Metabolic Imbalance Associated with Methylation Dysregulation and Oxidative Damage in Children with Autism

Melnyk, Stepan; Fuchs, George J.; Schulz, Eldon G.; Lopez, Maya; Kahler, Stephen G.; Fussell, Jill J.; Bellando, Jayne; Pavliv, Oleksandra; Rose, Shannon; Seidel, Lisa; Gaylor, David W.; James, S. Jill

doi:10.1007/s10803-011-1260-7

Cited by 211 publications

(236 citation statements)

References 81 publications

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“…Research studies have shown that insufficient dietary folate increases requirement for choline and betaine-derived methyl groups and conversely, choline and betaine deficiency increases the requirement for folate-derived methyl groups [17]. Thus, dietary deficits in both pathways for methionine synthesis may be compromised in children with ASDs and additively contribute to the low methionine and SAM levels previously reported in these children [8][9][10]. Importantly, reduced synthesis of SAM, the major intracellular methyl donor, can lead to DNA hypomethylation and epigenetic abnormalities associated with abnormal gene expression, genomic imprinting, and genomic instability [22].…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, reduced synthesis of SAM, the major intracellular methyl donor, can lead to DNA hypomethylation and epigenetic abnormalities associated with abnormal gene expression, genomic imprinting, and genomic instability [22]. Significant decreases in plasma methioinine and SAM associated with DNA hypomethylation have been reported in children with ASDs relative to age-matched control children [10]. It is not known whether supplemental choline or betaine would increase methionine and SAM synthesis in children with autism.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, James et al found that children with ASDs had significantly lower plasma concentrations of methionine, S-adenosylmethionine (SAM), cystathionine, cysteine, and total glutathione (GSH) and significantly higher concentrations of S-adenosylhomocysteine (SAH), adenosine, and oxidized glutathione (GSSG) when compared to age-matched control children [8][9][10]. These metabolic abnormalities can lead to compromised methylation (SAM/SAH) and antioxidant/detoxification capacity (GSH/GSSG).…”

Section: Introductionmentioning

confidence: 99%

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Nutrition as an Important Mediator of the Impact of Background Variables on Outcome in Middle Childhood

Hamlin¹,

Pauly²,

Melnyk³

et al. 2015

Prenatal and Childhood Nutrition

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Abnormalities in folate-dependent one-carbon metabolism have been reported in many children with autism. Because inadequate choline and betaine can negatively affect folate metabolism and in turn downstream methylation and antioxidant capacity, we sought to determine whether dietary intake of choline and betaine in children with autism was adequate to meet nutritional needs based on national recommendations. Three-day food records were analyzed for 288 children with autism (ASDs) who participated in the national Autism Intervention Research Network for Physical Health (AIR-P) Study on Diet and Nutrition in children with autism. Plasma concentrations of choline and betaine were measured in a subgroup of 35 children with ASDs and 32 age-matched control children. The results indicated that 60-93% of children with ASDs were consuming less than the recommended Adequate Intake (AI) for choline. Strong positive correlations were found between dietary intake and plasma concentrations of choline and betaine in autistic children as well as lower plasma concentrations compared to the control group. We conclude that choline and betaine intake is inadequate in a significant subgroup of children with ASDs and is reflected in lower plasma levels. Inadequate intake of choline and betaine may contribute to the metabolic abnormalities observed in many children with autism and warrants attention in nutritional counseling.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Nutrition as an Important Mediator of the Impact of Background Variables on Outcome in Middle Childhood

Hamlin¹,

Pauly²,

Melnyk³

et al. 2015

Prenatal and Childhood Nutrition

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“…A significant overrepresentation of genes with functions in chromatin regulation and early developmental expression was found in ASD probands but not in unaffected siblings [106]. Also, oxidative protein/DNA damage and DNA hypomethylation (epigenetic alteration) were found in autistic children but not paired siblings or controls [107]. So, nowadays attention has turned to environmental factors but also with epigenetic changes as potential etiological agents predisposing to autism susceptibility.…”

Section: Epigenetic Changes Involved In Asdmentioning

confidence: 99%

“…Low plasma SAM levels and DNA hypomethylation have been shown to be present in children with autism [107]. Choline deficiency has been also shown in animal models to contribute to global and gene-specific DNA hypomethylation and epigenetic abnormalities [317].…”

Section: Vitamin-like Substances: Cholinementioning

confidence: 99%

The Genetic and Epigenetic Basis Involved in the Pathophysiology of ASD: Therapeutic Implications

Carrascosa-Romero¹,

Cabo²

2017

Autism - Paradigms, Recent Research and Clinical Applications

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The prevalence of autism has increased in an exponential way in the past few years. Many monogenetic mutations as well as copy number variants and single nucleotide polymorphisms have been associated with autism spectrum disorders (ASD), a large proportion of which occur in genes associated with synaptogenesis and synaptic function. However, the increase in appearance of genetic alterations does not explain the etiology of an elevated number of ASD cases. Recent research is now focusing on the role of environmental/epigenetic factors, which by themselves and/or in combination with classical genetic factors, may be the root cause of a large number of ASDs. In this chapter we review the current literature regarding the epigenetic changes involved in ASD, including their possible mechanisms of action such as oxidative stress, altered fatty acid metabolism, mitochondrial dysfunction, DNA methylation and histone methylation (via the one-carbon metabolism cycle), histone variants, and ATP-dependent chromatin remodeling. We discuss possible new biochemical markers related to autism as well as new lines of research for therapeutic targets.

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Nitrosative Stress in Autism: Supportive Evidence and Implications for Mitochondrial Dysfunction

Frye,

Rose,

Voinsky

et al. 2024

Advanced Science

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A recent study by the Amal team published in this journal in May 2023 proved for the first time the link of nitric oxide (NO) with autism spectrum disorder (ASD), thereby opening new venues for the potential use of neuronal nitric oxide synthase (nNOS) inhibitors as therapeutics for improving the neurological and behavioral symptoms of ASD. The authors conclude that their findings demonstrate that NO plays a significant role in ASD. Indeed, earlier studies support elevated NO and its metabolites, nitrite, and peroxynitrite, in individuals diagnosed with ASD. Dysregulated NOS activity may underlie the well‐documented mitochondrial dysfunction in a subset of individuals with ASD. Strategies for treating ASD shall also consider NO effects on mitochondrial respiration in modulating NOS activity. Further experimental evidence and controlled clinical trials with NOS modifiers are required for assessing their therapeutic potential for individuals with ASD.

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Metabolic Imbalance Associated with Methylation Dysregulation and Oxidative Damage in Children with Autism

Cited by 211 publications

References 81 publications

Nutrition as an Important Mediator of the Impact of Background Variables on Outcome in Middle Childhood

Nutrition as an Important Mediator of the Impact of Background Variables on Outcome in Middle Childhood

The Genetic and Epigenetic Basis Involved in the Pathophysiology of ASD: Therapeutic Implications

Nitrosative Stress in Autism: Supportive Evidence and Implications for Mitochondrial Dysfunction

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