Don't panic! Folate receptor autoantibodies and autism

Don't panic @ Paul Whiteley

Those of you who, like me, enjoyed the adventures of Arthur Dent in the Hitchhiker's Guide to the Galaxy will know of the classic phrase associated with the book/series/film - 'Don't panic'. In the case of this post, I don't want readers to get too stressed or put off by the title and perceived content, as I attempt not to blind everyone with 'the appliance of science' while discussing a rather interesting piece of research. Let's see how I do..

The paper in question is by Richard Frye and colleagues* (open-access) part of the research tag-team that is Rossignol and Frye discussed in other posts. As a point of interest, the word on the cyberstreet is that Dr Rossignol has started a new programme with autism in mind called MAPS focused on the biomedical aspects of autism (no promotion intended).

I digress.

Alongside some other quite distinguished names in autism research including Jill James, Dr Frye reports on (a) the prevalence of folate receptor autoantibodies in a group of children diagnosed with an autism spectrum condition, (b) various measures compared with autoantibody negative children with autism and (c) what happens when folinic acid (leucovorin) is given. Folinic acid should not be confused with folic acid which whilst being an essential supplement during pregnancy has had a slightly bumpy ride these past few days following the publication of this meta-analysis.

OK softly, softly catchee monkey.

A good description of cerebral folate deficiency (CFD) syndrome is here. Basically diagnosis is based on low levels of 5-methyltetrahydrofolate (5MTHF) in cerebrospinal fluid (as Wikipedia when not in blackout describes it, the stuff the brain floats in). There are lots of behavioural manifestations of CFD syndrome which aid its description as a neurodevelopmental condition; autism has also been mentioned in some cases of CFD syndrome. Management of CFD syndrome is via the use of folinic acid (leucovorin) to normalise levels of 5MTHF by-passing folate receptors.

Based on the above paragraph coupled with the already suggested link between autism and possible issues with MTHFR (methylentetrahydrofolate reductase) (the enzyme which converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, 5MTHF) you can perhaps see why this study was done.

So:

• Ninety-three children (~ 7 years old) diagnosed with autism were screened for folate receptor autoantibodies (FRAs). FRAs are a slightly less invasive way of identifying people who might be at risk of CFD outside of doing a lumbar puncture. The folate receptor is a form of folate binding protein used to transport folate across the blood brain barrier. If you imagine that folate is essential for DNA synthesis, methylation and influences levels of homocysteine, you start to appreciate how important this chap is. FRAs impair the function of the folate receptor which might have knock-on effects similar to more genetically-linked effects on receptors. 
• Lots of other information was collected including whether or not participants were following a casein-free (milk-free) diet, given that such diets have been known to reduce FRAs (very, very interesting).
• Looking at both blocking (blocking folate transport) and binding FRAs, 56/93 (60%) of children were positive for blocking FRAs and 41/93 (44%) positive for binding FRAs. Twenty-nine percent of children were positive for both FRAs and 70/93 (75%) positive for at least one FRA. Interestingly, when it came to looking at rates of autoimmune conditions in the family history, more instances were found in those who did not have FRAs than those who did (60% vs. 24%). No other measures significantly differed between positive and negative autoantibody groups (aside from age at testing).
• A lumbar puncture was performed on 16 children included for study and levels of 5-methyltetrahydrofolate were found to be below the normative mean in every case (although not falling below the lower limit of normal though).
• A subgroup of 44 children from the 70 positive for at least one FRA were treated with leucovorin calcium tablets for at least 1 month (mean treatment time was 4 months). Based on parental responses to the Clinical Global Impression Scale - Improvement subscale on various items of cognition and behaviour, approximately two-thirds of children were deemed to have obtained some benefit.

There is a lot of detail to this paper which unfortunately I have neither the time nor space to go through in this post. Allowing for the fact that quite a few inferences were made during the study i.e. the 5MTHF levels found for those who underwent lumbar puncture would also be noted in those who were not tested, combined with the less than impressive way that the clinical effects of folinic acid were reported, there are some valuable details to be had from this report.

The rate of FRAs (blocking and/or binding) noted in the autism group (75%) is high and suggests that quite a bit more study is due in this area not least in comparison to other developmental conditions and control populations. I note for example that studies of blocking FRAs in Rett syndrome suggest that a smaller proportion of this group might be affected (24%). I do also wonder about whether there is any link with the timing of symptom onset, and in particular whether reported regression in behaviour has any effect on the likelihood of FRAs being present or not as per what happens in CFD. Speaking of regression and autism, how about this recent article?

Much like the recent findings from Jyonouchi and colleagues on SPAD and autism, the message yet again is don't stop looking for other things just because a diagnosis of autism is received (bearing in mind that I am not advocating invasive procedures like lumbar puncture unless clinically directed). The potential usefulness of a milk-free diet in cases where FRAs are present also opens up a whole new world of possibilities.

Hopefully you have not panicked and I have not left you dazed and confused with this post. If I have, I apologise; and paying homage to the classic Richard Linklater film Dazed and Confused I offer some light metal relief. Take it away Mr Alice Cooper... (he's such a nice guy).

* Frye RE. et al. Cerebral folate receptor autoantibodies in autism spectrum disorder. Molecular Psychiatry. January 2012.