Wednesday, 13 March 2013

Just say NO to sapropterin for autism

Actually the title of this post is a bit of a misnomer.

I'm not really asking readers to say 'no' to sapropterin, otherwise known as tetrahydrobiopterin or BH4, for autism as if it were some kind of Zammo-esque drugs in the toilet scenario (note: for anyone born post-Grange Hill golden era or for my non-UK readers, you might want to follow this link to see what I'm going on about). But neither am I saying yes, as per my prime directive on this blog: no medical or clinical advice given or intended (resistance is futile... and all that).
Mr Bronson / Admiral Ozzel @ BBC News

The 'no' actually refers to NO - nitric oxide - and in particular the findings reported by Richard Frye and colleagues* (including Jill James yet again) on the potential involvement of NO metabolism in the behavioural changes noted when BH4 was introduced to a small cohort of children diagnosed with autism. I think we might have seen shadows of this study presented at IMFAR 2012.

OK, a quick description might be in order first. I've covered BH4 previously on this blog (see here) and some of the various roles that it plays; not least in its co-factor duties for the metabolism of some important aromatic amino acids eventually into things like neurotransmitters. Also not forgetting the potential role for BH4 in relation to managing conditions like PKU also (see here). Similarly, NO has also appeared on this blog before (see here). The Frye paper stresses the important role that BH4 has in the production of NO.

A few details from the Frye paper bearing in mind it is open-access:

  • Starting with 10 participants (aged 2-6 years) diagnosed with an autism spectrum disorder (ASD) whose parents agreed "to not change any traditional or alternative medical or behavioral therapy during the study", various measures of behaviour and language function were charted over the course of a 16-week open-trial of BH4 (Kuvan).
  • Alongside the behavioural and psychometric measures used (which included the VABS and PLS), CSF samples were collected via lumbar puncture (not normally recommended because of its invasiveness) and blood samples used to measure for various marker compounds including BH4, the amino acids L-arginine and L-citrulline and everyone's favourite redox coverboy/covergirl, glutathione.
  • Results: bearing in mind that this was an open-trial and that no control group or placebo arm was used, the authors report some interesting changes to various parameters. So language (receptive at least) showed a significant improvement across the group across the testing periods (baseline, 8 weeks, 16 weeks). Some of the VABS subscales also indicated some positive changes (albeit one of them, VABS personal daily living, presented with a p-value of 0.061, I assume to denote Nick Berry style 'we nearly made it').
  • The biological stuff: well there was an increase in the reduced-to-oxidised glutathione ratio (good thing) and a decrease in levels of 3-Chlorotyrosine (3CT) (also a good thing) over the course of intervention, positive in terms of oxidative stress (redox status) and the presence of "reactive nitrogen species" respectively (see below).
  • Findings also pointed to "a fundamental change in pterin metabolism" coinciding with BH4 supplementation. I won't pretend to know all the ins-and-outs but it all has to do with supplementation modifying the reduced-to-oxidised pterin ratio and degradation of BH4 onwards to the appearance of something called peroxynitrite which is not particularly a good thing. I think this article** (open-access) might explain it a little better than I could.
  • The authors also reported that despite no significant change in NO metabolism markers (arginine and citrulline, and their ratio), it did appear that baseline levels of these compounds were allied to behavioural outcomes. Specifically improvements on the behavioural parameters "were related to higher baseline arginine and arginine-to-citrulline ratio".
  • Importantly, BHsupplementation was generally well tolerated with "only one patient discontinuing the medication because of mild adverse effects".

Yes, this was a very small trial, and yes again, there was no control group, no placebo and no blinding. It is preliminary work, of that there is no doubt. I find it a little unusual that the authors also chose HPLC with electrochemical detection when it came to the measurement of important metabolites like CSF levels of BH4. A little bit '80s' if you'll forgive me, given the startlingly increased precision offered by mass spec and NMR techniques as exemplified by papers like this one. Indeed even more odd that LC-MS was used for the analysis of amino acids: why not all metabolites? It should also be noted that Dr Frye is listed as having a potential conflict of interest in this paper via receipt of funding from the producers of Kuvan for this trial; not that this should or did influence the findings in any way, shape or form.

Nevertheless there are a number of interesting observations which might require some follow-up from this paper. That for example, a higher baseline level of arginine seemed to quite strongly correlate (r=0.91) with the PLS total raw score (language) as a result of BHsupplementation is a point worth following up, particularly in these days emphasising the identification of best- and non-responders to various interventions for the autisms. The implication being that "only some of the participants were able to significantly change their NO metabolism with the dose of Kuvan used in this study" potentially as a result of this correlate - or at least this studied and known about correlate. An endophenotype eh? Or even a biomarker for intervention response?

Given the body of work already published on BHsupplementation and autism and how BH4 levels might tie into lots of different areas outside of just being a co-factor (see this paper*** open-access) I'd like to see quite a bit more done on this compound and its relations. That it might also overlap with other conditions too - schizophrenia for example**** and other diagnoses***** - is also an important point given the genetic common ground being postulated between quite a few conditions (see here). One also wonders whether that recent vitamin B12-folate supplementation for schizophrenia paper****** by Roffman and colleagues (open-access) might also hint at some involvement of BH4 (more on that paper to come).

To finish, the old Grange Hill intro, including that sausage. Alongside due respect to actor Michael Sheard who played the unfortunate Kendal Ozzel ("he is as clumsy as he is stupid"). Steady on Darth.

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* Frye RE. et al. Metabolic effects of sapropterin treatment in autism spectrum disorder: a preliminary study. Transl Psychiatry. 2013; 3: e237.

** Pacher P. et al. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. 2007; 87: 315-424.

*** Frye RE. et al. Central tetrahydrobiopterin concentration in neurodevelopmental disorders. Front Neurosci. 2010; 4: 52.

**** Richardson MA. et al. Evidence for a tetrahydrobiopterin deficit in schizophrenia. Neuropsychobiology. 2005; 52: 190-201.

***** Coppen A. et al. Depression and tetrahydrobiopterin: the folate connection. J Affect Disord. 1989; 16: 103-107.

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

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ResearchBlogging.org Frye RE, Delatorre R, Taylor HB, Slattery J, Melnyk S, Chowdhury N, & James SJ (2013). Metabolic effects of sapropterin treatment in autism spectrum disorder: a preliminary study. Translational psychiatry, 3 PMID: 23462988