Thursday 1 November 2012

More sulphate and autism research (at last)

I've mentioned my interest in sulphation (sulfation) and autism in previous posts and how it always seemed like a real shame that the work of Rosemary Waring and others was never really followed up with any great enthusiasm.

To those who might not know about the whole autism-sulphate story, it goes something like this: higher levels of urinary sulphate (and related metabolites) detected accompanied by increased protein excretion in autism compared to controls. Plasma levels of sulphate (sulfate) by contrast tended to be reduced. Ergo, lots of dumping of sulphate in urine and reduced circulating sulphation capacity with some potentially important implications for mucoprotein sulphation and indeed the metabolism of certain drugs.

Enter then a study by Francis Bowling and colleagues* which (thankfully) did look at sulphation with autism in mind and indeed some interesting observations based on genetic sequence variants to a gene involved with renal sulphate transportation, NaS1, disruption to which might have some important implications**. I might add that I think this latest research is an extension to that presented on other occasions by the authors as per this abstract from the 2010 Australian Physiological Society meeting.

The details:

  • Based on a sample of 23 people diagnosed with an autism spectrum disorder (ASD) meeting ADOS criteria, several measures were taken or calculated including: (i) levels of creatinine-adjusted sulphate in plasma and urine, (ii) the calculated fractional excretion index (FEI) of sulphate (based on urine and plasma levels) and (iii) the frequency of two separate genetic point mutations affecting NaS1 function based on analysis of the NaS1 gene (SLC13A1) located on an interesting chromosome (7) for autism.
  • Results: the normal FEI sulphate values based on other data, was estimated as falling between the range 0.17  - 0.34. Eleven participants presented with elevated FEI sulphate (greater than 0.35). Importantly, no specific clinical features seemed to correlate with FEI sulphate (so things like comorbid gastrointestinal symptoms, self-injurious behaviour, seizures, etc.). That being said they did pick up one child with nephrolithiasis (kidney stones) "due to cystinuria" and another child with "probable mitochondrial disruption".
  • Genetic screening for the two variants - one of which (R12X) leads to a complete loss of sulfate transport function - was undertaken and lo and behold, mutation in one or both of the genes seemed to be linked to those elevated FEI sulphate results. Indeed an individual with the highest FEI sulphate reading (0.50) carried both mutations whilst those with no mutation generally showed the lowest FEI sulphate readings.

Quite rightly the authors are pretty buoyed by their results, concluding that their data "may explain the abnormally low sulphonation capacity previously reported in some autistic individuals". I have to say that looking at their data on SLC13A1 genotypes (Table 2 and Figure 1b if you are looking at the full-text), there is a very definite pattern emerging based on variants which is hard to question, bearing in mind the relatively small participant group. Another potential inborn error of metabolism linked to autism?

I suppose the next question is what can be done about this issue and if left as is, what is the long term prognosis of poor sulphate transporter function. With no medical advice given or intended, previously I've talked about efforts to supplement with things like MSM with autism and other conditions in mind, and whether such regimes will actually produce tangible effects on both the supply of sulphate and its usage. I'm going to have do a little bit more reading on the function of NaS1 before commenting any further it has to be said, given that just pumping sulphate in might not necessarily be the best strategy here. I'm also reminded of the emerging work being done on oxalates and autism as also potentially being relevant here.

The Bowling paper is an important one for quite a few reasons outside of just reinvigorating research into sulphation and autism. The results reiterate: (a) that universal genetic (and environmental) findings across all autism(s) are likely to be very few and far between, if any at all, and confirms the move towards studying endophenotypes, and (b) how marrying the disciplines of genetics and biochemistry together using something like a more systems-biology approach, might yet yield some interesting observations regarding the condition(s). Oh and again, that inborn errors of metabolism might actually be quite important to some cases of autism.


* Bowling FG. et al. Plasma and urinary sulfate determination in a cohort with autism. Biochem Genet. October 2012.

** Lee S. et al. Disruption of NaS1 sulfate transport function in mice leads to enhanced acetaminophen-induced hepatotoxicity. Hepatology. 2006; 43: 1241-1217.

---------- Bowling, F., Heussler, H., McWhinney, A., & Dawson, P. (2012). Plasma and Urinary Sulfate Determination in a Cohort with Autism Biochemical Genetics DOI: 10.1007/s10528-012-9550-0

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