Tuesday 29 May 2012

Co-factor this: tetrahydrobiopterin and autism

Tetrahydrobiopterin [tetra - hydro... yes the spelling is right] has made an appearance previously on this blog in relation to phenylketonuria (PKU) and its mopping up qualities when it comes to excessive blood phenylalanine. Also known as sapropterin or BH4, I want to quickly run through some of the (emerging) evidence for its potential connection to autism spectrum conditions in this post, spurred on by some interesting research recently presented at IMFAR 2012.

BH4 does have some history when it comes to autism. There was for example some suggestion of lower levels of 6R-5,6,7,8-tetrahydrobiopterin in samples of cerebrospinal fluid (CSF) from people with autism as per this study by Tani and colleagues. Likewise, experimental use of BH4 have hinted at some potential positive effects to be had in some cases of autism as per this trial by Danfors and colleagues. Social interaction seems to be a target behaviour in most of the trials described so far, perhaps mirroring another compound of interest at IMFAR 2012, oxytocin - the cuddle hormone. The caveat being that not everyone with autism seemed to benefit from BH4 supplementation. Now where have I heard that before?

Indeed Richard Frye, a name attached to the fairly recent folate receptor autoantibody story in autism, seems to have done quite a bit on BH4 as per this paper* and this review paper**. I'm not going through these papers with excruciating details or anything but do want to pick up on a few points raised in one or other.

The thing that always struck me about BH4 is its flexibility. In particular how it is used by three pretty important enzymes as a co-factor, tyrosine hydroxylase, tryptophan hydroxylase and phenylalanine hydroxylase; enzymes used in some pretty important reactions with regards to neurostransmitters like serotonin and dopamine. Avid readers might remember mention of the three amino acids (tyrosine, tryptophan and phenylalanine) in this post on the aromatic amino acids and their gut bacterial link which included some interesting speculation on an important compound to me, indolyl-3-acryloylglycine (IAG) derived from tryptophan. Indeed, if one is suggesting that levels of BH4 may be sub-optimal in some cases of autism, the potential knock-on effects for enzyme function and onward production of those all-important neurotransmitters and their intermediaries might be positively eyebrow raising.

I was interested in Dr Frye's paper* looking at markers which might determine lower and higher CSF levels of BH4. Anyone who has seen or experienced a lumbar puncture (don't click on the link if you don't like surgery) used to collect CSF samples will know that this is a very invasive procedure and is probably not something most people would like to undergo if they can help it. His suggestion therefore that serum levels of the amino acids citrulline and methionine (yes, the methionine cycle) might potentially match up with low and high BH4 concentrations noted in a group of people with autism amongst other diagnoses, is a welcome finding requiring further validation with larger participant numbers.

Given the way that BH4 is synthesized in the body, one has to wonder what processes might potentially be disrupted leading to BH4 deficiency in some cases of autism. I note that the purine nucleotide guanosine-5'- triphosphate (GTP) is the starting point for BH4 and couldn't help but wonder what, if any, effect all those early findings on the purines in some cases of autism might contribute. I hasten to add that I am not an expert on purine metabolism, so just speculating.

There are a few other points of interest tied into BH4 which I have neither the expertise nor time to discuss in detail aside from mentioning; not least how BH4 seems to be tied into nitric oxide (NO) production and the slightly unusual findings of elevated NO being reported in quite a few cases of autism. Whether or not PKU (or even elevated levels of phenylalanine or issues with phenylalanine hydroxylase) might show some link to cases of autism is another question which has received only limited investigation. Either way, I'd like to think that there is enough literature on tetrahydrobiopterin - BH4 - and autism for some serious larger scale research interest in both its measurement and use.

To finish and speaking of co-factors, I always thought that Jason & Kylie were like enzyme and co-factor; just not quite complete without each other...

* Frye RE. Central tetrahydrobiopterin concentration in neurodevelopmental disorders. Frontiers in Neuropharmacology. 2010; 4: 52.
DOI: 10.3389/fnins.2010.00052

** Frye RE. et al. Tetrahydrobiopterin as a novel therapeutic intervention for autism. Neurotherapeutics. 2010; 7: 241-249.
DOI: 10.1016/j.nurt.2010.05.004


  1. Hi Paul, very interesting post - as always. just a question on assessing BH4 as a potential issue in ASD children. You mention that looking at serum levels of citrulline and methionine can give clues about BH4 status - would it be possible to make such an assessment based on an urine organic acid test showing those markers?

  2. Hello Stella and thanks for the comment/question.

    Accepting that this is still preliminary work that needs further replication, Dr Frye reported on serum levels of citrulline and methionine as being potentially predictive rather than urine levels.

    One could assume there might be some correlation between serum and urine levels as per studies like this one:


    Having said that, I would probably like to see results replicated in a larger, more relevant group before any assumptions can be made; accepting also that other biological parameters might be equally predictive of BH4 status ...

    Same goes for methionine:



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