Sunday, 8 July 2012

Inborn errors of creatine metabolism and autism

I might have said it before but inborn errors of metabolism represent a particularly interesting group of conditions relevant to this blog. I have tended to focus on one particular metabolic condition, phenylketonuria (PKU), simply because it represents the archetypal 'diet-can-affect-behaviour-and-cognition' condition. That and the fact that PKU has been known to overlap with certain cases of autism.

In this post I turn my attention to another group of metabolic disorders related to creatine and its biosynthesis and metabolism. The papers that brought me to this post are this one from Chilosi and colleagues* (full-text) and this one from Kurosawa and colleagues** (full-text).

In brief, Chilosi et al describe how supplementation with the amino acid L-arginine (one of the precursor compounds used in the formation of creatine) might be able to positively affect some of the symptoms associated with creatine transporter deficiency. Kurosawa et al reported results following supplementation with cyclocreatine (CincY) in a mouse model of creatine transporter deficiency. I might add that I am not endorsing these or any other course of action without the proper medical advice, merely describing what was published.

Reversing a little, creatine (not to be confused with a relation, creatinine, something else that has cropped up on this blog - here and here) is probably best described as an energy supplier. A fusion of the amino acids L-arginine and glycine form guanidinoacetate which then goes on to creatine. Creatine continues onwards on to prop up production of ATP. It's obviously a little more complicated than just that but I'm not here to deliver a biochemistry lesson.

Inborn errors of creatine metabolism normally fall into one of a few categories best described here. You'll note that one of the conditions is something called X-linked SLC6A8 creatine-transporter deficiency.  Just keep that in mind for now; that and the words 'autistic-like' with reference to the behavioural presentation.

So what about with autism in mind:

  • Well, let just say that inborn errors of creatine metabolism are probably not going to be very common in autism as per this review by Schiff and colleagues*** (full-text) and this paper by a familiar name, Wang and colleagues**** (of SCFAs fame). That being said, I don't know if screening for creatine metabolism issues in cases of autism is widespread or not.
  • Bearing in mind the important energy function of creatine, in turns out that getting creatine into cells via the SLC6A8 gene is quite prevalent in certain areas of the body particularly the brain. Indeed there is some suggestion that moving from monkeys to humans might have had a lot to do with this and another gene and their transporting ability as per this study by Pfefferle and colleagues***** (full-text). With all this creatine floating around the grey stuff (well, the pink-red stuff), it is perhaps not surprising that a few imaging studies have looked at brain creatine distribution in cases of autism. Very much like the use of creatinine as a ratio marker for quantifying urinary metabolites, so creatine levels serve a similar function when it comes to the use of 1H magnetic resonance (MR) spectroscopy to quantify various brain metabolites. Much also like the suggestion of issues with the use of the ratio marker creatinine (see here) in autism so brain creatine levels also seem to be suggestive of certain 'findings' in various brain areas (see here, here and here).
  • Remember SLC6A8 and the 'X-linked' issue? Well, there has been some interesting research done there too with autism in mind (here, here and here). X-linked refers to the chromosomal make-up of boys and girls, such that girls have two X chromosomes (XX) and boys have two distinct chromosomes (XY). I should also make mention other conditions such as Klinefelter's syndrome where an extra X chromosome is present. The male bias noted in autism has led some people to speculate on some role for the X chromosome in relation to the condition, as detailed in this paper by Marco & Skuse****** (full-text). 

There are some interesting points to take from this collected research on creatine in relation to autism. Probably first and foremost is the further evidence for autism being a very complicated condition with seemingly lots of paths to the presentation of behaviours gathered under the autism label. I know many people won't find any new revelations in this statement but issues with creatine metabolism is a good example.

Second is a reiteration of the importance of the inborn errors of metabolism to concepts like autism. OK so these conditions are likely not going to be universal to all people with autism (as far as we know); but for a minority they might be, and as per the PKU connection and recent Chilosi / Kurosawa findings, there may very well be interventions which might impact upon behavioural presentation.

Finally, screening. I could be here all day reciting what screening 'could' be undertaken when a diagnosis of autism is received. I won't aside from mentioning things related to SPAD, PFIES, coeliac disease, inflammatory markers, antioxidant markers, iron levels, zinc levelsetc, etc. Assuming learning disability is also present alongside the presentation of autism, screening for errors in creatine metabolism might also be a possible addition to that list.


* Chilosi A. et alNeuropsychological profile and clinical effects of arginine treatment in children with creatine transport deficiency. Orphanet Journal of Rare Diseases. June 2012.
DOI: 10.1186/1750-1172-7-43

** Kurosawa Y. et al. Cyclocreatine treatment improves cognition in mice with creatine transporter deficiency. The Journal of Clinical Investigation. July 2012.
DOI: 10.1172/JCI59373

*** Schiff M. et alShould metabolic diseases be systematically screened in nonsyndromic autism spectrum disorders? PLoS ONE. 2011; 6: e21932.

**** Wang L. et al. Is there a role for routinely screening children with autism spectrum disorder for creatine deficiency syndrome? Autism Research. 2010; 3: 268-272.

***** Pfefferle AD. et al. Comparative expression analysis of the phosphocreatine circuit in extant primates: Implications for human brain evolution. Journal of Human Evolution. 2011; 60: 205-212.

****** Marco EJ. & Skuse DH. Autism-lessons from the X chromosome. Social Cognitive & Affective Neuroscience. 2006; 1: 183-193.


  1. Interesting subject.

    A year or two back a genetics group at our local research hospital told us that our twins daughters had a creatine transporter deficiency. The twins had this fun habit of having occasional but non-consistent spikes of creatine in their urine. But when this group when looking for mutations around the transporter gene they couldn't find anything. And, of course, our insurance didn't want to pay for the magnetic resonance spectroscopy (MRS) that is the definitive test for a transporter deficiency.

    The diagnosis was ruled out after I pointed out a study (Arias, Angela et al. 2007 that showed that the amount of creatine in urine is highly dependent on diet. (The twins eat a lot of foods that are high in creatine).

    The moral of the story is that it is easy to get false positives from the standard urine screening tests for the transporter deficiency.

    Also, that little bit about the cyclocreatine with the transporter deficiency is actually a pretty huge deal. The other disorders of creatine metabolism can be correct, in part, by supplementing with the various precursors of creatine. But there wasn't a way of correcting the lack of creatine in the brain caused by the transporter deficiency because creatine can't cross the blood brain barrier (see below *). The fact that is might be possible to get a form of creatine past the blood brain barrier and basically feed the brain properly is a big thing.

    It almost makes me wish my girls did have a transporter deficiency and not some other idiopathic form of autism.

    * The brain creates its own creatine from the precursors and the transport gene is actually involved in the synthesis of creatine inside the brain. So supplementing with the precursors doesn't help create more creatine inside the brain.

  2. Thanks MJ.

    I remember you mentioned about the creatine issue in your daughters previously.

    The whole area of creatine deficiency/transport is quite an untapped area for lots of different reasons. I too am very interested in the application of cyclocreatine particularly whether there may other knock-on effects for example, in relation to ATP production.

  3. hi i have a little girl who is being tested for mitochondrial disorders, she is globally developementally delayed, had a blood screening done which showed elevated proline, valine and leucine and lactate. fast forward 18 months of testing and we are still none the wiser and have no diagnoses but more recently she has been tested for SLC6A8 CTD, there were levels of creatine in her urine of 1568, her mri was clear thankfully but we are waiting on results of the gene test. She is doing well tires easily, gets physio and speech therapy, at the moment is on no supplements, she is on peadiatric seravit to compliment her diet and movicol daily for chronic constipation. We would so love an answer as to what is wrong with our little girl. Unfortunately the testing is very slow and tedious. She is under assessment for Autism also.

  4. Many thanks for the comment carava. I wish you and your daughter well.

  5. Thanks for this informative blog post. My 4 year old son has Creatine Transporter Deficiency and is not on the spectrum. I know my local Autism Treatment Network has screened all their clients (urine) and no cases of Creatine Transporter Deficiency turned up.

    We supplemented my son with l-arginine and l-glycine for over 2 years with no creatine uptake in the brain (as confirmed by MRS).

    Carry on the great work!

  6. Thanks for the comment doggles.

    Whilst not being surprised that no cases of CTD were detected in those with autism, it is heartening to hear that at least such conditions are being screened for.