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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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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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

L-methylfolate administration and autism: a case report

I should have really titled this post 'another case report' given yesterday's entry on this blog talking about a case of [untreated] PKU and autistic behaviours/diagnosis. Here I am again talking about another N=1 with autism in mind and specifically the findings reported by Kim Siscoe & David Lohr [1] on how: "L-methylfolate supplementation improved symptoms of aggression and disruptive behavior in a child with autism who tested positive for the C677TT allele of the methyltetrahydrofolate reductase enzyme gene."

First things first. This was a case report; please keep that in mind. Second, I am not a medical doctor and don't provide medical or clinical advice on this blog. Within those caveats I am however very interested in the Siscoe/Lohr observations.

Why? Well, methylene tetrahydrofolate reductase (MTHFR) (gene and enzyme) has featured quite a bit on this blog in light of findings linking gene and enzyme to cases of autism (see here and see here for examples). The idea is that MTHFR serves a primary function in reducing the compound 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. 5-methyltetrahydrofolate - another name for L-methylfolate -  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 (see here for a nice hand drawn graphic). The implications of disruptions to MTHFR (gene and enzyme) are potentially multiple but include effects on methyl group donor ability (methyl groups potentially linked to things like DNA methylation as part of all that epigenetics jazz that you hear so much about these days) and effects on downstream metabolites such as those related to homocysteine metabolism (see here).

So Siscoe & Lohr present data on what happened when the active form of folate was supplemented following the identified genetic issue with the MTHFR gene potentially affecting typical production of L-methlyfolate.

Where next with this work? Well, it stands to reason that in these days of personalised medicine percolating through to autism research and practice (see here), knowledge about a potential genetic issue identified in [some] cases of autism should be further investigated. We have other examples (see here). I'd like to see larger and more controlled trials of L-methlyfolate supplementation in relation to autism for example, based on screening for issues with the MTHFR gene. I'd like to see a few more biological measures incorporated in such study looking at other aspects of the folate and related cycles too (see here). I'd also like to see more discussion about any long-term implications and/or adverse effects associated with such supplementation along the lines of: should we really be tinkering with mechanisms linked to DNA methylation? Also in relation to some of the other diagnoses associated with issues with MTHFR there is similarly important work emerging [2] which could be quite important in certain instances...

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[1] Siscoe KS. & Lohr WD. L-Methylfolate supplementation in a child with autism and methyltetrahydrofolate reductase, enzyme gene C677TT allele. Psychiatr Genet. 2017 Mar 7.

[2] Roffman JL. et al. Biochemical, physiological and clinical effects of l-methylfolate in schizophrenia: a randomized controlled trial. Mol Psychiatr. 2017. Mar 14.

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Siscoe, K., & Lohr, W. (2017). L-Methylfolate supplementation in a child with autism and methyltetrahydrofolate reductase, enzyme gene C677TT allele Psychiatric Genetics DOI: 10.1097/YPG.0000000000000170

B vitamins for schizophrenia?

I'd like to briefly draw your attention to the results - systematic review and meta-analysis results - published by Joseph Firth and colleagues [1] observing that "certain vitamin and mineral supplements may reduce psychiatric symptoms in some people with schizophrenia" and specifically that certain B vitamins might be something to consider.

Such results come from a research team who are making significant waves in the field of meta-analyses and systematic reviews for all manner of different [important] topics. The additional inclusion of one Jerome Sarris to the authorship team adds a 'nutritional medicine as mainstream in psychiatry' touch to proceedings.

Drawing on data from 18 clinical trials - randomized controlled trials (RCTs) - cumulatively including over 800 participants, researchers reported that: "vitamin B supplementation (including B6, B8 and B12) reduced psychiatric symptoms significantly more than control conditions." Dose seemed to be important (higher doses appeared to be more effective than lower doses) as did timing of vitamin 'intervention'. Authors also indicated that subgroups of people with schizophrenia might be 'better responders' to this type of intervention, suggesting that either individual genetic differences or possibly nutritional deficiency before intervention might count in terms of effectiveness of B vitamin use. I was wondering whether those last points might tie into other discussions on this blog referencing genotype, B vitamins and [some] schizophrenia (see here).

In the context of the rise and rise of plurality in psychiatry ('the schizophrenias' and 'schizophrenia does not exist: discuss') there are some important research directions to be followed on the basis of the Firth findings. Identifying those people on the schizophrenia spectrum who might be potential best responders to this type of nutritional intervention is a research priority. Closely followed by further investigations on the hows-and-whys of such intervention potentially being useful. In that final respect, the peer-reviewed literature has already provided a few ideas for starters (see here and see here for examples).

To close, "I've got a good idea..."

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[1] Firth J. et al. The effects of vitamin and mineral supplementation on symptoms of schizophrenia: a systematic review and meta-analysis. Psychological Medicine. 2017. Feb 16.

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Firth J, Stubbs B, Sarris J, Rosenbaum S, Teasdale S, Berk M, & Yung AR (2017). The effects of vitamin and mineral supplementation on symptoms of schizophrenia: a systematic review and meta-analysis. Psychological medicine, 1-13 PMID: 28202095

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

Folate, autism and IMFAR: keep calm

IMFAR - The International Meeting for Autism Research - has just closed it's doors, bringing to an end one of the premier annual autism research conferences where one might expect quite a few of the presentations to eventually become (peer-reviewed) fodder for this blog.

This year (2016) has seen yet another startling array of research papers covering all manner of topics pertinent to autism; it's presumed aetiologies (plural as per the 'autisms'), diagnosis and management, all discussed and dissected. This year also saw some well needed focus on other important issues linked to autism such as various (medical and psychiatric) comorbidity linked to the label, the idea that children with autism become autistic adults (mostly) and the rather distressing idea that suicide (ideation or actual) seems to be over-represented when a diagnosis is received. Without trying to portray too negative an image of the very wide autism spectrum, autism can in some cases be a life-limiting as well as a life-changing condition (see here and see here).

As an outsider looking in on proceedings (#IMFAR2016) I was particularly interested in a few discussions that were covered during the event. This included the keynote address delivered by Irva Hertz-Picciotto on how, despite various environmental agents being traditionally correlated with some 'types' of autism (rubella, valproic acid), there are still challenges in terms of putting environmental factors on a par with genetic issues for example. Indeed, one or two tweets about her presentation kinda summed up the stark lack of knowledge and expertise in this area; specifically how 'chemical' insults (being careful with that word) potentially linked to cases of autism or at least autistic traits, already pervade the peer-reviewed literature (see here for example). It seems we need to further organise how research is done in this area, where exposure and genetic fragility are taken into account alongside the idea of synergy when it comes to the chemical soup that we all live in [1]; similar to the idea that multiple genes might be involved in multiple autisms so multiple non-genetic exposures might also show a connection (might I also suggest a greater focus on subgroups on the 'autisms' spectrum too?)

One of the other 'environmental' factors that was raised at IMFAR 2016 was that of folate (folic acid) and the possibility of a connection between pregnancy levels of this stuff and some autism as per the paper by Ramkripa Raghavan and colleagues [2]. For those who might already be well-read in autism research, the idea that maternal levels of folate during pregnancy might have a bearing on risk of offspring autism is not a new one (see here). With sentiments not a million miles away from those proposed by the late David Barker and the 'foetal programming hypothesis', the collected research on folate availability/supplementation during pregnancy impacting on the developing child is still the topic of some discussion (see here and see here). What is clear is that much like the need for folate during pregnancy to reduce the risk of neural tube defects, there may also be additional developmental requirements for suitable levels when it comes to other outcomes too.

Rather interestingly however, the data from Raghavan et al was not all one way when it came to 'risk' of offspring autism and levels of folate and a related nutrient, vitamin B12. To quote from their un-peer-reviewed paper: "In this urban low-income minority birth cohort, we observed an elevated risk of ASD [autism spectrum disorder] associated with high maternal plasma folate levels (>59 nmol/L), which far exceeds the excess cutoff suggested by the WHO (>45.3 nmol/L). Excess maternal vitamin B12 (>600 pmol/L) was also shown to be associated with greater ASD risk in offspring.  The risk of ASD was highest if mothers had both excess in folate and B12 levels." As you might imagine, the accompanying press release that followed this un-peer-reviewed paper was snapped up by various media outlets with titles like: "Taking too many vitamins during pregnancy 'can treble children's risk of being autistic'". Lo and behold, we have yet another 'scare story'...

Accepting that this was un-peer-reviewed research and that inflated press releases seem to abound in the domain of science communication (see here) I was a little less ruffled by the data reported by Raghavan and colleagues. I can see why such findings might make great headlines - "The risk was greatest for those children whose mothers had both high plasma folate (>59 nmol/L) and vitamin B12 (>600 pmol/L) (HR [adjusted hazard ratio]: 17.59; p value: <0.001)" - but this is not the first time that such sentiments have been expressed with relation to autism. Indeed, on a previous post asking whether some of the data of pregnancy folate levels/supplementation and offspring autism risk might not be just all about deficiency (see here) I discussed some rather speculative ideas (albeit peer-reviewed ideas) about how there may be a balance to be struck between potentially too little and too much of a good thing.

'Scientists urge caution over 'alarmist' claim of link between pregnancy folate and autism' was a rather more restrained headline in relation to the Raghavan report. I was much happier with this headline and coverage that put into perspective the preliminary nature of the report (yes, un-peer-reviewed) and how: “There are many epidemiologically based associations made of this sort – increasingly so in autism at the moment." Indeed there are, but unfortunately the commentator goes on to say that "Without details of the analysis, or any theory of action this looks like low-grade evidence."

Actually there are 'theories of action' and they've been discussed quite a bit in the peer-reviewed literature in this area. Not least, the idea that folate and vitamin B12 are important compounds in something called the folate cycle which intersects with another set of important metabolic process: the methylation cycle (see here) and all that DNA methylation stuff. There are a number of possible 'issues' that might be autism-relevant in these biological cycles, not least related to something called MTHFR (see here) and some emerging data on folate receptor autoantibodies (see here). Issues with these systems could very much impact on how folate is used and whether high plasma folate for example, might not be just as the result of too much supplementation. As per what we know from data from more formal medicines, drug metabolism can be quite an individual thing.

I do also want to bring in a little more data about vitamin B12 and 'some' autism as potentially being relevant. Accepting that there has been very little data on maternal vitamin B12 levels and offspring autism, there is certainly quite a bit of data out there about 'issues' with vitamin B12 being tied into specific cases of autism. This year (2016) we've seen the results of placebo-controlled study on the use of methyl B12 for aspects of autism (see here) as well as a suggestion that decreased brain levels of vitamin B12 might link cases of autism and schizophrenia (see here). That severe vitamin B12 deficiency has been linked to cases of Heller's syndrome is also potentially important (see here) given the focus on 'regression'...

Cumulatively what the Raghavan and other data point to is a potentially complicated relationship between mother's nutrition during pregnancy and offspring outcomes. I don't say this to somehow hark back to the darker days of autism theory in terms of 'blame' but rather, alongside other lines of evidence, to point out that nutrition during the nine months that made us (and perhaps earlier) plays an important role in making us who we are. The way that said nutrition is metabolised is also likely to vary from person to person. Minus sweeping generalisations and inflated media headlines, a greater research focus on how that nutrition might impact on at least some autism is very much implied again keeping in mind all that individuality in terms of how the body 'processes' nutrition. Indeed, for those mums identified in the Raghavan data as showing high levels of folate and vitamin B12, in the spirit of scientific endeavour, I'd be asking 'why?' and what does it mean for other related markers such as 'the big H' (homocysteine) for example?

For now however, keep calm and carry on with Love, love, peace, peace (song starts after 1 minute).

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[1] Boggess A. et al. Mean serum-level of common organic pollutants is predictive of behavioral severity in children with autism spectrum disorders. Sci Rep. 2016 May 13;6:26185.

[2] Raghavan R. et al. Maternal Plasma Folate, Vitamin B12 Levels and Multivitamin Supplement during Pregnancy and Risk of Autism Spectrum Disorders in the Boston Birth Cohort. IMFAR 2016; 22533. [NOT PUBLISHED IN A PEER-REVIEWED JOURNAL]

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Folate receptor autoantibodies (FRAAs) and a 'type' of autism?

"This study suggests that FRAAs [folate receptor α (FRα) autoantibodies] are associated with specific physiological and behavioral characteristics in children with ASD [autism spectrum disorder] and provides support for the notion that these biomarkers may be useful for subgrouping children with ASD, especially with respect to targeted treatments."

So said the study findings published by Richard Frye and colleagues [1] (open-access) who continued a research theme looking at FRAAs and their manifestation in 'some' autism. If you've already clicked that link in the last paragraph, you should have something of a flavour for what FRAAs are and what has already been discussed with autism in mind. If you didn't, the long and short of it is FRAAs describing the possibility of issues with folate transport as noted in the condition cerebral folate deficiency (CFD) are also being reported alongside some autism. The subsequent use of folinic acid (a vitamer of folic acid) to compensate might be something to consider for at least some on the autism spectrum bearing in mind my not giving any medical or clinical advice. I might also direct readers to a previous post with a helpful graphic on how the folate cycle also links in to some other important metabolic processes (see here) which is particularly timely in light of more publications on the topic of 'MTHFR'. I'll come back to this shortly.

This time around, Dr Frye and colleagues set about looking at whether those with autism also with issues around FRAAs present with a 'specific type' of autism, also taking into account different types of FRAAs - blocking and blinding. Serum samples for 94 children diagnosed with an ASD were analysed for blocking and binding FRAAs. At the same time, various markers covering redox, methylation, immune function and vitamin status were also determined and various measures of behaviour examined.

Results: "Fifty seven percent of the participants were positive for either the blocking or binding FRAAs, with 17% positive for blocking FRAA and 51% positive for the binding FRAA; 11% were positive for both FRAAs." From a behavioural/psychometric perspective: "ASD children positive for the blocking FRAA demonstrated better communication on the Vineland Adaptive Behavior Scale, stereotyped behavior on the Aberrant Behavioral Checklist and mannerisms on the Social Responsiveness Scale." In other words, those children with evidence of FRAAs, particularly blocking FRAAs, seemed to "have less severe ASD symptoms." The authors make mention of the term 'optimal outcome' with regards to this group, which is interesting when you consider the status of this often contentious line of research (see here).

The results of the various biological assays employed showed some interesting results. So: "ASD children with the blocking FRAA appear to have a more favorable redox and inflammation profile with relatively better glutathione and CT [3-Chlorotyrosine] indices than FRAA blocking negative children." Further, although folate levels were not significantly different between the groups on the basis of the presence of blocking or binding FRAAs (or neither), levels of vitamin B12 did show some differences: "Children positive for the binding FRAA were found to have higher serum B12 levels as compared to those negative for binding FRAAs."

Appreciating that it is still early days when it comes to FRAAs and autism, this and other research is crying out for independent replication with some appropriate cautions that FRAAs are not seemingly just confined to a diagnosis of autism (see here). The idea that those with autism with a specific type of FRAA (blocking) might present with a more favourable ASD profile in terms of symptoms and also biochemistry invites the question of whether the presence of such biology might actually be 'beneficial' bearing in mind the limited participant numbers included in the Frye study. I know that this might sound at odds with the whole folate-autism link that has been built up over the years, but as I've said before on this blog, folate metabolism and autism is a mighty complicated topic (see here). Likewise, is the idea that the presence of binding FRAAs might be something to 'target' given their seemingly less favourable biological and behavioural profile.

I do have one or two other points to make before I leave you. First, although mention is made of serum levels of the various biological analytes under investigation, one should be mindful of how representative these values are across the body. High serum vitamin B12 does not necessarily mean high brain levels of vitamin B12 for example (and alongside vitamin B12 I would have liked to have seen some data on the compound that is methylmalonic acid). Second, although mention is made of "methylenetetrahydrofolate reductase" (MTHFR), it would be interesting to see how many of the group presented with genetic issues with the production of this enzyme in light of previous findings (see here) and onwards the nature of any connection with FRAAs and autism.

This is interesting work but lots more investigation is implied.

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[1] Frye RE. et al. Blocking and Binding Folate Receptor Alpha Autoantibodies Identify Novel Autism Spectrum Disorder Subgroups. Front. Neurosci. 2016. March 9.

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Frye, R., Delhey, L., Slattery, J., Tippett, M., Wynne, R., Rose, S., Kahler, S., Bennuri, S., Melnyk, S., Sequeira, J., & Quadros, E. (2016). Blocking and Binding Folate Receptor Alpha Autoantibodies Identify Novel Autism Spectrum Disorder Subgroups Frontiers in Neuroscience, 10 DOI: 10.3389/fnins.2016.00080