Transsulfuration

The transsulfuration pathway is a metabolic pathway involving the interconversion of cysteine and homocysteine through the intermediate cystathionine. – Which form is that? The importance of selenium speciation and metabolism in the prevention and treatment of disease

Adenosine / Folate / Glutathione / Homocysteine / Methionine / Methylation / Oxidative Stress / Transsulfuration

Multivariate techniques enable a biochemical classification of children with autism spectrum disorder versus typically-developing peers: A comparison and validation study

Abstract

Autism spectrum disorder (ASD) is a developmental disorder which is currently only diagnosed through behavioral testing. Impaired folate‐dependent one carbon metabolism (FOCM) and transsulfuration (TS) pathways have been implicated in ASD, and recently a study involving multivariate analysis based upon Fisher Discriminant Analysis returned very promising results for predicting an ASD diagnosis. This article takes another step toward the goal of developing a biochemical diagnostic for ASD by comparing five classification algorithms on existing data of FOCM/TS metabolites, and also validating the classification results with new data from an ASD cohort. The comparison results indicate a high sensitivity and specificity for the original data set and up to a 88% correct classification of the ASD cohort at an expected 5% misclassification rate for typically‐developing controls. These results form the foundation for the development of a biochemical test for ASD which promises to aid diagnosis of ASD and provide biochemical understanding of the disease, applicable to at least a subset of the ASD population.

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  • May 14, 2018
20 Papers / Adjuvant / Aluminum / Apoptosis / COMT / Cytokines / Dendritic cells / Detoxification / Genes / GI / Glial Cells / Glutathione / Immune / Inflammation / Mercury / Methionine / Methylation / Mitochondria / MTHFR / Neuroinflammation / Neurons / Oxidative Stress / Pregnancy / Review / Seizure / Thimerosal / Toxicants / Transsulfuration

Autism is an Acquired Cellular Detoxification Deficiency Syndrome with Heterogeneous Genetic Predisposition

Excerpt:
“The literature strongly supports that autism is most accurately seen as an acquired cellular detoxification deficiency syndrome with heterogeneous genetic predisposition that manifests pathophysiologic consequences of accumulated, run-away cellular toxicity. At a more general level, it is a form of a toxicant-induced loss of tolerance of toxins, and of chronic and sustained ER overload (“ER hyperstress”), contributing to neuronal and glial apoptosis via the unfolded protein response (UPR). Inherited risk of impaired cellular detoxification and circulating metal re-toxification in neurons and glial cells accompanied by chronic UPR is key.”

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  • March 16, 2018
Folate / Methylation / Oxidative Stress / Transsulfuration

Classification and adaptive behavior prediction of children with autism spectrum disorder based upon multivariate data analysis of markers of oxidative stress and DNA methylation

Abstract
and psychometric tools. However, physiological measurements should support these behavioral diagnoses in the future in order to enable earlier and more accurate diagnoses. Stepping towards this goal of incorporating biochemical data into ASD diagnosis, this paper analyzes measurements of metabolite concentrations of the folate-dependent one-carbon metabolism and transulfuration pathways taken from blood samples of 83 participants with ASD and 76 age-matched neurotypical peers. Fisher Discriminant Analysis enables multivariate classification of the participants as on the spectrum or neurotypical which results in 96.1% of all neurotypical participants being correctly identified as such while still correctly identifying 97.6% of the ASD cohort. Furthermore, kernel partial least squares is used to predict adaptive behavior, as measured by the Vineland Adaptive Behavior Composite score, where measurement of five metabolites of the pathways was sufficient to predict the Vineland score with an R2 of 0.45 after cross-validation. This level of accuracy for classification as well as severity prediction far exceeds any other approach in this field and is a strong indicator that the metabolites under consideration are strongly correlated with an ASD diagnosis but also that the statistical analysis used here offers tremendous potential for extracting important information from complex biochemical data sets.

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  • March 16, 2017
C677T / Folate / Glutathione / Methionine / Methylation / MTHFR / Oxidative Stress / Transsulfuration

Classification and adaptive behavior prediction of children with autism spectrum disorder based upon multivariate data analysis of markers of oxidative stress and DNA methylation

Abstract
The number of diagnosed cases of Autism Spectrum Disorders (ASD) has increased dramatically over the last four decades; however, there is still considerable debate regarding the underlying pathophysiology of ASD. This lack of biological knowledge restricts diagnoses to be made based on behavioral observations and psychometric tools. However, physiological measurements should support these behavioral diagnoses in the future in order to enable earlier and more accurate diagnoses. Stepping towards this goal of incorporating biochemical data into ASD diagnosis, this paper analyzes measurements of metabolite concentrations of the folate-dependent one-carbon metabolism and transulfuration pathways taken from blood samples of 83 participants with ASD and 76 age-matched neurotypical peers. Fisher Discriminant Analysis enables multivariate classification of the participants as on the spectrum or neurotypical which results in 96.1% of all neurotypical participants being correctly identified as such while still correctly identifying 97.6% of the ASD cohort. Furthermore, kernel partial least squares is used to predict adaptive behavior, as measured by the Vineland Adaptive Behavior Composite score, where measurement of five metabolites of the pathways was sufficient to predict the Vineland score with an R2 of 0.45 after cross-validation. This level of accuracy for classification as well as severity prediction far exceeds any other approach in this field and is a strong indicator that the metabolites under consideration are strongly correlated with an ASD diagnosis but also that the statistical analysis used here offers tremendous potential for extracting important information from complex biochemical data sets.

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  • March 16, 2017
Androgens / Excitotoxicity / Glial Cells / Glutamate / Homocysteine / Immune / Inflammation / Mercury / Metallothionein / Mitochondria / Neurons / Review / Thimerosal / Toxicants / Transsulfuration

A possible central mechanism in autism spectrum disorders, part 2: immunoexcitotoxicity

Abstract

In this section, I explore the effects of mercury and inflammation on transsulfuration reactions, which can lead to elevations in androgens, and how this might relate to the male preponderance of autism spectrum disorders (ASD). It is known that mercury interferes with these biochemical reactions and that chronically elevated androgen levels also enhance the neurodevelopmental effects of excitotoxins. Both androgens and glutamate alter neuronal and glial calcium oscillations, which are known to regulate cell migration, maturation, and final brain cytoarchitectural structure. Studies have also shown high levels of DHEA and low levels of DHEA-S in ASD, which can result from both mercury toxicity and chronic inflammation. Chronic microglial activation appears to be a hallmark of ASD. Peripheral immune stimulation, mercury, and elevated levels of androgens can all stimulate microglial activation. Linked to both transsulfuration problems and chronic mercury toxicity are elevations in homocysteine levels in ASD patients. Homocysteine and especially its metabolic products are powerful excitotoxins. Intimately linked to elevations in DHEA, excitotoxicity and mercury toxicity are abnormalities in mitochondrial function. A number of studies have shown that reduced energy production by mitochondria greatly enhances excitotoxicity. Finally, I discuss the effects of chronic inflammation and elevated mercury levels on glutathione and metallothionein.

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  • January 1, 2015
Autism Biomarkers / Glutathione / Homocysteine / Methionine / Methylation / Oxidative Stress / Thioredoxin / Transsulfuration

Newborn screening for autism: in search of candidate biomarkers

Excerpts:

“GST [Glutathione S-transferase] is a metabolic biomarker directly associated with ASD. The human gene product for GST constitutes a candidate susceptibility protein due to its tissue distribution and role in oxidative stress and methionine metabolism, which results in neuronal injury and death.”

“Results of a recent study further demonstrated that glutathione, total glutathione and activity levels of GST were significantly lower in autistic patients as compared with control subjects; however, homocysteine, thioredoxin reductase and perioxidoxin levels were remarkably higher.”

“Autistic children with metabolic disturbances are known to display reduced metabolic activities of GST, cysteine, glutathione and methionine, which are associated with methionine transmethylation and trans-sulfation.”

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  • April 16, 2013
Antioxidant / COMT / Folate / Genes / Glutathione / Homocysteine / Methionine / Methylation / MTHFR / Oxidative Stress / Transsulfuration

Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism

Excerpt:
“The metabolic results indicated that plasma methionine and the ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH), an indicator of methylation capacity, were significantly decreased in the autistic children relative to age-matched controls. In addition, plasma levels of cysteine, glutathione, and the ratio of reduced to oxidized glutathione, an indication of antioxidant capacity and redox homeostasis, were significantly decreased. Differences in allele frequency and/or significant gene-gene interactions were found for relevant genes encoding the reduced folate carrier (RFC 80G > A), transcobalamin II (TCN2 776G > C), catechol-O-methyltransferase (COMT 472G > A), methylenetetrahydrofolate reductase (MTHFR 677C > T and 1298A > C), and glutathione-S-transferase (GST M1). We propose that an increased vulnerability to oxidative stress (endogenous or environmental) may contribute to the development and clinical manifestations of autism.”

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  • December 17, 2006

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