New Study-"A Prospective Study of Transsulfuration Biomarkers in Autistic Disorders"‏
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. James Adams 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(C)(3) Institute of Chronic Illnesses, Inc., and
> the non-profit 501(C)(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: mgeier@comcast.net 40comcast.net>
> David A. Geier
> Vice-President, The Institute of Chronic Illnesses,
Inc.