Mixed oddities in the chemistry of autism |
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This suggest how the advanced
glycation endpoints (AGEs) interact with the receptors (RAGE) and this has
various effects inside the cells e.g. the production of reactive oxygen
species (ROS), angiotensin II etc. All
this will depend on the cell type that is the recipient. |
Mixed oddities
They may well not be as odd as you think in that many findings simply have not been followed up or their significance indicated by other work. Often the work has not been fully published (e.g. the EGOT work here) but its also it is commonly extremely difficult for some authors to get findings published in major journals. As a result scientists will commonly find that, as they will not get much credit anyway, the work is not encouraging. Also, scientists generally require funding and, if official sources would either much rather the findings were not found, or if the opposite was found then the funding will go towards that end (this is not a good viewpoint for anyone outside the field!). The findings of the changes in RAGE are very interesting and discussions of these must be take place. A few findings have shown that Cholesterol levels are altered in autism, probably in association with Low Density Lipoproteini. |
Low EGOT (aspartate transferase) in 82% and all 12 subjects low in 4 amino acids (tyrosine, carnosine, lysine, hydroxylysine). Dietary analysis revealed below-RDA intakes in Zinc (12 of 12 subjects, Calcium (8 of 12), Vitamin D (9 of 12), Vitamin E (6 of 12) and Vitamin A (6 of 12) (G. Kotsanis, DAN Conf., Sept, 1996)
Altered calcium homeostasis in autism-spectrum disorders:
evidence from biochemical and genetic studies of the mitochondrial aspartate/glutamate
carrier AGC1. Palmieri L, Papaleo V, Porcelli V, Scarcia P, Gaita L,
Sacco R, Hager J, Rousseau F, Curatolo P, Manzi B, Militerni R, Bravaccio C,
Trillo S, Schneider C, Melmed R, Elia M, Lenti C, Saccani M, Pascucci T,
Puglisi-Allegra S, Reichelt KL, Persico AM. Mol
Psychiatry. 2008 Jul 8
Temporocortical gray matter from six matched patient-control pairs was
used to perform post-mortem biochemical and genetic studies of the
mitochondrial aspartate/glutamate carrier (AGC), which participates in the
aspartate/malate reduced nicotinamide adenine dinucleotide shuttle and is
physiologically activated by calcium (Ca(2+)). AGC transport rates were
significantly higher in tissue homogenates from all six patients, including
those with no history of seizures and with normal electroencephalograms prior
to death. Expression of AGC1, the
predominant AGC isoform in brain, and cytochrome c oxidase activity were both
increased in autistic patients, indicating an activation of mitochondrial
metabolism. Furthermore, oxidized mitochondrial proteins were markedly
increased in four of the six patients.
They could find no genetic changes in the gene involved. Excessive Ca(2+) levels are responsible for
boosting AGC activity, mitochondrial metabolism and, to a more variable degree,
oxidative stress in autistic brains.
A proteomic study of serum from children with autism
showing differential expression of apolipoproteins and complement proteins.
Corbett BA, Kantor AB, Schulman H,
Goldberg M, Hattab J, Meir D, Ebstein RP, Belmaker RH. Plasma cyclic AMP and cyclic GMP in childhood-onset psychoses. J Autism Dev Disord. 1984 Jun;14(2):159-64. (levels of cyclic AMP were found to be over 100% higher in the autistic group of 18 patients. The reason was uncertain).
Boso M, Emanuele E, Minoretti P, Arra M, Politi P, Ucelli di Nemi S, Barale F. Alterations of circulating endogenous secretory RAGE and S100A9 levels indicating dysfunction of the AGE-RAGE axis in autism. Neurosci Lett. 2006 Dec 27;410(3):169-73. (excess accumulation of advanced glycation end products – AGEs – in autistic brains. This article reports a significantly reduced peripheral level of their receptors (RAGE) coupled with an elevated s100A9 – its proinflammatory ligand – point to a subtle but definite dysfunction of the AGE/RAGE axis in autism. The authors do not say why whey feel this should be involved with autism but that the changes did indeed appear to be associated with the level of the autism rating scale. The mechanism was also not clear). The literature on AGEs and RAGEs are exceptionally complex but most of the work has appeared due to the appearance of AGEs in diabetics and the possibility that these glycations of proteins may be a cause of pathology. In fact this can be inhibited (although not pharmaceutically, currently). The findings here suggest that the glycated proteins no longer adequately interact with the receptors of them in such a way that particular factors may take place (e.g. involvement with immunity).
Junaid MA, Kowal D, Barua M, Pullarkat PS, Sklower Brooks S, Pullarkat RK. Proteomic studies identified a single nucleotide polymorphism in glyoxalase I as autism susceptibility factor. Am J Med Genet A. 2004 Nov 15;131(1):11-7. (they found an excess of certain nucletide formats for glyoxylase 1 in half the 8 patients with autism that they tested. They also found by Western blot analysis an accumulation of advanced glycation end products (AGE's) in autism brains, which they thought might be due to a genetic modification in autistic cases).
Factors that would need to be replicated before considered acceptable:
i) diminished platelet function, increased baseline CSF homovanillic acid,
ii) decreased nerve cell adhesion molecule serum fragment,
iii) blunted prolactin response to fenfluramine.
Cholesterol significance in autism
The exact mechanism by which this might be involved is not all that clear although this may well as part of LDL. However, it has become clear that cholesterol production and its presence in the neuronal membranes does seem to be involved in disease such as Alzheimer’s disease and that
Tierney E, Bukelis I, Thompson RE, Ahmed K, Aneja A, Kratz L, Kelley RI. Abnormalities of cholesterol metabolism in autism spectrum disorders. Am J Med Genet B Neuropsychiatr Genet. 2006 Sep 5;141(6):666-8. (They tested samples, with no specific association with symptoms apart from ‘autism’ with the levels of various cholesterols and derivatives in blood. They found 19% to be extremely low and the reason for this was not followed.)
A fresh look at an ancient receptor family: emerging
roles for low density lipoprotein receptors in synaptic plasticity and memory
formation. Qiu S, Korwek KM, Weeber EJ. Neurobiol Learn Mem.
2006 Jan;85(1):16-29. They look into the association between LDL and the
formation of the neural systems.
Mentions the association between LDL cholesterol and autism.
Hypercholesterolemia in Asperger syndrome: independence
from lifestyle, obsessive-compulsive behavior, and social anxiety. Dziobek
I, Gold SM, Wolf OT, Convit A.
Psychiatry
Res. 2007
Jan 15;149(1-3):321-4. report on elevated total cholesterol and low-density
lipoprotein (LDL) levels in 22 individuals with Asperger syndrome compared with
well-matched controls, after accounting for lifestyle variables and clinical
symptomatology that could affect them. A potential role for dyslipidemia in the
pathogenesis of some forms of autism is discussed.
Novel plasma phospholipid biomarkers of autism:
Mitochondrial dysfunction as a putative causative mechanism.Pastural
E, Ritchie S, Lu Y, Jin W, Kavianpour A, Khine Su-Myat K, Heath D, Wood PL,
Fisk M, Goodenowe DB. Prostaglandins Leukot Essent
Fatty Acids. 2009 Jul 14 Biomarkers of fatty acid elongation and
desaturation (poly-unsaturated long chain fatty acids (PUFA) and/or saturated
very long chain fatty acids (VLCFA)-containing ethanolamine phospholipids) were
statistically elevated in all autistic subjects.
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