Maternal prenatal vitamin use and reduced risk of offspring autism recurrence

Question: "Is maternal use of prenatal vitamins associated with decreased risk for autism recurrence in siblings of children with autism spectrum disorder?" Answer: "Maternal prenatal vitamin intake during the first month of pregnancy may reduce ASD [autism spectrum disorder] recurrence in siblings of children with ASD in high-risk families." So that looks like a 'very possibly' then.

That was the long-and-short of the findings reported by Rebecca Schmidt and colleagues [1]. Some notable names are included on the authorship list of the Schmidt paper who are no strangers to the idea that maternal prenatal vitamin use may very well impact on offspring risk of autism or ASD (see here and see here for examples).

The Schmidt study on this occasion relied on data from the MARBLES (Markers of Autism Risk in Babies: Learning Early Signs) study, an important longitudinal initiative originally designed to investigate "possible pre-natal and post-partum biological and environmental exposures and risk factors that may contribute to the development of autism." Yes, you read that right, that's 'biological and environmental' exposures and risk factors (see here)...

In this "prospective cohort study" younger brothers and sisters deemed to be at high-risk of autism (N=241) by virtue of their older sibling having been diagnosed with autism were the target participant group. Said group were followed from 6 months to around about their third birthday and developmentally assessed. Mums of the children were also asked about their vitamin use during pregnancy via interview. All the collected data was crunched and results presented.

"The prevalence of ASD was 14.1% (18) in children whose mothers took prenatal vitamins in the first month of pregnancy compared with 32.7% (37) in children whose mothers did not take prenatal vitamins during that time." As you can see, that is quite a stark [statistically significant] difference between the groups bearing in mind that around 25% of the total cohort were eventually diagnosed with autism (or at least met thresholds for a diagnosis based on the use of a gold-standard instrument). Authors also add that prenatal vitamin use did not seemingly impact on "other nontypical development" which included various other developmental 'outcomes'. They also reported that: "Children in the former maternal prenatal vitamin group also had statistically significantly lower autism symptom severity... and higher cognitive scores." This implies that even if such vitamin use did not 'halt' a/the pathway to an autism diagnosis in some, it might well have affected the presentation of their autism in terms of symptoms and intellectual functions (see here).

So an important question: what were the nutrients being supplemented that seemed to show such an effect? Well, as per that other previous research from Schmidt et al folic acid popped up again, as well as another important nutrient, iron (Fe) which she's also been previously interested in (see here).

As per some 'expert reaction' to the study (see here) there is a need for further research in this area before any sweeping generalisations are made. Ideally, I'd like to see Schmidt or others go further into the whole folate metabolism bit applied to autism (see here and see here) and what that means for supplementation levels in mums-to-be where offspring autism recurrence risk is potentially high. Indeed, whether folic acid is actually the ideal supplement for some pregnant mums (see here) is another potential route of investigation on the basis of what has previously turned up in 'some autism' (see here). By saying all that, I want to make it clear that I'm not giving anything that looks, sounds or smells like medical or clinical advice on this or any topic. The Schmidt findings also potentially tie into another area of autism research looking at the inter-pregnancy interval (IPI) with autism in mind (see here and see here). This, on the basis that words like 'depletion of micronutrients' have been banded around as being one possible explanation for the elevated risk of offspring autism correlating with a short IPI. Again, more study is indicated.

I try not to get too excited about new findings when it comes to autism because, inevitably, many end up falling by the wayside or being over-hyped. Given however the history of peer-reviewed science on the topic of pregnancy nutrition and risk of offspring autism, I'm inclined to think that there may be something quite special in the Schmidt findings and what directions they could eventually take with regards to both research and policy. Certainly when I read another study talking about siblings at 'high-risk' for autism, I'll be looking to see whether pregnancy nutrition has been considered as a potentially modifying variable...

28 February 2019: An addition. So, here I am talking about prenatal vitamin use and offspring autism risk and lo-and-behold, someone has just published a meta-analysis and systematic review of this topic [2]. The conclusion: "the likelihood of ASD in offspring whose mothers used multivitamin supplements during the prenatal period was significantly reduced compared with that in offspring of mothers without such supplementation."

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[1] Schmidt RJ. et al. Association of Maternal Prenatal Vitamin Use With Risk for Autism Spectrum Disorder Recurrence in Young Siblings. JAMA Psychiatry. 2019. Feb 27.

[2] Guo B-Q. et al. Maternal multivitamin supplementation is associated with a reduced risk of autism spectrum disorder in children: A systematic review and meta-analysis. Nutrition Research. 2019. Feb 24.

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Another blood test for autism?

"These results form the foundation for the development of a biochemical test for ASD [autism spectrum disorder] which promises to aid diagnosis of ASD and provide biochemical understanding of the disease, applicable to at least a subset of the ASD population."

OK, use of the word 'disease' in the context of autism is really, really not OK in this day and age. Researchers, peer reviewers and their publishing journals should be doing something about this kind of language. There are however some potentially important aspects to the work published by Daniel Howsmon and colleagues [1] worth talking about. Not least is their observation on how "folate‐dependent one carbon metabolism (FOCM) and transsulfuration (TS) pathways" that have been quite readily *associated* with autism might be linked to quite a bit more than just uncovering the biochemistry of at least some autism (see here for example).

Before progressing further into these findings, I note there has already been some media interest in them (see here) with a byline reading: "First physiological test for autism proves high accuracy in second trial." We'll see about that...

So, after quite a long introduction about 'biomarkers for autism' and how they "come with their own set of challenges before they reach clinical translation", authors report further results building on some of their previous work in this area [2] that I've already covered on this blog (see here). On that previous research occasion, the suggestion was that between 5 and 7 metabolites linked to folate and/or transsulfuration pathways provided a 'best fit' when it came to picking out children diagnosed with autism from those not diagnosed with autism.

This time around, there was an 'extension' to that work: "(a) By comparing univariate analysis with four different multivariate methods on FOCM/TS data for ASD biomarker development to ensure that the identified results are not restricted to FDA [Fisher Discriminant Analysis] and (b) to test and validate multivariate FOCM/TS biomarkers on data collected from a new cohort of ASD participants." The words 'training data' and 'validation data' are used quite a bit throughout the Howsmon article, illustrating how different statistical classification methods were initially applied to training data from the cohort used in their first paper, which were then tested on a new cohort of participants (n=154) diagnosed with an ASD. Given some of the names included on the authorship list, it's no surprise that participant data with regards to the metabolites being looked at were drawn from other studies looking at the possible clinical value of preparations like folinic acid (see here) and sapropterin (see here) with autism in mind.

When those different statistical classification methods were applied and data was crunched, a few observations were made. The headline result was that one model/method produced the best 'potential' biomarker results and it was the same/similar method to that previously discussed by the authors. To quote: "An FDA model using five variables was shown to slightly outperform the other models on this new validation data set." That being said, the accuracy rates (including false positive and false negative rates) hovering around the high 80%s have to take into account that two of the metabolites thought to be important on the last research occasion - % DNA methylation and 8‐OHG - "were not present in the validation set" on this research occasion. This is a pity and a weakness of the current study.

So, do we at last have a 'physiological test' with 'high accuracy' for picking out autism from not-autism? Erm, not quite yet. With all due respect to the authors, their data is interesting and does partially back up their original findings, but we're not quite there yet with regards to rolling out any sort of biological test for autism. Indeed, in these days of the plural 'autisms' (see here) and acknowledging that the diagnosis of autism rarely presents in some sort of diagnostic vacuum (see here) it could be worthwhile re-evaluating whether we're ever likely to see a 'one biological test to diagnose them all' situation.

Further investigations are however indicated and of course, this more recent information does add to the quite rich data already generated suggesting that quite a bit more focus on things like methionine, homocysteine, cysteine and glutathione in relation to autism could be an important research path to follow. I'm also minded to suggest that different research teams taking on a 'possible biomarker for autism' type research perhaps need to talk more to each other (see here) pooling findings, resources and perhaps participant groups too...

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[1] Howsmon DP. et al. Multivariate techniques enable a biochemical classification of children with autism spectrum disorder versus typically‐developing peers: A comparison and validation study. Bioengineering & Translational Medicine. 2018. May 14.

[2] Howsmon DP. et al. Classification and adaptive behavior prediction of children with autism spectrum disorder based upon multivariate data analysis of markers of oxidative stress and DNA methylation. PLoS Comput Biol. 2017 Mar 16;13(3):e1005385.

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Folate receptor autoantibodies and autism... replicated (yet again)

Ah yes, scientific replication. A cornerstone of good science, when findings are independently reproduced and confidence increases that A is linked to B or Y affects Z (insert other letter from the alphabet as appropriate). No, it doesn't prove anything - proof is not something that sits well with the scientific method - but it does imply that a particular relationship is much more likely not to be just due to chance given a similar answer being found across different investigations and hopefully, different cohorts of people.

The findings reported by Jiaxiu Zhou and colleagues [1] represent scientific replication in action. Not only that, they represent scientific replication covering an increasingly important issue in relation to [some] autism: a possible role for folate receptor autoantibodies (FRAA).

I don't really want to re-type everything describing FRAAs, what they and what they mean, because I've covered such descriptions before on this blog (see here and see here). Suffice to say these are autoantibodies - where the body mounts an immune response against 'self' - that target a particular protein called folate receptor protein alpha which plays an important role in transporting something called 5-methyltetrahydrofolate (5-MTHF) into the brain. 5-MTHF is a biologically active form of folate, a pretty important nutrient by all accounts; and something with some 'significant' autism research history (see here).

Building on various other reports suggesting that FRAAs might be *over-represented* in relation to the diagnosis of autism [2], Zhou et al examined serum samples provided by 40 children diagnosed with an autism spectrum disorder (ASD) and some 42 matched not-autism controls. They were specifically looking for FRAAs as "measured by enzyme-linked immunosorbent assay" bearing in mind there are blocking FRAAs and binding FRAAs.

They reported more frequently finding FRAAs in the serum samples from those with autism compared with controls (77% vs. 54%). The difference was significant and led researchers to conclude that "children with ASDs may have defects in folic acid absorption that play a role in the onset of ASDs."

As you can see, whilst the rates of detection of FRAAs in the serum samples of those with autism are quite frequent, the presence of FRAAs are not something 'autism-specific'. I say that bearing in mind that FRAAs have been reported in various other conditions/states/diseases and are also seemingly influenced by the presence of certain dietary components too, such as milk consumption [3]. But that doesn't mean that they aren't potentially important to [some] autism...

Then to the next question: intervention. What can be done as and when FRAAs are detected? Well, I've talked before about some of the the scientific evidence on the use of folinic acid (leucovorin) in the context of autism and FRAAs (see here), investigated under double-blind, placebo-controlled conditions. Folinic acid represents an alternative way of getting a biological active folate into circulation in the context of FRAAs being detected. It needs quite a bit more investigation with autism in mind, but could be a useful intervention (minus any medical or clinical advice given or intended).

Also, a milk-free diet. I know some people don't like the idea that [some] dietary elements might 'affect' [some] autism, but again, there is some initial peer-reviewed evidence to suggest that a milk-free diet might be able to dampen down things like folate receptor autoimmunity [4]. This added to the already quite voluminous peer-reviewed science suggesting a possible 'diet-related phenotype' in relation to autism [5] that mentions milk (casein) as well as other dietary components (see here).

In short, folate receptor autoantibodies are probably important to at least some autism.

Oh, and while we're on the topic of folate, I see that someone recently has been talking about why a 'one-size-fits-all' model of folic acid use during pregnancy isn't going to cover all the biological bases (see here). The MTHFR (methylenetetrahydrofolate) gene that is mentioned, has also got quite a bit of peer-reviewed research history with autism in mind (see here)...

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[1] Zhou J. et al. High prevalence of serum folate receptor autoantibodies in children with autism spectrum disorders. Biomarkers. 2018 Mar 26:1-9.

[2] Quadros EV. et al. Folate receptor autoantibodies are prevalent in children diagnosed with autism spectrum disorder, their normal siblings and parents. Autism Res. 2018 Feb 2.

[3] Berrocal-Zaragoza MI. et al. High milk consumers have an increased risk of folate receptor blocking autoantibody production but this does not affect folate status in Spanish men and women. J Nutr. 2009 May;139(5):1037-41.

[4] Ramaekers VT. et al. A milk-free diet downregulates folate receptor autoimmunity in cerebral folate deficiency syndrome. Dev Med Child Neurol. 2008 May;50(5):346-52.

[5] Whiteley P. Nutritional management of (some) autism: a case for gluten- and casein-free diets? Proc Nutr Soc. 2015 Aug;74(3):202-7.

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Folate receptor autoantibodies and autism... replicated

I should warn you that this is another of my long posts, so make yourself a cup of tea/coffee/other, get comfy and read on...

"Overall, 76% of the affected children, 75% of the unaffected siblings, 69% of fathers and 59% of mothers were positive for either blocking or binding Ab, whereas the prevalence of this Ab in the normal controls was 29%."

'Normal controls' is not a term that I would use in the context of autism research, but the findings reported by Edward Quadros and colleagues [1] are a cause for some excitement as the topic of folate receptor alpha (FRα) autoantibodies (Abs) and autism receives some welcome interest and importantly, scientific replication (see here).

Just in case you're new to the concept of folate receptor autoantibodies, it all starts with folate (folic acid). Folates are a pretty important range of nutrient for lots of different reasons, not least the role they play in various brain functions. There are however, a variety of conditions where folate and its various metabolites are 'atypical', one of which is called cerebral folate deficiency (CFD). CFD is characterised by low levels of 5-methyltetrahydrofolate (5-MTHF) in cerebrospinal fluid (CSF) despite fairly typical levels of circulating folates in blood. One of the ways that 5-MTHF gets to the brain is via something called the folate receptor protein alpha. It is this pathway that appears to be 'aberrant' in cases of CFD, and hence use of a compound called folinic acid (leucovorin) (also called 5-formyltetrahydrofolic acid), another 'type' of folate', is used as a result of it utilising an alternative system for getting to the brain (the reduced folate carrier, RFC).

Still here? Good. The hows-and-whys of the folate receptor protein alpha being 'dysfunctional' in relation to CFD has focused on particular autoantibodies (where the immune system starts to mount a response against 'self' tissues) called folate receptor autoantibodies. There are two types of autoantibody: blocking and binding antibodies [2]. These autoantibodies block the transport of folate metabolites to places like the CFS and brain. Finally, there are ways and means that these autoantibodies can be detected in serum samples and, outside of CFD, autism has been a focus for such analyses [3] alongside other, potentially related, diagnoses (see here).

Clear as mud right?

So: "families of 82 children with ASD [autism spectrum disorder], 53 unaffected siblings, 65 fathers, and 70 mothers, along with 52 unrelated... controls" were tested for folate receptor alpha (FRα) autoantibodies in the current Quadros study. I should also mention that Quadros is a name that comes up quite a bit with folate receptor alpha (FRα) autoantibodies in mind. As per the opening line of this post, those autoantibodies were detected in a fairly high frequency in families where autism has been diagnosed. The authors note that the presence of such antibodies "may have a familial origin but the risk of developing ASD is likely influenced by other mitigating factors since some siblings who had the antibodies were not affected." True, absolutely true bearing in mind other work on things like the broader autism phenotype for example (see here).

But there's another strand to this work worthwhile talking about... milk. Milk and autism has been something of real interest to my autism research career down the years (see here) and continues to be. Use of a milk-free - casein-free - diet has filled quite a few peer-reviewed science column inches in relation to both behaviour (see here for example) and physiology (see here) for some on the autism spectrum. In relation to those folate receptor alpha (FRα) autoantibodies, consumption of milk seems to have some rather interesting effects on their presence [4]. The suggestion is that there may be some kind of 'cross-reactivity' going on given the 'homology' between human folate receptor alpha (FRα) and bovine (from cows) folate receptor alpha (FRα). This biological mix-up means that "repeated exposure to milk FR in the digestive tract is the likely mechanism for autoantibody generation" [5]. I'm left wondering a few things: (a) did Quadros and colleagues ask about milk consumption and/or was it recorded? and (b) regarding the 'heritability' issue, could this be part of a wider 'autoantibody heritability' issue among families where autism is present? Y'know, based on the idea that autoantibodies and autoimmunity seems to be a recurring theme for at least some people diagnosed with autism (see here) and in their families (see here)?

And finally, a few research direction suggestions to perhaps take this area forward: (a) wide-scale screening for those for those folate receptor autoantibodies when autism is diagnosed to see if the pretty high 'positives' numbers continue, (b) the requirement for a large (LARGE) study looking at both supplementation with folinic acid and use of a milk-free diet to ascertain exactly what symptoms/traits can potentially be impacted, and finally (c) the inclusion of other parameters when looking at the familial element to folate receptor autoantibodies, such as everyone's favourite 'leaky gut' (also reported in other family members [6]) as a 'vehicle' for possible antibody production. Speculative, yes. Testable, also yes.

Oh, and perhaps a little more inquiry into the thyroid connection (see here) too (with links to yet another autoimmune condition mentioned with autism in mind)...

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[1] Quadros EV. et al. Folate receptor autoantibodies are prevalent in children diagnosed with autism spectrum disorder, their normal siblings and parents. Autism Res. 2018 Feb 2.

[2] Frye RE. et al. Blocking and Binding Folate Receptor Alpha Autoantibodies Identify Novel Autism Spectrum Disorder Subgroups. Frontiers in Neuroscience. 2016;10:80.

[3] Ramaekers V. et al. Clinical recognition and aspects of the cerebral folate deficiency syndromes. Clin Chem Lab Med. 2013 Mar 1;51(3):497-511.

[4] Berrocal-Zaragoza MI. et al. High milk consumers have an increased risk of folate receptor blocking autoantibody production but this does not affect folate status in Spanish men and women. J Nutr. 2009 May;139(5):1037-41.

[5] Ramaekers VT. et al. A milk-free diet downregulates folate receptor autoimmunity in cerebral folate deficiency syndrome. Developmental medicine and child neurology. 2008;50(5):346-352.

[6] de Magistris L. et al. Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J Pediatr Gastroenterol Nutr. 2010 Oct;51(4):418-24.

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Pre- and peri-pregnancy use of folic acid and multivitamins and risk of offspring autism

The findings reported by Stephen Levine and colleagues [1] observing that: "Maternal exposure to folic acid and multivitamin supplements before and during pregnancy is associated with a reduced risk of ASD [autism spectrum disorder] in the offspring compared with the offspring of mothers without such exposure" provides the blogging fodder today.

Accompanied by media headlines such as 'Taking vitamins before and during pregnancy slashes autism risk by 75%, new study shows' the Levine paper adds to the growing research literature suggesting that certain nutrients taken during critical periods of pregnancy *might* be important when it comes to offspring development (see here).

"Epidemiologic studies report inconsistent associations between maternal supplementation with multivitamins or FA [folic acid] before and during pregnancy and the risk of ASD in offspring." I'm glad the authors have mentioned that the peer-reviewed literature on folic acid in relation to offspring autism risk is not all one-way. It's something that I've been particularly interested in on this blog for some time (see here and see here for examples) in terms of countering the often simplistic view that mothers-to-be should all be loading up on folic acid for example, to offset any enhanced risk of offspring autism. Yes, folic acid is a required supplement during pregnancy when it comes to something like reducing the risk of  neural tube defects (NTDs) in offspring, but with autism in mind, the evidence is not yet so clear-cut.

Levine et al report results based on Israeli children born between 2003 and 2007 and followed-up until early 2015. Their cohort included "all children with ASD and a randomly selected one-third of all children" born during their index dates including some 45,000 participants in total. When it came to exposure patterns (exposure to folic acid and/or multi-vitamins during pregnancy), the authors relied on a prescription register that included "drug names, prescription and dispensation dates, number of pills dispensed, and ATC codes." Importantly, this meant that researchers were able to classify some important details: "vitamin supplements were classified as FA and/or multivitamin supplements, an FA supplement, and a multivitamin supplement" and the timing of their dispensation: "before pregnancy (540-271 days before childbirth) and during pregnancy (270 days before childbirth up to the date of childbirth)." This is something rather different from some other previous research attempts that have for example, tended to rely on maternal recall of pregnancy supplements.

Results: "This study of 45 300 children revealed a decreased risk of ASD in children born to mothers who used FA and/or multivitamin supplements before and/or during pregnancy compared with those who had not." Among all supplement combinations - FA and/or Multivitamin Supplements, FA Supplements, Multivitamin Supplements - there was a reduced relative risk (RR) of offspring autism compared with 'unexposed' children that was present both before pregnancy and during pregnancy supplementation and took into account various covariates such as "sex, birth year, socioeconomic status (high vs low),17 a maternal and paternal psychiatric diagnosis by childbirth (present or absent), maternal and paternal age at childbirth, and parity." The sorts of risk reduction statistics being talked about - above 50% and even approaching that 75% risk reduction - are not to be sniffed at.

Although quite a good study design, the Levine results are to be treated with some caution. Not least that the authors noted: "causality cannot be inferred from observational epidemiologic studies such as this one" so one has to be careful.

But... yet again, this is further research talking about pregnancy folic acid and offspring autism. This is an area that requires further investigation in relation to possible mechanisms (or combinations of mechanisms) [2] potentially involved. Also, whether specific groups of women taking other important medicines during pregnancy, might benefit from something like folic acid supplementation in the context of enhanced offspring risk of autism [3].

To close, a musical choice to mark the passing of Mark E Smith: Mr Pharmacist (my favourite) or the more widely known, Hit the North?

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[1] Levine SZ. et al. Association of Maternal Use of Folic Acid and Multivitamin Supplements in the Periods Before and During Pregnancy With the Risk of Autism Spectrum Disorder in Offspring. JAMA Psychiatry. 2018. Jan 3.

[2] Goodrich AJ. et al. Joint effects of prenatal air pollutant exposure and maternal folic acid supplementation on risk of autism spectrum disorder. Autism Res. 2017 Nov 9.

[3] Bjørk M. et al. Association of Folic Acid Supplementation During Pregnancy With the Risk of Autistic Traits in Children Exposed to Antiepileptic Drugs In Utero. JAMA Neurol. 2017 Dec 26.

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Meta-analysing risk factors for schizophrenia spectrum disorders

"Despite identifying 98 associations, there is only robust evidence to suggest that cannabis use, exposure to stressful events during childhood and adulthood, history of obstetric complications, and low serum folate level confer a higher risk for developing schizophrenia spectrum disorders."

So said the 'umbrella review of meta-analyses' published by Lazaros Belbasis and colleagues [1] looking at the current collected scientific literature on "risk factors and peripheral biomarkers for schizophrenia spectrum disorders." Their settling on only five factors reliably linked to schizophrenia spectrum disorder (SSD) did not mean that other associations may not be important, particularly in the context of pluralisation of labels (see here); merely that the current weight of robust evidence 'prefers' the five factors highlighted.

Having quite recently talked about 'symptom clusters' around one possible clinical sign of SSD: psychosis (see here), I continue to appreciate just how complicated an area that this is. Added to other recent-ish research upsetting the apple cart that is inflammatory markers and schizophrenia (see here) and you might see how one has to be quite careful that dogma does not take over in this area.

The mix of biological and social factors identified by Belbasis et al is important to mention. The link for example, between cannabis use and SSD perhaps ties into other chatter about how serious delinquency may potentially be linked to onset of schizophrenia (see here) if one assumes that such illicit drug use might be heightened where delinquency is a feature. That also goes for the idea that childhood and adulthood adversity (particularly trauma?) can and does seemingly impact on risk of schizophrenia or SSD.

Likewise the chatter about low serum folate levels being potentially relevant to SSD is intriguing and not something entirely new to this blog (see here). I've been particularly interested in at least one of the reason(s) why folic acid levels might not be what they should be with some schizophrenia in mind: MTHFR (methylenetetrahydrofolate reductase) (see here) or rather a point mutation potentially over-represented when it comes to schizophrenia (and seemingly other labels too).

More investigation is indicated.

Totally unrelated to today's topic, a few decades back a show called the Day Today began and 'fake news' has never been the same since...

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[1] Belbasis L. et al. Risk factors and peripheral biomarkers for schizophrenia spectrum disorders: an umbrella review of meta-analyses. Acta Psychiatrica Scandinavica. 2018. Dec 30.

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"we found no association between maternal folic acid supplementation and offspring ASD" but...

The findings reported by Marit Strøm and colleagues [1] observing "no association between maternal folic acid supplementation and offspring ASD [autism spectrum disorder]" throw yet another research 'spanner in the works' when it comes to the [very generalised] idea that pregnancy folic acid supplementation might affect risk of offspring autism.

Don't get me wrong, I appreciate all the data suggesting that folic acid supplementation during pregnancy is a useful thing for helping to reduce the risks of neural tube defects (NTDs) for example. But when it comes to pregnancy folic acid (folate) potentially impacting on offspring risk of autism, I've always been a little cautious of the collected data so far and how its been interpreted/generalised in certain quarters (see here and see here for examples).

So, drawing on data from the "entire DNBC [Danish National Birth Cohort]" initially including nearly 100,000 singleton, live born children, researchers set out to find female "users" of folic acid supplements either just before conception or during the earliest stages of their pregnancy. Not just content with folic acid, they also looked at available data on "periconceptional vitamin B12" use too on the basis of some connection between the two vitamins. They then searched connected databases to find those offspring with a diagnosis of autism spectrum disorder (ASD): "identified by International Classification of Diseases (ICD)-10 diagnosis codes F840, F841, F845, F848, and F849; ‘childhood autism’ by diagnosis code F840." Analyses of these collected variables were undertaken, as well as adjusting for potentially confounding variables such as maternal age, parity, education level and the like.

Results: well, as per the title of this post, researchers reported finding very little when it came to pre-pregnancy or early pregnancy folate use: "There was no detectable association between maternal folic acid supplementation in the periconceptional period and offspring ASD" and: "Results from the analyses using midpregnancy exposure data were similar: there was no association with ASD/childhood autism neither for folic acid supplementation nor for dietary folate intake." Such results held when various 'corrections' were made for variables such as "sex specific effects" and cases where intellectual (learning) disability was present for example.

I have to say that the authors do seem genuinely surprised that their results did not tally with other large, population studies on this topic: "At present we are not able to present any viable explanation for these discrepant results." They do mention one particularly important point insofar as the usefulness of looking at small changes to something called the methylenetetrahydrofolate reductase (MTHFR) gene in the context of autism and folic acid as other authors have done [2]. This, on the basis that MTHFR plays an important role in folate metabolism (see here) and issues with this gene are no stranger to the autism research landscape (see here). I'm also minded to refer readers back to another potentially important issue identified in relation to some autism that might also affect folate metabolism: folate receptor autoantibodies (FRAAs) (see here).

I still think there is a place for further investigations on folic acid use during pregnancy and offspring autism risk. But like many things in the context of the plural 'autisms' (see here), it perhaps makes more sense to zoom in on potentially relevant sub-groups on the autism spectrum rather than treating all autism as being homogeneous in either aetiology or presentation. I might add that folic acid use as part of wider range of nutritional supplements potentially used during early pregnancy remains an important area of research attention in the context of offspring autism [3].

And also just to complicate things even further, the results from Wang and colleagues [4] add: "this comprehensive meta-analysis suggested that maternal use of folic acid supplements during pregnancy could significantly reduce the risk of ASD in children regardless of ethnicity, as compared to those women who did not supplement with folic acid." I don't think the debate is finished yet on this topic.

Music to close, and since my brood and I are competing again today, Sia (again) and some brilliant kata (hopefully our Heian Sandan will be as good).

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[1] Strøm M. et al. Research Letter: Folic acid supplementation and intake of folate in pregnancy in relation to offspring risk of autism spectrum disorder. Psychol Med. 2017 Sep 26:1-7.

[2] Schmidt RJ. et al. Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study. Am J Clin Nutr. 2012 Jul;96(1):80-9.

[3] DeVilbiss EA. et al. Antenatal nutritional supplementation and autism spectrum disorders in the Stockholm youth cohort: population based cohort study. BMJ 2017; 359: j4273.

[4] Wang M. et al. The association between maternal use of folic acid supplements during pregnancy and risk of autism spectrum disorders in children: a meta-analysis. Molecular Autism. 2017; 8: 51.

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Risperidone administration affects homocysteine levels in first episode schizophrenia

Of the many themes that seem to quite consistently surface on this blog looking at the peer-reviewed science in relation to various behavioural/psychiatric labels, the idea that various pharmacological interventions might do quite a bit more than 'what they say on the tin' is a recurring one. Take one case in point (see here)...

Today's offering adds to that theme as the results reported by Ning Fan and colleagues [1] are presented for your reading pleasure and the particular finding that: "Serum Hcy [homocysteine] levels were significantly decreased in schizophrenia patients after risperidone treatment."

OK, a few points need explaining first. Homocysteine is a compound that has also received considerable attention on this blog as per it's involvement in a particular group of intersecting biological cycles with relevance to various diagnostic labels including schizophrenia (see here for example). Alongside other independent pieces of research (see here), the diagnosis of schizophrenia seems to have some important connections to homocysteine although the precise details still need to be properly elucidated.

High levels of homocysteine are generally not thought to be a good thing for quite a few reasons [2] and that goes as much for persons diagnosed with schizophrenia as it does for everyone else. So when elevated plasma levels of homocysteine are recorded, medicine really does need to do something to (a) identify why and (b) try and bring levels back to within a more typical range.

Fan et al reported a few important things in their study of 56 participants "first-episode and drug-naïve inpatients with schizophrenia" compared with a similar number of sex- and age-matched asymptomatic controls. First, plasma homocysteine levels were elevated in those with schizophrenia. Nothing new there. They also reported on some potentially interesting *associations* between elevated homocysteine levels and specific symptoms relevant to schizophrenia: "a significant positive correlation between Hcy levels and PANSS negative sub-score was observed." Finally, they reported that risperidone use seemed to affect homocysteine levels in their clinical group. Interesting.

That last point is rather intriguing. Risperidone is a treatment of choice as per its second generation antipsychotic label and accompanying properties. Despite quite a lot of focus on the side-effects associated with such a medicine (see here for example) it does serve an important purpose for many people. It's mode of action is still under debate but it is generally thought to have some action in relation to effects on one or more neurotransmitter receptors. But... other potential effects have also been noted in the peer-reviewed research literature pertinent to mode of action including some in relation to immune function (see here) and how schizophrenia (some schizophrenia?) *might* have a significant immune component attached to it (see here for example). The Fan results add another potential mode of action to risperidone use and why it may impact on symptom presentation for some diagnosed with schizophrenia and related conditions. I'm not by any means saying that homocysteine is 'causative' of schizophrenia but the Fan results do suggest that quite a few more investigations may be warranted on the connection between schizophrenia, homocysteine and risperidone. Indeed, whether also other homocysteine-lowering compounds may provide some novel intervention options for some diagnosed with schizophrenia (see here) (with no medical or clinical advice given or intended).

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[1] Fan N. et al. Effect of Risperidone on Serum Homocysteine Levels in First-episode, Drug-naïve Patients with Schizophrenia. Neurosci Lett. 2017 Apr 15. pii: S0304-3940(17)30326-9.

[2] Zhang D. et al. Elevated Homocysteine Level and Folate Deficiency Associated with Increased Overall Risk of Carcinogenesis: Meta-Analysis of 83 Case-Control Studies Involving 35,758 Individuals. PLoS ONE. 2015; 10(5): e0123423. 

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Fan N, Tan Y, Yang F, Tian L, Chen S, Li J, Wang Z, & Zhang X (2017). Effect of Risperidone on Serum Homocysteine Levels in First-episode, Drug-naïve Patients with Schizophrenia. Neuroscience letters PMID: 28419824

One more time folks... pregnancy folate and autism risk

Folate yet again on this blog? Sorry but that's just how the peer-reviewed papers have fallen...

"Maternal folate supplementation during pregnancy may reduce the risk of ASD [autism spectrum disorder] in the offspring, especially in the Western population."

So said the meta-analysis by Yu and colleagues [1] reporting on a topic that has seen quite a lot of research interest down the years (see here). Authors this time around cumulatively examined data for some 4,500 cases of autism compared with well over a million control (not-autism) cases and determined that on the whole "maternal folate supplementation during pregnancy significantly reduced the risk of ASD in the offspring in the total population (OR=0.798, 95%CI: 0.669-0.952, P=0.012)."

What more is there to say on this topic? Well, potentially quite a bit, not least that not every study has suggested that folate is necessarily a risk reducer when it comes to offspring autism (see here) bearing in mind the potential number of confounders affecting any relationship. Of the multiple occasions that I've talked about folate and autism on this blog, I'm also minded to bring back into the frame how (a) the folate cycle, dealing with the biological metabolism of folate, and its related components is pretty complicated when it comes to a label like autism (see here) and (b) one area that is becoming particularly interesting is in relation to antibodies and folate receptors (see here for example) with autism in mind. Science still needs to do quite a bit more in relation to mechanics of any link between pregnancy folate use/levels and offspring autism risk.

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[1] Yu XF. et al. Association between maternal folate supplementation during pregnancy and the risk of autism spectrum disorder in the offspring: a Meta analysis. Zhongguo Dang Dai Er Ke Za Zhi. 2017 Mar;19(3):286-291.

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Yu XF, Li M, & Zheng Y (2017). [Association between maternal folate supplementation during pregnancy and the risk of autism spectrum disorder in the offspring: a Meta analysis]. Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics, 19 (3), 286-291 PMID: 28302198

Folate-dependent one carbon metabolism and transsulfuration pathways: biomarkers for autism?

I found it a little unusual that the findings reported by Daniel Howsmon and colleagues [1] (open-access) talking about "multivariate statistical analysis presented herein [provided] unprecedented quantitative classification results for separating participants into ASD [autism spectrum disorder] and NEU [neurotypical] cohorts based solely on biochemical data" merited a rapid reply in a prominent science magazine pouring cold water on the results (see here). Not least because one of the commentators interviewed in said science magazine article is also not seemingly immune when it comes to sweeping claims being made on the basis of preliminary research findings about autism (see here as per the previous headline: 'Super-parenting' improves children's autism).

No mind, the Howsmon paper - including a notable research name on the authorship list - mentions a few important compounds and biological processes in their discussions on: "Stepping towards this goal of incorporating biochemical data into ASD diagnosis." The sorts of things covered included various biological 'markers' pertinent to folate-dependent one-carbon metabolism (FOCM) and transsulfuration (TS) some of which have been fodder for this blog previously (see here and see here for examples). Researchers looked at these various compounds in blood samples from some 80 children diagnosed with an ASD and compared levels with 47 siblings and 76 age-matched controls. They applied some nifty statistics to try and determine whether any combination of the 24 analytes examined might be potential biomarker-material for an autism diagnosis. You'll note that once again the quite problematic binary description of 'neurotypical' was used to define 'not-autism' leading onwards to the inevitable questions: 'what is neurotypical?' and 'what are the boundaries of being neurotypical?' Sensible [evidence-based] answers on a postcard please.

Results: "FDA [Fisher Discriminant Analysis] on seven metabolites allows sufficient separation such that a linear classifier can correctly resolve 96.9% of participants." But actually this was not the whole story as the authors also report that five compounds/variables - GSSG, tGSH/GSSG, Nitrotyrosine, Tyrosine, and fCysteine - provided the best 'fit' when it came to potentially picking out children with autism. You might note that some of those 'famous five' have some autism research history (see here). The authors similarly note that: "these variables are affected by high quality vitamin supplementation that also decreases ASD severity in at least a subset of cases." Mmm.

There is definitely more science to do in this area. Biomarkers in relation to autism have come and gone down the years (see here for example) and I'm not altogether sure that using the label 'autism' as a starting point for this kind of research is necessarily the best idea (see here). Outside of just the heterogeneity and plurality - the autisms - associated with the label autism, there are other considerations to take on board such as the impact of all that over-represented comorbidity too (something that continues to 'mess around' with various 'autism is linked to..' studies).

But that shouldn't stop further efforts in this area including those also looking to expand into the 'genetics' of folate metabolism alongside the biochemistry, as per everyone's favourite scrabble word 'MTHFR' (see here) and its [meta-analysed] potential contribution to some autism. I agree that we are not quite there when it comes to folate metabolism as providing a generic biomarker or set of biomarkers for autism, but there again, the authors never said that it definitively did: "it should be noted that these studies should be replicated and empirically tested on a wider scale before more definite conclusions can be drawn." Too true but the Howsmon results represent an interesting first attempt...

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[1] Howsmon DP. et al. Classification and adaptive behavior prediction of children with autism spectrum disorder based upon multivariate data analysis of markers of oxidative stress and DNA methylation. PLoS Comput Biol. 2017 Mar 16;13(3):e1005385.

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Howsmon DP, Kruger U, Melnyk S, James SJ, & Hahn J (2017). Classification and adaptive behavior prediction of children with autism spectrum disorder based upon multivariate data analysis of markers of oxidative stress and DNA methylation. PLoS computational biology, 13 (3) PMID: 28301476

Mitochondria support for mitochondrial activity in [some] autism

"This study examined the effect of common mitochondrial treatments on specific mitochondrial components in a group of children diagnosed with ASD [autism spectrum disorder], some of which also were diagnosed with co-morbid mitochondrial disease."

That was the premise of the study results published by Leanna Delhey and colleagues [1] (open-access available here) and follows previous discussions suggesting that mitochondrial disease might not be totally unfamiliar to at least some autism (see here). Including some notable names on the authorship list previously linked to the area of mitochondrial functions in relation to autism (see here), the authors provide some important information about how specific mitochondrial function might be 'supported' by various interventions.

I'm not on this occasion going to venture into all the details discussed by Delhey but I do want to pick out some interesting titbits. First, of the 127 children diagnosed with an autism spectrum disorder (ASD), we are told that "15% of the sample was clinically diagnosed with mitochondrial disease." Bearing in mind this particular cohort might not be totally representative of the autistic population at large, 15% is not an insignificant figure. What this tells us is that as and when a diagnosis of autism is received, screening for a possible mitochondrial disorder should be initiated (yes, an autism diagnosis is a starting point not the finishing line and the diagnosis rarely exists in a diagnostic vacuum).

Next, various supplements were taken by participants, some of which have recognised effects on mitochondrial functions. Of particular note was the use of coenzyme Q10 (CoQ10) and carnitine; both of which have been discussed on this blog previously (see here and see here respectively) with the word 'mitochondrial' also being mentioned. Interestingly, a couple of other supplements are also included in the Delhey paper including fatty acids and folate; some of which I have to say, didn't immediately pop into my mind as being primarily mitochondrial-related (folate is though, still a hot topic when it comes to autism). The authors head into how said supplements might affect specific facets of mitochondrial function. It also reminded me that I really need to brush up on my knowledge of mitochondrial functions...

"This study provides empirical support for common mitochondrial treatments and demonstrates that the relationship between activities of mitochondrial components might be a marker to follow in addition to absolute activities." I'd agree that there is the beginnings of a roadmap for further study based on the Delhey results. That and including important parameters related to the presentation of autism and how it may/may not be affected by treating underlying mitochondrial disorder, and the scene is set for further recognition of how indeed, autism rarely exists in a diagnostic vacuum...

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[1] Delhey LM. et al. The Effect of Mitochondrial Supplements on Mitochondrial Activity in Children with Autism Spectrum Disorder. J Clin Med. 2017 Feb 13;6(2). pii: E18.

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Delhey LM, Nur Kilinc E, Yin L, Slattery JC, Tippett ML, Rose S, Bennuri SC, Kahler SG, Damle S, Legido A, Goldenthal MJ, & Frye RE (2017). The Effect of Mitochondrial Supplements on Mitochondrial Activity in Children with Autism Spectrum Disorder. Journal of clinical medicine, 6 (2) PMID: 28208802

Pregnancy folic acid and offspring autism systematically reviewed

"A total of 22 original papers that examined the association between folic acid supplementation in human pregnancy and neurodevelopment/autism were identified after the screening, with 15 studies showing a beneficial effect of folic acid supplementation on neurodevelopment/autism, 6 studies showed no statistically significant difference, while one study showed a harmful effect in > 5 mg folic acid supplementation/day during pregnancy."

That rather long quote taken from the paper published by Yunfei Gao and colleagues [1] (open-access) opens today's post and provides a welcome [peer-reviewed] overview of where science is up to when it comes to the effects (or not) of pregnancy folic acid supplementation on 'risk' of offspring autism. I say 'where the science is up to' but at the same time note that the various searches of databases for material relevant to this topic/review was carried out up to the end of 2014. There have been other reports since that date including other reviews [2]...

Folic acid or folate in the context of autism has been a recurrent research theme down the years. Outside of the protective effects of pregnancy folate use with regards to reducing the risk of offspring neural tube defects (NTDs), the suggestion that pregnancy folic acid may confer a protective effect against offspring autism has been highlighted in several studies (see here).

Gao et al trawled the research literature and "included randomized controlled trials (RCTs), cohort studies, and case control studies that examined the association between folic acid supplementation during pregnancy and neurodevelopment/autism in the offspring children." As per that lengthy opening sentence from their paper, the authors found data that on the whole suggested that folate supplementation was protective rather than harmful when it came to offspring developmental outcomes. Given that most/many pregnant women are already taking folic acid during pregnancy to counter the risk of NTDs, this is good news indeed.

Without giving any undue weight to those studies that have perhaps not been so enthusiastic about the link between pregnancy folate use and offspring autism risk (see here) I do think there are words of caution in this area too. We're still for example, waiting for research to be published that was raised at this years IMFAR event in relation to folic acid and autism (see here). Indeed, in my discussion of that so-far-unpublished work, I mentioned that the genetics of folic acid metabolism also needs to be further inspected when it comes to autism (see here) and that screening for particular issues linked to folate might be something to consider for people on the autism spectrum and their significant others (see here). Both these areas are potentially relevant to that recent chatter on how folinic acid might be useful for some aspects of some autism (see here).

"Large scale RCTs with validated diagnosis and high follow up rate are needed in order to produce robust evidence regarding the effects of folic acid supplementation in pregnancy on fetal neurodevelopment" conclude the authors. Yes, we need more investigation of this area - including what effect certain medicines used during pregnancy might have had on folate levels -  but for now, the data seems to side with a protective effect of folate supplementation in pregnancy when it comes to offspring risk of autism or related neurodevelopmental issues.

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[1] Gao Y. et al. New Perspective on Impact of Folic Acid Supplementation during Pregnancy on Neurodevelopment/Autism in the Offspring Children – A Systematic Review. PLoS ONE. 2016; 11(11): e0165626.

[2] DeVilbiss EA. et al. Maternal folate status as a risk factor for autism spectrum disorders: a review of existing evidence. Br J Nutr. 2015 Sep 14;114(5):663-72.

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Gao Y, Sheng C, Xie RH, Sun W, Asztalos E, Moddemann D, Zwaigenbaum L, Walker M, & Wen SW (2016). New Perspective on Impact of Folic Acid Supplementation during Pregnancy on Neurodevelopment/Autism in the Offspring Children - A Systematic Review. PloS one, 11 (11) PMID: 27875541

Hyperhomocysteinemia as a significant risk factor for autism?

The findings reported by Naushad Shaik Mohammad and colleagues [1] provide some blogging fodder today and the suggestion of a link between some of the genetics of the folate pathway and the finding of elevated levels of homocysteine with [some] autism in mind.

OK, from the start, the genetics of folate metabolism mentioned in the context of autism typically means reference to the quite well replicated finding of issues with the gene methylenetetrahydrofolate reductase (MTHFR) (see here for some background). This gene (product) serves an important purpose in relation to the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate; the latter helping to convert the amino acid homocysteine to methionine. Outside of the importance of methionine to the process of DNA methylation (yep, some of that epigenetics stuff that you keep hearing about), there is quite a body of literature emerging to suggest that elevated levels of homocysteine might also have some important health effects.

For quite a few years now, a specific genetic issue with MTHFR - MTHFR C677T - has been reported in quite a few people on the autism spectrum (see here). This allied to other independent research suggesting that the downstream effects of issues with MTHFR linked to elevations in levels of homocysteine may not also be an uncommon finding (see here). Shaik Mohammad et al therefore set about looking at the relationship between genetic issues with MTHFR and hyperhomocysteinemia in the context of autism.

They did this by use of an "artificial neural network (ANN) model" where data initially from "138 autistic and 138 nonautistic children" on various genetic issues linked to folate metabolism (including MTHFR) were used as potential "predictors of autism risk." We are also told that: "Meta-analyses were carried out on 1361 ASD children and 6591 nonautistic children to explore the association of MTHFR C677T and homocysteine with the risk for ASD [autism spectrum disorder]."

Results: well, the model wasn't exactly brilliant at predicting the risk of autism (63.8% accuracy). The authors call this a 'moderate' finding but I'd probably suggest that their results are yet another very good example of how heterogeneous the autism spectrum actually is. The idea of not using the term 'autism' as a research starting point in this context (see here) also receives support. Perhaps of greater importance were their findings linked to homocysteine and autism and how: "Hyperhomocysteinemia was observed in autistic children" to a greater extent that controls. They did also confirm that the MTHFR C677T genetic polymorphism was linked to 'inflating homocysteine levels' alongside another genetic issue called MTRR A66G (methionine synthase reductase). This is not an unusual finding in the context of what is already known about MTRR and homocysteine. The MTRR bit potentially linked to autism is however, something that this research group have previously suggested to 'reduce the risk' of autism [2].

In terms of what these results mean in the context of autism, there are a few possibilities. First, screening. Knowing what we now seem to know about MTHFR and homocysteine in relation to quite a lot of people with autism, I would have thought it would be good practice to screen genetics/biochemistry. Minus any scaremongering or sweeping generalisations, the observation that hyperhomocysteinemia 'may' have links to cardiovascular disease and other adverse states for example, also perhaps implies screening save any further charges of health inequality when it comes to the label of autism. Next management. Far from being a 'nothing can be done about it' state, there is some good evidence that small adjustments to nutrition can potentially have positive effects on some of these parameters. With no medical or clinical advice given or intended, high levels of homocysteine seem in some cases, to be reactive to certain vitamin supplementation. The focus on vitamin B12 could also be set in the context of other recent studies of this vitamin (and its vitamers) with autism in mind (see here) (but I am careful not to link the two parameters just yet). And just recently there is news that there is a new way of assaying for vitamin B12 on the horizon which could also be useful. Finally, more research is indicated. As per my discussions not so long ago about another potentially important link to folate metabolism and autism (see here), there does appear to be quite a bit more to see when it comes to the folate cycle intersecting with homocysteine metabolism (and it's downstream effects). Yes, we can talk about whether folate is 'protective' or not when it comes to 'risk' of autism (see here and see here) but what this latest work suggests is that this area is complicated and potentially includes many genetic/epigenetic/biochemical variables that need to be taken into account.

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[1] Shaik Mohammad N. et al. Clinical utility of folate pathway genetic polymorphisms in the diagnosis of autism spectrum disorders. Psychiatr Genet. 2016 Oct 17.

[2] Mohammad NS. et al. Aberrations in folate metabolic pathway and altered susceptibility to autism. Psychiatr Genet. 2009 Aug;19(4):171-6.

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Shaik Mohammad N, Sai Shruti P, Bharathi V, Krishna Prasad C, Hussain T, Alrokayan SA, Naik U, & Radha Rama Devi A (2016). Clinical utility of folate pathway genetic polymorphisms in the diagnosis of autism spectrum disorders. Psychiatric genetics PMID: 27755291

"Folinic acid improves communication in childhood autism"

A quote to begin: "... in this small trial of children with non-syndromic ASD [autism spectrum disorder] and language impairment, treatment with high-dose folinic acid for 12 weeks resulted in improvement in verbal communication as compared with placebo, particularly in those participants who were positive for FRAAs [folate receptor-α autoantibody]."

Those were the findings reported by Richard Frye and colleagues [1] (open-access) continuing a research theme from this group looking at how folinic acid - a reduced form or vitamer of folate - may "markedly" improve symptoms in some children diagnosed with ASD (see here). Some media reporting about these latest results are available (see here for example) but if you're sticking with my interpretation there are a few important points to note.

So:

• This was a gold-standard "double-blind, randomized placebo-controlled" study meaning that as well as pitting folinic acid against a placebo, both researchers and participants were blind to 'who got what' during the 12 weeks of study. The aim was to compare a "target dose" of folinic acid "(2 mg kg−1 per day)" with said placebo formulation. It also appears that the authors went to some lengths to ensure that folinic acid and placebo capsules were "indistinguishable by sight and feel" as well as odour and taste.
• Participants (~7 years old) (N=48) were allocated to the folinic acid (n=23) or placebo group (n=25). All had a diagnosis of ASD and importantly, "Reconfirmation of the diagnosis using the lifetime version of the Autism Diagnostic Interview-Revised by an independent research reliable rater was requested from all participants." Participants were also required to have "documentation of language impairment" accompanying their autism as well as being free from current antipsychotic medication use alongside various other inclusion/exclusion criteria.
• "Verbal communication was the primary outcome" we are told, offering a rather refreshing prospect insofar as the focus being on symptoms rather than syndromes. That's not to say that various behavioural schemes pertinent to the presentation of autism and other general 'adaptive behaviours' weren't also included, but this was a study looking specifically at what happened to verbal communication.
• Results: well, first and foremost folinic acid seemed to be pretty safe and well tolerated as we are told that "no serious adverse effects" were recorded for the folinic acid group when blinding was broken. First, do no harm and all that. As per the opening sentence of this post, there were some significant group improvements noted for the group taking folinic acid in relation to verbal communication ("an important core ASD symptom") compared with the placebo group.
• Going back to the whole 'positive for FRAAs' there were also some results to be seen. "This study suggests that FRAAs predict response to high-dose folinic acid treatment. This is consistent with the notion that children with ASD and FRAAs may represent a distinct subgroup." Without turning this post into some grand explanation of what FRAAs are (bearing in mind I'm barely getting my head around this myself), this ties into other findings (see here) and how these autoantibodies work to impair folate transport and 'block' or 'bind' to the folate receptor. One explanation is that folinic acid is able to 'bypass the FRα [folate receptor-α] when it is blocked and/or dysfunctional' particularly at higher doses. The use of the term "distinct subgroup" when it comes to autism is music to many ears in these days of the more plural 'autisms' and recognition that certain inborn errors of metabolism seem to be associated with 'some types' of autism [2] (more on this paper to come soon).

Of course there is more to do in this area as the authors themselves identify the small participant numbers as one limitation and the future requirement to "determine the optimal folinic acid dose". Although no adverse effects were reported during the 12-week period, I'd also suggest that longer-term follow-up is needed to make sure that this effect extends a little longer too. Given the folate connection evident in this line of research, I'd for example, also be interested to see a little more work done on whether everyone's favourite scrabble gene - methylenetetrahydrofolate reductase (MTHFR) - potentially linked to some autism (see here) might also be an important player with regards to folinic acid use and response. Finally, minus any sweeping generalisations, the idea that FRAAs might also extend across labels to schizophrenia (see here) for example, is also potentially worthy of further investigation insofar as the 'links' that still remain when it comes to the autism and schizophrenia spectrums (see here) (remembering too the important work of Mildred Creak).

Having said all that, these are important results as they stand. Not least because under rigorous methodological conditions, folinic acid has seemingly passed yet another scientific hurdle with regards to its potential relevance to at least some autism. We will no doubt see more on this topic in the peer-reviewed literature in times to come...

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[1] Frye RE. et al. Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial. Molecular Psychiatry. 2016. Oct 18.

[2] Simons A. et al. Can psychiatric childhood disorders be due to inborn errors of metabolism? European Child & Adolescent Psychiatry. 2016. Sept 30.

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Frye, R., Slattery, J., Delhey, L., Furgerson, B., Strickland, T., Tippett, M., Sailey, A., Wynne, R., Rose, S., Melnyk, S., Jill James, S., Sequeira, J., & Quadros, E. (2016). Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial Molecular Psychiatry DOI: 10.1038/mp.2016.168