Mixed oddities in the chemistry of autism

  

 

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.

 

 

 

 

 

 

Mixed oddities

In a way these are important to publish in that it is always difficult in science to move forward and it is essential that even minor findings do come forward.  What it does mean, however, is that they need to be repeated. 

 

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, Walker WL, Lit L, Ashwood P, Rocke DM, Sharp FR.  Mol Psychiatry. 2007 Mar;12(3):292-306.  Children with autism 4-6 years of age (n=69) were compared to typically developing children (n=35) with similar age and gender distributions. A total of 6348 peptide components were quantified. Of these, five peptide components corresponding to four known proteins had an effect size >0.99 with a P<0.05 and a Mascot identification score of 30 or greater for autism compared to controls. The four proteins were: Apolipoprotein (apo) B-100, Complement Factor H Related Protein (FHR1), Complement C1q and Fibronectin 1 (FN1). In addition, apo B-100 and apo A-IV were higher in children with high compared to low functioning autism.  It is essential to be aware that if you are looking at such a huge number of plasma proteins with a relatively low number of comparison patients, then by accident there will be a certain number that will appear (to p<0.05) to be significant to separate the groups.  However, in a further patient this may not be true.  This article did, however go into this factor. 

 

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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