Sulphate metabolism in autism

Normal biochemistry

This is a complex subject in which the sulphate ion can be both produced in the body through biochemical formation (generally from methionine and cysteine aminoacids) and absorbed from the gut.

It is transported across membranes by various transporter protein molecules, which are found almost universally in the body. The ion is activated into PAPS (adenosine 3’-phosphate 5’-sulphatophosphate) which is a donor molecule to cause the sulphation through the formation of an ester.

This causes the formation of highly soluble molecules that are good for urinary or biliary elimination. The body also forms heparans and glycans using PAPS in a complex method.

In the gut sulphate is absorbed in the small intestine through deliberate transporter molecules, about which little is known concerning their regulation. In an adult the whole body inorganic sulphate turnover is represented by the 841 +/- 49 micromol/hr and average urinary inorganic sulphate excretion is around 600 micromol/hr. Following injection of sulphate into the body around 50% is excreted as esters and whole body sulphation accounted for around 27% of inorganic sulphate turnover. Exracellular inorganic sulphate is an important pool for intracellular sulphation.

Sulphate in autism

It should be noted that sulphate, because of its interaction with cysteine and methionine formation must be viewed with the formation of other sulphur containing compounds e.g. glutathione and oxidative stress

Levels of blood sulphate found in autism (not available but considered to be low)
Urinary sulphate (often as esters) found to be relatively high
Involvement with the formation of antioxidant substances i.e. the inadequacy of these compounds e.g. glutathione. See oxidative stress.
Treatment using sulphate

Glycosaminoglycans in autism

We do know that these compounds (like heparin, and chondroitin sulphate, and the glycosaminoglycans that are present in large amounts in the basal membranes of the gut, kidney and skin) may well be modified but the research in this respect is missing from major literature.

formula of heparinetal

Glycosaminoglycans are long chains of sugar molecules with sulphate modification of some of the ester linked elements. They can be variants and vary dramatically in the amount of sulphate depending on the amount of sulphate available when they are being made.

Normal sulphate biology

Markovich D. Physiological role and regulation of mammalian sulfate transporters. Physiological reviews. 2001;81:1499-1533. also see: Cole D, Evrosvski J. The clinical chemistry of inorganic sulfate. Crit Rev Clin Lab Sci 2000 37(4);299-44. Also see: Hoffer LJ et al. Human sulfate kinetics. Am J Physiol Regul Integr Comp Physiol 2005;289;R1372-80.

Hoffer LJ, Hamadeh MJ, Robitaille L, Norwich KH. Human sulfate kinetics. Am J Physiol Regul Integr Comp Physiol. 2005 Nov;289(5):R1372-80. Epub 2005 Jul 28.

Cole DE, Evrovski J. The clinical chemistry of inorganic sulfate. Crit Rev Clin Lab Sci. 2000 Aug;37(4):299-344.

Alterations seen in autism

McFadden SA.Toxicology. Phenotypic variation in xenobiotic metabolism and adverse environmental response: focus on sulfur-dependent detoxification pathways. 1996 Jul 17;111(1-3):43-65. (autism only used as an example in the impaired sulphation of xenobiotic compounds)

Alberti A, Pirrone P, Elia M, Waring RH, Romano C. Sulphation deficit in "low-functioning" autistic children: a pilot study. Biol Psychiatry. 1999 Aug 1;46(3):420-4. (also found low levels of sulphotransferase in platelets and low plasma sulphate).

Urinary increased sulphate (inorganic, organic), sulphite, thiocyanite (by about 50%) in autism vs control. Also d-glucaric acid was very high, which is also used as a modifier for toxins. Original source is not clear. This is quoted under Adams work, who is clearly wanting to press ahead with sulphate research.

Waring RH, Klovrza LV. Sulphur metabolism in autism. J Nutritional and Environmental Medicine 2000;1:25-32 (Urinary excretion of sulphate sulphate, thiocyanate and thiosulphate were measured in 232 autistic children and compared with 68 controls. Significantly higher excretion was seen in all of these compounds except thiocyanate).

Geier DA, Geier MR. A clinical and laboratory evaluation of methionine cycle-transsulfuration and androgen pathway markers in children with autistic disorders. Horm Res. 2006;66(4):182-8. (this has been followed up by several groups but nobody has found the reason or prevalence behind it. The effect it would have on the androgen pathways is also unclear)

Waring RH, Ngong JM, Klovrza L, Green S, Sharp H. Biochemical parameters in autistic children. Dev Brain Dystunction 1997;10:40-43. (a short review, particularly showing the changes in autism)

Associations with other sulphur molecules

Whiteley, P, Waring R, Shattock P, Hooper M. Correlation of urinary exretion of cysteine – sulphate metabolites and trans-indolyl-3-3acryloylglicine in 10 children diagnosed with pervasive developmental disorders. Durham conference proceedings 2004. This shows a relationship between IAG and urinary cysteine but with little else.

Waring R, Klovrza L. Sulphur metabolism in autism. J Nutr Envir Med 10;25-32 2000. (Ros Waring is particularly interested in cysteine dioxidase as a limiting enzyme in the internal production of sulphate. She realises that the requirement of sulphate may be dramatically higher in autism than cysteine dioxidase can supply).

Glycosaminoglycans

These are compounds as indicated as above with long chains of disaccharides (as shown), possibly with molecular weights of over 5000. They make up important parts of basal membranes and the borders between tissues. The large amounts of sulphate on the surface of the molecules makes them exceptionally soluble and interact precisely with sites on cells. They are not penetrable into the brain.

van der Kraan PM, de Vries BJ, Vitters EL, van den Berg WB, van de Putte LB. The effect of low sulfate concentrations on the glycosaminoglycan synthesis in anatomically intact articular cartilage of the mouse. J Orthop Res. 1989;7(5):645-53. (this would suggest that the relatively low sulphate levels seen in autism may modify the glycosaminoglycans).

Murch SH, MacDonald TT, Walker-Smith JA, Levin M, Lionetti P, Klein NJ. Disruption of sulphated glycosaminoglycans in intestinal inflammation. Lancet 341:711–741, 1993. (although this has been demonstrated by Murch in other IBDs, all that seems to have been shown in autism is that there is a thickening of the basal membrane in the autistic gut biopsies and this has not been published)

Non sourced data:

Sulphation low in 15 of 17 (mean 5 vs. nl 10-18) Glutathione Conjugation low in 14 of 17 (mean 0.55 vs 1.4-2.9) Glucuronidation low in 17 of 17 (mean 9.6 vs. 26.0-46.0) Glycine Conjugation low in 12 of 17 (15.4 vs. 30.0-53.0)

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