The rise and rise of CM-AT for autism

Today's post surrounds a poster presentation delivered at INSAR 2019, the (still) premier international autism conference, albeit not without its battles. The poster was delivered by Heil and colleagues [1] and talks about a compound / preparation that has been discussed a few years back on this blog: CM-AT (see here).

CM-AT is described as a "pancreatic enzyme preparation" with chymotrypsin - a digestive enzyme - seemingly placed quite prominently in its list of ingredients. CM-AT is, from what I understand, something that is still going through the research processes with regards to its use in the context of autism. Heil and colleagues presented data on part of that research agenda, specifically pertinent to ascertaining "whether or not behavior (e.g., symptoms of irritability, hyperactivity) in preschoolers with autism could be improved with CM-AT."

Bearing in mind a conference poster presentation is not necessarily the same as a published peer-reviewed research article, the Heil data was based on the use of a "randomized, placebo-controlled, 12-week clinical trial" methodology where 92 children, aged between 3-5 years, diagnosed with an autism spectrum disorder (ASD) received CM-AT "as granules sprinkled on food" and almost a hundred boys with ASD received a placebo "which consisted of visually identical inert sprinkles." The 'Irritability' scale of the Aberrant Behavior Checklist (ABC) was the primary outcome measure.

Results: "children receiving CM-AT (relative to those receiving placebo) demonstrated significant reductions in Irritability... Hyperactivity... Inappropriate Speech... over the 12 weeks of the trial." Researchers further reported that those children with higher levels of irritability at baseline tended to show a greater positive response than when the participant sample as a whole was analysed.

I think you can perhaps see why these results - preliminary as they are - are worthy blogging material. Irritability, perhaps listed as a 'challenging behaviour' in the context of autism is something that many, many people would love to be able to effectively tackle; if not just because of the impact it can have on those with autism and those around them who have to 'cope' with such behaviours. Indeed, given the other options for managing such behaviour such as the antipsychotic risperidone (see here) and the issues which that drug and its similars can bring (see here), the idea that there may be other, less side-effect heavy options (see here) is definitely something to consider.

I'm hopeful that soon, very soon, I can talk more about CM-AT in the context of irritability and beyond in relation to autism...

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[1] Heil MF. et al. Pancreatic Replacement Therapy with CM-at Is Associated with Reduction in Maladaptive Behaviors in Preschoolers with Autism. INSAR 2019.

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Baclofen is back: "Baclofen as an adjuvant therapy for autism"

"Our data support [the] safety and efficacy of baclofen as an adjuvant to risperidone for improvement of hyperactivity symptoms in children with ASD [autism spectrum disorder]."

So said the findings reported by Seyedeh-Mahsa Mahdavinasab and colleagues [1] talking about the use of baclofen as an add-on medicine in the context of risperidone use in relation to autism. Baclofen by the way, is typically known as "a gamma-aminobutyric acid (GABA) agonist" (binds to the GABA receptors and activates them) which accounts for its use as "a skeletal muscle relaxant" given the inhibitory function of GABA and GABA receptors.

Why the 'baclofen is back' sentiment expressed in the title of this post? Well, a few years back there was some excitement about a compound called STX209 otherwise known as arbaclofen in the context of a genetic condition manifesting autistic signs and symptoms (see here) and autism itself. Arbaclofen is an enantiomer (mirror image in a chemical sense) of baclofen, but unfortunately fell by the wayside after some less than impressive results emerged from clinical trials (see here). Arbaclofen might have been kicked into the long grass for now but baclofen it seems, is still on the autism research agenda...

Researchers report results based on a "10-week randomized-controlled study aimed at evaluating the potential of baclofen as an adjuvant therapy to enhance the effect of risperidone in children with ASD." Risperidone is an antipsychotic which is indicated for selective use with children with autism (see here) specifically to treat/manage aggressive and challenging behaviours. They reported that several outcome measures saw a change - a positive change - specifically in relation to hyperactivity behaviours which can often accompany aggression. Importantly, they also noted that during and after 10 weeks of add-on baclofen use, adverse events were reported to be at a minimum.

There is more to do in this area before any sweeping generalisations are made. I personally would like to see more data on potential best- and non-responders in the context that GABA is still a topic of interest to autism research (see here). I know also that some people might be a little put-out by the idea that more medication is added to the lives of young children with autism and worries about how this might impact them in later years. We need a lot more data.

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[1] Mahdavinasab SM. et al. Baclofen as an adjuvant therapy for autism: a randomized, double-blind, placebo-controlled trial. Eur Child Adolesc Psychiatry. 2019 Apr 12.

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"two in five young people scoring above thresholds for emotional problems, conduct problems or hyperactivity"

The quote titling this post - "two in five young people scoring above thresholds for emotional problems, conduct problems or hyperactivity" - comes from the eye-opening findings published by Jessica Deighton and colleagues [1] (open-access available here).

It's based on a study of over 28,000 adolescents here in Blighty: "51.2% of whom were in Year 7 (age 11–12) and 48.8% of whom were in Year 9 (age 13–14) in 97 state-maintained secondary schools across six geographical locations in England."

Said young people were given the "child self-report Strengths and Difficulties Questionnaire (SDQ)" to complete, and the received data were analysed alongside other information collected by the authors "from the National Pupil Database: SEN status; FSM eligibility; child in need status (CIN, this is a child who either (a) is unlikely to achieve/maintain a reasonable standard of health and development without local authority provision; (b) is likely to be impaired without local authority provision; or (c) is disabled); and ethnicity (Asian, Black, Chinese, Mixed, White or any other ethnic group)."

In more detail: "18.4% scored above the abnormal threshold for emotional symptoms, 18.5% for conduct problems, 25.3% for inattention/hyperactivity and 7.3% for peer-relationship problems." Going back to the title of this post, researchers mention how "around two in five young people scoring above ‘abnormal’ thresholds for three of the four problem areas measured (emotional problems, conduct problems and hyperactivity)." They also observed that:

• SEN - special educational needs - status played a role in those figures (those with SEN were consistently more likely to provide an above-threshold response to all the areas measured, particularly peer-relationship problems). 
• Entitlement to free school meals (FSM), a potential marker of deprivation, was also associated with an above-threshold response to all areas.
• "Being male significantly increased the odds of scoring above threshold for behavioural problems and inattention/hyperactivity, whereas being female significantly increased the odds of experiencing emotional symptoms."

There are caveats attached to the Deighton findings; not least the sole reliance on "child self-report data from a very brief assessment tool" without any accompanying further analysis on the presence (or not) of diagnosable psychopathology. But, in the context of the large participant number included for study and that most adolescents aren't likely to 'lie' about their positive responses to items such as "I get very angry and often lose my temper" or "I take things that are not mine from home, school or elsewhere" I'd be inclined to view the Deighton findings as a pretty accurate representation of their 'in the thousands' cohort.

So where next? Well, if we're talking about findings observing that "42.5% scored above threshold for any one of the first three problem scales (emotional symptoms, conduct problems or inattention/hyperactivity)" we have to talk about what services are in place (and should be in place) to support this large group. This, on the basis that, such 'problems' can potentially lead to various other 'adverse' outcomes both in later childhood and beyond. And when I talk about 'support', I mean both support and intervention to help those young adults to manage such issues. All of this set in the context of a continually squeezed financial and resource position (at least here in Blighty).

The other question has to be 'why'? Why have so many young people reported as they have? Deighton et al talk about various factors as potentially being important: "the impact of austerity, increasing experience of academic pressures, reduced rates of sleep and increased use of social media", to a large extent talking about the social environment as playing a significant role. I don't doubt that these external factors and other related variables will play a role in how young people are reporting, but I'm not convinced that the social environment is the only important factor to consider. It's not, for example, beyond the realms of possibility that other genetic and non-genetic variables (i.e. in the physical environment) could also play a role; something I say in the context of a 'growth' in the number of children and young adults being diagnosed with all-manner of different behavioural and/or psychiatric labels (see here and see here for examples).

Something important seems to be going on with our young people (see here and see here). We have to assume that such an issue is not going to resolve itself and may even increase in terms of numbers as time goes on. We really need to find out what factors are behind this and start taking action... like now.

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[1] Deighton J. et al. Prevalence of mental health problems in schools: poverty and other risk factors among 28 000 adolescents in England. Br J Psychiatry. 2019 Jan 30:1-3.

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"Vitamin D and omega-3 reduced irritability symptoms in children with ASD"

The title heading this post - "Vitamin D and omega-3 reduced irritability symptoms in children with ASD [autism spectrum disorder]" - comes from the findings reported by Hajar Mazahery and colleagues [1] discussing the results of their clinical trial. I have already mentioned the Mazahery trial before on this blog (see here) as a 'study to watch' based on the publication of their study protocol [2]. It looks like the wait is finally over...

So, as researchers previously reported, there were four arms to this clinical trial: supplementation with vitamin D alone ("2000 IU/day, VID"), supplementation with an omega-3 fatty acid ("722 mg/day DHA, OM"), vitamin D plus fatty acid supplementation together ("2000 IU/day vitamin D + 722 mg/day DHA, VIDOM") and a placebo group (olive oil). Results are reported for over 70 children diagnosed with an autism spectrum disorder (ASD) - "VID = 19, OM = 23, VIDOM = 15, placebo = 16" - over a 12-month period, with the primary outcome being "the Aberrant Behaviour Checklist (ABC) domains of irritability and hyperactivity."

Aside from the main finding - "vitamin D and omega-3 LCPUFA [long chain polyunsaturated fatty acid] reduced irritability symptoms in children with ASD" (compared against placebo) - a few other observations are noteworthy: "Compared to placebo, children on VID [vitamin D] also had greater reduction in hyperactivity." All this bearing in mind that the biological testing to examine for vitamin D and fatty levels reported "a good compliance rate" indicating that supplements were routinely being taken as required by the study.

Implications? Well, strike up more peer-reviewed evidence that nutrition is important not just for physiological health but also for psychological/behavioural health and wellbeing too (see here). Add this research also to other peer-reviewed science that suggests that at least 'some autism' might be particularly 'sensitive' to elements of such nutritional medicine (see here).

I could go on about how vitamin D in particular seems to be something important to autism (see here and see here for examples). I could also go on about how fatty acids have some important evidence-based history with autism in mind (see here). But do I really need to? Minus any medical or clinical advice given or intended, the Mazahery results really speak for themselves.

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[1] Mazahery H. et al. A randomised controlled trial of vitamin D and omega-3 long chain polyunsaturated fatty acids in the treatment of irritability and hyperactivity among children with Autism Spectrum Disorder. The Journal of Steroid Biochemistry and Molecular Biology. 2018. Oct 26.

[2] Mazahery H. et al. Vitamin D and omega-3 fatty acid supplements in children with autism spectrum disorder: a study protocol for a factorial randomised, double-blind, placebo-controlled trial. Trials 2016; 17:295.

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The links between autism and ADHD: sibling study adds a new layer

'A diagnosis of autism or autism spectrum disorder (ASD) does not typically appear in a diagnostic vacuum'. I've said that sentence several times on this blog (see here for example) in line with how science has shown that many different labels (both behavioural and somatic) are over-represented when it comes to a diagnosis of autism. All very ESSENCE like (see here)...

Of the various over-represented comorbidity, attention-deficit hyperactivity disorder (ADHD) - either in symptoms or in diagnosis - is one of the more common ones (see here); something that has implications for screening (see here) and also management. The findings reported by Yi-Ling Chien and colleagues [1] (open-access) add something to the research looking at the possible hows-and-whys of ADHD appearing alongside autism with their focus on "unaffected siblings of probands with autism and Asperger syndrome (AS)." Such work ties into that observing 'unaffected by autism' does not necessarily mean 'symptom or trait-free' in the context of ideas such as the broader autism phenotype (BAP) (see here).

With the aim to "investigate the ADHD-related traits and attention performance in unaffected siblings of probands with autism and Asperger syndrome (AS), as well as the clinical correlates of ADHD-related traits" researchers concluded that generally, unaffected siblings (unaffected by autism) of those diagnosed with an ASD "were more hyperactive/impulsive and oppositional" than those so-called typically developing controls. The finding was based on the use of various questionnaires/schedules pertinent to both the "the core symptoms of DSM-IV ADHD" and also tests to "assess attention performance."

Of particular note was the observation of "more ADHD and oppositional traits in unaffected siblings of AS probands" when looking at subgroups on the autism spectrum. With caution, the authors suggest that such a finding may be evidence "that these traits might be a broader phenotype for AS." They also posit that "more severe ADHD-related symptoms in AS probands rather than autism probands suggest that these two subtypes may not be the same in their clinical expression regarding ADHD symptoms." In these days of plural autisms (see here), things seemingly get even more complicated when diagnostic subgroup x comorbidity is also thrown into the mix.

Although quite a bit more investigation is required in this area, there is at least one important point to take from the Chien work: unaffected siblings of those diagnosed with autism - particularly Asperger syndrome - may benefit from preferential clinical assessment for something like ADHD. I say that with the understanding that a diagnosis of ADHD has been linked to a heightened risk of various 'adverse' outcomes in the longer term (see here and see here) and again, minus any sweeping generalisations, specific interventions for ADHD can seemingly mitigate quite a bit of that excess risk (see here) and onward improve quality of life and more.

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[1] Chien Y-L. et al. ADHD-related symptoms and attention profiles in the unaffected siblings of probands with autism spectrum disorder: focus on the subtypes of autism and Asperger’s disorder. Molecular Autism. 2017; 8: 3.

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ALSPAC says maybe to link between prenatal paracetamol exposure and childhood behavioural difficulties

ALSPAC - the Avon Longitudinal Study of Parents and Children - continues to give in research terms as today I approach the findings reported by Evie Stergiakouli and colleagues [1]. They observed that: "Children exposed to acetaminophen [paracetamol] prenatally are at increased risk of multiple behavioral difficulties, and the associations do not appear to be explained by unmeasured behavioral or social factors linked to acetaminophen use insofar as they are not observed for postnatal or partner’s acetaminophen use." Some media attention for the study can be found here.

Continuing the research journey on a topic not unfamiliar to this blog (see here and see here for example) that exposure to paracetamol during the nine months that made us might not be a totally benign affair, Stergiakouli et al analysed data for some 7,700 mothers included in the initiative between 1991 and 1992. Questions about paracetamol use at 18 and 32 weeks of pregnancy were asked of mothers and maternal reports of child behaviour problems at 7 years using the Strengths and Difficulties Questionnaire (SDQ) were thrown into the research mix.

Results: those behavioural difficulties potentially associated with maternal paracetamol use at both 18 and 32 weeks of pregnancy included both conduct problems and hyperactivity symptoms. Researchers were also able to record no (significant) connection between post-natal paracetamol use nor partner paracetamol use and childhood behavioural problems. They concluded that "the timing of acetaminophen use might be important" and that "the association between prenatal acetaminophen exposure and childhood behavioral problems is not explained by unmeasured familial factors linked to both acetaminophen use and childhood behavioral problems and that the findings are consistent with an intrauterine effect."

Combined with the various other studies suggesting an association between prenatal exposure to paracetamol and offspring behavioural 'issues' the case for a possible link is growing. ALSPAC has a number of methodological strengths to its design, not least "the availability of prospective information on acetaminophen use during the second and third trimesters of pregnancy and postnatally by the mother and by her partner." The fact that numerous potentially confounding variables were also controlled for is another bonus for the study results: "maternal age at birth, parity, socioeconomic status, smoking and alcohol consumption during pregnancy, prepregnancy body mass index (BMI), maternal self-reported psychiatric illness, and possible indications for acetaminophen use." This is pretty strong data (or at least as strong as the other data published on this topic).

Mechanism(s) of effect? Still something that needs a little more work I'm afraid, before any precise information is revealed. The authors go with some ideas based on the "endocrine-disrupting properties of acetaminophen" for example, but let's wait and see before anyone makes too many sweeping generalisations. I might however suggest that the possibility of a link between paracetamol exposure and asthma (see here) could be important in light of what asthma might mean for the risk of presentation of ADHD (attention-deficit hyperactivity disorder) for example (see here). Just a thought and bearing in mind the evidence linking paracetamol use and asthma is not always all on-way.

Further studies are required on this increasingly important topic. Please also bear in mind no medical or clinical advice is given or intended on this blog. Speak to your physician if you need more information about pain relief during pregnancy.

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[1] Stergiakouli E. et al. Association of Acetaminophen Use During Pregnancy With Behavioral Problems in Childhood. JAMA Pediatrics. 2016. Aug 15.

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Stergiakouli, E., Thapar, A., & Davey Smith, G. (2016). Association of Acetaminophen Use During Pregnancy With Behavioral Problems in Childhood JAMA Pediatrics DOI: 10.1001/jamapediatrics.2016.1775

On fatty acid metabolism and autism and ADHD (again)

"Children with ADHD [attention-deficit hyperactivity disorder] and ASD [autism spectrum disorder] had low levels of EPA [eicosapentaenoic acid], DHA [docosahexaenoic acid] and AA [arachidonic acid] and high ratio of n-6/n-3 PUFAs [polyunsaturated fatty acid] and these correlated significantly with symptoms. Future research should further investigate abnormal fatty acid metabolism in these disorders."

So said the research publication by Natalie Parletta and colleagues [1] (open-access available here) who completed assessments on erythrocytes in blood samples from "565 children aged 3-17 years with ADHD (n = 401), ASD (n = 85) or controls (n = 79)." Alongside fatty acid analyses (undertaken at "a commercial Pathology Laboratory") researchers also included various behavioural measures with their participant group looking at aspects such as attention and impulsivity and also autistic symptoms (via the CARS). Importantly we are told that: "Participants who had taken any nutritional supplement during the previous year were excluded" from the study.

Results:  well as I've mentioned, compared to the asymptomatic (not autism nor ADHD) controls, group values for those with autism or ADHD were lower in terms of EPA and DHA among other things. In fact we are told that: "Children with ASD had lower DHA, EPA and AA and higher n-3/n-6 ratio than children with ADHD" suggesting that fatty acid metabolism might be even more irregular in this group compared to the others. EPA and DHA specifically fall under the banner of omega-3 fatty acids and are generally thought to be the 'good guys' when it comes to all-manner of health effects. I might particularly mention the word 'inflammation' when it comes to this class of fatty acids [2] which could be relevant to quite a bit of the autism spectrum as well (see here). When it however came to the overall ratio between omega 3 and omega 6 fatty acids (sometimes thought of the not-so-good guys), it was ADHD that beat autism that beat controls. The authors make a case for some interesting correlations between fatty acids levels and the various behavioural scores obtained but to be honest, I'm not all that impressed with the figures as they stand.

I've used the word 'again' in the title of this post to denote how this is not the first time that unusual fatty acid metabolism has been described with both autism and ADHD in mind (see here and see here respectively). Minus any sweeping generalisations, the body of peer-reviewed evidence looking at fatty acids and autism or ADHD is pretty consistent in the the findings being reported that one for reason or another, there seems to be 'issues' with fatty acids and screening services should perhaps be preferentially offered as and when a diagnosis (or both) is received."This cross-sectional study is the largest of its kind, supporting previous work that showed low n-3 PUFA levels, particularly DHA, in children with neurodevelopmental disorders." Indeed.

Then comes the question of whether supplementation as and when an atypical fatty acid profile is detected might be useful or not. The jury is still out on this side of things particularly when it comes to autism and the possible effects of supplementation (see here). For ADHD the evidence is a little stronger (see here) and continues to garner research attention [3] as a potentially cost-effective intervention option for some. I was also intrigued to read the authors' reasoning on a possible role for the trillions of wee beasties that call us home (the gut microbiota) and how: "Another explanation could involve the influence of gut microbiota on PUFA uptake and metabolism." In an unrelated post, I've talked about research suggesting a possible role for fatty acids in terms of gut bacteria and something like obesity (see here). One therefore wonders how deep the rabbit hole might go?

For now however, we have more scientific evidence for a potential role for fatty acid metabolism and at least some autism and ADHD...

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[1] Parletta N. et al. Omega-3 and Omega-6 Polyunsaturated Fatty Acid Levels and Correlations with Symptoms in Children with Attention Deficit Hyperactivity Disorder, Autistic Spectrum Disorder and Typically Developing Controls. PLoS One. 2016 May 27;11(5):e0156432.

[2] Simopoulos AP. Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr. 2002 Dec;21(6):495-505.

[3] Gow RV. et al. Current evidence and future directions for research with omega-3 fatty acids and attention deficit hyperactivity disorder. Curr Opin Clin Nutr Metab Care. 2015 Mar;18(2):133-8.

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Parletta N, Niyonsenga T, & Duff J (2016). Omega-3 and Omega-6 Polyunsaturated Fatty Acid Levels and Correlations with Symptoms in Children with Attention Deficit Hyperactivity Disorder, Autistic Spectrum Disorder and Typically Developing Controls. PloS one, 11 (5) PMID: 27232999

Bisphenol A (BPA) and autism continued

"Descriptive analyses indicated that prenatal exposure to maternal BPA [Bisphenol A] concentrations were related to higher levels of anxiety, depression, aggression, and hyperactivity in children. BPA exposure in childhood was associated with higher levels of anxiety, depression, hyperactivity, inattention, and conduct problems."

That was the conclusion reached in the systematic review by Maede Ejaredar and colleagues [1], that provides one of two studies brought to the blogging table today. With the aim of looking at the current collected peer-reviewed literature on the topic of "prenatal and childhood BPA exposure" and offspring/childhood outcomes, the authors suggest that there may indeed be more to see in this area, but with the important requirement for further "Prospective cohort studies" to clarify any relationship.

BPA, by the way, is a chemical of some note in modern society given its quite widespread use in plastics and related materials. Although some agencies have provided current guidance to the effect that BPA is 'safe' and poses no health risk at current levels of exposure, not everyone is so convinced by such sweeping statements about safety.

Indeed to make the point, the findings reported by Meda Kondolot and colleagues [2] add to an existing body of scientific literature suggesting that when it comes to at least 'some' autism, there may be something of an increased biological burden of BPA present. Based on the analysis of 50+ children diagnosed with an autism spectrum disorder (ASD) and an equivalent number of asymptomatic - not autism - controls, a range of metabolites were looked for including "plasma phthalates and BPA" and compounds linked to "oxidant/antioxidant status." The authors reported that: "Plasma BPA levels of children with PDD-NOS [Pervasive Developmental Disorder-Not Otherwise Specified] were significantly higher than both classic autistic children and controls." Combined with some interesting findings potentially reflective of issues with oxidative stress in relation to their participant group, authors speculate that there may be some issues with the metabolism of things like BPA in relation to some autism. I might however also add that the chosen method of analysis of samples used by Kondolot et al - high performance liquid chromatography (HPLC) - is not the most sensitive of methods when used minus it's important detection counterpart, mass spectrometry; particularly when analysing such a complicated medium such as plasma. It implies that further, more technical investigation of samples, is perhaps required.

Being careful not the fall into any 'chemophobic' traps ('chemicals' is a word that has received a bad rap in my opinion), I continue to believe that there is more to see in this area of research. I draw back from any sweeping generalisations that have been put forward with other chemicals in relation to autism (see here for example) because I'm not convinced that all autism is due to BPA or any other single compound. Anyone who follows this blog regularly knows about my fascination with plural autisms (see here) and the fact that autism rarely exists in some sort of diagnostic vacuum (see here). That also takes into account the range of 'chemical exposures' that modern-day life brings.

I would however like to see further investigation on a few aspects: (i) is autism (some autism) associated with an increased exposure risk to certain chemicals? Y'know, the sort of data that is coming out of Vietnam for example (see here); and (ii) are there genetic and/or biological reasons why some people on the autism spectrum have issues with the metabolism of a range of xenobiotics? Under that last category, there are numerous examples in the literature of various compounds being elevated in terms of biological load (see here for example) combined with quite a bit of discussion about 'issues' with methods/systems for removing such compounds from the body (see here). Such findings could be just epiphenomenal to autism but could also represent something rather more central and important [3].

There is quite a bit more science to do in this area.

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[1]  Ejaredar M. et al. Bisphenol A exposure and children’s behavior: A systematic review. Journal of Exposure Science and Environmental Epidemiology. 2016. March 9.

[2] Kondolot M. et al. Plasma Phthalate and Bisphenol A Levels and Oxidant-Antioxidant Status in Autistic Children. Environmental Toxicology and Pharmacology. 2016. March 9.

[3] Kardas F. et al. Increased Serum Phthalates (MEHP, DEHP) and Bisphenol A Concentrations in Children With Autism Spectrum Disorder: The Role of Endocrine Disruptors in Autism Etiopathogenesis. J Child Neurol. 2016 Apr;31(5):629-35.

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Ejaredar M, Lee Y, Roberts DJ, Sauve R, & Dewey D (2016). Bisphenol A exposure and children's behavior: A systematic review. Journal of exposure science & environmental epidemiology PMID: 26956939




Kondolot, M., Ozmert, E., Ascı, A., Erkekoglu, P., Oztop, D., Gumus, H., Kocer-Gumusel, B., & Yurdakok, K. (2016). Plasma Phthalate and Bisphenol A Levels and Oxidant-Antioxidant Status in Autistic Children Environmental Toxicology and Pharmacology DOI: 10.1016/j.etap.2016.03.006

Childhood inattention and later academic outcome

"Across the full range of scores at a population level, each 1-point increase in inattention at age 7 years is associated with worse academic outcomes at age 16."

That was one of the conclusions reached in the study by Kapil Sayal and colleagues [1] (open-access) drawing on data derived from the Avon Longitudinal Study of Parents and Children or ALSPAC to those in the know. This initiative has also recently produced some other intriguing results on the potential long-term effects of bullying for example (see here).

"Matching of the ALSPAC database with the administrative National Pupil Database (NPD, the central repository in England for pupil-level educational data) provided details of the children's results in the General Certificate of Secondary Education (GCSE) examinations at age 16 years." For those resident in England, Wales and Northern Ireland, GCSEs are probably a familiar concept (they were the starting point for my own academic achievement record). For everyone else, GCSEs are normally sat at the end of the school journey (16 years) and form the start of the typical educational achievement hierarchy leading into A-levels, university degree and beyond. "In total, GCSE attainment data were available for 11,640 children (83% of the core ALSPAC sample)."

The Development and Well-Being Assessment (DAWBA) was completed by parents and teachers of participating children when aged 7 years old. Similar to other discussions on this blog mentioning the DAWBA (see here) it relates "closely to DSM-IV items and focus on current problems and associated impairment." For the purposes of the Sayal study "the key variables of interest relate to inattention, hyperactivity/impulsivity, and oppositional/defiant behaviors." Various other potential confounders such as child cognitive abilities and parental social class were also measured and taken into account when it came to the final analyses.

Following some number-crunching the authors concluded that their results potentially "highlights the adverse effects of early childhood behavioral difficulties on educational outcomes in adolescence" specifically based on inattention symptoms: "inattention, particularly if noticeable to a parent or teacher, is a stronger predictor than hyperactivity/impulsivity of later academic difficulties." Disruptive behaviour disorder (DBD) and oppositional/defiant symptoms were also independently linked to worse academic outcomes in boys.

I know that such findings are probably not totally unexpected in terms of issues such as inattention potentially impacting on learning ability/capacity/enthusiasm subsequently also being reflected in exam results, but the results do put a peer-reviewed, evidence-based perspective on things. Authors also note that: "teachers and parents should be aware of the academic impact of early behavioral difficulties, and, in particular, the risk associated with subthreshold difficulties." I might add that such results do not rule out other factors as playing a role in academic outcome as per other recent data [2].

Insofar as what can be potentially done to mitigate such symptoms and their potential impact on academic performance, the authors offer a few suggestions including: "strategies that might help to optimize examination performance during teenage years include time management and organization skills (throughout the course of study), prioritization of key work, minimizing distractions, examination revision, and within-examination strategy." All well and good (and discussed by other authors [3]) I say but perhaps one might also look to 'tackling' issues such as inattention in other ways too. Take for example the recent paper from Bos and colleagues [4] (see this post) discussing their results based on supplementation with omega-3 fatty acids specifically on inattention symptoms. Probably not suitable or useful for every child with attentional issues, but certainly worth quite a bit more investigation looking for potential best responders based on the idea that good nutrition might be an important part of good mental health. Oh, and how about looking at sleep and even chess? [5]

Music: Cannonball - The Breeders.

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[1] Sayal K. et al. Childhood behavior problems and academic outcomes in adolescence: longitudinal population-based study. J Am Acad Child Adolesc Psychiatry. 2015 May;54(5):360-368.e2.

[2] Peyrot WJ. et al. The association between lower educational attainment and depression owing to shared genetic effects? Results in ~25 000 subjects. Molecular Psychiatry. 2015. April 28.

[3] Ciesielski HA. et al. Academic Skills Groups for Middle School Children With ADHD in the Outpatient Mental Health Setting: An Open Trial. J Atten Disord. 2015 Apr 29. pii: 1087054715584055.

[4] Bos DJ. et al. Reduced Symptoms of Inattention after Dietary Omega-3 Fatty Acid Supplementation in Boys with and without Attention Deficit/Hyperactivity Disorder. Neuropsychopharmacology. 2015 Mar 19.

[5] Blasco-Fontecilla H. et al. Efficacy of chess training for the treatment of ADHD: A prospective, open label study. Rev Psiquiatr Salud Ment. 2015 Apr 21. pii: S1888-9891(15)00048-8.

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Sayal K, Washbrook E, & Propper C (2015). Childhood behavior problems and academic outcomes in adolescence: longitudinal population-based study. Journal of the American Academy of Child and Adolescent Psychiatry, 54 (5), 360-36800 PMID: 25901772

UK Millennium Cohort Study: School and the disabled child

Quite recently the BBC News online ran with the headline: "Disabled children's behaviour 'deteriorates at school'". The story revolved around the findings reported by Rebecca Fauth and colleagues [1] (open-access) looking at "the extent to which the associations between disability and behaviour are linked to children’s developmental stage and thus may be ‘grown out of’ as children enter school and move out of the early years". I should add that, at the time of writing, the Fauth paper is described as a 'working paper' and further "Citation of such a paper should account for its provisional character". So noted.

But why Earth, Jor-El? They're primitives...

With apologies for all the quotations included in this entry, participants for this trial were drawn from the UK Millennium Cohort Study (MCS) [2] which has previously reported on the topic of autism [3] - "Pre-diagnostic data showed early health problems differentiated children later diagnosed with autism from non-diagnosed peers" - Mmm.

In the Fauth paper it included over 6000 UK children covering various ages at different times over the course of the study (referred to as 'sweeps'). Children without reported disability were compared against 3 primary groups defined as 'disabled':

• Children with developmental delay (DD) at 9 months of age. This was assessed via "a set of 8 questions... that were taken from the Denver Developmental Screening Test" and "five items from an UK adaptation of the MacArthur Communicative Development Inventories (CDI) were used to identify early communicative gestures".
• Children with a "Long-standing limiting illness [LSLI] at 3, 5 or 7 years". LSLI was defined "if they had an LSLI at one or more of the occasions it was asked between age 3 and age 7" and included various conditions covering 'mental health' and physical health (asthma, type 1 diabetes and vision impairment).
• Children with Special Educational Needs (SEN) at age 7. Those familiar with the UK system will probably already know about SEN, but for those that don't, it covers "those children who need additional support with their learning" (see here). Further: "SEN may relate to learning difficulties or impairments such as hearing loss, ADHD or dyslexia".

Researchers tracked participants looking at various measures covering areas of "children's emotional, relationship and behavioural issues at the ages of three, five and seven" according to the BBC report. Fauth and colleagues list the dependent variables as being derived from "the four ‘problem’ subsets of the parent-reported Strengths and Difficulties Questionnaire (SDQ)". They also took into account various other factors based on family background and constitution, the parent-child relationship (including discipline practices) and child characteristics.

Based on some nifty statistical modelling, the authors reported on a few key points:

• So: "in their early preschool years disabled children do suffer from more challenging expressions of behaviour". 
• With some caveats: "disabled children exhibit a divergent trajectory from the ‘average’ child, showing increases over time in peer problems, hyperactivity and emotional problems, but not for conduct problems".
• Also: "family and individual characteristics that are associated with both disability and behaviour (such as poverty, family structure, cognitive ability and home environment) mediate the effects of disability in these instances".
• The authors talk about sex differences in their results: "overall girls face lower levels of peer, conduct and hyperactivity behavioural problems across the early years than boys". This is perhaps not an unexpected result as any parent with both boys and girls will perhaps tell you. But: "disabled boys consistently demonstrated more hyperactive problems than non disabled boys, and that these differences grew over time for boys with LSLI and SEN". Additionally: "The differences between disabled and non-disabled children is much greater for boys than for girls, and this divergence between disabled and non-disabled boys grows more over time than it does for girls".
• Parenting styles also get a mention in the results: "harsh discipline being consistently associated with higher levels of problem behaviours, and parent-child closeness being linked to lower rates of problem behaviours". With disability in mind however, the authors saw: "very little evidence of parenting moderating the relationship between disability and problem behaviours, either at age 3 or over time".

I should also add that when it came to looking at developmental delay (DD) the authors noted: "the developmental trajectories of children identified as DD did not diverge from those without DD" although measurement of peer and hyperactivity issues for example, did still not 'close the gap' compared with non-DD participants.

The authors conclude: "Child behavioural difficulties can have far reaching consequences and hence, without appropriate support or intervention, young disabled children may face an accumulation of adverse consequences that serve to compromise their well-being in adolescence and adulthood".

I'm sure you can appreciate how important this work is in terms of both how disability impacts on childhood and what strategies might be put in place to reduce some of the more adverse effects of such issues and lessen any inequality as a result. I note for example, that the BBC write-up of this research has given quite a lot of weight with regards to bullying and the notion that schools should adopt "more stringent anti-bullying strategies for those identified as different" as a result of the findings. I would very much agree with this position; with the caveat of ensuring that children with disability are not further plunged into the 'victim' label as a result of any strategies. This can sometimes itself have consequences for things like future independence and self-esteem; thus helping individuals to help themselves - instilling confidence and resilience and building up feelings of self-worth - is another strand to any discussions (and I have a few ideas on that without making any sweeping generalisations). I'm also wondering whether the debate on home-schooling might also come into play here too?

I'd finally also like to pass some comment about the issue of parenting styles discussed in the findings. Although no large effect appeared to be observed from parenting style and problem behaviours in those with disability, the more general association between harsh parenting style and hyperactive behaviours for example, offers a fascinating opportunity and potentially offers some, more general lessons on child development and rearing. I might add that the parenting style - disability non-event - "does not have much role in modifying the specific trajectories of problem behaviours associated with disability" - might also carrying some lessons for particular conditions like autism for example too (see here).

Now, how about looking at other potential mediators of behaviour such as adequate sleep [4], regular exercise and good nutrition [5] (including a possible role for supplementation)? Too much...?

Music to close. Love Me Like You from the Magic Numbers (although my brood prefer their cameo performance in the Harry Hill Movie...)

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[1] Fauth R. et al. Convergence or divergence? A longitudinal analysis of behaviour problems among disabled and non-disabled children aged 3 to 7 in England. Department of Quantitative Social Science. Institute of Education, University of London. Working Paper No. 14-13. Sept 2014.

[2] Connelly R. & Platt L. Cohort Profile: UK Millennium Cohort Study (MCS). Int J Epidemiol. 2014 Feb 17.

[3] Dillenburger K. et al. he Millennium child with autism: Early childhood trajectories for health, education and economic wellbeing. Dev Neurorehabil. 2014 Oct 7:1-10.

[4] Lee HK. et al. Sleep and cognitive problems in patients with attention-deficit hyperactivity disorder. Neuropsychiatr Dis Treat. 2014 Sep 17;10:1799-805.

[5] Bellisle F. Effects of diet on behaviour and cognition in children. Br J Nutr. 2004 Oct;92 Suppl 2:S227-32.

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Connelly R, & Platt L (2014). Cohort Profile: UK Millennium Cohort Study (MCS). International journal of epidemiology PMID: 24550246

Ear, ear and hyperactivity

The BBC headline - Inner ear disorders 'linked to hyperactivity' - caught my eye recently. Detailing a fascinating piece of research by Michelle Antoine and colleagues* published in the journal Science the suggestion is that issues with the inner ear that affect hearing and balance might also show some relationship with hyperactivity and in mice at least, might be amendable to treatment.

van Gogh @ Wikipedia  

Before going on, I'd like to point out that Science (the publishing journal) has produced some pretty interesting papers at a similar time to the publication of the Antoine research. I'm talking specifically about the gut bacteria from obese discordant twins producing obese mice research (see here) which discusses the 'transmissibility of obesity' among other things (see here for my previous blogging interest in this area of research). There was also that letter on MAR autism which I've covered recently....

Back to the ears - and no, not whale ears either. Apparently this is not the first time that the presence of inner ear disorders have been linked to behavioural issues as per the description from other media on this research (see here). The long-and short of the paper was the study of mice who were bred to carry a mutation in the Slc12a2 gene (see here for more information about the gene) involved with the transportation and reabsorption of sodium and chloride ions. Said mice with genetic mutation in the inner ear were observed to show "increased locomotor activity".

It was then a case of finding out why this genetic glitch produced such effects which eventually led to a part of the brain dealing with motor output: the striatum and the over-production of two proteins (pERK and pCREB) linked to the control of some important neurotransmitters: glutamate and dopamine (and GABA). Confirmation of these proteins as being involved also led to speculation that something could be done about the behaviours noted in their mouse model as per the use of a pERK inhibitor: SL327 wherein "Hyperactivity was remedied by local administration of the pERK inhibitor SL327".

I'll reiterate that as with many experimental studies these days involving knocking out genes and looking at the effects of genetic mutations, this was a study of mice and so one needs to be cautious about making too many sweeping generalisations to humans and the particular complexities that we have. I note that at least one quite prominent ADHD researcher (whose work has appeared previously on this blog) has cautioned against assuming that all ADHD is just a one gene disorder, much in the same light that autism is seemingly getting past that research hurdle too (see here).

A little light background reading on the Slc12a2 gene reveals some other interesting factoids. Schizophrenia for example, has more than one mention when it comes to looking at the expression of the gene; mainly tied back to that GABA link (see the paper by Hyde and colleagues** for example). Panichareon and colleagues*** (open-access) also detailed some potential connection between gene polymorphisms as being associated with cases of schizophrenia.

Taking into account one of the synonyms for the gene - NKCC1 - I note some mention of the drug bumetanide (see this previous post) as being involved (see here****) which 'potentially' suggests some cross-over into cases of autism too. That and the fact that hyperactivity as part of the diagnosis of ADHD may be part of the ESSENCE of at least some autism, although I hasten to add that the Antoine work did not explicitly mention autism. Ears and hearing, have been talked about previously on this blog with autism in mind though (see here and here).

I suppose the thing that really fascinates me about this work is the link between physical presentation and behavioural presentation not necessarily just exclusive to the brain in terms of origin. To me at least, it's of a similar ilk to other research; for example the observation that lower airway abnormalities might be linked with autism (see here) which still requires some follow-up. A real mind-body or body-mind connection you might say?

Some music. How about The Pixies and Here Comes Your Man.

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* Antoine MW. et al. A Causative Link Between Inner Ear Defects and Long-Term Striatal Dysfunction. Science. 2013; 341: 1120-1123.

** Hyde TM. et al. Expression of GABA signaling molecules KCC2, NKCC1, and GAD1 in cortical development and schizophrenia. J Neurosci. 2011 Jul 27;31(30):11088-95.

*** Panichareon B. et al. Association of CTXN3-SLC12A2 polymorphisms and schizophrenia in a Thai population. Behav Brain Funct. 2012; 8: 27.

**** Lemonnier E. & Ben-Ari Y. The diuretic bumetanide decreases autistic behaviour in five infants treated during 3 months with no side effects. Acta Paediatr. 2010 Dec;99(12):1885-8.

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Antoine MW, Hübner CA, Arezzo JC, & Hébert JM (2013). A causative link between inner ear defects and long-term striatal dysfunction. Science (New York, N.Y.), 341 (6150), 1120-3 PMID: 24009395

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.

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* 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.

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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

MTHFR and autism reloaded

MTHFR @ Paul Whiteley

I've talked before about the enzyme methylenetetrahydrofolate reductase, or MTHFR to its friends, and the suggested link with autism.

A few points are worth remembering:

• MTHFR serves a primary function in reducing the compound 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. 
• On a grander scale, 5-methyltetrahydrofolate, the reduced and methylated form of folic acid, is an important methyl group donor for the recycling of homocysteine back to methionine utilising vitamin B12 along the way. 

'What's the big deal?' you might be thinking to yourself, as hopefully you are still reading this post. Well, there may be a few consequences of disruption along this pathway: elevated levels of homocysteine (discussed in this post), reduced levels of S-adenosylmethionine (SAMe), etc.

If I had to boil it down to a single important effect, it would probably be that reductions in the levels of SAMe might have some profound effects on methylation patterns in DNA (see here). Indeed with autism in mind, methlylation capability has been questioned in both people with autism (here) and their parents (here) bearing in mind the need for a lot more investigation in this area and my continued fixation on methylation (see a previous post). So then the MTHFR enzyme serves an important function. 

In my first post about MTHFR and autism, I talked about point mutations, SNPs, of the MTHFR gene (which control production of the enzyme) and how one particular SNP, C677T (whether homozygous or heterozygous) might show some link to cases of autism and onwards to the production of MTHFR (see this example study by Goin-Kochel and colleagues*). That and the recent suggestion that increasing doses of folic acid might affect the 'risk' of offspring autism as a function of maternal C677 status (see here), makes for some interesting observations on this very interesting SNP.

A recent paper by Guo and colleagues** extends the interest in the MTHFR C677T SNP in relation to autism, with their suggestion, quote: "MTHFR C677T is a risk factor of autism in Chinese Han children". 

Guo et al reported the presence of the C677T SNP in 16% of their cohort of children with autism, compared with 8.6% of their asymptomatic controls. This contrast between the groups is pretty similar to that reported by Mohammad and colleagues*** (16.3% autism vs. 6.5% controls) in a different ethnic population. Perhaps also just as interesting was the suggestion by Guo that 'overactivity' based on selected ADI-R scores seemed to be related to the presence of the SNP. A pretty similar finding to that presented by Goin-Kochel* bearing in mind the ins and outs of the ADI-R.

Taken cumulatively, it does appear as though there might be some connection between the C677T SNP, MTHFR and autism, albeit in a relatively small proportion of cases. Before however we get carried away, bear in mind that the same SNP has been linked to lots and lots of other different conditions including type-2 diabetes (here) and hypertension (here) in specific populations. There is even the suggestion that this SNP might be a risk allele for decreased kidney function too (see here full-text). The specificity of the finding is therefore something that requires quite a bit more research and whether such findings might actually indicate a subset of people with autism at potentially greater risk of such conditions either currently or in later life.

Indeed with that 'overactivity' finding in mind - I assume to be related to something like hyperactivity - the results looking at the C677T SNP in relation to conditions exemplified by hyperactivity such as ADHD, are less than impressive at the current time as per this paper by Ergul and colleagues****. That being said, other psychiatric diagnoses looked at by Ergul et al have shown some possible relationship (here) but I'm going to leave that for another day.

I admit to being slightly less than impressed with the whole area of genetic markers related to autism given the genetic complexity that surrounds the condition and all the additional issues relating to heterogeneity and comorbidity. This despite the recent gene pathway analysis paper from Skafidas and colleagues which, as several people have pointed out, didn't seem to talk too much about false-positives and the like. That's not to say however that genetics may not be an important part of autism but rather as we are starting to realise from the whole epigenetics revolution for example, that genomic changes might not the 'be all and end all'. There's so much more to DNA.

Bearing this in mind however, I'm intrigued by the suggestion that a SNP in MTHFR, most probably with other SNPs in other genes too, might have the capacity to trigger a cascade of biochemical actions which potentially ends up with reduced DNA methylation, and likely more issues with the function of DNA in cases of autism as in other conditions. A sort of 'genes causing an epigenetic effect' model if you like, which itself raises quite a lot of important questions about how we are the way we are.

To finish, it's been a while since I offered some musical accompaniment to my posts. To correct this I link to a song which I've been hearing a lot on the radio recently Razorlight and In the Morning.

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* Goin-Kochel RP. et al. The MTHFR 677C-->T polymorphism and behaviors in children with autism: exploratory genotype-phenotype correlations. Autism Research. 2009; 2: 98-108.

** Guo T. et al. Methylenetetrahydrofolate reductase polymorphisms C677T and risk of autism in the Chinese Han population. Genetic Testing & Molecular Markers. July 2012.

*** Mohammad NS. et al. Aberrations in folate metabolic pathway and altered susceptibility to autism. Psychiatric Genetics. 2009; 19: 171-176.

**** Ergul E. et al. Methylenetetrahydrofolate reductase gene polymorphisms in Turkish children with attention-deficit/hyperactivity disorder. Genetic Testing & Molecular Biomarkers. 2012; 16: 67-69.

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Guo T, Chen H, Liu B, Ji W, & Yang C (2012). Methylenetetrahydrofolate Reductase Polymorphisms C677T and Risk of Autism in the Chinese Han Population. Genetic Testing and Molecular Biomarkers PMID: 22775456