Clinical utility of folate pathway genetic polymorphisms in the diagnosis of autism spectrum disorders

Naushad, Shaik Mohammad; Shruti, P.; Bharathi, Venkat; Prasad, Chintakindi Krishna; Hussain, Tajamul; Alrokayan, Salman A.; Naik, Usha; Devi, Akella Radha Rama

doi:10.1097/ypg.0000000000000152

Cited by 43 publications

(37 citation statements)

References 23 publications

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“…The effects of the SNP risk alleles in this case are thought to be increased sensitivity to oxidative stress and the enhancement of mitochondrial degeneration (31). The presence of multiple SNPs of 1‐carbon pathway genes, including MTRR and MTHFR variants, can have an additive effect on the lowering of folate status (13, 33) and the synergistic effects on serum homocysteine concentrations in models of neurocognitive disorders, such as autism (34).…”

Section: Evaluation Of the Hypothesismentioning

confidence: 99%

Astronaut ophthalmic syndrome

Zwart¹,

Gibson²,

Gregory

et al. 2017

The FASEB Journal

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During and after missions on the International Space Station, some astronauts experience ophthalmic changes, including choroidal folds, optic disc edema, cotton-wool spots, globe flattening, and refraction changes. Astronauts with ophthalmic issues had significantly higher plasma concentrations of metabolites that are associated with the 1-carbon metabolic pathway than those without ophthalmic issues. We hypothesized that genetic differences might explain the metabolite differences. Indeed, genetics and B vitamin status were significant predictors of ophthalmic issues. We now have developed a hypothesis regarding the mechanisms that link 1-carbon pathway genetics and the condition that we suggest calling, "astronaut ophthalmic syndrome." We maintain that this condition is genetically predisposed and is associated with endothelial dysfunction that is induced by oxidative stress. Subsequent edema can hinder cerebrospinal fluid efflux and can lead to locally increased pressures in the subarachnoid space within the orbit, which impinges on the optic nerve and/or eye in affected individuals. Confirming this hypothesis will help characterize the genetics of 1-carbon pathway metabolism, homocysteine, oxidative stress, endothelial dysfunction, and cardiovascular and potentially other diseases.-Zwart, S. R., Gibson, C. R., Gregory, J. F., Mader, T. H., Stover, P. J., Zeisel, S. H., Smith, S. M. Astronaut ophthalmic syndrome.

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Section: Evaluation Of the Hypothesismentioning

confidence: 99%

Astronaut ophthalmic syndrome

Zwart¹,

Gibson²,

Gregory

et al. 2017

The FASEB Journal

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“…Abnormalities in metabolites linked to methylation have been described in children diagnosed with neurodevelopmental disorders. [67][68][69] A decrease in methionine levels and in the ratio of plasma SAM to Sadenosylhomocysteine were found in autistic children, 70 whereas increased level of homocysteine was reported for children affected by intellectual disability 71 and ADHD. 72 In this review, we summarize all studies that attempted to correlate folate genetic variants with increasing risk of neurodevelopmental disorders.…”

Section: Folate Is Critical During Neurodevelopment: Dietary and Gementioning

confidence: 98%

“…Indeed, many polymorphisms in folate and folate‐related genes have been shown to be functional. Abnormalities in metabolites linked to methylation have been described in children diagnosed with neurodevelopmental disorders . A decrease in methionine levels and in the ratio of plasma SAM to S‐adenosylhomocysteine were found in autistic children, whereas increased level of homocysteine was reported for children affected by intellectual disability and ADHD …”

Section: Folate Is Critical During Neurodevelopment: Dietary and Genementioning

confidence: 99%

Linking genetics to epigenetics: The role of folate and folate‐related pathways in neurodevelopmental disorders

Lintas

2018

Clinical Genetics

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There is growing evidence that epigenetic dysregulation plays a role in neurodevelopmental disorders. In humans, folate is one of the main donors of the methyl group required for the synthesis of S-adenosylmethionine, which in turn is needed for DNA and histone methylation as key neurodevelopment processes. Folate deficiency during pregnancy has been correlated with neural tube defects and with a higher incidence of neurocognitive and/or neurobehavioral deficits. A similar outcome may be exerted by gene polymorphisms in folate or folate-related pathways. This has been documented by numerous case/control association studies performed on neurodevelopmental disorders such as autism spectrum disorder and attention deficit hyperactivity disorder. In this regard, the folate cycle represents a "perfect model" of how genetics influences epigenetics. Gene variants in folate and folate-related pathways can be considered risk factors for neurodevelopmental disorders and should therefore be assessed by genetic testing in pregnant women. High-risk women should be considered for folate supplementation during pregnancy. Here, we review all published case/control association studies on gene polymorphisms in folate and folate-related pathways performed on neurodevelopmental disorders, provide an overview of neurodevelopment and DNA methylation changes occurring at this time, and describe the biological basis of neurodevelopmental disorders and recent evidence of their epigenetic dysregulation.

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“…Although MTHFR has been postulated to be a genetic factor for autism, there is still very limited clinical indications for testing the polymorphisms in the MTHFR gene in a diagnostic clinical setting . This could be due to complications by other modifier genes of the folate metabolism pathway, and inclusion of other genes in the folate metabolism pathway; also, the level of homocysteine (HCy) appears to increase the utility of using this pathway as a moderate predictor for the diagnosis of autism …”

Section: Epigenetics Of Autismmentioning

confidence: 99%

“…73 This could be due to complications by other modifier genes of the folate metabolism pathway, and inclusion of other genes in the folate metabolism pathway; also, the level of homocysteine (HCy) appears to increase the utility of using this pathway as a moderate predictor for the diagnosis of autism. 74…”

Section: Folate-methionine Pathway Enzymesmentioning

confidence: 99%

Genetics and epigenetics of autism: A Review

Waye

Cheng

2017

Psychiatry Clin Neurosci

111

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Autism is a developmental disorder that starts before age 3 years, and children with autism have impairment in both social interaction and communication, and have restricted, repetitive, and stereotyped patterns of behavior, interests, and activities. There is a strong heritable component of autism and autism spectrum disorder (ASD) as studies have shown that parents who have a child with ASD have a 2-18% chance of having a second child with ASD. The prevalence of autism and ASD have been increasing during the last 3 decades and much research has been carried out to understand the etiology, so as to develop novel preventive and treatment strategies. This review aims at summarizing the latest research studies related to autism and ASD, focusing not only on the genetics but also some epigenetic findings of autism/ASD. Some promising areas of research using transgenic/knockout animals and some ideas related to potential novel treatment and prevention strategies will be discussed.

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Clinical utility of folate pathway genetic polymorphisms in the diagnosis of autism spectrum disorders

Abstract: Genetic polymorphisms of the folate pathway were moderate predictors of autism risk. MTHFR C677T and hyperhomocysteinemia have been identified as risk factors for autism worldwide. Synergistic interactions between MTHFR C677T and MTRR A66G increase homocysteine.

Cited by 43 publications

References 23 publications

Astronaut ophthalmic syndrome

Astronaut ophthalmic syndrome

Linking genetics to epigenetics: The role of folate and folate‐related pathways in neurodevelopmental disorders

Genetics and epigenetics of autism: A Review

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