Metabolic pathology of autism in relation to redox metabolism (original) (raw)
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Redox Imbalance and the Metabolic Pathology of Autism
Developmental …, 2011
Recently higher rates of autism diagnosis suggest involvement of environmental factors in causing this developmental disorder, in concert with genetic risk factors. Autistic children exhibit evidence of oxidative stress and impaired methylation, which may reflect effects of toxic exposure on sulfur metabolism. We review the metabolic relationship between oxidative stress and methylation, with particular emphasis on adaptive responses that limit activity of cobalamin and folate-dependent methionine synthase. Methionine synthase activity is required for dopamine-stimulated phospholipid methylation, a unique membrane-delimited signaling process mediated by the D4 dopamine receptor that promotes neuronal synchronization and attention, and synchrony is impaired in autism. Genetic polymorphisms adversely affecting sulfur metabolism, methylation, detoxification, dopamine signaling and the formation of neuronal networks occur more frequently in autistic subjects. On the basis of these observations, a ''redox/methylation hypothesis of autism'' is described, in which oxidative stress, initiated by environment factors in genetically vulnerable individuals, leads to impaired methylation and neurological deficits secondary to reductions in the capacity for synchronizing neural networks. #
Journal of Autism and Developmental Disorders, 2012
Oxidative stress and abnormal DNA methylation have been implicated in the pathophysiology of autism. We investigated the dynamics of an integrated metabolic pathway essential for cellular antioxidant and methylation capacity in 68 children with autism, 54 age-matched control children and 40 unaffected siblings. The metabolic profile of unaffected siblings differed significantly from case siblings but not from controls. Oxidative protein/DNA damage and DNA hypomethylation (epigenetic alteration) were found in autistic children but not paired siblings or controls. These data indicate that the deficit in antioxidant and methylation capacity is specific for autism and may promote cellular damage and altered epigenetic gene expression. Further, these results suggest a plausible mechanism by which pro-oxidant environmental stressors may modulate genetic predisposition to autism.
The role of glutathione redox imbalance in autism spectrum disorder: A review
Free Radical Biology and Medicine, 2020
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Redox metabolism abnormalities in autistic children associated with mitochondrial disease
Translational Psychiatry, 2013
Research studies have uncovered several metabolic abnormalities associated with autism spectrum disorder (ASD), including mitochondrial disease (MD) and abnormal redox metabolism. Despite the close connection between mitochondrial dysfunction and oxidative stress, the relation between MD and oxidative stress in children with ASD has not been studied. Plasma markers of oxidative stress and measures of cognitive and language development and ASD behavior were obtained from 18 children diagnosed with ASD who met criteria for probable or definite MD per the Morava et al. criteria (ASD/MD) and 18 age and gender-matched ASD children without any biological markers or symptoms of MD (ASD/NoMD). Plasma measures of redox metabolism included reduced free glutathione (fGSH), oxidized glutathione (GSSG), the fGSH/GSSG ratio and 3-nitrotyrosine (3NT). In addition, a plasma measure of chronic immune activation, 3-chlorotyrosine (3CT), was also measured. Language was measured using the preschool language scale or the expressive one-word vocabulary test (depending on the age), adaptive behaviour was measured using the Vineland Adaptive Behavior Scale (VABS) and core autism symptoms were measured using the Autism Symptoms Questionnaire and the Social Responsiveness Scale. Children with ASD/MD were found to have lower scores on the communication and daily living skill subscales of the VABS despite having similar language and ASD symptoms. Children with ASD/MD demonstrated significantly higher levels of fGSH/GSSG and lower levels of GSSG as compared with children with ASD/NoMD, suggesting an overall more favourable glutathione redox status in the ASD/MD group. However, compare with controls, both ASD groups demonstrated lower fGSH and fGSH/GSSG, demonstrating that both groups suffer from redox abnormalities. Younger ASD/MD children had higher levels of 3CT than younger ASD/NoMD children because of an agerelated effect in the ASD/MD group. Both ASD groups demonstrated significantly higher 3CT levels than control subjects, suggesting that chronic inflammation was present in both groups of children with ASD. Interestingly, 3NT was found to correlate positively with several measures of cognitive function, development and behavior for the ASD/MD group, but not the ASD/NoMD group, such that higher 3NT concentrations were associated with more favourable adaptive behaviour, language and ASDrelated behavior. To determine whether difference in receiving medications and/or supplements could account for the differences in redox and inflammatory biomarkers across ASD groups, we examined differences in medication and supplements across groups and their effect of redox and inflammatory biomarkers. Overall, significantly more participants in the ASD/MD group were receiving folate, vitamin B12, carnitine, co-enzyme Q10, B vitamins and antioxidants. We then determined whether folate, carnitine, co-enzyme Q10, B vitamins and/or antioxidants influenced redox or inflammatory biomarkers. Antioxidant supplementation was associated with a significantly lower GSSG, whereas antioxidants, co-enzyme Q10 and B vitamins were associated with a higher fGSH/GSSG ratio. There was no relation between folate, carnitine, co-enzyme Q10, B vitamins and antioxidants with 3NT, 3CT or fGSH. Overall, our findings suggest that ASD/MD children with a more chronic oxidized microenvironment have better development. We interpret this finding in light of the fact that more active mitochondrial can create a greater oxidized microenvironment especially when dysfunctional. Thus, compensatory upregulation of mitochondria which are dysfunctional may both increase activity and function at the expense of a more oxidized microenvironment. Although more ASD/MD children were receiving certain supplements, the use of such supplements were not found to be related to the redox biomarkers that were related to cognitive development or behavior in the ASD/MD group but could possibly account for the difference in glutathione metabolism noted between groups. This study suggests that different subgroups of children with ASD have different redox abnormalities, which may arise from different sources. A better understanding of the relationship between mitochondrial dysfunction in ASD and oxidative stress, along with other factors that may contribute to oxidative stress, will be critical to understanding how to guide treatment and management of ASD children. This study also suggests that it is important to identify ASD/MD children as they may respond differently to specific treatments because of their specific metabolic profile.
Autism-Open Access, 2016
Autism spectrum disorder (ASD) is a pervasive broad-spectrum disorder that involves multifaceted delays in the development of many basic, social, and communication skills. The etiology of ASD is multifactorial and involves interplay among genetic, neurologic, hormonal, metabolic, immune-inflammatory, and environmental factors; which further complicate both the diagnosis and management in affected individuals. This review delineates the underpinnings of clinical challenges posed by ASD, like clinical heterogeneity of patient presentation, unresolved ASD genomic map and deficient drug therapy. Besides, it addresses the emerging pathogenic, etiologic, and diagnostic clues of diverse origins, encompassing genetic-, neurotransmitter-, androgenic-and immunoinflammatory-anomalies in ASD patients, as availed by advances in Omics technologies (like genomics and proteomics). Moreover, as unravelled by metabolomics studies, metabolic flaws that pertain to amino acids, fatty acids, mitochondrial anomalies, and oxidative-stress are highlighted and further correlated with the extent of clinical picture and malbehaviors coherent with ASD patients. Lastly, future directions are underlined to promote and rationalize ASD research so as to help translate its findings into remedy.
Oxidative stress-related biomarkers in autism: Systematic review and meta-analyses
Free Radical Biology and Medicine, 2012
Autism spectrum disorders (ASDs) are rarely diagnosed in children younger than 2 years, because diagnosis is based entirely on behavioral tests. Oxidative damage may play a central role in this pathogenesis, together with the interconnected transmethylation cycle and transsulfuration pathway.
Glutathione-Related Factors and Oxidative Stress in Autism, A Review
Autism spectrum disorders are complex neuro-developmental disorders whose neurobiology is proposed to be associated with oxidative stress which is induced by reactive oxygen species. The process of oxidative stress can be a target for therapeutic interventions. In this study, we aimed to review the role of oxidative stress, plasma glutathione (GSH), and related factors as the potential sources of damage to the brain as well as the possible related factors which reduce the oxidative stress. Methylation capacity, sulfates level, and the total glutathione level are decreased in autism. On the other hand, both oxidized glutathione and the ratio of oxidized to reduced glutathione are increased in autism. In addition, the activity of glutathione peroxidase, superoxide dismutase, and catalase, as a part of the antioxidative stress system are decreased. The current literature suggests an imbalance of oxidative and anti-oxidative stress systems in autism. Glutathione is involved in neuro-protection against oxidative stress and neuro-inflammation in autism by improving the anti-oxidative stress system. Decreasing the oxidative stress might be a potential treatment for autism.
Impaired Redox Control in Autism Spectrum Disorders: Could It Be the X in GxE?
Current Psychiatry Reports, 2017
Purpose of Review This review aims to provide a brief description of the complex etiology of autism spectrum disorders (ASD), with special emphasis on the recent findings of impaired redox control in ASD, and to suggest a possible model of oxidative stress-specific gene-environment interaction in this group of disorders. Recent Findings Recent findings point out to the significance of environmental, prenatal, and perinatal factors in ASD but, at the same time, are in favor of the potentially significant oxidative stress-specific gene-environment interaction in ASD. Available evidence suggests an association between both the identified environmental factors and genetic susceptibility related to the increased risk of ASD and the oxidative stress pathway. Summary There might be a potentially significant specific gene-environment interaction in ASD, which is associated with oxidative stress. Revealing novel susceptibility genes (including those encoding for antioxidant enzymes), or environmental factors that might increase susceptibility to ASD in carriers of a specific genotype, might enable the stratification of individuals more prone to developing ASD and, eventually, the possibility of applying preventive therapeutic actions.
Folate metabolism abnormalities in autism: potential biomarkers
Biomarkers in Medicine, 2017
Autism spectrum disorder (ASD) has been linked to abnormalities in folate metabolism. Polymorphisms in folate genes may act in complex polygenic ways to increase the risk of developing ASD. Autoantibodies that block folate transport into the brain have been associated with ASD and children with ASD and these autoantibodies respond to high doses of a reduced form of folate known as folinic acid (leucovorin calcium). Some of the same abnormalities are also found in mothers of children with ASD and supplementing folate during preconception and gestational periods reduces the risk to the offspring from developing ASD. These data suggest that folate pathway abnormalities may be a major metabolic disturbance underlying ASD that can be leveraged as biomarkers to improve symptoms and prevent ASD.