development at lobule junctions. J Neurosci. 1998; 18: 1763-1773.

****** McCarthy MM. et al. The epigenetics of sex differences in the brain. J Neurosci. 2009; 29: 12815-12823.

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James SJ, Shpyleva S, Melnyk S, Pavliv O, & Pogribny IP (2013). Complex epigenetic regulation of Engrailed-2 (EN-2) homeobox gene in the autism cerebellum. Translational psychiatry, 3 PMID: 23423141

Vitamin B12 and autism: more to do

The short report by Malhotra and colleagues* linking a case of the regressive condition childhood disintegrative disorder, CDD (otherwise known as Heller's syndrome) with vitamin B12 deficiency and hyperhomocysteinemia has grabbed my attention.

Malhotra et al report that following the identification of said nutritional issues, supplementation with vitamin B12 and a few other nutrients, seemed to correlate with some improvements in the 14 year old at the centre of this paper, according to parental reports. The authors suggest: "A case is made for vitamin B12 deficiency syndrome presenting as CDD".

Methyl Curt Cobain... er, cobalamin @ Wikipedia  

Bearing in mind the overlap between CDD with autism or autistic-like behaviours, and that the Malhotra paper was a case report (good news when it comes to the autism and n=1 philosophy), one has to caution against making any sweeping generalisations to the autisms as a whole. That being said and bearing in mind others have talked about developmental regression** being linked to hypocobalaminemia, it did make me take a look at some of the other scientific literature on any link between vitamin B12 and autism.

I have actually talked about vitamin B12 before on this blog. A few times in fact; ranging from vitamin B12 optic neuropathy presenting in cases of autism (see here and the paper is here), to vitamin B12 deficiency being picked up in cases of autism (see here), to the very much under-investigated issue of methylmalonic acid (MMA) alongside cases of autism (see here). Slightly outside of autism research, vitamin B12 has also been discussed with thin-fat bodies in mind (see here) and its relationship with the epigenome.

Given also the connection between vitamin B12 and that other B-vitamin of the moment with autism in mind, folic acid, this post turns out to be quite timely.

Whilst there is not a great expanse of literature on the topic of vitamin B12 and autism, there are a few other points worth noting:

• Not all vitamin B12 is equal (or some are more equal than others, to coin a phrase). As with the example of folic acid, vitamin B12 can appear in more than one form (the so-called vitamers) seemingly also related to how we ingest/supplement with the stuff and what form our body actually use.
• Methyl B12 (methylcobalamin) has been looked at as a possible intervention for cases of autism as per the study by Bertoglio and colleagues***. The results on that occasion were not exactly universally successful in terms of behavioural outcomes, although there was the suggestion of a sub-group of possible responders to this intervention. Indeed based on an abstract presented at IMFAR 2012, it appears that responders might be linked to another favourite topic of this blog, glutathione (see here).
• The combinatorial use of methylcobalamin and another compound of interest, folinic acid (see this post) has also been the topic of some investigation with autism in mind as reported by Jill James and colleagues**** (open-access). The intervention appeared to affect several important biochemical parameters but some unanswered questions on clinical outcome remained.
• Although seemingly unrelated to vitamin B12, I was alerted to a recent study by Parks and colleagues***** on how specific strains of bacteria have the ability to turn inorganic mercury into methylmercury. Whilst this biochemical process may not initially seem particularly exciting or relevant to this post, when you conisder the role of cobalmin (vitamin B12) in this process (as per the result reported by Choi and Bartha****** for example and the action of being a methyl donor), one becomes slightly more interested in light of reports of elevated heavy metals being present in cases of autism and of course all that gut bacteria work being undertaken. I'm not making too much of this research at the moment despite it being mentioned by others, aside from illustrating how even vitamins are pharmaceutics and their use should be treated as such.

Accepting again that the literature on vitamin B12 and autism is not exactly voluminous, there are some interesting strands of research which potentially connect the two things together requiring much greater study. Outside of the autism connection (or not), vitamin B12 has some interesting links with other things such as propionic acid for example (itself covered in separate posts on this blog, see here and here) which might also be a source of discussion.

One of the main drawbacks of supplementing with vitamin B12 (or specifically methyl B12) where indicated is the requirement for delivery by subcutaneous injection. This might be OK if you are used to repeated injections such as those required for type 1 diabetes for example, but probably a little more invasive if you're not used to having them, given also that children with autism in particular might not be too taken with visiting the doctor or indeed other healthcare professionals such as the dentist.

Without making any recommendations or anything like that, one would assume that some kind of reformulation might be possible to 'rebrand' methly B12 to make it more palatable, either based on a cream, even something like a microneedle preparation or some other transdermal delivery system******* as per other recent news in an unrelated area.

The emphasis however has to be on the requirement for further research in this area and an extension of the notion that a diagnosis of autism or conditions which manifest as autistic symptoms, are seemingly protective of nothing when it comes to other conditions or physiological states including the presence of things like vitamin B12 deficiency.

A song to finish. Sunday Bloody Sunday by U2.

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* Malhotra S. et al. Brief report: Childhood disintegrative disorder as a likely manifestation of vitamin B12 deficiency. J Autism Dev Disord. January 2013.

** Dror DK. & Allen LH. Effect of vitamin B12 deficiency on neurodevelopment in infants: current knowledge and possible mechanisms. Nutr Rev. 2008; 66: 250-255.

*** Bertoglio K. et al. Pilot study of the effect of methyl B12 treatment on behavioral and biomarker measures in children with autism. J Altern Complement Med. 2010; 16: 555-560.

**** James SJ. et al. Efficacy of methylcobalamin and folinic acid treatment on glutathione redox status in children with autism. Am J Clin Nutr. 2009; 89: 425-430.

***** Parks JM. et al. The genetic basis for bacterial mercury methylation. Science. January 2013.

****** Choi S-C. & Bartha R. Cobalamin-mediated mercury methylation by
Desulfovibrio desulfuricans LS. Appl Environ Microbiol. 1993; 59: 290-295.

******* Madhaiyan K. et al. Vitamin B(12) loaded polycaprolactone nanofibers: A novel transdermal route for the water soluble energy supplement delivery. Int J Pharm. January 2013.

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Malhotra S, Subodh BN, Parakh P, & Lahariya S (2013). Brief Report: Childhood Disintegrative Disorder as a Likely Manifestation of Vitamin B12 Deficiency. Journal of autism and developmental disorders PMID: 23334842

The common ground

Today's post is all about common ground. I'm not necessarily making a plea for common ground to be found in any specific area or community, but rather how the concept of common ground runs through a few important discussions which I recently found interesting.

A short while ago the BBC ran with the headline 'Five psychiatric disorders linked' built on the study findings reported by the Cross-Disorder Group of the Psychiatric Genomics Consortium* (et al?) published in The Lancet. The authors findings, discussed shortly, highlighted: "the goal of moving beyond descriptive syndromes in psychiatry, and towards a nosology informed by disease cause". Shared genes (or at least shared SNPs) and common ground.

Next was the very interesting blog post from Tom Insel at the NIMH titled 'The Four Kingdoms of Autism'. In it, Dr Insel quite cleverly describes the four big schools of autism thought: illness, identity, injury and insight, based on how autism is represented, and how "as long as each kingdom stays behind its own walls, there is little hope for progress overall". I'm not normally too interested in discussing non peer-reviewed blog posts here, but there was something about this entry, which many people probably had thought about but have never really put into words, as a consequence of the very, very wide heterogeneous spectrum that is autism and the resultant views about that spectrum. Dr Insel's solution: "to find some common ground where the entire community can work together".

Back to the Lancet paper. As with other high-profile results discussed in quite a few online outlets, there is little point in me regurgitating what has already been said. To summarise: based on a huge bank of cases of people diagnosed with conditions like autism, ADHD, schizophrenia, bipolar disorder and major depressive disorder (n=33,332), "genome-wide single-nucleotide polymorphism (SNP) data" were analysed and compared with an equally large bank of asymptomatic (at least for these conditions) control samples (n=27,888). The results: the single letter genetic glitches - SNPs - which we all have scattered throughout our genome, seemed in the symptomatic group to congregate in some cases more frequently in parts of the genome associated with these overlapping conditions. Ergo, SNPs in certain genes seemed to do more for uniting these conditions over dividing them to varying degrees.

I hope I'm not over-exaggerating things when I say that the Lancet study is potentially really quite a big deal. Regular readers might know that I'm quite interested in the whole comorbidity side of things when it comes to autism, and how the presentation of autism is so much more than the sum of the triad (dyad). That for example, the risk of overlap between autism and schizophrenia spectrums is an area of considerable interest and how modern medicine has chosen to compartmentalise many of these 'overlapping' conditions are important parts of this debate. Indeed, not wishing to glorify Dr Insel, but the issue of classification has also cropped up previously on his blog too (see here).

Granted, I'm not totally sold on the idea that SNPs are the magical 'be-all-and-end-all markers' of conditions like autism (or ADHD or anything else) given that (a) things are complicated when it comes to genes and mutation as I found out on a recent post looking at HERVs and autism, (b) related to (a), that new sheriff in the town of -omics called epigenetics which might imply other influences on the expression of the genome, and (c) the various gaps in the genomic work including the phrase 'de novo' when it comes to mutations, which is just a little bit too nebulous for me in terms of these SNPs just spontaneously appearing. What is described as spontaneous now, might not be so described in 10 or 20 years time.

But that's not to say that the science of genes is all bunk. Indeed, the very nice systems biology that it starting to filter through this area of endeavour, realising that genes are not just coding proteins for one specific system in the brain for example, is for me a step in the right direction. Also it appears flowing from the Lancet paper force with their use of the term 'pathway analyses' and the potential link with "calcium-channel activity genes" for example, which have been mentioned before with conditions like autism in mind** (open-access).

I'd like to think that the Lancet paper and Insel post whilst dealing with quite different material, reflect the principle of common ground when it comes to appreciating that the real-life presentation and manifestation of autism or ADHD or schizophrenia are not just diagnostic criteria in a textbook. Alongside, realising that blanket debates such as 'disorder or difference' where autism is concerned, while emotive and dependent to some extent where you come from and your own experiences, tend to take little consideration of the wide, very wide, heterogeneity present in conditions like autism. I can't say that there is an easy solution to bringing such a debate to resolution but at least some writers are thinking about this issue.

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* Cross-Disorder Group of the Psychiatric Genomics Consortium. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis The Lancet. February 2013.

** Lu. A et al. Support for calcium channel gene defects in autism spectrum disorders. Molecular Autism 2012; 3: 18.

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Cross-Disorder Group of the Psychiatric Genomics Consortium (2013). Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis The Lancet DOI: 10.1016/S0140-6736(12)62129-1

In relation to chelation and autism

OK, just to make sure we're straight on this matter:

I am not endorsing chelation therapy for autism in this post.

Carry on Private...

I might have said it before but a few areas of the autism landscape have been, and still, are a bit of a sticking point when it comes to their discussion. Mention for example bowel issues and autism and, in at least some quarters, you can see the eyebrows raising and the eyes beginning their short rolling journey around the eye socket. This despite the fact that bowel issues are to some extent entering the mainstream autism research consciousness as witnessed for example by that recent paper from Susie Chandler and colleagues (discussed here). Dare I even mention gut bacteria and autism as per the recent write-up of Paul Patterson's [pending] work in the New Scientist? Too much?

My hand @ Miss Whiteley  

So it is with some degree of eye-rolling anticipated that I set about discussing the paper by Eleonor Blaucok-Busch and colleagues* (open-access) describing the results of their small trial based on the use of the oral chelator meso-2,3-dimercaptosuccinic acid (DMSA) in cases of autism.

I'm not altogether sure, but I wondered whether we might have already seen some part of this trial published in another paper**.

In truth I wouldn't normally be minded to talk about something like DMSA and autism given that (a) chelation - with general health in mind - is still a bit of a hot potato in many science/medical circles even despite some evidence that the 'metal-snaring' intervention might have some effects, and (b) with autism in mind, chelation is even more of a hot potato given some safety concerns and its link to heavy metals - in particular one heavy metal - onward to a suggested role in the rising numbers of cases of autism by some.

But science is science, and the manuscript by Blaucok-Busch is peer-reviewed science (the journal also indexed in PubMed). Added to the fact that some people have reported positive changes to some features associated with autism following such intervention*** alongside some recent publicity for related work by people like Jim Adams (see this previous post), this post may be timely.

The Blaucok-Busch paper is open-access but a few details might be of some use:

• I don't mean to be a stickler but the opening line of the abstract read slightly unusual to me: "the aim of this study was to provide evidence that DMSA detoxification treatments cause a reduction of the heavy metal burden in the autistic, and that this reduction lessens neurological symptoms associated with ASD". A research paper designed to provide evidence that something works? Mmm, I perhaps would have worded this differently with regards to things like hypothesis-testing over evidence-producing, but maybe that's just me.
• Anyhow, 44 children diagnosed with an ASD - most boys and most diagnosed with autism - aged between 3-9 years old were included for study. The children were all attending a child development centre in Saudi Arabia. Quite a bit of background data were available for participants and in among the various entry/exclusion criteria were the none use of regular medication including neuroleptics and antiepileptics. 
• The Childhood Autism Rating Scale (CARS) (translated into Arabic) was used to score the presence of autism-related behaviours; both before DMSA use and "six months after treatment". This actually translates as a single dose of DMSA per month (10mg/kg body weight) for a total of 6 months.
• Prior to any use of DMSA, participants were provided with a nutritional supplement including "a multi-mineral-vitamin-amino acid complex" which included zinc gluconate given once-a-day for 3 months prior to chelation.
• Baseline urine samples pre-chelation were collected and alongside (I assume first supplementation) post-DMSA administration urine samples (over 4 hours), analysis was conducted on them using everyone's favourite metal analysis technique, ICP-MS.
• Results: based on analysis for a number of metals, urine samples showed a number of differences between pre- and post-DMSA administration, most notably for increases in cadmium (p=0.006) and lead (p=0.008) excretion. Mercury also showed some difference, but only just from a statistical point of view (p=0.049). Another quote: "For this autistic group, the baseline urine concentration of all metals tested exceeded the given reference range".
• For the CARS, pre- and post-DMSA scores - bearing in mind we are talking 6-months after treatment - showed a few interesting trends in terms of items like sensory-perceptual issues and verbal and non-verbal communication, potentially indicative of positive changes to symptoms.
• The authors conclude: "Our evaluation confirmed specific metals as neuro-developmental toxins, and we observed that a reduction in toxic metals is helpful in reducing some symptoms typically associated with autism".

OK first things first. This was a simple before-and-after study based on the use of DMSA. There was no control group, no randomisation, no placebo, and everything was unblinded. This is not a great example of providing evidence for a cause-and-effect relationship.

Aside from reporting that 2-3 days prior to the DMSA challenge "no fish was eaten" and "all nutritional supplements were stopped" we know very little about what else might have happened in that intervening 6 month period between CARS assessments. Without any sample control group to compare against, we might just as well say that the changes to the CARS might be down to maturation or some other intervention put in place. Indeed I don't know whether this cohort were more or less likely to be using other interventions which might have affected results as a result of their participation in the trial; not least whether anyone went back on to the nutritional supplement after the first chelation event. There are methodological holes in this trial; of this there is no doubt.

But... [cue any eye-rolling] I am particularly interested in the pre- and post-challenge DMSA urine results detailed. Interested that even in the pre-DMSA samples, children with autism were presenting with levels of heavy metals that exceeded reference ranges. Granted, one could ask: from where the reference range is derived and whether it is truly reflective of this particular participant group in terms of age, sex, ethnicity, etc. and the myriad of other potentially influential demographic and geographic factors. I have to take the authors' word for it that it is accurate although I would like to have seen the unit of measurement when it comes to reporting metal excretion levels displayed somewhere in the paper.

Of course this is not the first time that metals like lead have for example cropped up with autism and quite a few other conditions/states in mind. Even superman had problems with lead, so went a past post on this blog. Indeed my discussion on the paper by Yasuda and colleagues quite recently (see here) and their metallomic analysis of children with autism suggested that lead, cadmium and aluminium in relation to some cases of autism were of potential importance, particularly where zinc deficiency was present. This follows similar findings previously reported (yep that Jim Adams study again) and some case studies (see here for example).

I was also interested in the variation in metal excretion following DMSA challenge. Increasing mean levels of urinary lead in the cohort follow what DMSA is supposed to do and add to the evidence already presented with autism in mind**** (open-access). But, as the authors point out, several metals were actually lower in the post challenged samples. Even the mercury results whilst showing a mean higher level showed a vastly increased standard deviation pre- and post-challenge (3.35±3.81 vs. 16.12±36.57) which probably accounts for the relatively modest p-value reported. I assume this denotes that some children were better excretors of things like mercury than others following DMSA challenge? My next question would be: why?

Evidence for the use of chelation in cases of autism is still wanting in terms of research results as per the review by Davis and colleagues*****. This trial by Blaucok-Busch is, unfortunately, unlikely to add anything significant to the existing research literature. The tragic case of Abubakar Tariq Nadama who died following intervention with a chelating agent****** (albeit a different chelating agent) still also hangs over the whole area of metal removal and autism and serves as an important but very unfortunate reminder about what can happen; also re-emphasizing the first law of any intervention: do no harm. No doubt why the NIH trial fell as it did (see here).

That's not however to say that the research door should be slammed shut, bolted, padlocked and alarmed, as several questions still remain unanswered: why for example some kids with autism present with elevations in certain heavy metals in the first place (see the paper by Levallois et al******* for one possibility) and what their relationship might or might not be to presented symptoms. One could argue that getting to the bottom of these questions is the first step, and thereafter to the question of what can or can't be done about it in a more scientifically-rigorous fashion bearing in mind safety first and the fact that not all chelating methods are the same********.

To finish, a final mention: I am not endorsing chelation therapy for autism in this post. Just in case I hadn't got my message across.

Now away from metal, how about listening to The Specials and 'Gangsters' including one of the best lines in music... "Don't call me Scarface". So, don't.... (and as it happens, thanks to a childhood prank gone wrong, I do actually have a scar on my face).

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* Blaucok-Busch E. et al. Efficacy of DMSA therapy in a sample of Arab children with autistic spectrum disorder. Maedica (Buchar). 2012; 7: 214-221.

** Amin OR. P-252 - Efficacy of oral dimercaptosuccinic acid (DMSA) therapy in a sample of arab children with autistic spectrum disorder. European Psychiatry. 2012; 27 (suppl 1).

*** Senel HG. Parents' views and experiences about complementary and alternative medicine treatments for their children with autistic spectrum disorder. J Autism Dev Disord. 2010; 40: 494-503.

**** Adams JB. et al. Safety and efficacy of oral DMSA therapy for children with autism spectrum disorders: Part A--medical results. BMC Clin Pharmacol. 2009; 9:16.

***** Davis TN. et al. Chelation treatment for autism spectrum disorders: a systematic review. Research in Autism Spectrum Disorders. 2013; 7: 49-55.

****** Baxter AJ. & Krenzelok EP. Pediatric fatality secondary to EDTA chelation. Clinical Toxicology. 2008; 46: 1083-1084.

******* Levallois P. et al. The impact of drinking water, indoor dust and paint on blood lead levels of children aged 1–5 years in Montréal (Québec, Canada). Journal of Exposure Science and Environmental Epidemiology. January 2013.

******** Cohen JP. et al. Plasma and Urine Dimercaptopropanesulfonate Concentrations after Dermal Application of Transdermal DMPS (TD-DMPS). J Med Toxicol. 2013; 9: 9-15.

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Blaucok-Busch E, Amin OR, Dessoki HH, & Rabah T. (2012). Efficacy of DMSA Therapy in a Sample of Arab Children with Autistic Spectrum Disorder. Maedica (Buchar), 7 (3), 214-221

Memantine and autism

As part of their review of autism research in 2012, the Simons Foundation Autism Research Initiative (shortened to the very catchy SFARI) had an interesting blogpost on all things drug development with autism spectrum disorders (ASD) in mind.

It was an interesting entry insofar as they had categorised the various medicines potentially indicated for some of the symptoms of ASD according to the stage of drug development including some formulations that have previously been fodder for this blog such as arbaclofen (see here), NAC (see here), minocycline (see here and here) and of course melatonin (see here). Without wishing to nit-pick, there was one important omission from the list - at least when I looked at it (29/12/12) - in the form of Dr Joan Fallon's CM-AT preparation which has also started making waves, but I'll put that to one side for now.

Tacuinum Sanitatis @ Wikipedia

Another compound which I've been hearing rumblings about for some time now was also included as a drug in phase II development.

The name: memantine, known under various trade names but with autism in mind, specifically Namenda by Forest Laboratories.

Searching through my blogpost archives I have made brief mention of memantine in a previous entry on some research looking at amyloid precursor protein in cases of autism. In that context, memantine was discussed with the management of symptoms related to Alzheimer's disease although touching upon the open-label study by Chez and colleagues* with autism in mind.

Given the very visible focus on glutamate and autism (see my post on GABA for an overview) it was always likely that memantine would get a look in when it comes to autism and autistic-like conditions. Memantine, I am reliably informed, blocks the action of glutamate by binding to NMDA receptors. That and a few other potentially important modes of action including some effect on cholinergic activity which I've always thought to be a rather interesting area as per articles like this one from Elaine Perry and colleagues** (open-access) and some potential synapse formation effects*** (open-access). It's probably no surprise that memantine has also been tentatively suggested for quite a few more psychiatric-based conditions**** including depression and schizophrenia.

I am rather interested in memantine and its possible uses (and misuses) when talking about autism. A quick trawl of the available literature suggests that an awful lot more needs to be done on this medicine with autism in mind as per its inclusion in the very useful pharmacologic autism treatment review by Doyle & McDougle***** (open-access) and its proposed effects particularly on the social interactive side of autism. Indeed trials are on-going (see here). Not least to also bear in mind are the various contra-indications and side effects (see here) which as always need to be balanced against potential therapeutic gains as required by good medicines management.

We wait and see... And while waiting, let's do some jammin' with Bob.

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* Chez MG. et al. Memantine as adjunctive therapy in children diagnosed with autistic spectrum disorders: an observation of initial clinical response and maintenance tolerability. J Child Neurol. 2007; 22: 574-579.

** Perry EK. et al. Cholinergic activity in autism: abnormalities in the cerebral cortex and basal forebrain. Am J Psychiatry. 2001; 158: 1058-1066.

*** Wei H. et al. The therapeutic effect of memantine through the stimulation of synapse formation and dendritic spine maturation in autism and fragile X syndrome. PLoS ONE. 2012; 7: e36981.

**** Zdanys K. & Tampi RR. A systematic review of off-label uses of memantine for psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2008; 32: 1362-1374.

***** Doyle CA. & McDougle CJ. Pharmacologic treatments for the behavioral symptoms associated with autism spectrum disorders across the lifespan. Dialogues Clin Neurosci. 2012; 14: 263–279.

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Chez MG, Burton Q, Dowling T, Chang M, Khanna P, & Kramer C (2007). Memantine as adjunctive therapy in children diagnosed with autistic spectrum disorders: an observation of initial clinical response and maintenance tolerability. Journal of child neurology, 22 (5), 574-9 PMID: 17690064