Friday, 1 February 2013

Acyl-carnitine profiles and autism

No doubt alongside quite a few others, I was interested to read the latest paper from Richard Frye and colleagues* (open-access) discussing the potential links between an animal model of autism spectrum disorder (ASD) and real-world ASD in a particular cohort of participants.

This is not the first time that I've talked about (a) the work of Dr Frye - as per my [don't panic] post on folate receptor autoantibodies in cases of autism (see here) and (b) some of the difficulties attached to translating rat/mouse model findings in autism research into 'real-world' findings (see here). Indeed this last point might also tie into my recent musings on the use of LPS in autism research (see here).
Daddy o' microbiology @ Wikipedia  

My interest in the latest Frye paper was further piqued upon realising that Derrick MacFabe was also part of the authorship team given his insightful work on how administration of propionic acid - a short chain fatty acid - to rodents might provide some interesting perspectives overlapping with various findings noted in cases of autism (see my previous post here).

The Frye paper is open-access and available to all but here are a few points worth mentioning:

  • Based on the animal model work looking at propionic acid (PPA) infusions and some of the collected effects (presentation of autism-type behaviours**, mitochondrial issues***, abnormal measures of glutathione, etc.), the aim of the current study was to map out whether some of the observations in the PPA rodent model were also present in real-life autism.
  • Based on a clinic-based sample of children with autism (N=326), acyl-carnitine panels were conducted on about two-thirds of participants (n=213).
  • Acyl-carnitines, as their name suggests, are related to carnitine which has previously been tied back to autism (see here) and represent a number of different compounds - complexes of carnitine and various fatty acids - involved in the transport of fatty acids into the mitochondrial matrix.
  • The previous PPA rodent model indicated some disturbance in the amount of various acyl-carnitines, particularly with regards to short- and long-chain fatty acids (not so much in the medium-chain fatty acids) reflective of some mitochondrial dysfunction.
  • So the authors looked at short-, medium- and long-chain acyl-carnitines in their autism cohort to see if there were any overlaps compared with the PPA treated animals.
  • Results: 35% of the autism cohort showed "an increase in three or more acyl-carnitines when initially measured". When further testing were conducted on some of these participants showing elevation, this figure was revised to 17% of the cohort who "demonstrated consistent elevations in short-chain and long-chain, but not medium-chain, acyl-carnitines". You'll note the similarity with PPA animal model in terms of the short- and long-chain acyl-carnitines.
  • Furthermore, four participants were also examined with regards to glutathione and oxidative stress markers. As per the quite consistent literature on things like total- and free-reduced glutathione (see this post), compared with controls, there were some familiar trends emerging.

And relax.

There is a lot to take in from this paper both in the protocol and testing undertaken and the possible interpretation of findings. A quote best sums up the results: "This study has demonstrated that ~17% of children with ASD manifest biomarkers of abnormal mitochondrial fatty-acid metabolism that parallel similar biomarkers in the PPA rodent model of ASD".

As perhaps expected, there has been some press attention following the publication of this paper. The headline: Researchers discover link between certain types of autism and gut bacteria has been a common one, reflective of the fact that when it comes to the production of PPA outside of injecting the stuff directly into the rodent brain, the gut and in particular, certain types of gut bacteria, have been suggested as a route to PPA production in cases of autism. Indeed, I'm taken back to the findings by Wang and colleagues from Oz (see this post) on levels of fecal short chain fatty acids (SCFAs) in their cohort of children with autism which included propionic acid (propionate). I'm also reliably informed that there is 'more to come' from the Australian research group in the coming months.

There are a few final aspects to the Frye study which I should have mentioned earlier. This includes the notion that "it is very likely that MD [mitochondrial dysfunction] is acquired" given that in the most part, both nuclear and mitochondrial DNA examinations in their cohort were negative for anything that might genetically account for the results. I'll be coming to DNA and mitochondrial issues in a subsequent 'training' post scheduled quite soon but one can perhaps see how this might strengthen any argument of disruptions to gut bacteria/microflora facilitating the production of elevated PPA onwards to disrupting acyl-carnitine chemistry.

Additionally there is the implication based on the PPA rodent model that affecting PPA production could be a potential therapeutic route for some cases of autism at some point. I don't really want to go too far into the hows and whys of this suggestion at the current time given the current lack of evidence for any effect. Aside that is, from drawing your attention to a related field of inquiry into how disrupting PPA-producing gut bacteria might have some important implications for those suffering from conditions like propionic acidaemia****.

I'm not going to get too carried away with the Frye results as they stand. As per my previous post on PPA, there is still a bit of a stretch from injecting rodent brains with PPA and recording outcomes to suggesting that gut bacteria will be able to produce enough PPA so as to exert a similar effect in cases of autism. At least one group is asking the same question***** (open-access). That being said, I am still interested in the details of this study and how the authors have at least tried to model animal findings into real-life autism. Indeed how we really should be putting a lot more research effort into looking at mitochondria and autism as we potentially also should gut bacteria and autism.

A song to finish... something mellow yet catchy.... Lovefool by the Cardigans.

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* Frye RE. et al. Unique acyl-carnitine profiles are potential biomarkers for acquired mitochondrial disease in autism spectrum disorder. Translational Psychiatry. 2013; 3: e220.

** MacFabe DF. et al. Effects of the enteric bacterial metabolic product propionic acid on object-directed behavior, social behavior, cognition, and neuroinflammation in adolescent rats: Relevance to autism spectrum disorder. Behav Brain Res. 2011; 217: 47-54.

*** Thomas RH. et al. Altered brain phospholipid and acylcarnitine profiles in propionic acid infused rodents: further development of a potential model of autism spectrum disorders. J Neurochem. 2010; 113: 515-529.

**** Mellon AF. et al. Effect of oral antibiotics on intestinal production of propionic acid. Arch Dis Child 2000; 82: 169-172.

***** El-Ansary AK. et al. Comparative study on the protective effect of carnosine and carnitine against pro-inflammatory/pro-oxidant effects of clindamycin and propionic acid administrations to hamsters. African Journal of Microbiology Research. 2013; 7: 103-114.

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ResearchBlogging.org Frye RE, Melnyk S, & Macfabe DF (2013). Unique acyl-carnitine profiles are potential biomarkers for acquired mitochondrial disease in autism spectrum disorder. Translational psychiatry, 3 PMID: 23340503