The potential impact of COMT gene variants on dopamine regulation and phenotypic traits of ASD patients

Esmaiel, Nora N.; Ashaat, Engy A.; Mosaad, Rehab M.; Fayez, Alaaeldin; Ibrahim, Mona M.; Abdallah, Zeinab Y.; Issa, Mahmoud Y.; Salem, Sohair; Ramadan, Abeer; Wakeel, Maged A. El; Ashaat, Neveen A.; Zaki, Maha S.; Ismail, Samira

doi:10.1016/j.bbr.2019.112272

Cited by 18 publications

(18 citation statements)

References 31 publications

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“…Metabolism of catechol involves several enzymes including Catechol-O-methyltransferase (COMT), which catalyzes the O-methylation of various endogenous and exogenous catecholic substrates (54,55). It has been suggested that altered methylation metabolism of endogenous catechols due to COMT polymorphism may be a risk factor for the development of certain neurodegenerative disorders, as well as ASD (55)(56)(57)(58)(59). Additionally, this catechol-metabolizing system may be affected by exogenous factors such as catechol-containing polyphenols, which provide a feedback inhibition of methylation of endogenous catechols in vivo (54,60).…”

Section: Discussionmentioning

confidence: 99%

“…Changes of catechol levels may also be related to alterations in gut microbiota, since gut microorganisms play critical roles in the production of catecholic substrates in gut lumen (65,66), and these biologically active catecholic substrates may also affect the growth rates of some pathogenic bacteria (67,68). Endogenous catechols in plasma were found to be abnormal in some autistic individuals and levels of catechols and their metabolites were found to be decreased in urine samples in ASD (59,69). However, only plasma or urine samples were collected and measured in these previous studies.…”

Section: Discussionmentioning

confidence: 99%

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Comparison of the Metabolic Profiles in the Plasma and Urine Samples Between Autistic and Typically Developing Boys: A Preliminary Study

Cai

Meng

et al. 2021

Front. Psychiatry

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Background: Autism spectrum disorder (ASD) is defined as a pervasive developmental disorder which is caused by genetic and environmental risk factors. Besides the core behavioral symptoms, accumulated results indicate children with ASD also share some metabolic abnormalities.Objectives: To analyze the comprehensive metabolic profiles in both of the first-morning urine and plasma samples collected from the same cohort of autistic boys.Methods: In this study, 30 autistic boys and 30 tightly matched healthy control (HC) boys (age range: 2.4~6.7 years) were recruited. First-morning urine and plasma samples were collected and the liquid chromatography–mass spectrometry (LC-MS) was applied to obtain the untargeted metabolic profiles. The acquired data were processed by multivariate analysis and the screened metabolites were grouped by metabolic pathway.Results: Different discriminating metabolites were found in plasma and urine samples. Notably, taurine and catechol levels were decreased in urine but increased in plasma in the same cohort of ASD children. Enriched pathway analysis revealed that perturbations in taurine and hypotaurine metabolism, phenylalanine metabolism, and arginine and proline metabolism could be found in both of the plasma and urine samples.Conclusion: These preliminary results suggest that a series of common metabolic perturbations exist in children with ASD, and confirmed the importance to have a comprehensive analysis of the metabolites in different biological samples to reveal the full picture of the complex metabolic patterns associated with ASD. Further targeted analyses are needed to validate these results in a larger cohort.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Comparison of the Metabolic Profiles in the Plasma and Urine Samples Between Autistic and Typically Developing Boys: A Preliminary Study

Cai

Meng

et al. 2021

Front. Psychiatry

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“…These genes were selected because of previous studies related to prefrontal brain function and social/behavioral dysfunction, which is linked to psychiatric disorders, including ASD [ 33 , 34 , 35 ] and schizophrenia [ 36 , 37 , 38 ]. We aimed to provide insight into the genetic influence on brain development to identify infants with an inherent vulnerability to reduced development of the cerebral cortex after preterm birth.…”

Section: Introductionmentioning

confidence: 99%

Altered Cerebral Curvature in Preterm Infants Is Associated with the Common Genetic Variation Related to Autism Spectrum Disorder and Lipid Metabolism

Kim

Ahn

Lee

et al. 2022

JCM

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Preterm births are often associated with neurodevelopmental impairment. In the critical developmental period of the fetal brain, preterm birth disrupts cortical maturation. Notably, preterm birth leads to alterations in the fronto-striatal and temporal lobes and the limbic region. Recent advances in MRI acquisition and analysis methods have revealed an integrated approach to the genetic influence on brain structure. Based on imaging studies, we hypothesized that the altered cortical structure observed after preterm birth is associated with common genetic variations. We found that the presence of the minor allele at rs1042778 in OXTR was associated with reduced curvature in the right medial orbitofrontal gyrus (p < 0.001). The presence of the minor allele at rs174576 in FADS2 (p < 0.001) or rs740603 in COMT (p < 0.001) was related to reduced curvature in the left posterior cingulate gyrus. This study provides biological insight into altered cortical curvature at term-equivalent age, suggesting that the common genetic variations related to autism spectrum disorder (ASD) and lipid metabolism may mediate vulnerability to early cortical dysmaturation in preterm infants.

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“…Hyperserotonemia has been associated with the induction of ASD in animal models [30]; conversely, melatonin levels decrease, and its compensation has been clinically studied in ASD [31]. BH4 also enables the synthesis of l-3,4-dihydroxyphenylalanine (L-DOPA) and a recent study showed abnormal levels of dopamine in patients with ASD [32].…”

Section: Introductionmentioning

confidence: 99%

The Key Role of Purine Metabolism in the Folate-Dependent Phenotype of Autism Spectrum Disorders: An In Silico Analysis

et al. 2020

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Folate deficiency in the critical developmental period has been repeatedly associated with an increased risk of Autism spectrum disorders (ASD), but the key pathophysiological mechanism has not yet been identified. In this work, we focused on identifying genes whose defect has similar consequences to folate depletion in the metabolic network. Within the Flux Balance Analysis (FBA) framework, we developed a method of blocked metabolites that allowed us to define the metabolic consequences of various gene defects and folate depletion. We identified six genes (GART, PFAS, PPAT, PAICS, ATIC, and ADSL) whose blocking results in nearly the same effect in the metabolic network as folate depletion. All of these genes form the purine biosynthetic pathway. We found that, just like folate depletion, the blockade of any of the six genes mentioned above results in a blockage of purine metabolism. We hypothesize that this can lead to decreased adenosine triphosphate (ATP) and subsequently, an S-adenosyl methionine (SAM) pool in neurons in the case of rapid cell division. Based on our results, we consider the methylation defect to be a potential cause of ASD, due to the depletion of purine, and consequently S-adenosyl methionine (SAM), biosynthesis.

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The potential impact of COMT gene variants on dopamine regulation and phenotypic traits of ASD patients

Cited by 18 publications

References 31 publications

Comparison of the Metabolic Profiles in the Plasma and Urine Samples Between Autistic and Typically Developing Boys: A Preliminary Study

Comparison of the Metabolic Profiles in the Plasma and Urine Samples Between Autistic and Typically Developing Boys: A Preliminary Study

Altered Cerebral Curvature in Preterm Infants Is Associated with the Common Genetic Variation Related to Autism Spectrum Disorder and Lipid Metabolism

The Key Role of Purine Metabolism in the Folate-Dependent Phenotype of Autism Spectrum Disorders: An In Silico Analysis

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