I’m going to be quite frank in this post on the tripeptide glutathione and suggest that the evidence is starting to point to a real issue with glutathione in quite a few cases of autism spectrum disorder (ASD). What this means for autism in terms of symptom presentation and short- and long-term physical health is still however the source of some speculation.
OK, let’s start from the beginning. Glutathione is an antioxidant. Imagine if you will a constant balancing act on-going between oxidation and antioxidation in your body. We need oxidation for lots of different biochemical processes. But as with everything in life, an excess (of oxidation) potentially leads to a few not so nice things, such as oxidative stress and an excess of free radicals; a scenario implicated in all manner of diseases and conditions.
The marvellous machine that is the human body has a system of checks and balances to help ward off any unfortunate biochemical consequences of oxidative stress; among them a range of antioxidant mechanisms including those derived from our diet such as important compounds like vitamin C and vitamin E. Glutathione is also a potent part of that protective antioxidant mechanism.
Indeed, amongst other things, one of the most important functions for glutathione is its antioxidant capability and the links being forged between low levels of glutathione and oxidative stress. So, the reduced form of glutathione is basically the active, able to “grab a free radical” version of glutathione and should be present in the greatest proportion when compared with the oxidized form, the “I already have a free radical” form (glutathione disulfide), which is then recycled back to its reduced form to continue its scavenge. Who said recycling doesn’t work?
The thing is that when it comes to autism, quite a bit of research seems to be suggesting a few issues with both the availability of glutathione and the function of one or two glutathione related enzymes involved in the important process of antioxidation.
Findings of issues with glutathione are not new news to autism research. Indeed, the paper by Jill James and colleagues1 way back in 2004 implicated under-performing glutathione parameters and quote “chronic oxidative stress” in their group of children diagnosed with autism. Indeed, they reported on a wider range of related methylation parameters which I personally think is going to be pretty important to future autism research (thinking about important things like DNA methylation).
More recent findings add to the interest in glutathione in relation to ASD. Al-Yafee and colleagues2 also reported on issues with glutathione and its relations in cases of ASD. A similar story of low levels of total glutathione presenting in their cohort is described again implicating less than ideal antioxidant function. Based on their findings, they also made an interesting suggestion: glutathione levels at a certain cut-off point seemed to distinguish 100% of children with autism from control samples (and on more than one parameter). Of course the sample groups, autism and controls, were small (n=20 apiece) so perhaps we should not read too much into this finding at the present time. But it is interesting.
Not yet convinced about glutathione and autism? Well how about a systematic review and meta-analysis to really put some flesh on the bones of the glutathione story. And that’s just what Main and colleagues3 did, in their review of the trans-sulfuration pathway in autism including glutathione. They did a very good job of reviewing the data and concluded “evidence for the involvement of the γ-glutamyl cycle and trans-sulphuration pathway in autistic disorder is sufficiently consistent, particularly with respect to the glutathione redox ratio, to warrant further investigation to determine the significance in relation to clinical outcomes”.
I was also struck by their suggestion of potential issues with cysteine, an important part of the starting material for making glutathione which was noted to be low in some cases of autism. Cysteine has cropped up before in the autism research literature alongside some very important (and under-rated) research by Rosemary Waring – she of the sulfation story of autism. My mind also wanders back to the quite recent findings of supplementation with N-acetylcysteine (NAC) for cases of autism as described by Hardan and colleagues4 bearing in mind no medical advice is given or intended about this supplement.
I think there is enough evidence to start seriously thinking about glutathione, its role, function and the various findings in relation to ASD. I would hasten to add that I am not uniformly suggesting that everyone with autism has issues with glutathione or cysteine as per the important focus on heterogeneity and comorbidity in ASD. Assuming however that a sub-group of people with ASD exists who manifest issues with glutathione and chemical relations, they might offer some interesting directions for autism research and importantly, a promise of some novel interventions.
1. James SJ. et al. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. The American Journal of Clinical Nutrition. 2004; 80: 1611-1617.
2. Al-Yafee A. et al. Novel metabolic biomarkers related to sulfur-dependent detoxification pathways in autistic patients of Saudi Arabia. BMC Neurology. 2011; 11: 139.
3. Main PAE. et al. The potential role of the antioxidant and detoxification properties of glutathione in autism spectrum disorders: a systematic review and meta-analysis. Nutrition & Metabolism. 2012; 9: 35.
4. Hardan AY. et al. A randomized controlled pilot trial of oral N-Acetylcysteine in children with autism. Biological Psychiatry. 2012; 71: 956-961.