Coenzyme Q10 and autism

The paper by Frederick Crane and colleagues [1] (open-access here) caught my eye recently and their suggestion that when it comes to autism there may be more research to do on coenzyme Q10. Indeed, the old grey-pinkish matter started grinding into action as to whether there may be a wider research literature on CoQ10 with a focus on autism...

A helping hand? @ Wikipedia 

Coenzyme Q10 otherwise known as ubiquinone, has appeared before on this blog for various reasons (see here and see here). Described as a fat soluble vitamin-like substance, there are apparently a few important steps in the production of CoQ10 implicating one to two old friends - aromatic amino acid friends - involving the "synthesis of the benzoquinone structure" from said aromatic friends (tyrosine or phenylalanine) alongside the "synthesis of the isoprene side chain from acetyl-coenzyme A (CoA) via the mevalonate pathway". It's then a case of marrying the two reaction products together to form something which as the name 'co-enzyme' suggests, is pretty important to quite a few enzymatic reactions.

In terms of the functions of CoQ10, well quite a few of them overlap with areas of interest when it comes to autism. The word 'mitochondria' springs up quite a bit and the important role CoQ10 plays in the production of energy or involvement with ATP (adenosine triphosphate) at least. The antioxidant activity that CoQ10 also seems to possess, at least in it's reduced form - ubiquinol - is also something pretty important. Both mitochondrial function and the concept of oxidative stress have surfaced in the autism research literature in recent years (see here and see here).

The Crane paper presents quite a bit of biochemistry pertinent to "a hypothesis that autism is controlled by a coenzyme Q-dependent redox system in the porin channels". Putting aside my reluctance towards grand, over-arching theories about autism (sorry, the autisms) I'll be honest and tell you that I found the reading pretty heavy going on this topic bearing in mind my very limited knowledge on porin channels and all-things when it comes to transportation in and out of cells. I'm not then going to provide some detailed critique of the author's hypothesis aside from mentioning the paper by Freedenfeld and colleagues [2] on the use "of ribose therapy and NADH therapy on children with autism" (NADH being oxidised by coenzyme Q). NADH is something that Crane et al have talked about in other papers too [3].

The wider autism literature on CoQ10 and autism is best described as limited at the moment. I came across the paper by Gvozdjáková and colleagues [4] (open-access here) talking about results from a preliminary open trial of ubiquinol in a small number of children diagnosed with an autism spectrum disorder (ASD). Following an initial daily dose starting at 50mg of "Liquid liposomal ubiquinol" increased to 100mg daily, authors reported on both behaviour and various biochemical measures including CoQ10 (total) and TBARS "the end product of lipid peroxidation in the body". Bearing in mind the study methodology, the authors reported that a: "Beneficial effect of ubiquinol in children with autism has been demonstrated for the first time". That being said, I note that only the 'CoQ10-TOTAL' biochemical measure came out as significantly affected by ubiquinol supplementation (which is kinda what one would expect) and as someone has already [slightly harshly] noted using PubMed Commons "There is no way in which these observations can be interpreted as a "demonstration" of a "beneficial effect".

I do however believe that there may be more to do from a research point of view when it comes to coenzyme Q10 and autism. Thinking back to the Jim Adams double-blind, placebo-controlled trial looking at a vitamin and mineral supplement for autism (see here) I note that their preparation included CoQ10 (see here) among lots of other things. Granted, lots of other nutrients might have been contributory to the effects they noted, but one cannot, at the moment, rule out any specific effect from CoQ10 either. This is something also mentioned in the new-ish paper from Frye & Rossignol [5]. I'm also minded to mention the various discussions about the use of CoQ10 in relation to cases of chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME) too (see here) as per papers like the one from Maes and colleagues [6]. Following my mantra about autism seemingly not being protective against any other condition or state, one might further consider additional research as to whether overlap or similar processes might unite at least some autism and at least some CFS/ME or not?

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[1] Crane FL. et al. Plasma membrane coenzyme Q: evidence for a role in autism. Biologics. 2014 May 29;8:199-205.

[2] Freedenfeld SH. et al. Biochemical Effects of Ribose and NADH Therapy in Children with Autism. Autism Insights. 2011; 3: 3-13.

[3] Löw H. et al. Putting together a plasma membrane NADH oxidase: a tale of three laboratories. Int J Biochem Cell Biol. 2012 Nov;44(11):1834-8.

[4] Gvozdjáková A. et al. Ubiquinol improves symptoms in children with autism. Oxid Med Cell Longev. 2014;2014:798957.

[5] Frye RE. & Rossignol D. Treatments for Biomedical Abnormalities Associated with Autism Spectrum Disorder. Front. Pediatr. 2014. doi: 10.3389/fped.2014.00066

[6] Maes M. et al. Coenzyme Q10 deficiency in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is related to fatigue, autonomic and neurocognitive symptoms and is another risk factor explaining the early mortality in ME/CFS due to cardiovascular disorder. Neuro Endocrinol Lett. 2009;30(4):470-6.

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Crane FL, Löw H, Sun I, Navas P, & Gvozdjáková A (2014). Plasma membrane coenzyme Q: evidence for a role in autism. Biologics : targets & therapy, 8, 199-205 PMID: 24920882

Phenylalanine and schizophrenia: new directions for intervention?

As regular readers might already have noticed, amino acids are a bit of a obsession of mine on this blog. Out of all of them - and there are quite a few - I'm particularly interested in the aromatic amino acids and the their various connections to health and wellbeing. I've talked at length about some of the proposed connections made between amino acids such as tryptophan, tyrosine and phenylalanine to all manner of conditions but specifically with the autism spectrum in mind (see here).

The conversion. Matthews (2007) J Nutr. 137: 15495-15555.

Phenylalanine (or Phe) has been a particular favourite on this blog, not least because of its connection to that most classical 'diet can affect mental health' condition known as Phenylketonuria (PKU). As per other research chatter however, the connection between phenylalanine and PKU might just be the tip of the iceberg (see here). Indeed, today that iceberg just got a little bigger as I discuss the paper by Olaoluwa Okusaga and colleagues* (open-access) and their observations of elevated blood levels of phenylalanine in cases of schizophrenia. Such findings might indeed have some important management consequences as you'll see shortly when it comes to the use of something called BH4.

The Okusaga paper is open-access but a few of the important details:

• Well, one can't say that this was an under-powered study from a participant number point of view, as blood samples from 950 adult participants with a confirmed diagnosis of schizophrenia via the SCID were compared with 1000 asymptomatic controls for levels of phenylalanine and tyrosine.
• Analysis of samples was via HPLC with fluorescence detection, which whilst OK as a separative-detection method is not exactly the gold-standard that is mass spectrometry (MS) or nuclear magnetic resonance (NMR). 
• From the measures of phenylalanine and tyrosine, an estimate of the activity of phenylalanine hydroxylase (PAH) was also calculated and expressed as a phenylalanine: tyrosine ratio**. PAH represents an important step in the conversion of phenylalanine to tyrosine, which then proceeds down a metabolic pathway to eventually end up as dopamine. It's worth pointing out that dopamine has some important research history when it comes to the presentation of schizophrenia or at least, that's the suggestion (see here).
• Results: well bearing in mind some issues with the matching of the two sample groups in terms of age and BMI (a higher BMI in the schizophrenia group bearing in mind that these were not medication-naive participants), the schizophrenia group "had significantly higher Phe (geometric mean difference 1.26 µmol/L; CI 1.18 to 1.36, p<0.0001) and Phe:Tyr ratio (geometric mean difference 1.41; CI 1.33 to 1.48, p<0.0001) compared to healthy controls and this finding persisted after controlling for gender, age, education, and BMI differences between the 2 groups". As a group however, there was no significant differences for the schizophrenia and control groups when it came to measures of tyrosine although "lower levels of Tyr are more common among schizophrenia patients".
• The authors conclude that alongside further, more controlled study with regards to sample collection (including looking at measures of inflammation), there may also be some merit in looking at the potential effects of "Phe-lowering interventions in schizophrenia".

As I mentioned before, Phe-lowering interventions very much includes the use of BH4, but could also mean the rather more invasive use of a low phenylalanine diet (and then tyrosine supplements?) more commonly indicated for cases of PKU. I should point out that this does not mean I am in any way endorsing such a dietary change or pharmacological action at this time as a function of my caveat on this blog about not giving medical or clinical advice. That being said, the research gauntlet has been thrown down by the results of the Okusaga study so I'll be keeping my eyes open for future work in this area. 

There is other evidence suggestive of issues with the availability of BH4 in cases of schizophrenia as per the results from Richardson and colleagues*** which also extended to related schizoaffective disorder too****. Given that BH4 provides an important support service to a variety of enzymes relevant to the metabolism of aromatic amino acids (think tryptophan hydroxylase, TPH, for example), lower levels are probably not all that desirable. This might be particularly important to ensuring phenylalanine does not build up to too higher levels and the effects that can have*****.

Aside from the phenylalanine-lowering interventions call made from the Okusaga study, a few other questions are floating round my mind. So, at what point do phenylalanine levels become elevated in some cases of schizophrenia? I'd assume that as per the quite comprehensive use of the Guthrie test these days, we aren't talking about participants reaching the cut-off points for PKU in early infancy, so when does this issue present itself in cases of schizophrenia and why? I'm also interested in the cognitive effects of [chronic] elevated phenylalanine levels and how this might also map onto similar elevations noted in cases of schizophrenia too. Noting the increasing interest in cognition and schizophrenia (see this paper****** for example) and the growing  importance of cognitive impairment to cases, could the elevated phenylalanine results merely reflect this one facet of schizophrenia?

So you can see that there is a lot more to do in this area. Given also that schizophrenia, like autism, is probably better represented on a spectrum model, the question is also whether hyperphenylalaninemia in relation to cases of schizophrenia might represent one particular part of that schizophrenia spectrum? At least one other study suggests possibly******* (open-access) with quite a novel alternative method for detecting phenylalanine used. A lot more to do in this area methinks.

Music to close. Driftwood by Travis.

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* Okusaga O. et al. Elevated Levels of Plasma Phenylalanine in Schizophrenia: A Guanosine Triphosphate Cyclohydrolase-1 Metabolic Pathway Abnormality? PLoS ONE 2014. 9(1): e85945.

** Matthews DE. An Overview of Phenylalanine and Tyrosine Kinetics in Humans. J. Nutr. 2007; 137: 15495-15555.

*** Richardson MA. et al. Evidence for a tetrahydrobiopterin deficit in schizophrenia. Neuropsychobiology. 2005;52(4):190-201.

**** Richardson MA. et al. Analysis of plasma biopterin levels in psychiatric disorders suggests a common BH4 deficit in schizophrenia and schizoaffective disorder. Neurochem Res. 2007 Jan;32(1):107-13.

***** Pascucci T. et al. Behavioral and neurochemical characterization of new mouse model of hyperphenylalaninemia. PLoS One. 2013 Dec 20;8(12):e84697.

****** Keefe RS. & Harvey PD. Cognitive impairment in schizophrenia. Handb Exp Pharmacol. 2012;(213):11-37.

******* Teraishi T. et al. 13C-phenylalanine breath test detects altered phenylalanine kinetics in schizophrenia patients. Translational Psychiatry 2012; 2: e119.

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Olaoluwa Okusaga, Olesja Muravitskaja, Dietmar Fuchs, Ayesha Ashraf, Sarah Hinman, Ina Giegling, Annette M. Hartmann, Bettina Konte, Marion Friedl, Jason Schiffman, Elliot Hong, Gloria Reeves, & et al (2014). Elevated Levels of Plasma Phenylalanine in Schizophrenia: A Guanosine Triphosphate Cyclohydrolase-1 Metabolic Pathway Abnormality? PLoS ONE, 9 DOI: 10.1371/journal.pone.0085945

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, BH4 supplementation 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 BH4 supplementation 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 BH4 supplementation 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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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

Amino acids and autism in China

Many happy returns @ Paul Whiteley

Questioning Answers is 2 years old today (19th February 2013). Happy Birthday to 'me', or should that be 'it'?

Still a relative newcomer to the blogosphere but still churning out posts on all things autism research and beyond. Just in case you thought that I did actually bake a cake for the occasion, I didn't. But if I had have done (and yes a man can make a cake), it would have looked like the cake shown alongside. So please loyal readers, take an imaginary bite and enjoy.

To task. I've had hold of the short paper by Wen-Jun Tu and colleagues* (open-access) for a few weeks/months but have only now have got round to posting about it. It continues some familiar themes on this blog on (a) the focus on the -omics and application of technologies like mass spectrometry to autism and (b) amino acids revealing some really quite interesting differences in cases of autism vs. not-autism, as they are doing in conditions like schizophrenia and chronic fatigue syndrome also. A bit out of left field but I was also interested to read the paper by Shingyoji et al on plasma amino acid profiles potentially predicting lung cancer too. Wow, these guys get around.

Anyhow. I say it is a short paper but actually the Tu paper is a letter, and although there is relatively little novelty in just looking at amino acid chemistry in autism - what's up and what's down - these days, it does look at autism in quite a different ethnic population (Chinese) compared to quite a lot of the other papers in this area.

Indeed China, as well as emerging as a world superpower albeit with some peculiarities, is also starting to put quite a bit more effort into autism as per papers like this one from McCabe** with the very interesting title: Bamboo shoots after the rain... (hence the cute picture of the baby panda shown below looking so inquiring).

The net findings reported by Tu and colleagues reflect a few things:

• Based on quite a small participant group of children diagnosed with DSM-IV autism (n=20) compared with asymptomatic controls (n=20), there were some very distinguishing plasma amino acid results found.
• Tandem mass spectrometry was the main analytical method for determining amino acids complemented by immunoassay for detecting circulating neurotransmitters such as plasma dopamine.
• Levels of some amino acids were significantly elevated (lysine, glutamate - glutamic acid and homocysteine); others were depressed (tryptophan, tyrosine, glutamine) in the autism group compared with controls.



Ailuropoda melanoleuca @ Wikipedia  

• When it came to the level of significance, the biggest group differences were in the elevated levels of leucine (p=0.000 apparently), higher homocysteine (same p-value again) and elevated plasma dopamine (ditto on the p-value).

Of course I don't really need to say too much about these findings that have not already been said. Glutamate and glutamine are already on the autism research radar for quite a few reasons; same goes for homocysteine and it's link into things like methylation and the folate metabolic pathway. Tryptophan is a potentially important one bearing in mind its metabolism into things like melatonin among other things. Leucine? Well think branched chain amino acids and that rather interesting study by Novarino and colleagues*** (see this post) in relation to autism, and one cannot help but wonder if there might be some overlap.

Interestingly, one of my papers on the gluten- and casein-free (GFCF) diet (open-access) gets a mention in the text, with the authors seemingly worried about how their results might be further worsened if and when a GFCF diet is instigated following on from some similar suggestion by Arnold and colleagues****. Indeed this is an issue which has more recently been discussed in the meta-analysis by Sharp and colleagues*****. I'm minded to respond that rather than worry about how things could 'get any worse', a closer inspection of why they have the results they have and indeed, dealing with what they actually found, might be a good starting point, accepting the study by Jim Adams and colleagues (see this post) on what might be achieved by micronutrient supplementation. That and the fact that they reference gastrointestinal (GI) issues as potentially being involved with their results which begs the question: why not try and 'sort out' the GI issues or least one of them?

From the ethnicity point of view, the Tu study is an important one given the overlap between their observations and what has been found in other more Western populations allowing for the genetic, environmental and epigenetic differences that one might envisage and the eternal question of whether autism is presented the same worldwide. Such research actually makes a really good case for doing a little bit more cross-collaborative work among different peoples in different countries with autism, based not just on genetics as seems to have been the case so far, but also more functional biochemistry too.

Because this blog is the big 2 now, and given the association between this age and the word 'terrible', a song which I always thought best encapuslates a toddler tantrum from Nirvana (sorry about the language). Toodle pip.

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* Tu WJ. et al. Application of LC-MS/MS analysis of plasma amino acids profiles in children with autism. J Clin Biochem Nutr. 2012; 51: 248-249.

** McCabe H. Bamboo shoots after the rain: Development and challenges of autism intervention in China. Autism. November 2012.

*** Novarino G. et al. Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy. Science. 2012; 338: 394-397.

**** Arnold GL. et al. Plasma amino acids profiles in children with autism: potential risk of nutritional deficiencies. J Autism Dev Disord. 2003; 33: 449-454.

***** Sharp WG. et al. Feeding Problems and Nutrient Intake in Children with Autism Spectrum Disorders: A Meta-analysis and Comprehensive Review of the Literature. J Autism Dev Disord. February 2013.

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Tu WJ, Chen H, & He J (2012). Application of LC-MS/MS analysis of plasma amino acids profiles in children with autism. Journal of clinical biochemistry and nutrition, 51 (3), 248-9 PMID: 23170055

Stop that phenylalanine now!

I'm going slightly off-piste with this post not strictly related to autism; however remaining true to my interest in all things amino acids, and in particular one of those most interesting aromatic amino acids, phenylalanine.

Phenylalanine @ Wikipedia

A few months back Chemistry World carried a very interesting article by Jon Evans* on how the amino acid phenylalanine might very well have the capacity to form amyloid-like fibrils classically related to conditions like Alzheimers disease. The article was based on this study by Adler-Abramovich and colleagues** which reported on a few pretty important observations.

I've done amyloid or rather amyloid precursor protein (in relation to autism) on this blog before (see here). Fibrils as their name suggests, are fibre-like structures. Without trying to plagiarise the article or study, a few points are worth noting:

• The starting point was the metabolic condition phenylketonuria (PKU), probably the most famous of the inborn errors of metabolism.
• PKU... the problems with metabolising phenylalanine as a result of issues with phenylalanine hydroxylase leads to a build up of the amino acid which has some particularly nasty effects on the developing body and brain. Said phenylalanine levels normally controlled by lifetime dietary restriction of phenylalanine but also potentially another intervention (BH4).
• Adler-Abramovich et al observed that phenylalanine in solution tended to 'clump' together forming something that looked like amyloid-like fibrils. Further when such phenylalanine fibrils were added to cell lines, the fibrils showed some degree of toxicity. Even further, rabbits injected with said fibrils started to generate antibodies against them. Finally, after imaging the phenylalanine fibrils, there was a match between what they saw in the laboratory and what they saw in an engineered mouse model of PKU and indeed in real people diagnosed with PKU.
• Ipso facto: phenylalanine can form amyloid-like fibrils and such fibrils might account for the tissue damage observed in PKU.

I admit to being really quite excited about this work. Modern science knows quite a bit about PKU following the very astute observations made by Dr. Asbjørn Følling. One area however that has always required a little more study was exactly how the build-up of phenylalanine caused the problems that it does; maybe part of that question has been answered with this work.

My mind also goes back to those other aromatic amino acids like tryptophan and tyrosine and whether similar fibrils could be formed from these compounds. The answer, according to the published scientific literature so far, is a very possible yes; as per studies like this one from Cecchini and colleagues*** although quite a lot of the investigations in this area goes well above my state of knowledge.

So, once again amino acids do their stuff. It makes you wonder whether Alzheimer's disease, at least some cases, might also reflect issues with phenylalanine. Logically also whether interventions like a low phenylalanine diet or even BH4 supplementation (see here) might reflect possible areas of intervention requiring much further study?

To finish, I'm sure many of you had the same 'could try harder' reports from school as I did when I was a kid. But to get something like this.... from your Dad?

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* Evans J. Anti-social amino acids gang up. Chemistry World. August 2012.

** Adler-Abramovich L. et al. Phenylalanine assembly into toxic fibrils suggests amyloid etiology in phenylketonuria. Nat Chem Biol. 8: 701-706.

*** Cecchini P. et al. The role of tryptophan in protein fibrillogenesis: relevance of Trp7 and Trp14 to the amyloidogenic properties of myoglobin. PEDS. 2012; 25: 199-203.

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Adler-Abramovich L, Vaks L, Carny O, Trudler D, Magno A, Caflisch A, Frenkel D, & Gazit E (2012). Phenylalanine assembly into toxic fibrils suggests amyloid etiology in phenylketonuria. Nature chemical biology PMID: 22706200