Fw: New Study - Dr. Mark Geier & Geier

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M wrote: Einstein once said, "A foolish faith in authority is the worst enemy of the truth". ----- Forwarded Message ----From: Weinmaster

<lindaweinogmail>To: nebraskaparentsasd Sent: Sunday, July 13, 2008 6:39:00 PMSubject: [nebraskaparentsasd] New Study - Dr. Mark Geier & Geier Dear Everyone, Please, find attached to this email a copy of our newest peer-reviewed study, "A Prospective Study of Transsulfuration Biomarkers in Autistic Disorders" published in Neurochemical Research saved as A Prospective Study of Transsulfuration Biomarkers in Autistic Disorders1.pdf in Adobe Acrobat format. This study was a collaboration between us and Dr. Janet Kern of the University of Texas, Southwestern Medical Center, Dr. Carolyn Garver of the Autism Treatment Center, Dallas TX, Dr. of Arizona State

University, and Dr. Tapan Audhya of Vitamin Diagnostics. The study was jointly funded by the Autism Research Institute, the non-profit 501©(3) Institute of Chronic Illnesses, Inc., and the non-profit 501©(3), CoMeD, Inc. The importance of this new study stems from the fact that in attempting to understand the underlying pathogenesis of autism spectrum disorders (ASDs), a considerable body of research has been conducted to evaluate potential candidate causal genes. Genetic studies, to date, have not uncovered genes of strong effect. It has recently been postulated that increasing rates of ASDs and less than 100% monzygotic concordance of ASDs support a more inclusive reframing of ASDs as a multisystem disorder with genetic influence and environmental contributors. Several studies have recently focused on the transsulfuration

pathway in ASDs. ASD children were found to have significant decreases in blood total and reduced glutathione (the major intracellular antioxidant), whereas oxidized glutathione was significantly increased in comparison with controls. Other researchers reported that blood levels of sulfate were significantly decreased in ASD children in comparison with controls. Cysteine (the rate limiting substrate for intracellular glut athione synthesis) in ASD children was also found to be significantly decreased in the plasma relative to controls. The transsulfuration pathway starts with homocysteine, which can either be remethylated to methionine or irreversibly removed from the methionine cycle by cystathionine beta-synthase (CBS). This is a one way reaction that permanently removes homocysteine from the methionine cycle and initiates the transsulfuration pathway for the synthesis of cysteine, glutathione, sulfate, and taurine. The present study was

undertaken to confirm and extend previous observations in patients diagnosed with ASDs by examining a different cohort of children diagnosed with ASDs using routine, clinically available lab testing. The purpose of the present study was to further evaluate an entire metabolic pathway (i.e. the transsulfuration pathway), as opposed to isolated single gene products, to provide a greater mechanistic insight into disease pathology, so that new options for targeted treatment strategies may be further explored. Transsulfuration metabolites, including: plasma reduced glutathione (GSH), plasma oxidized glutathione (GSSG), plasma cysteine, plasma taurine, plasma sulfate, and plasma free sulfate among participants diagnosed with ASDs (n = 38) in comparison to age-matched neurotypical controls were prospectively evaluated. Testing was conducted using Vitamin Diagnostics, Inc. (CLIA-approved). Participants diagnosed with ASDs had significantly (P<0.001) decreased plasma reduced GSH, plasma cysteine, plasma taurine, plasma sulfate, and

plasma free sulfate relative to controls. By contrast, participants diagnosed with ASDs had significantly (P<0.001) increased plasma GSSG relative to controls. The present observations are compatible with increased oxidative stress and a decreased detoxification capacity, particularly of mercury, in patients diagnosed with ASDs. Glutathione is a tripeptide of cysteine, glycine, and glutamate that is synthesized in every cell of the body. The essential intracellular reducing environment is maintained by the high ratio of reduced glutathione to the oxidized form of glutathione. The glutathione redox equilibrium regulates a wide range of functions that include nitrogen and oxygen free radical scavenger, protein redox status and enzyme activity, cell membrane integrity and signal transduction [22, 23], transcription factor binding and gene expression, phase II detoxification, and apoptosis. Under normal physiologic conditions, glutathione reductase enzyme activity is sufficient to maintain the high reduced/oxidized glutathione redox ratio. However, excessive intracellular oxidative stress that exceeds the capacity of glutathione reductase will result in oxidized glutathione export to the plasma in attempt to regain intracellular redox homeostasis.

Thus, an increase in plasma oxidized glutathione is a strong indication of intracellular oxidative stress. Further, oxidized glutathione export represents a net loss of glutathione to the cell and increases the requirement for cysteine, the rate-limiting amino acid for glutathione synthesis. Of possible relevance, plasma cysteine levels were significantly reduced in almost 40% of the participants diagnosed with ASDs relative to controls. It is important to note that cysteine is a ''conditionally'' essential amino acid that is dependent on adequate

methionine status; thus, a decrease in methionine precursor levels effectively increases the requirement for preformed cysteine. The significant decrease in plasma cysteine and plasma glutathione and the increase in plasma oxidized glutathione observed among the study participants with ASDs su ggest that precursor availability is insufficient to maintain glutathione levels and normal redox homeostasis. Further, an important relationship between glutathione availability and mercury excretion has been found. Bile is the main route of elimination for many metals, and the rate of secretion of methyl and inorganic mercury into bile was low in suckling rats but rapidly increased to adult rates soon after weaning. These changes closely paralleled similar developmental changes in the biliary secretion of reduced glutathione. It was observed that when reduced glutathione secretion into bile was completely inhibited, without changing hepatic levels of reduced glutathione or mercury, mercury secretion was also completely blocked. These researchers concluded that their results indicated a close correspondence between the secretion of

mercury and reduced glutathione. It is important to note that the liver is the major site of glutathione synthesis and also the major supplier of plasma and bile glutathione. Additionally, the finding of significantly decreased plasma sulfate and plasma free sulfate among participants diagnosed with ASDs in comparison to neurotypical controls is concerning. Alberti et al. showed impaired sulfation capacity in patients diagnosed with ASDs. These researchers concluded that their observations were compatible with a fault in the production of sulfate or a problem in its utilization at rates that exceed the speed which cells can process cysteine to sulfate in patients diagnosed with ASDs. Decrease d sulfation capacity can result in decreased detoxification of xenobiotics. Within the ASD population, the apparent inability to properly respond to toxins (phenolic compounds and heavy metals) may be due, in part, to an undersupply of sulfate substrate for the sulfotransferases, resulting in impaired sulfur-dependent detoxification pathways. Sulfate is essential for detoxification and plays a critical role in heavy metal detoxification. Research in rats has

also shown gender differences in detoxification, with females excreting significantly higher levels of mercury than males. Other researchers found that males are more dependent on sulfotransferase activity for the removal of xenobiotics. In addition, researchers reported CBS, which catalyzes the committing step in the transsulfuration pathway, is down-regulated by testosterone in hum an cells. This results in a significant decrease in flux through the transsulfuration pathway and lower intracellular glutathione levels. Furthermore, it was observed in some animal models and in human fetal/infant populations, that exposure to low-dose mercury induced significant increases in neurotoxic effects in males when compared to females. Overall, these observations may be particularly important to patients diagnosed with ASDs, since the

male/female ratio in ASDs is at least 3:1, and since researchers have reported significant increases in testosterone in patients diagnosed with ASDs. Because sulfate and glutathione are essential for effective detoxification, the effects of a lack of availability of free sulfate and reduced glutathione on detoxification are far-reaching. Exposure to toxins in children with compromised detoxification capability has an even greater potential to disrupt critical developmental processes and result in developmental neurotoxicity. Lack of availability of free sulfate and reduced glutathione may be only one part of the issue. Examination of the effects of heavy metals reveals that the presence of heavy metals, e.g., mercury, can disrupt the very processes needed to excrete the metals. Evidence shows that metal ions disrupt methionine synthetase which then, results in the inhibition of glutathione production. In addition, the presence of metals causes oxidative stress, and since glutathione has the dual function of both reducing of oxidative stress and detoxifying heavy metals, glutathione may be become rapidly depleted as a result of demand. The overall importance of these phenomena in relation to individuals diagnosed with ASDs, as observed in the present study, is that plasma cysteine, plasma sulfate, plasma taurine, and plasma reduced

glutathione were all significantly decreased in participants diagnosed with ASDs, whereas by contrast, plasma oxidized glutathione was significantly increased in participants diagnosed with ASDs. These findings are in agreement with observations made by previous researc hers. Like the current study, these previous studies have shown that, relative to the controls, individuals with ASDs had significant reductions in blood levels of glutathione, cysteine,

and sulfate, whereas by contrast, plasma oxidized glutathione was significantly increased. If anyone has any questions/comments concerning our new study, please do not hesitate to contact us. Sincerely, Mark R. Geier, M.D., Ph.D., FACMG, FACE President, The Genetic Centers of America Phone: (301)989-0548 Fax: (301)989-1543 email: mgeiercomcast (DOT) net A. Geier Vice-President, The Institute of Chronic Illnesses, Inc.