Friday, 22 April 2011

PKU: Food can affect mental health

Despite the seemingly daily helping of new research and opinion suggesting that what we eat can influence our mental as well as physical health, there are still doubters. I have to say that I don't generally mind doubters. As long as the debate is polite and cordial and does not descend into mud-slinging, doubters sometimes bring a new perspective to an issue/problem/debate which might otherwise not be thought about or raised.

In the case of diet affecting mental health we have however a prototypical condition in Phenylketonuria (PKU). A condition which places the doubters in a bit of a quandry because PKU is a very, very widely accepted condition and is routinely screened for via the Guthrie test. Diet can very much affect mental health (at least in PKU).

For those really interested in the story of PKU, there is an excellent historical piece here. I will apologise in advance for some of the terminology used which is perhaps reflective of a different era of political correctness. For those like me, who prefer the Mr Men version it goes something like this.

Many years ago, a Doctor was presented with 2 children with developmental problems who had wee that 'smelled' a little bit funny. He looked in the patients' urine samples and found an interesting compound called phenylpyruvic acid using the most basic chemistry kit compared to today's high-spec methods. He realised that said toxic compound was related to the amino-acid phenylalanine and hey presto, one of the first documented inborn errors of metabolism is discovered, laying the foundation to saving and improving thousands of lives by a simple dietary modification. Yes sir, Dr Folling was a quite astonishing man.

Over the years PKU has recieved a lot of research interest from lots of different perspectives. I have an obvious interest from the (comorbidity) autism research side of things but also because of the dietary element integral to PKU. Indeed, the traditional treatment for PKU comprising of a low phenylalanine diet and tyrosine supplements is being slightly overshadowed by a few newer developments in the PKU intervention field which have caught my eye.

One such intervention is the use of tetrahydrobiopterin or BH4 or sapropterin. BH4 is an interesting (and quite expensive!) compound. BH4 is quite good at mopping up phenylalanine - hence the problems you get when you have BH4 deficiency. Would you believe me if I said that it might show some promise as a pharmacotherapy for certain aspects of autism also?

Well there is this paper which suggested that in a quite small participant group, levels of endogenous BH4 might be slightly reduced in some cases of autism. By the same author group (including Christopher Gillberg) supplementation with BH4 also showed some initial promise in an even smaller participant group, alleviating certain core symptoms in some children with autism. BH4 has also cleared the hurdle of the double-blind, placebo-controlled cross-over methodology to show some effect and is undergoing other trials at the moment.

So why might a compound initially used for PKU work for some cases of autism? The simple answer is I don't know. Nobody does at the moment. Outside of again mopping up excess phenylalanine, there might be some other clues to illuminate our way.

I was involved (very, very peripherally) in writing this paper some time ago on tryptophan metabolism and autism. It is not a peer-reviewed paper per se before you ask, but rather an information piece. The crux of the paper is that the amino acid tryptophan and its various manifestations seems to be important to some cases of autism.

The interest is specifically in one enzyme involved in the tryptophan pathway called tryptophan hydroxylase (TPH) (actually there are two known TPH isoforms). TPH has already popped up on the radar of autism a few times (here for example) but nothing too significant has thus far been noted. TPH is interesting because in order to do its enzymatic duties coverting tryptophan to 5-hydroxytryptophan (5-HTP), the precursor of serotonin, it needs BH4 as well as iron (as a cofactor). It's a sort of "all hold hands" (TPH, iron, BH4, etc) to make the reaction work.

BH4 as well as iron? Mmm, I wonder. Well we know that iron / ferritin levels are sometimes aberrant in autism; this paper from Latif and colleagues from a few years back told us that, despite the fact that it is still not routinely screened for. Hence, in some cases iron as a cofactor might be in short supply. Coupled with lower levels of BH4, the possibility exists that TPH might not be able to do its job as effectively as it should in that vital step from tryptophan to serotonin.

There is a degree of speculation in this entry and whilst I would love to take credit for working this out, I can't (standing on the shoulders of giants and all that). I don't think we will ever quite be able to put PKU and autism 'together' given the differences in presentation, possible aetiologies, etc. I would however like to think that within autisms (note the 's') there might be one small phenotypic group which share enough overlapping biochemistry with PKU so as to perhaps benefit from things like BH4 and provide further answers to the role that diet plays outside of just physical health.