Treatable inborn errors of metabolism in cases of autism

Happy New Year! Καλή Χρονιά (in Greek).

Welcome back to Questioning Answers in 2014. Let's continue our journey across the autism research landscape.

Party time, excellent @ Wikipedia 

Holidays. Whilst never regretting the opportunity to go on holiday/vacation, I am the type of person who has a strong desire to stay connected to the (research) world. I wouldn't necessarily say that I'm a product of the age of social media, more of late convert who ran enthusiastically towards the light.

A few months back however, I missed something important. It was the chance to peer review the paper by Martha Spilioti and colleagues* (open-access here) and some very interesting information following the screening of 187 children presenting with an autism spectrum disorder (ASD) for the signs and symptoms of various inborn errors of metabolism.

Actually it wasn't all my fault that I didn't accept this review. Granted I didn't access my email on holiday as often as I do when working, but more than that, the publishing journal seemed to expect quite a prompt reply on whether or not I was willing to review. I didn't reply in time, so I missed out. That's what happens in August, the holiday month, the time the kids are off school, y'know, the summer (at least here in my part of the World). No mind, I am happy to see that the Spilioti paper has seen the light of scientific day and hence become fodder for this blog.

Anyhow, inborn errors of metabolism. I've talked about them before in relation to autism (see here and here) and how at least some of them might actually be pretty revealing when it comes to at least some autism (as per those interesting findings in relation to the branched-chain amino acids). More recently I've been reading the paper by Stockler-Ipsiroglu and colleagues** talking about outcomes with regards to a diagnosis of guanidinoacetate methyltransferase (GAMT) deficiency which included some chatter on autistic behaviours (or should that just be autism?) as being involved.

The Spilioti paper evaluated 187 Greek children diagnosed with an autism spectrum condition on the basis of quite a few parameters. We're told that alongside taking quite a bit of information about family history and dietary habits, quite a few laboratory investigations were initiated, too numerous to all mention here. I have to say I was particularly impressed by the authors talking about a glucose loading test (with mitochondrial issues in mind) alongside serum and urine amino and organic acid screens; even looking at carnitine levels. The Greeks seem to be taking a lead in this 'look-see' approach when it comes to the autisms.

Their results: well, only a small proportion of their cohort turned up an inborn error of metabolism. Two participants with Lesch-Nyhan syndrome linked to the overproduction of uric acid (see here for a post of impulsivity and uric acid). Two further participants were identified with succinic semialdehyde dehydrogenase (SSADH) deficiency (which is a very, very rare condition indeed). One child was also diagnosed with PKU (see here).

Perhaps of more interest were the findings related to that glucose loading test and the suggestion that there was an increase in serum beta hydroxybutyrate (β-OH-b) in around 8% of participants. Although not an expert on this particular metabolite, I understand that elevations can indicate one or several possible scenarios (see here). The authors elaborate that some of those with elevations in β-OH-b also "manifested exacerbation of symptoms during high carbohydrate intake" which brings in an interesting dietary element. Indeed, further when a ketogenic diet (high fat, low carbohydrate intake) was initiated in [some of] those with increased β-OH-b, some interesting behavioural changes were reported; one participant was reported to show "remarkable improvement" in his CARS scores, which was followed by a cessation of medication and attendance at a "public elementary school without clinical problems". Yes, I know this was a case series (an optimal outcomer?) and not a controlled trial of the ketogenic diet where increased serum β-OH-b levels have been identified. Perhaps this is the next experimental step?

Other interesting findings. Well, yes. Around 7% of participants also showed elevated levels of urinary 3-hydroxyisovaleric acid (3-OH-IVA). Assuming that these child participants were not smokers (see here***) we are also told that none of these 7% were also "undergoing valproate intervention" which is another potential way of elevating 3-OH-IVA (see here****). And when it came to intervening with biotin as a function of the connection between 3-OH-IVA and biotin*****, authors again reported some interesting outcomes leading to "clear therapeutic benefit" noted in CARS scores for some. Please note I'm not suggesting anything based on these findings as per my caveat about no medical or clinical advice given or intended.

There is a lot more, data-wise, in the Spilioti paper which I've not been able to include in this post. As per the growing literature on autism perhaps being better defined as the 'autisms' I would echo the sentiments of Spilioti and colleagues when they say: "further consideration be given to the selected analysis of IEM [inborn errors of metabolism] in ASD". That dietary and nutritional supplementation might also be a road to improvement in the presentation of symptoms for some on the spectrum with identified metabolic parameters is also a very important consideration too.

Some music to close, and for those of who watched the New Year festivities from the comfort of your own home like I did to the tune of offspring chatter of 'can I stay up late please?', Alfie and Gary sing a classic...

----------

* Spilioti M. et al. Evidence for Treatable Inborn Errors of Metabolism in a Cohort of 187 Greek Patients with Autism Spectrum Disorder (ASD). Front. Hum. Neurosci. 2013; 7:858. doi: 10.3389/fnhum.2013.00858

** Stockler-Ipsiroglu S. et al. Guanidinoacetate methyltransferase (GAMT) deficiency: Outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring. Mol Genet Metab. 2013 Nov 7. pii: S1096-7192(13)00366-1. doi: 10.1016/j.ymgme.2013.10.018.

*** Sealey WM. et al. Smoking accelerates biotin catabolism in women. Am J Clin Nutr. 2004 Oct;80(4):932-5.

**** Mock DM. et al. Disturbances in biotin metabolism in children undergoing long-term anticonvulsant therapy. J Pediatr Gastroenterol Nutr. 1998 Mar;26(3):245-50.

***** Mock NI. et al. Increased urinary excretion of 3-hydroxyisovaleric acid and decreased urinary excretion of biotin are sensitive early indicators of decreased biotin status in experimental biotin deficiency. Am J Clin Nutr. 1997; 65: 951-958.

----------

Martha Spilioti, Athanasios Evangeliou, Despoina Tramma, Zoe Theodoridou, Spyridon Metaxas, Eleni Michailidi, Eleni Bonti, Helen Frysira, Katerina Haidopoulou, Despoina Asprangathou, Aggelos Tsalkidis, Panagiotis Kardaras, Ron Wevers, Cornelis Jakobs, & Michael Gibson (2013). Evidence for Treatable Inborn Errors of Metabolism in a Cohort of 187 Greek Patients with Autism Spectrum Disorder (ASD) Front. Hum. Neurosci.