Biological Treatments for Autism and PDD Online > Chapter 3: Part I | Part II | Part III
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Arabinose, pentosidine, and protein crosslinks
The aldehyde group of arabinose can react with the extra amino chemical group(called an epsilon amino group) of an amino acid called lysine that is present in a wide variety of proteins. This combined arabinose-lysine molecule may then form cross-links with an amino acid called arginine in an adjoining protein (25), forming a compound called a pentosidine (Figures10 A,B,C). The formation of a pentosidine may cross-link different proteins (Figure 11) and may alter both the biological structure and function of a wide variety of proteins(25). The effect on all of the body's functions may be devastating.
Let's use the LA freeway analogy again to understand. Suppose that on a very foggy day during the rush hour Gremlins hiding under your moving car and those of your neighbors took strong steel bars and welded them to the frames of the moving cars. The steel bars stick out at a perpendicular angle for about three feet from the side of your car without you or any other driver noticing because of the fog. Arabinose would be like the steel bar and the proteins would be like the cars. Suppose the gremlins welded the other end of the steel bars to the frames of neighboring cars. Then suppose they welded a bar between that neighboring car and a third car and so forth. Furthermore, some cars might be welded to each other by their bumpers in addition to their sides. Now imagine what will happen when one or more of the drivers wanted to exit or change lanes. Chaos and carnage would ensue. The combined molecule of arabinose, lysine, and arginine is called a pentosidine and is like the two cars welded together. The undoing of these cross-links will become a major challenge in the future for treating older individuals with autism in which many of these cross-links have already been established.
I suspect that autism was reversed in the children of Pam Scott and Karyn Seroussi because they started therapy at a very young age. However, I have received reports of some improvements after antifungal therapy in people with autism in their twenties. Antifungal therapy cannot undo any of the cross-links; such therapy can only prevent the formation of new cross-links by reducing the production of yeast arabinose. The tissue concentration of this combined molecule is almost linearly related to age (25); the increase in crosslinks (steel bars) in this molecule is one of the main reasons we lose flexibility as we age.
One child with autism with a very high urine arabinose(1144 mmol/mol creatinine) was examined by MRI (a type of brain scan) and found to have diffuse demyelination (loss of myelin) of the white matter of the brain.(Values as high as 4000 mmol/mol creatinine have been found in children with autism who have not been eating apple products.) It is possible that pentosidine formation could account for this demyelination. Myelin is the material that covers the axons of the brain in much the same way that plastic insulating material is wrapped around copper electrical wire. Without an intact myelin cover, the nerve impulses in the brain are short-circuited just like an electrical wire with torn insulation. Most children with autism are not examined by MRI but such an examination on a research basis of children with high urine arabinose values might be helpful to prove a link between high arabinose and demyelination. A summary of the possible adverse effects of pentosidine is given in Table 1.
Arabinose and impaired vitamin function
The epsilon amino group of lysine is a critical functional group of many enzymes to which the vitamins pyridoxal (vitamin B-6), biotin, and lipoic acid are covalently bonded during coenzymatic reactions (26); the blockage of these active lysine sites by pentosidine formation may cause functional vitamin deficiencies (Figure12) even when nutritional intake is adequate. In addition, the epsilon amino groups of lysine may also be important in the active catalytic site of many enzymes.
Pentosidines, tangled nerves, Alzheimer's disease, and autism
Protein modification caused by pentosidine formation is associated with crosslink formation, decreased protein solubility, and increased protease resistance. The characteristic pathological structures called neurofibrillary tangles associated with Alzheimer disease contain modifications typical of pentosidine formation. Specifically, antibodies against pentosidine react strongly to neurofibrillary tangles and senile plaques in brain tissue from patients with Alzheimer disease (27). In contrast, little or no reaction is observed in apparently healthy neurons of the same brain. Thus, it appears that the neurofibrillary tangles of Alzheimer's disease may be caused by the pentosidines. The modification of protein structure and function caused by arabinose could account for the biochemical and insolubility properties of the lesions of Alzheimer disease through the formation of protein crosslinks. Similar damage to the brains of autistic children might also be due to the pentosidines and neurofibrillary tangles have also been reported in the brain tissue of an individual with autism (28). It has been reported that frequent urinary tract infections are associated with more severe Alzheimer's disease (29). The use of antibiotics to treat urinary tract infections would of course lead to yeast overgrowth. I have found that urine arabinose is elevated in some cases of Alzheimer's disease and have received a report of a favorable response from antifungal therapy to treat Alzheimer's disease from a woman with a child with autism and a father with Alzheimer's disease.
Prevention of pentosidine formation with high doses of vitamin B-6 and other vitamins?
Glutathione has been reported to inhibit pentosidine formation (24). Supplementation with the vitamins biotin, pyridoxal (B-6), and lipoic acid (whose function at protein epsilon amino groups may be blocked by pentosidines derived from arabinose) might also be beneficial. Addition of vitamin B-6 derivatives or vitamin C to proteins helps to prevent pentosidine formation (30). In fact, I suspect that the beneficial effects of vitamin B-6 in autism reported in multiple studies (31) may be mediated by prevention of pentosidine formation. Pamela Scott used the Super-Nuthera which contains high amounts of vitamin B-6 for her child who recovered from autism prior to starting antifungal therapy and I suspect that this reduced somewhat the effects of the yeast die-off reaction. One way to test this idea would be to do a formal study to see if vitamin B-6 supplementation was less effective in treating autistic symptoms after antifungal therapy compared to supplementation before antifungal therapy.
Other
compounds called furans that are occasionally elevated in the urine of autistic
children are probably derived from fungus such as Aspergillus (32-34) rather
than yeast although it is possible they may be produced by yeast as well.
The names of these compounds are called 5-hydroxymethyl-2-furoic acid, furan-2,5-carboxylic
acid, and furancarbonylglycine. The concentration of furan compounds in the
urine also dropped markedly in children with elevated values after nystatin
therapy, indicating to me a probable yeast and/or fungal origin of these compounds.
Other investigators (35,36) noted that these compounds increased after sugar
consumption and assumed that these compounds were sugar products of human
metabolism but neglected to take into account the Japanese work and the role
of gastrointestinal microorganisms in modification of sugars in the food.
My interpretation is that these compounds may be derived from sugar but that
they are converted to these furan products by the metabolism of yeast and/or
fungi in the intestinal tract.
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