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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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