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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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 multivitamins 'are a waste of money' (except when they're not)

Science headlines eh? Who would trust them and their sometimes inflated press releases?

I start today with a science headline taken from the BBC website reading: "Pregnancy multivitamins 'are a waste of money'" based on the findings of a review article [1] published in the journal Drug and Therapeutics Bulletin.

In it we are told that complex multi-vitamin and mineral supplements are 'unlikely to be needed and are an unnecessary expense' during the nine months that made us. Further that certain vitamins are not indicated for supplementation during pregnancy including that contributory to excess vitamin A. All pregnant women have to do, we are told is "to have a healthy, varied diet including fresh fruit and vegetables" and avoid the old phrase 'eating for two'. What could be simpler?

The irony behind such findings and those BBC and other media headlines is that although one needs to be careful about one's vitamin and mineral intake (treat them as what they are, medicines) there is a long tradition of vitamin supplementation being indicated when it comes to that special time called pregnancy. Indeed, and I quote from the BBC article: "pregnant women should make sure they take folic acid and vitamin D, as well as eating a well-balanced diet, as per NHS guidelines, they add."

So let me get this straight: don't take a multi-vitamin supplement but makes sure that you take a (multi) supplement containing folic acid and vitamin D? You can perhaps see how confusing such headlines are and how grandiose ideas that every woman pre-conceptual and during pregnancy is feasting down on 5-a-day (or even 8-a-day if you actually believe it will make you happier!) are not necessarily based in reality. We would all love to think that important health messages about maternal fruit and vegetable consumption during pregnancy for example, are being heard loud and clear but the reality is that they aren't for everyone. The reality is that people are using vitamin and mineral supplements to supplement their dietary needs for whatever reasons and headlines further confusing the population about such supplementation being a 'waste of money' is only likely to put more people off using them without perhaps giving greater thought about the ways and means to help people alter their diet accordingly. The net result: more pregnant women potentially becoming deficient in certain core nutrients during pregnancy and more potential effects/risks for her and her offspring.

I do have a bee in my bonnet about this issue because time after time the research evidence points to how important pregnancy nutrition is for a variety of maternal and offspring outcomes [2]. Outside of folic acid and vitamin D, various other nutrients are also pretty important during pregnancy (i.e. iodine - 'good for baby, good for the economy') and the unfortunate reality is that most people can't or don't get enough of them from their diet alone. The late David Barker was a pioneer in the area of foetal programming including that related to pregnancy nutrition; one can only wonder what he would make of the suggestion that universally, supplementary multivitamin use during pregnancy is a 'waste of money'?

And finally, you want more people to eat fruit and vegetables? Don't focus too much on just price and positioning at the supermarket, focus on home economics (or just cookery!) classes at school [3] for starters and make fruit and vegetables interesting...

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[1] Vitamin supplementation in pregnancy. Drug & Therapeutics Bulletin. 2016. July 11.

[2] Harding JE. The nutritional basis of the fetal origins of adult disease. Int J Epidemiol. 2001 Feb;30(1):15-23.

[3] McMorrow L. et al. Perceived barriers towards healthy eating and their association with fruit and vegetable consumption. J Public Health (Oxf). 2016 May 24.

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Drug and Therapeutics Bulletin (2016). Vitamin supplementation in pregnancy Drug and Therapeutics Bulletin DOI: 10.1136/dtb.2016.7.0414

Add-on nutraceuticals for depression?

It came as no surprise to me that the systematic review and meta-analysis article by Jerome Sarris and colleagues [1] found what it did in relation to the use of [certain] adjunctive (add-on) nutraceuticals alongside antidepressants to reduce depressive symptoms: some of them might actually be clinically useful.

With no medical or clinical advice given or intended, the authors report that "adjunctive use of SAMe, methylfolate, omega-3, and vitamin D with antidepressants" might be something to consider "for improving inadequate response to antidepressants." Dr Sarris was one among many authors who contributed to the 'personal view' paper titled: 'Nutritional medicine as mainstream in psychiatry' [2] which was also covered a while back on this blog (see here). This latest addition to that and other opinions [3] which covered the peer-reviewed literature on a variety of nutrients also found something of a mixed bag of results for various other compounds including the aromatic amino acid tryptophan, zinc, folic acid and vitamin C.

Quite a bit more science needs to be done in this area, not least around the hows and whys that the various preparations might exert some effect. Vitamin D has of course been covered quite a bit on this blog in relation to something like depression (see here for example) so that particular nutraceutical might already have a research head start compared to others. I'm also minded to suggest that the involvement of something like SAMe (S-adenosylmethionine) as an add-on treatment might also imply a role for epigenetic variables in relation to at least some depression [4]. And then there is the question of who might be best responders to such nutraceutical use which implies heterogeneity and possible plural depressions...

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[1] Sarris J. et al. Adjunctive Nutraceuticals for Depression: A Systematic Review and Meta-Analyses. American Journal of Psychiatry. 2016. April 26.

[2] Sarris J. et al. Nutritional medicine as mainstream in psychiatry. Lancet Psychiatry. 2015 Mar;2(3):271-4.

[3] Sarris J. et al. International Society for Nutritional Psychiatry Research consensus position statement: nutritional medicine in modern psychiatry. World Psychiatry. 2015 Oct;14(3):370-1.

[4] McGowan PO. & Kato T. Epigenetics in mood disorders. Environ Health Prev Med. 2008 Jan;13(1):16-24.

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Sarris J, Murphy J, Mischoulon D, Papakostas GI, Fava M, Berk M, & Ng CH (2016). Adjunctive Nutraceuticals for Depression: A Systematic Review and Meta-Analyses. The American journal of psychiatry PMID: 27113121

Pregnancy folic acid and offspring autism risk: just one minute...

So: "We did not find any evidence to corroborate previous reports of a reduced risk for autism spectrum disorders in offspring of women using folic acid supplements in early pregnancy."

The findings reported by Jasveer Virk and colleagues [1] prove once again that when it comes to autism, universal 'truths' are very much few and far between.

Actually, I'm not particularly surprised that Virk et al found what they did when it came to the idea that "early folic acid supplementation during pregnancy prevents diagnosis of autism spectrum disorders in offspring" (their words, not mine). As I've indicated before on this blog, the buzz about how folic acid intake during the nine months (plus) that made us might reduce the risk of offspring autism has not been all one way traffic (see here). Even recent meta-analyses have agreed on this point (see here).

Based on data derived from some familiar registries (Denmark does it again) researchers "estimated risk ratios for autism spectrum disorders for children whose mothers took folate or multivitamin supplements from 4 weeks prior from the last menstrual period through to 8 weeks after the last menstrual period (-4 to 8 weeks) by three 4-week periods." They concluded that there wasn't too much to see when it came to early folate or multivitamin intake in terms of offspring autism outcomes or not compared with women reporting no supplement use during the same period.

That all being said, I don't think it is yet time to trash the whole idea that pregnancy folic acid supplementation might not show some relationship to offspring outcomes with autism in mind. Bearing in mind other data in this area (see here) including the idea that genetic factors might intersect with things like folate availability and utility (see here) I'd be minded to suggest that there is still quite a bit more science to do in this area. Oh, and that issues with folate receptors in relation to some autism, might extend a lot further than just pregnancy (see here) also needs to be kept in mind...

Music: George Ezra - Listen to the Man (in this case, Magneto).

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[1] Virk J. et al. Preconceptional and prenatal supplementary folic acid and multivitamin intake and autism spectrum disorders. Autism. 2015 Sep 25. pii: 1362361315604076.

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Virk J, Liew Z, Olsen J, Nohr EA, Catov JM, & Ritz B (2015). Preconceptional and prenatal supplementary folic acid and multivitamin intake and autism spectrum disorders. Autism : the international journal of research and practice PMID: 26408631

Persistent hyperlactacidemia in cases of autism

The paper from José Guevara-Campos and colleagues [1] (open-access can be downloaded here) is fodder for today's short post, and a topic that has not been seen on this blog for quite a while: hyperlactacidemia (elevated plasma lactate levels) and autism.

Previous mentions of lactate and autism on this blog (see here and see here) were potentially pretty important; specifically, how elevated plasma lactate levels might (a) not be an unfamiliar finding for quite a few people on the autism spectrum [2] and (b) might provide further evidence for the involvement of mitochondria in cases of autism among other things [3]. Mitochondria and autism, I might add, is still quite a complicated topic but a research area in the ascendancy.

Guevara-Campos et al reported on case reports for "three patients diagnosed with developmental delay, ID [intellectual disability] and ASD [autism spectrum disorder], and also with a possible mitochondrial disease accompanied by an ETC [electron transport chain] deficiency accompanied by hyperlactacidemia." There are various data provided following some clinical investigations including that based on muscle biopsy data. Just as important are some of the details on 'pharmacological treatment' of said issues and the observed impact on presented symptoms. Without cherry-picking too much, carnitine, a vitamin B complex, co-enzyme Q10 and folic acid combined seemed to have quite an effect on participants, particularly on "intellectual abilities". Some of these interventions have been trialled in other conditions where mitochondria or their important processes are suspected to show involvement (see here). I say this without providing endorsement or recommendation.

Appreciating that there is quite a bit more to do (experimentally) when it comes to "suspected mitochondrial involvement" specifically where autism is mentioned, and in particular, the need for quite a bit more controlled study on how such interventions might impact on symptoms in this group, I'm interested in the Guevara-Campos report. How many people on the autism spectrum their results hold true for is as yet unknown. With the growth in this area of research however, I'd be minded to suggest that we should really start directing a lot more resources to trying to answer that question if we are indeed going to start taking the plural autisms a little more seriously. Oh, and as per the sentiments of the paper by Zilberter and colleagues [4] there may yet be related factors which might be of "potential therapeutic significance."

Music: Roots Manuva - Witness. Brilliant.

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[1] Guevara-Campos J. et al. Autism and Intellectual Disability Associated with Mitochondrial Disease and Hyperlactacidemia. Int J Mol Sci. 2015 Feb 11;16(2):3870-3884.

[2] Oliveira G. et al. Mitochondrial dysfunction in autism spectrum disorders: a population-based study. Dev Med Child Neurol. 2005 Mar;47(3):185-9.

[3] Andersen LW. et al. Etiology and therapeutic approach to elevated lactate levels. Mayo Clin Proc. 2013 Oct;88(10):1127-40.

[4] Zilberter Y. et al. A unique array of neuroprotective effects of pyruvate in neuropathology. Front. Neurosci. 2015. Feb 17.

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Guevara-Campos J, González-Guevara L, & Cauli O (2015). Autism and Intellectual Disability Associated with Mitochondrial Disease and Hyperlactacidemia. International journal of molecular sciences, 16 (2), 3870-3884 PMID: 25679448

Maternal iron intake and offspring autism risk

Much like the discussions around the paper by Rogers and colleagues (see here) on treating autism in the first year of life, the media scrum around the findings from Rebecca Schmidt and colleagues [1] talking about maternal iron supplements and offspring autism spectrum disorder (ASD) risk preceded the publication of the paper by a few days. It's getting to be a pet-hate of mine that big headlines are being generated sometimes days before your average Jane or Joe can see the data upon which they're based...

Grumbling aside, here are a few factoids from the now published Schmidt paper:

• CHARGE was the source initiative for participants, as it has been for various studies, and following on from other research on nutrition during pregnancy potentially affecting offspring autism risk from this group (see here), the idea was to look at pre- and pregnancy maternal iron intake in relation to autism risk.
• Data for mothers of children with autism (n=520) were compared against mothers with children who did not have autism (n=346) and "maternal daily iron intake was quantified on the basis of frequency, dose, and brands of supplements and cereals consumed each month from 3 months before pregnancy through the end of pregnancy and during breastfeeding (the index period), as reported in parental interviews". You'll note the words 'parental interviews' there.
• Results: well, the mothers of children with autism were less likely to report taking 'iron-specific supplements' than control mothers and overall, a "lower mean daily iron intake" in the order of 5-6 mg/day less than controls was observed.
• "Low iron intake significantly interacted with advanced maternal age and metabolic conditions; combined exposures were associated with a 5-fold increased ASD risk". Advanced maternal age by the way, refers to women who were 35 or older at the time of their child's birth, and metabolic conditions means obesity, diabetes or hypertension (in line with other evidence).

These are interesting findings which add to the growing literature on how maternal nutrition before and during the nine months that made us potentially impacts on offspring development and outcome. Certainly, there are hints of the foetal programming hypothesis in there, for which the late David Barker receives quite a bit of credit. I was also wondering whether other issues potentially affecting foetal nutrition such as the inter-pregnancy interval (see here) might also tie into these findings too?

But there are some obvious cautions to take on board when it comes to these findings. First is the continued reliance on self-report, which even under the most controlled of situations, is always going to be an estimate at best. Next, and I might be completely wrong about this, but even with the report of a mean daily intake of ~51 mg/day, the mothers with children with autism group were still quite a bit above the daily recommendations in the United States (see here) for pregnant or lactating women. Finally, I'm wondering whether the idea of "combined exposures" when it comes to maternal age and the presence of metabolic syndrome might actually be the more important issue raised in this paper...

Iron and autism is a topic which has been discussed a few times on this blog (see here). The data is slightly mixed when it comes to looking at iron levels in children with autism as per my discussions on the Reynolds paper [2] versus the Hergüner findings [3]. Dr Schmidt and colleagues did not directly assay for iron or ferritin levels in their current paper so we can't really say much more at this point on how actual maternal iron levels translated into offspring iron levels and what effect(s) this may have had on offspring autism or other risks. That and whether other factors might also have played some role as per the rodent findings from Harvey & Boksa [4] talking about an additive effect from iron deficiency and prenatal immune activation (a topic that has cropped up a few times with autism in mind). These are perhaps the next studies that need to be done alongside what biological effects supplementation may have [5].

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[1] Schmidt RJ. et al. Maternal Intake of Supplemental Iron and Risk of Autism Spectrum Disorder. Am J Epidemiol. 2014. 22 September.

[2] Reynolds A. et al. Iron status in children with autism spectrum disorder. Pediatrics. 2012; 130 Suppl 2:S154-S159.

[3] Hergüner S. et al. Ferritin and iron levels in children with autistic disorder. Eur J Pediatr. 2012; 171: 143-146.

[4] Harvey L. & Boksa P. Additive effects of maternal iron deficiency and prenatal immune activation on adult behaviors in rat offspring. Brain Behav Immun. 2014 Aug;40:27-37.

[5] Dosman CF. et al. Children with autism: effect of iron supplementation on sleep and ferritin. Pediatr Neurol. 2007 Mar;36(3):152-8.

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Rebecca J. Schmidt, Daniel J. Tancredi, Paula Krakowiak, Robin L. Hansen, & Sally Ozonoff (2014). Maternal Intake of Supplemental Iron and Risk of Autism Spectrum Disorder American Journal of Epidemiology : doi: 10.1093/aje/kwu208

Homocysteine, MTHFR and schizophrenia studied AND meta-analysed

"Our study suggests that increased plasma total homocysteine levels may be associated with an increased risk of schizophrenia". Further: "The meta-analysis of the Japanese genetic association studies demonstrated a significant association between the MTHFR C677T polymorphism and schizophrenia".

MTHFR (again!) @ Paul Whiteley

So said the results of the study and meta-analysis carried out by Akira Nishi and colleagues [1] (open-access) looking at the 'big H' alongside everyone's genetic Scrabble favourite MTHFR (methylenetetrahydrofolate reductase (NAD(P)H)).

The Nishi paper represents pretty good scientific value for money given that authors not only looked at plasma levels of total homocysteine in nearly 400 participants diagnosed with schizophrenia compared with nearly 1000 controls, they also genotyped for the MTHFR C677T polymorphism [2] (describing an amino acid substitution which reduces the activity of the enzyme methylenetetrahydrofolate reductase and results in elevated homocysteine levels) in a further 1700 participants with schizophrenia compared against over 3000 asymptomatic controls. For good measure, the authors then carried out a meta-analysis of the scientific literature looking at homocysteine and schizophrenia as a function of gender. Phew.

As per the opening paragraph, authors reported "significantly elevated plasma total homocysteine levels in patients with schizophrenia compared with controls, in both male and female subjects". The results of their meta-analysis confirmed such elevations in homocysteine "although antipsychotic medication might influence this outcome". Combined with the association made between a diagnosis of schizophrenia and the MTHFR SNP studied, all adds up to "disrupted 1-carbon metabolism [having] an important role in the pathophysiology of schizophrenia".

I don't mind saying that the Nishi results are really rather interesting to me. The links between schizophrenia and homocysteine have been talked about previously on this blog (see here) including the potential usefulness of folic acid and vitamin B12 for some cases of schizophrenia (see here). Nishi et al also talk about another potentially important part of their results with some mention of DNA methylation, something which also crosses over into other areas of research interest too (see here).

And so the evidence continues to stack up for the big H and MTHFR in some cases of schizophrenia...

Music then. The Pixies and Debaser.

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[1] Nishi A. et al. Meta-analyses of Blood Homocysteine Levels for Gender and Genetic Association
Studies of the MTHFR C677T Polymorphism in Schizophrenia. Schizophrenia Bulletin. 2014; 40: 1154-1163.

[2] Gilbody S. et al. Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review. Am J Epidemiol. 2007 Jan 1;165(1):1-13.

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Nishi A, Numata S, Tajima A, Kinoshita M, Kikuchi K, Shimodera S, Tomotake M, Ohi K, Hashimoto R, Imoto I, Takeda M, & Ohmori T (2014). Meta-analyses of Blood Homocysteine Levels for Gender and Genetic Association Studies of the MTHFR C677T Polymorphism in Schizophrenia. Schizophrenia bulletin PMID: 24535549

Autism risk and interpregnancy interval

Pregnancy issues and adverse birth factors 'associated' with the development of autism in offspring is a topic which has cropped up more than once on this blog, as autism research strives to identify as many possible 'risk' factors potentially linked to symptom onset. Lots of different birth-related variables have been analysed and put forward as potential candidates related to risk (see this post) ranging from birth weight (see here) to birth order (see here) and even season of conception/birth (see here).

Let me out... @ Wikipedia  

That's not to say however that anything concrete in terms of generalised offspring risk of autism has emerged from these various lines of research inquiry. Indeed, as per the study by Schieve and colleagues* (which I've already blogged about) hinted, many of these factors may be contributory but not necessarily 'causative' of autism when looked at on a population scale. This bearing in mind that I've not introduced the various 'exposure' events during pregnancy which have also been linked to offspring autism risk (e.g. the emerging valproate story) and the idea that population risk does not necessarily always translate into personal circumstances and risk.

Another factor which has seen some research action is the idea that having children in close temporal succession to one and another - a short interpregnancy interval - might also elevate the risk of the second child presenting with autism. The paper by Cheslack-Postava and colleagues** (full-text) hinted at this effect as per their conclusion: "children born after shorter intervals between pregnancies are at increased risk of developing autism". I note that Dr Emily Deans over at Evolutionary Psychiatry carried some discussion on this paper too (see here).

The more recent paper by Nina Gunnes and colleagues*** adds to the literature on this topic; indeed coming to pretty much the same conclusion: "interpregnancy intervals shorter than 1 year were associated with increased risk of autistic disorder in the second-born child". Based on yet more analysis out of Norway (although I am unsure whether this was a MoBa study or not), researchers looked at the records of several thousand sibling pairs in order to identify the length of the interpregnancy interval (IPI) and whether autism was mentioned in the records of second-born children. Their conclusion about short IPI and an elevated risk of autism in second-born children seemed to be particularly pertinent to those children born 9 months after their sibling compared with those born 3 years or later after their sibling.

A few points are worthy of mention. The very discerning readers out there might have already spotted a couple of familiar names attached to the Gunnes paper authorship in the form of Mady Hornig and Ian Lipkin (see this quite recent post).

I note also the authors suggest that a "depletion of micronutrients" might have something to do with the explanation for the short IPI-autism association, which carries hints of the late David Barker's hypothesis (see here) and is pretty much in line with what Dr Deans previously mentioned. Indeed, to reiterate her discussion about baby 'sucking out' whatever nutrients it needs from its host (i.e. mum) I can remember similar words being told when my/our brood were due for an appearance. With all the current fascination on things like folic acid and autism (see here and here), one might very easily say that there is a possible link to be had there, bearing in mind Gunnes and colleagues did not assay for or report on maternal or offspring folic acid levels at any point during their study.

If also I had to play devil's advocate on such 'association' research I might point out that looking at the IPI alone and knowing relatively little about the family or offspring in terms of their lives is still methodologically problematic. We don't for example know about any medical or psychiatric familial history which might also be an important modifier of offspring risk. I assume the authors already controlled for whether sibling number one had a formal diagnosis of autism (as per the autism recurrence data previously discussed), but did they for example, ask about the potential presence of sub-clinical signs and symptoms associated with something like the broader autism phenotype for example? Were they also able to comment on any additional siblings after child number two and the elevated risk or not for them presenting on the autism spectrum either alone or as a function of IPI?

Then there's the volume of research suggesting that a short IPI might also increase the risk of reduced birth weight**** or the risk of preterm birth***** which I assume have been controlled for, but still one wonders about their impact on the presentation of offspring autism and any wider links (see here). I might also draw readers' attention to an interesting correspondence from Downs & Jonas****** (full-text) with regards to research suggesting a link between short IPI and risk of offspring schizophrenia. In short(!), one has to be careful of making too much of such association data at the current time.

That being said, I don't want to take anything away from the Gunnes study and results. It was a well-powered study and they got what they got. Their data also add to the various other information suggesting that when it comes to having children, mums (and dads) are advised to give themselves a bit of breather between kids.

Some music to finish. How about Robbie & Kylie?

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* Schieve LA. et al. Have secular changes in perinatal risk factors contributed to the recent autism prevalence increase? Development and application of a mathematical assessment model. Ann Epidemiol. 2011 Dec;21(12):930-45.

** Cheslack-Postava K. et al. Closely spaced pregnancies are associated with increased odds of autism in California sibling births. Pediatrics. 2011 Feb;127(2):246-53.

*** Gunnes N. et al. Interpregnancy Interval and Risk of Autistic Disorder. Epidemiology. 2013 Sep 16.

**** Smits LJ. et al. The association between interpregnancy interval and birth weight: what is the role of maternal polyunsaturated fatty acid status? BMC Pregnancy Childbirth. 2013 Jan 25;13:23.

***** De Franco EA. et al. A short interpregnancy interval is a risk factor for preterm birth and its recurrence. Am J Obstet Gynecol. 2007 Sep;197(3):264.e1-6.

****** Downs JM. & Jonas S. Short inter-pregnancy interval and schizophrenia: overestimating the risk. Br J Psychiatry. 2012; 200: 160.

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Gunnes N, Surén P, Bresnahan M, Hornig M, Lie KK, Lipkin WI, Magnus P, Nilsen RM, Reichborn-Kjennerud T, Schjølberg S, Susser ES, Oyen AS, & Stoltenberg C (2013). Interpregnancy Interval and Risk of Autistic Disorder. Epidemiology (Cambridge, Mass.) PMID: 24045716

Meta-analysing MTHFR and autism

I told you so.

I'm talking about the paper by Pu and colleagues* who meta-analysed the currently available literature looking at two SNPs in everyone's favourite Scrabble classic gene, MTHFR in relation to autism spectrum disorders (ASDs). Said gene controls production of methylenetetrahydrofolate reductase (MTHFR) which fits very snugly into the whole one carbon metabolism cycle (see here).

Love at first sight? @ Wikipedia  

Regular readers might know that I have a bit of a thing for MTHFR with autism in mind. And how MTHFR serves an important purpose in reducing the compound 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate and onward its links to homocysteine (see here) and methionine (see here) and all that methylation palava.

For a good summary (well, at least I think so) you might also want to have a look at this older post detailing the process, complete with hand-drawn diagram by yours truly.

In essence, Pu et al reiterated the important role than the MTHFR C677T SNP might have to some cases of autism; in particular how "the C677T polymorphism was found to be associated with ASD only in children from countries without [folic acid] food fortification" denoting the potentially important link with the vitamin of the hour, folate (folic acid, vitamin B9) (see here).

There's little more for me to add to this post that hasn't already been said. MTHFR is probably not going to be an issue for everyone with autism, and indeed might also be potentially important to other conditions outside of the autism spectrum (see here for a discussion of that recent schizophrenia paper). Mmm... perhaps another part of that common ground and potential RDoC variable?

The nutrition link is perhaps something which adds to the view that environment might be a modifier of risk of some ASDs bearing also in mind the overlap with things like vitamin B12 (see here). That being said I'm also going to draw your attention back to all that folate receptor autoantibody stuff too just to bear in mind.

I told you so.

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* Pu D. et al. Association between MTHFR gene polymorphisms and the risk of autism spectrum disorders: a meta-analysis. Autism Res. May 2013.

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Pu D, Shen Y, & Wu J (2013). Association between MTHFR Gene Polymorphisms and the Risk of Autism Spectrum Disorders: A Meta-Analysis. Autism research : official journal of the International Society for Autism Research PMID: 23653228

Autism and the methylome

Q: When is an identical twin not an identical twin? A: Pretty much all the time (at least according to some people) as our increasing understanding of the complexity of genetics stretches and modifies long-held beliefs about the building blocks of life and their role in our health and wellbeing.

DNA methylation differences? @ Wikipedia  

Today I'm talking about identical (monozygotic) twins - siblings derived from one fertilised egg - and how the science of epigenetics might have some interesting implications for autism research as per the study by Chloe Wong and colleagues* (open-access). I should perhaps also direct you to some other interesting research recently discussed in this area too (see here) which might be relevant.

Regular readers will probably already know about my amateur interest in epigenetics (see here and here) and how the area of the epigenome - those chemical marks which have the ability to influence the expression of the genome - has started to yield some potentially important observations. At times I'll admit to being slightly too over-excited at the possibilities of epigenetics. Subsequently brought back down to earth by more sobering accounts (see here**) but not yet ready to poo-poo the whole science just yet***.

I don't want to rehash the whole epigenetic story in this one post, so instead am going to concentrate on the particular area covered by Wong et al and their analysis of the methylome (yes, another -ome for you) which is concerned with the addition of methyl groups to various regions of the genome and how that subsequently alters the expression of genes. DNA methylation has been a sort of peripheral topic in relation to cases of autism for quite some time now; brought to the forefront by all that folic acid (see here) and MTHFR research (see here) and the availability of those lovely methyl groups. Suffice to say that we are still very much at the beginning when it comes to looking at the relationship between all these elements and very complicated conditions like autism.

Anyhow, after that very long introduction (I am only an amateur science blogger after all), a few details from the Wong paper might be in order, bearing in mind it is open-access:

• Part of the UK TEDS initiative and partly sponsored by Autism Speaks who were involved in that recent environmental epigenetics symposium (see here), researchers looked at 50 monozygotic (MZ) twin pairs. It wasn't just a case of 25 twin pairs where one twin was diagnosed with an autism spectrum disorder (ASD) compared with 25 twin pairs where both were concordant for ASD. No, instead the authors looked at a variety of phenotypic combinations based on concordance/discordance for ASD and various core traits based on the Childhood Autism Symptom Test (CAST) schedule. Supplementary table 1 shows the combinations (see here).
• A genome-wide analysis of DNA methylation was undertaken on blood samples provided by participants. I can't pretend to intimately know all the techniques that were employed so won't profess to do so. What I can glean from the paper is that both DNA methylation differences between MZ twin pairs discordant for ASD and analyses between groups scoring high and low on the various core symptom areas were completed with "the aim of identifying real, biologically relevant within-twin and between group DNA methylation differences".
• Results: "ASD is not associated with systemic differences in global DNA methylation". In other words, within the twins, there is quite a high degree of similarity when it comes to patterns of DNA methylation. This might tie in with other work looking at methylation in cases of autism and other family members (see here). 
• When looking at DNA methylation patterns between twin pairs discordant for ASD, specific sites of the genome however seemed to show some variability as a function of ASD diagnosis or not. The authors list the top 50 "differentially methylated CpG sites" (see here) showing gene and position, with a combination of hyper- and hypo-methylated regions identified. Top of the methylation differences pops was the NFYC promoter which was "consistently hypermethylated in affected individuals" (see here for some additional papers on this gene). Hypermethylation by the way, generally means gene silencing as per its function when it comes to transposons (think HERVs). 
• Various other data are presented based on either syndrome or trait specific differences across the twins. I'm not going to go through all of these because, well because that's called plagiarism. I will draw your attention to one particular finding which might be important as they identified "one MZ twin pair, concordant for a very severe autistic phenotype, that appear to represent epigenetic outliers at multiple CpG sites across the genome". I'm immediately drawn back to my autism or autisms post and that all-important phenotypic variability as potentially being relevant here too. That and the tie-up with more structural changes to the genome as per the mention of CNVs and hotspots.

I know I've gone on a bit in the post but this is potentially a very important paper. Not only does it put the epigenome, or at least one part of the epigenome, firmly on the autism research map, but it offers something of a partial explanation for [some of] that 'missing heritability' which was talked about not so many years ago (see here).

The fact also that methylation patterns might be variable both intra-twins and intra-ASD is also important; suggesting that as with more traditional genomic findings in relation to autism, there isn't going to be just one epigenomic factor affecting risk or presentation, but rather a plethora of sites which are hyper- or hypo-methylated, potentially also linked to (affecting?) more structural changes to the genome in cases of ASD.

Don't get me wrong, the same questions remain as are seen in other areas of biological functioning with autism in mind: the heterogeneity, the reliance on diagnosis by observation and note-taking, the (elevated) risk of comorbidities, etc. All of which cloud the waters of association. Distinct however from the question of whether there is anything that can be done when structural changes to the genome are observed (outside of gene therapy for example), when talking about methylation, one speculates that this might be something that lends itself to pharmacotherapy as per the already use of DNA methyltransferase inhibitors for example. Yes, going back to that folic acid-autism link work, the possibility also that environment might help shape gene function and some new light on other external factors (noting that I am not advocating anything at the current time).

So endth the lesson for today.

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* Wong CC. et al. Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traits. Molecular Psychiatry. April 2013.

** Ptashne M. Epigenetics: core misconcept. PNAS. April 2013.

*** Fraga MF. et al. Epigenetic differences arise during the lifetime of monozygotic twins. PNAS. 2005; 102: 10604-10609.

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Wong, C., Meaburn, E., Ronald, A., Price, T., Jeffries, A., Schalkwyk, L., Plomin, R., & Mill, J. (2013). Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traits Molecular Psychiatry DOI: 10.1038/mp.2013.41

Folic-ing around in schizophrenia

I seem to have been focusing a lot on folic acid (vitamin B9) and vitamin B12 these days. It's not that I'm in anyway choosing the direction taken, it just happens that the published papers are appearing that way.

And as if to prove my point, enter the paper by Joshua Roffman and colleagues* (open-access) reporting results from a gold-standard, randomised, double-blind, placebo-controlled study on the addition of folic acid and vitamin B12 supplement to antipsychotic medication for a group of adults with chronic schizophrenia.

MTHFR, FOLH = word score @ Wikipedia  

The paper is open-access but a few summary points are worth mentioning bearing in mind Dr Emily Deans has already discussed this research:

• One hundred and forty participants diagnosed with schizophrenia but psychiatrically stable were included for initial study. They were all taking an antipsychotic for 6 months "but displayed persistent symptoms despite antipsychotic treatment".
• As per the study protocol, participants were randomly split into folate-vitamin B12 supplementation or placebo. Actually whilst it was random, it was stratified random, meaning that randomisation took into account serum folate levels which were measured at baseline and formed an important part of the study outcomes. Indeed, the split was also not 50:50 in each group; instead weighted towards the supplementing group. 
• On most other variables the groups showed no significant difference (age, gender splits, medications, SES). That is aside from serum vitamin B12 levels, where the experimental group showed a significantly higher mean level at baseline compared to the placebo group (631 pg/ml vs. 511 pg/ml respectively).
• The primary outcome measure was the change in negative symptoms as judged by the SANS. Not being an expert on schizophrenia, I was interested to read about the characterisation of positive and negative symptoms in schizophrenia and, as the authors put it, "considerable disability is associated with negative symptoms and cognitive deficits, for which effective treatment is not available".
• Results: after 16 weeks of study, there were lots and they were mixed in with some DNA genotyping data pertinent to genes involved in the folate metabolism cycle. So our old Scrabble friend MTHFR (see here) got a look in, as did MTR (methionine synthase) - as per my previous post. 
• One gene in particular seemed to get quite well caught up in the study results: FOLH1 - which among other things is involved in folate transfer and absorption. Mention of the words 'glutamate excitotoxicity' alongside FOLH1 also stirs up some interesting thoughts. 
• So, yadda, yadda, "folate and vitamin B12 improves negative symptoms of schizophrenia" but only modestly given the "15% difference in SANS scores" between the experimental and placebo groups. Importantly in these days of personalised medicine, the FOLH1 gene was the focus, in that FOLH1 484C>T variant seemed to tie into treatment response. This was slightly at odds with what had been noted on another occasions**.
• So, if a participants was homozygous - as in identical copies of the same allele - for FOLH1 484T,  they were more likely to show greater benefit from the supplements. I'll come back to this shortly.
• That's not also to say that there weren't other gene related findings tied into intervention response. As the authors note about MTHFR 677C>T "only T allele carriers exhibited a significant benefit for active treatment over placebo for negative symptoms". Thankfully in line with what has previously been discussed***.

Every paper covered on this blog is a learning journey for me and this one is no exception. Likewise, it is always interesting to see when results don't exactly pan out as they are predicted to. In the case of the Roffman paper, it was the FOLH1 gene findings which didn't go to plan, and how contrary to the expected role of the 484C variant, the so-called low-functioning variant which one would expect to have reduced folate absorption - as was demonstrated in a separate asymptomatic cohort - it was actually the presence of the high-functioning variant (484T) which governed a positive treatment response.

In light of these findings, and the fact that red blood cell (RBC) levels of folate grew and grew in the experimental group over the course of the trial (although not significantly related to the change in negative symptoms), one starts to ponder other explanations to account for the results.

I've gone over MTHFR so won't say much more on that. The authors touch upon one potentially pertinent issue - DNA methylation - which is where I always seem to end up back to when talking about folate and MTHFR and the like. That for example, the supplementation of folic acid and vitamin B12 might, just might, impact on important reactions such as the recycling of homocysteine back to methionine onward to the production of SAMe is one possible effect. Indeed, it is a shame that elements of the methionine cycle were not measured over the course of the current trial.

I could go on. I could ask what kind of vitamin B12 was used as a supplement, whether the oral dosage form is the ideal way to get vitamin B12 into the body, whether outside of the reported symptoms, there may have been other variables affected by the results and whether despite increasing levels of folate, there were corresponding increases to levels of the active form of folic acid, 5-methyltetrahydrofolate? Indeed on that last point apparently there are plans afoot to look at the use of 5-methyltetrahydrofolate (or as the authors call it 1-methylfolate)...

Please stop now... and so I shall.

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

** Roffman JL. et al. Genetic variation throughout the folate metabolic pathway influences negative symptom severity in schizophrenia. Schizophr Bull. 2013; 39: 330-338.

*** Hill M. et al. Folate supplementation in schizophrenia: a possible role for MTHFR genotype. Schizophr Res. 2011; 127: 41-45.

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Roffman JL, Lamberti JS, Achtyes E, Macklin EA, Galendez GC, Raeke LH, Silverstein NJ, Smoller JW, Hill M, & Goff DC (2013). Randomized Multicenter Investigation of Folate Plus Vitamin B12 Supplementation in Schizophrenia. JAMA psychiatry (Chicago, Ill.), 1-9 PMID: 23467813