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Ezedinma U, Jones E, Ring A, Miller S, Ladhams A, Fjaagesund S, Downer T, Campbell G, Oprescu F. Short report on a distinct electroencephalogram endophenotype for MTHFR gene variation co-occurring in autism spectrum disorder. AUTISM : THE INTERNATIONAL JOURNAL OF RESEARCH AND PRACTICE 2025; 29:1080-1086. [PMID: 39673442 DOI: 10.1177/13623613241305721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2024]
Abstract
Anecdotal reports link a distinct, bilateral, parieto-temporally generated 4.5-Hz rhythm on an electroencephalogram to a methylenetetrahydrofolate reductase gene variant co-occurring in autism spectrum disorder, but the validation of its precision is needed. The electroencephalograms of children with autism spectrum disorder showing the distinct bilateral parieto-temporally generated 4.5-Hz rhythm and their clinical chart report on polymerase chain reaction screening for methylenetetrahydrofolate reductase gene variants, 677C>T and 1298A>C, were retrieved from an outpatient clinic between February 2019 and April 2024. Twenty-five cases were identified. Patients were between 2 and 12 (7 ± 3) years old from Asian (n = 16, 64%), European (n = 5, 20%), African (n = 1, 4%) and mixed (n = 3, 12%) ethnicities. Twenty patients (80%) were positive for 677 C>Theterozygous (n = 3, 15%), 1298A>Cheterozygous (n = 8, 40%) or both (n = 9, 45%). The polymerase chain reaction testing detected neither variant in 5 (20%) patients. Therefore, the electroencephalogram-endophenotype showed 80% precision in identifying methylenetetrahydrofolate reductase gene variant within the sample. This preliminary data support the precision of the proposed distinct, bilateral, parieto-temporally generated 4.5-Hz rhythm in identifying methylenetetrahydrofolate reductase gene variants and its potential clinical applications as a valuable, non-invasive and objective measure within the population.Lay abstractMethylenetetrahydrofolate reductase mutations refer to genetic variations in the methylenetetrahydrofolate reductase enzyme, which plays an important role in folate metabolism. Folate is essential for neural development and signalling. Children with autism spectrum disorder have atypical neural signals compared with control. This study used a non-invasive method to identify a distinct neural signal that may be useful in future screening for methylenetetrahydrofolate reductase mutation in children with autism spectrum disorder. Given that the underlying causes of autism spectrum disorder have multiple genetic factors and often require subjective assessment, this study introduces a potential non-invasive screening method for methylenetetrahydrofolate reductase gene mutation. This method could provide valuable biomarkers for screening and personalised treatments, offering hope for improved risk stratification and bespoke nutritional support and supplements to mitigate the impact on affected individuals and their descendants.
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Affiliation(s)
- Uchenna Ezedinma
- Brain Treatment Centre Australia, Australia
- University of the Sunshine Coast, Australia
| | - Evan Jones
- Brain Treatment Centre Australia, Australia
- University of the Sunshine Coast, Australia
- Health Developments Corporation, Australia
| | | | - Spencer Miller
- Baylor Scott & White Health, USA
- Brain Treatment Center Dallas, USA
| | | | - Shauna Fjaagesund
- University of the Sunshine Coast, Australia
- Health Developments Corporation, Australia
- The University of Queensland, Australia
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Bragg MG, Rando J, Carroll KN, Eick SM, Karagas MR, Lin PI, Schmidt RJ, Lyall K. The Association of Prenatal Dietary Factors with Child Autism Diagnosis and Autism-Related Traits Using a Mixtures Approach: Results from the Environmental influences on Child Health Outcomes Cohort. J Nutr 2025:S0022-3166(25)00165-8. [PMID: 40107454 DOI: 10.1016/j.tjnut.2025.02.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 02/06/2025] [Accepted: 02/13/2025] [Indexed: 03/22/2025] Open
Abstract
BACKGROUND Previous research on the role of maternal diet in relation to autism has focused on examining individual nutrient associations. Few studies have examined associations with multiple nutrients using mixtures approaches, which may better reflect true exposure scenarios. OBJECTIVES This study aims to examine associations of nutrient mixtures with children's autism diagnosis and trait scores within a large, diverse population. METHODS Participants were drawn from the United States Environmental influences on Child Health Outcomes (ECHO) consortium. Maternal prenatal diet was reported via validated food frequency questionnaires. Children's autism-related traits were measured using the Social Responsiveness Scale (SRS) and autism diagnoses were from parent reports of physician diagnosis. Bayesian kernel machine regression was used to examine the overall mixture effect and interactions between a set of 5 primary nutrients (folate, vitamin D, omega 3 and omega 6 fatty acids, and iron), adjusted for potential confounders, in relationship to child outcomes. Secondary analyses were conducted in a subset of cohorts with an expanded set of 14 nutrients. Traditional linear and logistic regression models were also analyzed for comparison of results to mixture models. RESULTS A total of 2614 participants drawn from 7 ECHO cohorts were included in primary analysis. Mixture analyses suggested that increasing the overall 5-nutrient mixture was associated with lower SRS scores. Individual U-shaped associations and bivariate interactions between folate and omega 3 fatty acids were suggested. In the subset included in the secondary analyses of the 14-nutrient mixture, a modest inverse trend remained, but individual nutrient associations were altered, with vitamin D demonstrating higher relative importance than other nutrients. Strong associations with autism diagnosis were not observed. CONCLUSIONS In this large sample, we found evidence for combined nutrient effects with broader autism-related traits. Because results for individual nutrients were sensitive to mixture components, replication of combined associations between nutrients and autism-related outcomes is needed.
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Affiliation(s)
- Megan G Bragg
- AJ Drexel Autism Institute, Drexel University, Philadelphia, PA, United States
| | - Juliette Rando
- AJ Drexel Autism Institute, Drexel University, Philadelphia, PA, United States
| | - Kecia N Carroll
- The Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Stephanie M Eick
- Rollins School of Public Health, Emory University, Atlanta, GA, United States
| | - Margaret R Karagas
- Geisel School of Medicine, Dartmouth College, Hanover, NH, United States
| | - Pi-I Lin
- Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, United States
| | - Rebecca J Schmidt
- Department of Public Health Sciences, School of Medicine, University of California Davis, Davis, CA, United States
| | - Kristen Lyall
- AJ Drexel Autism Institute, Drexel University, Philadelphia, PA, United States.
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Vasconcelos C, Perry IS, Gottfried C, Riesgo R, Castro K. Folic acid and autism: updated evidences. Nutr Neurosci 2025; 28:273-307. [PMID: 38968136 DOI: 10.1080/1028415x.2024.2367855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/07/2024]
Abstract
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that impairs communication, socialization, and behavior. The association of ASD with folic acid has been investigated due to the importance of this vitamin for neurological health. This study is an update of the publication 'Folic acid and autism: What do we know?' and aims to systematically review studies examining the relationship between folic acid and ASD. The search resulted in 2,389 studies on folic acid and ASD, which were selected by two reviewers based on their titles and abstracts. Studies meeting the inclusion criteria were fully read. The 52 included studies involved 10,429 individuals diagnosed with ASD and assessed the intake of vitamin B6, folic acid, and vitamin B12; serum levels of these vitamins, homocysteine, and methionine; therapeutic interventions using folic acid; and the association between maternal exposure to this vitamin and the risk of ASD. The evidence of insufficient folic acid intake in most individuals with ASD remains consistent in this update. No association was found between maternal exposure to folic acid and the risk of ASD in their children. Despite observed improvements in communication, socialization, and behavior in individuals with ASD following folic acid interventions, it is crucial to consider the individuality and complexity of ASD. Given the relevance of the topic, there remains a need for more high-quality research and clinical trials characterized by rigorous methodological designs.
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Affiliation(s)
- Cristiane Vasconcelos
- Postgraduate Program in Child and Adolescent Health, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Ingrid Schweigert Perry
- Food and Nutrition Research Center (CESAN), Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Carmem Gottfried
- Translational Research Group in Autism Spectrum Disorders-GETTEA, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
- Department of Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
- National Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Rio de Janeiro, Brazil
- Autism Wellbeing And Research Development (AWARD) Initiative, BR-UK- CA, Porto Alegre, Brazil
| | - Rudimar Riesgo
- Postgraduate Program in Child and Adolescent Health, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
- Translational Research Group in Autism Spectrum Disorders-GETTEA, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
- Child Neurology Unit, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Kamila Castro
- Postgraduate Program in Child and Adolescent Health, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
- Food and Nutrition Research Center (CESAN), Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
- Translational Research Group in Autism Spectrum Disorders-GETTEA, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
- Child Neurology Unit, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
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Olson A, Krall JR, Baranova A, Slavin M. Nutritional Intake and Sensory Processing in School-Aged Children with Autism Spectrum Disorder. Nutrients 2025; 17:604. [PMID: 40004933 PMCID: PMC11858489 DOI: 10.3390/nu17040604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 01/28/2025] [Accepted: 01/29/2025] [Indexed: 02/27/2025] Open
Abstract
Background: Individuals diagnosed with autism spectrum disorder (ASD) commonly experience sensory processing that differs from general-population norms, and the autistic lived experience of eating includes preferences for routine, and sensory processing difficulty related to scents, tastes, temperatures, and textures of food. Meanwhile, research indicates that nutrients involved in one-carbon metabolism (OCM) may be related to sensory processing. Methods: This study enrolled 33 school-aged children with autism to assess whether OCM nutrient intake is associated with sensory processing. Parents completed two parent-report assessments: the youth and adult food frequency questionnaire (YAFFQ), and a sensory processing tool, Sensory Profile 2 (SP2). Results: Participant data showed generally good nutritional profiles mirroring those of general-population U.S. children. A group-binarized linear regression model showed the following relationships (p < 0.05): vitamin B12 consumption had a negative association with the SP2 Oral and Sensor domain scores. Choline intake had a positive association with the SP2 Avoider domain score. Vitamin B1 showed a positive association with the SP2 Visual domain score. Conclusions: These results support the possible existence of a relationship between sensory symptoms and OCM nutrient consumption levels in school-aged children diagnosed with autism. Future research is needed to confirm and explore the potential for causality.
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Affiliation(s)
- Audrey Olson
- School of Systems Biology, George Mason University, Manassas, VA 20110, USA; (A.O.); (A.B.)
| | - Jenna R. Krall
- Department of Global and Community Health, George Mason University, Fairfax, VA 22030, USA;
| | - Ancha Baranova
- School of Systems Biology, George Mason University, Manassas, VA 20110, USA; (A.O.); (A.B.)
| | - Margaret Slavin
- Department of Nutrition and Food Studies, George Mason University, Fairfax, VA 22030, USA
- Department of Nutrition and Food Science, University of Maryland, College Park, MD 20742, USA
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Wong CM, Tan CS, Koh HC, Gan X, Hie SL, Saffari SE, Yeo JG, Lam JCM. Folinic acid as a treatment for autism in children: A within-subjects open-label study on safety and efficacy. Int J Dev Neurosci 2025; 85:e10402. [PMID: 39703043 DOI: 10.1002/jdn.10402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Revised: 11/29/2024] [Accepted: 11/29/2024] [Indexed: 12/21/2024] Open
Abstract
The folate cycle has been implicated in the pathophysiology of autism due to its role in the glutathione oxidative stress pathway, amino acid and DNA methylation reactions, and neurotransmitter synthesis pathway. Previous research on folinic acid supplementation in autistic children has suggested potential benefits. The primary aim of this pilot study was to determine the safety, feasibility and efficacy of oral folinic acid in improving communication and behaviour in autistic children. Ten autistic children were recruited into an open-label pre-post treatment within-subjects design study. At T = 0, 12 and 24 weeks, participants underwent safety evaluations, standardized assessments of language, autism symptoms, adaptive skills and global illness severity, and eye-gaze tracking. During the control period (0-12 weeks), participants continued with standard care. In the treatment period (12-24 weeks), participants took oral folinic acid at 2 mg/kg/day. All 10 children (nine boys, one girl; aged 4-8 years), successfully consumed oral folinic acid supplements with no adverse events. There was a reduction in Pervasive Developmental Disorder Behavior Inventory (PDDBI) Autism Composite T-score with treatment (mean [SD] T-score 49.2 [8.89] pre-treatment, 44.6 [6.19] post-treatment, p = 0.103). Although this difference was not statistically significant due to the small sample size, the effect size was medium-large, indicating that, as a group, there were clinically meaningful changes in PDDBI T-scores. There were also trends towards gains in communication scores and overall Clinical Global Impression scores. Folinic acid is a safe and feasible potential treatment for autism, and results from this pilot justify the need for a larger placebo-controlled trial.
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Affiliation(s)
- Chui Mae Wong
- Department of Child Development, KK Women's and Children's Hospital, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Duke-NUS Medical School, Singapore
- Lee Kong Chian School of Medicine, Singapore
| | | | - Hwan Cui Koh
- Department of Child Development, KK Women's and Children's Hospital, Singapore
| | - Xinyi Gan
- Department of Child Development, KK Women's and Children's Hospital, Singapore
| | - Szu Liang Hie
- Outpatient Pharmacy, KK Women's and Children's Hospital, Singapore
| | | | - Joo Guan Yeo
- Duke-NUS Medical School, Singapore
- Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore
| | - Joyce Ching Mei Lam
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Duke-NUS Medical School, Singapore
- Lee Kong Chian School of Medicine, Singapore
- Children's Blood and Cancer Centre, KK Women's and Children's Hospital, Singapore
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Kolanis S, Kotanidou EP, Tsinopoulou VR, Georgiou E, Hatzipantelis E, Fidani L, Galli-Tsinopoulou A. MTHFR Gene Polymorphisms and Cancer Risk in Children and Adolescents: A Systematic Review and Meta-Analysis. CHILDREN (BASEL, SWITZERLAND) 2025; 12:108. [PMID: 39857939 PMCID: PMC11764102 DOI: 10.3390/children12010108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/05/2025] [Accepted: 01/13/2025] [Indexed: 01/27/2025]
Abstract
Background/Objectives:MTHFR gene polymorphisms (677C>T and 1298A>C) correlate with various types of cancer across all age groups; however, a small number of studies have included solely children and adolescents. The aim of this systematic review and meta-analysis was to present and synthesize all the available evidence on the association between MTHFR gene polymorphisms and the incidence of all types of cancer in children and adolescences. Methods: After a systematic search of all of the available data, original case-control studies involving children or adolescents with a confirmed diagnosis of any type of cancer and a molecular genetic test of MTHFR gene polymorphisms were included. Results: A total of 53 original studies in children and adolescents with cancer were included in the systematic review. Among these, 40 studies reviewed children and adolescents with Acute Lymphoblastic Leukemia (ALL), 4 those with Acute Myeloblastic Leukemia (AML), 8 those with central nervous system (CNS) tumors and 3 those with other types of cancer. Children and adolescents with ALL had less frequent T allele sequences (CT and TT variations) of the 677C>T polymorphism compared to a healthy population (OR: 0.85; CI: 0.80-0.91; p < 0.00001). Concerning the 1298A>C polymorphism, the C allele sequences (AC and CC) did not present a statistically significant difference in frequency compared to a healthy population (OR: 1.01; CI: 0.95-1.08; p = 0.69). Conclusions: Children and adolescents with ALL appeared to have the T allele sequences of the 677C>T polymorphism of the MTHFR gene less frequently compared to a healthy population.
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Affiliation(s)
- Savvas Kolanis
- 2nd Department of Paediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, AHEPA University Hospital, 54636 Thessaloniki, Greece; (S.K.); (E.P.K.); (V.R.T.); (E.H.); (L.F.)
| | - Eleni P. Kotanidou
- 2nd Department of Paediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, AHEPA University Hospital, 54636 Thessaloniki, Greece; (S.K.); (E.P.K.); (V.R.T.); (E.H.); (L.F.)
| | - Vasiliki Rengina Tsinopoulou
- 2nd Department of Paediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, AHEPA University Hospital, 54636 Thessaloniki, Greece; (S.K.); (E.P.K.); (V.R.T.); (E.H.); (L.F.)
| | - Elisavet Georgiou
- Laboratory of Biological Chemistry, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
| | - Emmanuel Hatzipantelis
- 2nd Department of Paediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, AHEPA University Hospital, 54636 Thessaloniki, Greece; (S.K.); (E.P.K.); (V.R.T.); (E.H.); (L.F.)
| | - Liana Fidani
- 2nd Department of Paediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, AHEPA University Hospital, 54636 Thessaloniki, Greece; (S.K.); (E.P.K.); (V.R.T.); (E.H.); (L.F.)
- Laboratory of Medical Biology-Genetics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Assimina Galli-Tsinopoulou
- 2nd Department of Paediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, AHEPA University Hospital, 54636 Thessaloniki, Greece; (S.K.); (E.P.K.); (V.R.T.); (E.H.); (L.F.)
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Ekundayo BE, Adewale OB, Obafemi TO. Neuroprotective Effects of Folic Acid: A Review. J Diet Suppl 2024; 22:345-363. [PMID: 39648692 DOI: 10.1080/19390211.2024.2436842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/10/2024]
Abstract
Folic acid also known as folate and vitamin B9 is of the class of B complex vitamins. It is crucial for homeostatic function of the biological system and is not endogenously produced. It is medically approved for the treatment of megaloblastic anemia. Neurological conditions describe a class of disease conditions that affect the brain, spinal cord and nerves impacting several important functions such as cognition, movement, emotion and sensation. They can arise from a number of causes which may include one or more of genetic factors, infections, injuries, toxins and degenerative process. Homocysteine, a neurotoxic amino acid converted by folic acid has been identified in the pathology of many neurological conditions while folic acid on the other hand has been investigated multiple times for its neuroprotective function and mechanism. Folic acid is involved in the neutralization of homocysteine to its nontoxic form. This article highlights some of the reports of the neuroprotective effect of folic acid against homocysteine toxicity, neurodegenerative diseases, neuropsychiatric conditions, fetal and neonatal neuronal health.
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Affiliation(s)
| | | | - Tajudeen Olabisi Obafemi
- Department of Life and Consumer Sciences, University of South Africa, Johannesburg, South Africa
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Xu T, Na J, Liu Q, Kuang G, Zhang Q, Zhao Y. The function of albumin and its application in tumor therapy. MATERIALS TODAY COMMUNICATIONS 2024; 41:110575. [DOI: 10.1016/j.mtcomm.2024.110575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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9
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Kong AX, Johnson M, Eno AF, Pham K, Zhang P, Geng Y. Proteome-wide reverse molecular docking reveals folic acid receptor as a mediator of PFAS-induced neurodevelopmental toxicity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.11.623082. [PMID: 39605555 PMCID: PMC11601370 DOI: 10.1101/2024.11.11.623082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
Per- and polyfluoroalkyl substances (PFAS) are a class of long-lasting chemicals with widespread use and environmental persistence that have been increasingly studied for their detrimental impacts to human and animal health. Several major PFAS species are linked to neurodevelopmental toxicity. For example, epidemiological studies have associated prenatal exposure to perfluorooctanoate (PFOA) and perfluorononanoate (PFNA) with autism risk. However, the neurodevelopmental toxicities of major PFAS species have not been systematically evaluated in an animal model, and the molecular mechanisms underlying these toxicities have remained elusive. Using a high-throughput zebrafish social behavioral model, we screened six major PFAS species currently under regulation by the Environmental Protection Agency (EPA), including PFOA, PFNA, perfluorooctane sulfonate (PFOS), perfluorohexanesulfonic acid (PFHxS), perfluorobutane sulfonate (PFBS), and hexafluoropropylene oxide dimer acid ammonium salt (GenX). We found that embryonic exposure to PFNA, PFOA, and PFOS induced social deficits in zebrafish, recapitulating one of the hallmark behavioral deficits in autistic individuals. To uncover protein targets of the six EPA-regulated PFAS, we screened a virtual library containing predicted binding pockets of over 80% of the 3D human proteome through reverse molecular docking. We found that folate receptor beta (FR-β, encoded by the gene FOLR2) interacts strongly with PFNA, PFOA, and PFOS but to a lesser degree with PFHxS, PFBS, and GenX, correlating positively with their in vivo toxicity. Embryonic co-exposure to folic acid rescued social deficits induced by PFAS. The folic acid pathway has been implicated in autism, indicating a novel molecular mechanism for PFAS in autism etiology.
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Affiliation(s)
- Ally Xinyi Kong
- Department of Environmental and Occupational Health Sciences, Seattle, WA 98105, USA
| | - Maja Johnson
- Department of Environmental and Occupational Health Sciences, Seattle, WA 98105, USA
| | - Aiden F Eno
- Department of Environmental and Occupational Health Sciences, Seattle, WA 98105, USA
| | - Khoa Pham
- Department of Environmental and Occupational Health Sciences, Seattle, WA 98105, USA
| | - Ping Zhang
- Department of Environmental and Occupational Health Sciences, Seattle, WA 98105, USA
| | - Yijie Geng
- Department of Environmental and Occupational Health Sciences, Seattle, WA 98105, USA
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10
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Liu Q, Yu D. Interaction and association between multiple vitamins and social adaptability and severity of autism: A large-scale retrospective study from China. Autism Res 2024. [PMID: 39327156 DOI: 10.1002/aur.3241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Accepted: 09/19/2024] [Indexed: 09/28/2024]
Abstract
Since children with autism spectrum disorder (ASD) often exhibit selective eating behaviors, it is generally believed that they may have abnormal nutrient structure, leading to aberrant concentrations of some serum vitamins. However, previous studies on serum vitamins in individuals with ASD are mixed. Additionally, the interaction and association between multiple serum vitamin and ASD-related symptoms remain unclear. This study utilized a cross-sectional survey with a large sample size (n = 1235) from China to clarify previous mixed findings, and examine the interaction and association between multiple serum vitamins (including folic acid [FA], vitamin A [VA], vitamin E [VE], vitamin B12 [VB12], and vitamin D [VD]) and social adaptability and symptom severity in children with ASD. Findings found that symptom severity was negatively associated with concentrations of serum VA, VE, VB12, and VD; while, social adaptability was significantly associated with the natural log-transformed concentrations of FA and VB12. Finding also revealed the interaction of VA and VE on the association between both vitamins and severity of ASD symptoms, as well as the interaction of VB12 and FA on the association between both vitamins and social adaptability. In particular, the combination of low concentration of VA and high concentration of VE is associated with the lowest risk of being "severely autistic"; while, the combination of low concentration of FA and high concentration of VB12 is associated with the lowest risk of being "poor social adaptability". This study offers the evidence for the requirement of considering multiple vitamins comprehensively, as well as valuable references for revealing the association between vitamin disparities and food selectivity in children with ASD.
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Affiliation(s)
- Qi Liu
- Henan Provincial Medical Key Lab of Child Developmental Behavior and Learning, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Provincial Engineering Research Center of Children's Digital Rehabilitation, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Dongchuan Yu
- Henan Provincial Medical Key Lab of Child Developmental Behavior and Learning, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Provincial Engineering Research Center of Children's Digital Rehabilitation, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou, China
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11
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Zou M, Zhang Y, Li D, Li S, Hu J, Gao Y, Cheng Z, Liu S, Wu L, Sun C. Correlation of Co-Morbidities with Symptom Severity of Children with Autism Spectrum Disorder: A Cross-Sectional Survey. Nutrients 2024; 16:2960. [PMID: 39275276 PMCID: PMC11397295 DOI: 10.3390/nu16172960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 08/23/2024] [Accepted: 08/30/2024] [Indexed: 09/16/2024] Open
Abstract
This study aims to identify potential correlations of the severity of symptoms of children with autism spectrum disorder (ASD) with serum nutritional levels, body composition indicators, diet partiality, and sleep disturbances. The cohort of this cross-sectional study included 120 children with ASD and 110 typically developing (TD) children to assess symptoms of ASD, and to measure serum levels of vitamins and minerals and the body composition values. Diet partiality and sleep disturbances were assessed by administering questionnaires. The serum levels of folic acid, copper, and vitamin B were lower in children with ASD than in TD children, while magnesium and homocysteine were higher (p < 0.05). Children with ASD had greater chest circumference, abdominal skinfold thickness, and body mass index (BMI) than TD children (p < 0.05), and higher prevalences of diet partiality and sleep disturbances (p < 0.001). Lower vitamin A levels and higher vitamin D levels were related to social impairment in children with ASD. Moreover, there were significantly positive correlations of BMI, chest circumference, diet partiality, and sleep disturbances with severity of ASD symptoms (p < 0.05). Collectively, rational nutritional supplementation, dietary management, and behavioral interventions are essential for children with ASD.
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Affiliation(s)
- Mingyang Zou
- Department of Children's and Adolescent Health, College of Public Health, Harbin Medical University, Harbin 150081, China
| | - Yilin Zhang
- Department of Children's and Adolescent Health, College of Public Health, Harbin Medical University, Harbin 150081, China
| | - Dexin Li
- Department of Children's and Adolescent Health, College of Public Health, Harbin Medical University, Harbin 150081, China
| | - Shengqi Li
- Beijing Normal University-Hong Kong Baptist University United International College, Zhuhai 519087, China
| | - Jingyi Hu
- Department of Children's and Adolescent Health, College of Public Health, Harbin Medical University, Harbin 150081, China
| | - Ya Gao
- Department of Children's and Adolescent Health, College of Public Health, Harbin Medical University, Harbin 150081, China
| | - Zeyu Cheng
- Department of Children's and Adolescent Health, College of Public Health, Harbin Medical University, Harbin 150081, China
| | - Shidan Liu
- Department of Children's and Adolescent Health, College of Public Health, Harbin Medical University, Harbin 150081, China
| | - Lijie Wu
- Department of Children's and Adolescent Health, College of Public Health, Harbin Medical University, Harbin 150081, China
| | - Caihong Sun
- Department of Children's and Adolescent Health, College of Public Health, Harbin Medical University, Harbin 150081, China
- Department of Developmental Behavioral Pediatrics, The Sixth Affiliated Hospital of Harbin Medical University, Harbin 150023, China
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12
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Bragg MG, Gorski-Steiner I, Song A, Chavarro JE, Hart JE, Tabb LP, Weisskopf MG, Volk H, Lyall K. Prenatal air pollution and children's autism traits score: Examination of joint associations with maternal intake of vitamin D, methyl donors, and polyunsaturated fatty acids using mixture methods. Environ Epidemiol 2024; 8:e316. [PMID: 38919264 PMCID: PMC11196080 DOI: 10.1097/ee9.0000000000000316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 05/21/2024] [Indexed: 06/27/2024] Open
Abstract
Background Maternal nutrient intake may moderate associations between environmental exposures and children's neurodevelopmental outcomes, but few studies have assessed joint effects. We aimed to evaluate whether prenatal nutrient intake influences the association between air pollutants and autism-related trait scores. Methods We included 126 participants from the EARLI (Early Autism Risk Longitudinal Investigation, 2009-2012) cohort, which followed US pregnant mothers who previously had a child with autism. Bayesian kernel machine regression and traditional regression models were used to examine joint associations of prenatal nutrient intake (vitamins D, B12, and B6; folate, choline, and betaine; and total omega 3 and 6 polyunsaturated fatty acids, reported via food frequency questionnaire), air pollutant exposure (particulate matter <2.5 μm [PM2.5], nitrogen dioxide [NO2], and ozone [O3], estimated at the address level), and children's autism-related traits (measured by the Social Responsiveness Scale [SRS] at 36 months). Results Most participants had nutrient intakes and air pollutant exposures that met US standards. Bayesian kernel machine regression mixture models and traditional regression models provided little evidence of individual or joint associations of nutrients and air pollutants with SRS scores or of an association between the overall mixture and SRS scores. Conclusion In this cohort with a high familial likelihood of autism, we did not observe evidence of joint associations between air pollution exposures and nutrient intake with autism-related traits. Future work should examine the use of these methods in larger, more diverse samples, as our results may have been influenced by familial liability and/or relatively high nutrient intakes and low air pollutant exposures.
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Affiliation(s)
- Megan G. Bragg
- AJ Drexel Autism Institute, Drexel University, Philadelphia, Pennsylvania
| | - Irena Gorski-Steiner
- Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland
| | - Ashley Song
- Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland
| | - Jorge E. Chavarro
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Jaime E. Hart
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Loni P. Tabb
- Department of Epidemiology and Biostatistics, Dornsife School of Public Health, Drexel University, Philadelphia, Pennsylvania
| | - Marc G. Weisskopf
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Heather Volk
- Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland
| | - Kristen Lyall
- AJ Drexel Autism Institute, Drexel University, Philadelphia, Pennsylvania
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13
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Abedini SS, Akhavantabasi S, Liang Y, Heng JIT, Alizadehsani R, Dehzangi I, Bauer DC, Alinejad-Rokny H. A critical review of the impact of candidate copy number variants on autism spectrum disorder. MUTATION RESEARCH. REVIEWS IN MUTATION RESEARCH 2024; 794:108509. [PMID: 38977176 DOI: 10.1016/j.mrrev.2024.108509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Revised: 04/14/2024] [Accepted: 07/02/2024] [Indexed: 07/10/2024]
Abstract
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder (NDD) influenced by genetic, epigenetic, and environmental factors. Recent advancements in genomic analysis have shed light on numerous genes associated with ASD, highlighting the significant role of both common and rare genetic mutations, as well as copy number variations (CNVs), single nucleotide polymorphisms (SNPs) and unique de novo variants. These genetic variations disrupt neurodevelopmental pathways, contributing to the disorder's complexity. Notably, CNVs are present in 10 %-20 % of individuals with autism, with 3 %-7 % detectable through cytogenetic methods. While the role of submicroscopic CNVs in ASD has been recently studied, their association with genomic loci and genes has not been thoroughly explored. In this review, we focus on 47 CNV regions linked to ASD, encompassing 1632 genes, including protein-coding genes and long non-coding RNAs (lncRNAs), of which 659 show significant brain expression. Using a list of ASD-associated genes from SFARI, we detect 17 regions harboring at least one known ASD-related protein-coding gene. Of the remaining 30 regions, we identify 24 regions containing at least one protein-coding gene with brain-enriched expression and a nervous system phenotype in mouse mutants, and one lncRNA with both brain-enriched expression and upregulation in iPSC to neuron differentiation. This review not only expands our understanding of the genetic diversity associated with ASD but also underscores the potential of lncRNAs in contributing to its etiology. Additionally, the discovered CNVs will be a valuable resource for future diagnostic, therapeutic, and research endeavors aimed at prioritizing genetic variations in ASD.
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Affiliation(s)
- Seyedeh Sedigheh Abedini
- UNSW BioMedical Machine Learning Lab (BML), The Graduate School of Biomedical Engineering, UNSW Sydney, Sydney, NSW 2052, Australia; School of Biotechnology & Biomolecular Sciences, UNSW Sydney, Sydney, NSW 2052, Australia
| | - Shiva Akhavantabasi
- Department of Molecular Biology and Genetics, Yeni Yuzyil University, Istanbul, Turkey; Ghiaseddin Jamshid Kashani University, Andisheh University Town, Danesh Blvd, 3441356611, Abyek, Qazvin, Iran
| | - Yuheng Liang
- UNSW BioMedical Machine Learning Lab (BML), The Graduate School of Biomedical Engineering, UNSW Sydney, Sydney, NSW 2052, Australia
| | - Julian Ik-Tsen Heng
- Curtin Health Innovation Research Institute, Curtin University, Bentley 6845, Australia
| | - Roohallah Alizadehsani
- Institute for Intelligent Systems Research and Innovation (IISRI), Deakin University, Victoria, Australia
| | - Iman Dehzangi
- Center for Computational and Integrative Biology, Rutgers University, Camden, NJ 08102, USA; Department of Computer Science, Rutgers University, Camden, NJ 08102, USA
| | - Denis C Bauer
- Transformational Bioinformatics, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Sydney, Australia; Applied BioSciences, Faculty of Science and Engineering, Macquarie University, Macquarie Park, Australia
| | - Hamid Alinejad-Rokny
- UNSW BioMedical Machine Learning Lab (BML), The Graduate School of Biomedical Engineering, UNSW Sydney, Sydney, NSW 2052, Australia; Tyree Institute of Health Engineering (IHealthE), UNSW Sydney, Sydney, NSW 2052, Australia.
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14
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Wei Q, Xiao Y, Yang T, Chen J, Chen L, Wang K, Zhang J, Li L, Jia F, Wu L, Hao Y, Ke X, Yi M, Hong Q, Chen J, Fang S, Wang Y, Wang Q, Jin C, Xu X, Li T. Predicting autism spectrum disorder using maternal risk factors: A multi-center machine learning study. Psychiatry Res 2024; 334:115789. [PMID: 38452495 DOI: 10.1016/j.psychres.2024.115789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 02/02/2024] [Accepted: 02/11/2024] [Indexed: 03/09/2024]
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a complex environmental etiology involving maternal risk factors, which have been combined with machine learning to predict ASD. However, limited studies have considered the factors throughout preconception, perinatal, and postnatal periods, and even fewer have been conducted in multi-center. In this study, five predictive models were developed using 57 maternal risk factors from a cohort across ten cities (ASD:1232, typically developing[TD]: 1090). The extreme gradient boosting model performed best, achieving an accuracy of 66.2 % on the external cohort from three cities (ASD:266, TD:353). The most important risk factors were identified as unstable emotions and lack of multivitamin supplementation using Shapley values. ASD risk scores were calculated based on predicted probabilities from the optimal model and divided into low, medium, and high-risk groups. The logistic analysis indicated that the high-risk group had a significantly increased risk of ASD compared to the low-risk group. Our study demonstrated the potential of machine learning models in predicting the risk for ASD based on maternal factors. The developed model provided insights into the maternal emotion and nutrition factors associated with ASD and highlighted the potential clinical applicability of the developed model in identifying high-risk populations.
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Affiliation(s)
- Qiuhong Wei
- Children Nutrition Research Center, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Chongqing, China
| | - Yuanjie Xiao
- Children Nutrition Research Center, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Chongqing, China
| | - Ting Yang
- Children Nutrition Research Center, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Chongqing, China
| | - Jie Chen
- Children Nutrition Research Center, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Chongqing, China
| | - Li Chen
- Department of Children's Healthcare, Children's Hospital of Chongqing Medical University, China
| | - Ke Wang
- Children Nutrition Research Center, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Chongqing, China; Big Data Center for Children's Medical Care, Children's Hospital of Chongqing Medical University, No. 136. Zhongshan Er Rd, Yuzhong District, Chongqing 400014, China
| | - Jie Zhang
- Xi'an Children's Hospital, Xi'an, China
| | - Ling Li
- Department of Children Rehabilitation, Hainan Women and Children's Medical Center, Haikou, China
| | - Feiyong Jia
- Department of Developmental and Behavioral Pediatric, The First Hospital of Jilin University, Changchun, China
| | - Lijie Wu
- Department of Children's and Adolescent Health, Public Health College of Harbin Medical University, Harbin, China
| | - Yan Hao
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoyan Ke
- Child Mental Health Research Center of Nanjing Brain Hospital, Nanjing, China
| | - Mingji Yi
- Department of Child Health Care, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Qi Hong
- Maternal and Child Health Hospital of Baoan, Shenzhen, China
| | - Jinjin Chen
- Department of Child Healthcare, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Shuanfeng Fang
- Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, China
| | - Yichao Wang
- NHC Key Laboratory of Birth Defect for Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, China
| | - Qi Wang
- Deyang Maternity & Child Healthcare Hospital, Deyang, China
| | - Chunhua Jin
- Department of Children Health Care, Capital Institute of Pediatrics, Beijing, China
| | - Ximing Xu
- Big Data Center for Children's Medical Care, Children's Hospital of Chongqing Medical University, No. 136. Zhongshan Er Rd, Yuzhong District, Chongqing 400014, China.
| | - Tingyu Li
- Children Nutrition Research Center, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Chongqing, China.
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15
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Shi A, Liu D, Wu H, Zhu R, Deng Y, Yao L, Xiao Y, Lorimer GH, Ghiladi RA, Xu X, Zhang R, Xu H, Wang J. Serum binding folate receptor autoantibodies lower in autistic boys and positively-correlated with folate. Biomed Pharmacother 2024; 172:116191. [PMID: 38320332 DOI: 10.1016/j.biopha.2024.116191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 01/15/2024] [Accepted: 01/18/2024] [Indexed: 02/08/2024] Open
Abstract
Folate receptor autoantibody (FRAA) has caught increasing attention since its discovery in biological fluids of patients with autism spectrum disorder (ASD), but quantification and understanding of its function are still in their infancy. In this study, we aimed to quantify serum binding-FRAA and explore its relation with serum folate, vitamin B12 (VB12) and ferritin. We quantitated serum binding-FRAA in 132 ASD children and 132 typically-developing (TD) children, as well as serum levels of folate, VB12 and ferritin. The results showed that serum binding-FRAA in the ASD group was significantly lower than that in the TD group (p < 0.0001). Further analysis showed that the difference between these two groups was attributed to boys in each group, not girls. There was no statistically significant difference in folate levels between the ASD and TD groups (p > 0.05). However, there was significant difference in boys between these two groups, not girls. Additionally, the combination of nitrite and binding-FRAA showed potential diagnostic value in patients with ASD (AUC > 0.7). Moreover, in the ASD group, the level of folate was consistent with that of binding-FRAA, whereas in the TD group, the binding-FRAA level was high when the folate level was low. Altogether, these differences revealed that the low serum FRAA in autistic children was mediated by multiple factors, which deserves more comprehensive investigation with larger population and mechanistic studies.
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Affiliation(s)
- Ai Shi
- Center for Redox Biology & Precision Medicine of Hubei Province, Hubei University of Technology, Wuhan, Hubei Province, China; Department of Child Health Care, Hubei Maternity and Child Health Care Hospital, Wuhan, Hubei Province, China; Cooperative Innovation Center of Industrial Fermentation, Ministry of Education & Hubei Province, Hubei University of Technology, Wuhan, Hubei Province, China
| | - Di Liu
- Center for Redox Biology & Precision Medicine of Hubei Province, Hubei University of Technology, Wuhan, Hubei Province, China; Department of Child Health Care, Hubei Maternity and Child Health Care Hospital, Wuhan, Hubei Province, China; Cooperative Innovation Center of Industrial Fermentation, Ministry of Education & Hubei Province, Hubei University of Technology, Wuhan, Hubei Province, China
| | - Huiwen Wu
- Cooperative Innovation Center of Industrial Fermentation, Ministry of Education & Hubei Province, Hubei University of Technology, Wuhan, Hubei Province, China; Autism & Depression Diagnosis and Intervention Institute, Hubei University of Technology, Wuhan, Hubei Province, China
| | - Rui Zhu
- Center for Redox Biology & Precision Medicine of Hubei Province, Hubei University of Technology, Wuhan, Hubei Province, China; Department of Child Health Care, Hubei Maternity and Child Health Care Hospital, Wuhan, Hubei Province, China; Cooperative Innovation Center of Industrial Fermentation, Ministry of Education & Hubei Province, Hubei University of Technology, Wuhan, Hubei Province, China
| | - Ying Deng
- Center for Redox Biology & Precision Medicine of Hubei Province, Hubei University of Technology, Wuhan, Hubei Province, China; Department of Child Health Care, Hubei Maternity and Child Health Care Hospital, Wuhan, Hubei Province, China; Cooperative Innovation Center of Industrial Fermentation, Ministry of Education & Hubei Province, Hubei University of Technology, Wuhan, Hubei Province, China
| | - Lulu Yao
- Center for Redox Biology & Precision Medicine of Hubei Province, Hubei University of Technology, Wuhan, Hubei Province, China; Department of Child Health Care, Hubei Maternity and Child Health Care Hospital, Wuhan, Hubei Province, China; Cooperative Innovation Center of Industrial Fermentation, Ministry of Education & Hubei Province, Hubei University of Technology, Wuhan, Hubei Province, China
| | - Yaqian Xiao
- Center for Redox Biology & Precision Medicine of Hubei Province, Hubei University of Technology, Wuhan, Hubei Province, China; Department of Child Health Care, Hubei Maternity and Child Health Care Hospital, Wuhan, Hubei Province, China; Cooperative Innovation Center of Industrial Fermentation, Ministry of Education & Hubei Province, Hubei University of Technology, Wuhan, Hubei Province, China
| | | | - Reza A Ghiladi
- Department of Chemistry, North Carolina State University, North Carolina, USA
| | - Xinjie Xu
- Medical Science Research Center, Research Center for Translational Medicine, Department of Scientific Research, Peking Union Medical College Hospital, China
| | - Rong Zhang
- Neuroscience Research Institute, Peking University, Beijing 100191, China
| | - Haiqing Xu
- Cooperative Innovation Center of Industrial Fermentation, Ministry of Education & Hubei Province, Hubei University of Technology, Wuhan, Hubei Province, China; Autism & Depression Diagnosis and Intervention Institute, Hubei University of Technology, Wuhan, Hubei Province, China.
| | - Jun Wang
- Center for Redox Biology & Precision Medicine of Hubei Province, Hubei University of Technology, Wuhan, Hubei Province, China; Department of Child Health Care, Hubei Maternity and Child Health Care Hospital, Wuhan, Hubei Province, China; Cooperative Innovation Center of Industrial Fermentation, Ministry of Education & Hubei Province, Hubei University of Technology, Wuhan, Hubei Province, China.
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16
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Zhou Z, Wang M, Fan Q, Zhao Y, Wang N. The function of chemical folic acid in calibration methods and neurodevelopmental disorders. Front Chem 2024; 12:1355848. [PMID: 38456186 PMCID: PMC10917952 DOI: 10.3389/fchem.2024.1355848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Accepted: 01/31/2024] [Indexed: 03/09/2024] Open
Abstract
Functional molecules have been attracting increasing attention in environmental and physiological studies. In particular, folic acid (FA) could be considered a key factor in estimating, adjusting, and making decisions in the treatment of neurodevelopmental disorders. It promotes the general significance and conceptual for considering FA molecular scientific research detections, which implies related advancement in both of biological structure and detection methods. Among these applications, the FA molecule acts as a coenzyme that incorporates carbon atoms and synthesizes purines and pyrimidines. Therefore, the calibration method has real applications and can be used as a sensing platform and for detection approaches, which conveys the internal relationship between the FA molecule and physiological characterization. This mini review briefly discusses multiple FA application fields and detection pathways and could supplement their utilization in anticipation of the onset of disease.
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Affiliation(s)
- Ziqi Zhou
- Department of Children Healthcare, Chongqing Health Center for Women and Children, Chongqing, China
| | - Meng Wang
- Child and Adolescent Department of Chongqing Mental Health Center, Chongqing, China
| | - Qiongli Fan
- Department of Pediatrics, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Yan Zhao
- Department of Children Healthcare, Chongqing Health Center for Women and Children, Chongqing, China
| | - Nianrong Wang
- Department of Children Healthcare, Chongqing Health Center for Women and Children, Chongqing, China
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17
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Mashayekhi F, Hadipour E, Shabani S, Salehi Z. Folate receptor alpha autoantibodies in the serum of patients with relapsing-remitting multiple sclerosis (RRMS). Clin Neurol Neurosurg 2024; 237:108161. [PMID: 38325038 DOI: 10.1016/j.clineuro.2024.108161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 01/30/2024] [Accepted: 02/01/2024] [Indexed: 02/09/2024]
Abstract
OBJECTIVE Multiple sclerosis (MS) is a potentially progressive, autoimmune neurologic disorder of the central nervous system (CNS), resulting from an autoimmune attack on central nervous system white matter. Folate deficiencies are linked to DNA instability and breakdown of phospholipid membranes and thus might affect myelin integrity. Folic acid exerts its effects through its receptors (FRs). Folate receptor alpha autoantibodies (FRAA) can block folate transport to the brain. Due to important role of folate in the pathogenesis of MS, in this project we aimed to study FRAA serum levels in patients with relapsing remitting multiple sclerosis (RRMS). METHODS Fifty-four patients with RRMS and 58 healthy individuals were enrolled in this study. Serum samples were collected from all participants and folate receptor alpha autoantibody (FRAA) serum concentration was measured by Enzyme-linked immunosorbent assay (ELISA). RESULTS The results showed that FRAA serum levels in patients with RRMS is 67.20 ± 19.79 ng/ml as compared to controls which was 37.32 ± 13.26 ng/ml. Significant increase in folate receptor autoantibody serum concentration was seen in patients with RRMS when compared to control group (P = 0.007). The results showed that a high concentration of folate receptor autoantibody is associated with RRMS. We have also found that 85.18% (46/54) of patients with RRMS were positive for serum FRAA, whereas the prevalence in controls was only 46.55% (27/58). CONCLUSIONS It is concluded that serum FRAA are more prevalent in RRMS patients than controls. The findings also suggest that FRAA might be involved in the pathophysiology of RRMS.
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Affiliation(s)
- Farhad Mashayekhi
- Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran.
| | - Elham Hadipour
- Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran
| | - Somayeh Shabani
- Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran
| | - Zivar Salehi
- Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran
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18
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Jiang Y, Guo C, Kuang M, Lin L, Xu G, Pan N, Weng X, Jing J, Shi L, Yi Q, Wang X. Examining associations of folic acid supplements administered to mothers during pre-conceptional and prenatal periods with autism spectrum disorders in their offspring: insights from a multi-center study in China. Front Public Health 2024; 12:1321046. [PMID: 38299071 PMCID: PMC10827999 DOI: 10.3389/fpubh.2024.1321046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Accepted: 01/02/2024] [Indexed: 02/02/2024] Open
Abstract
Objective To investigate the relationship between maternal folic acid (FA) supplementation during the pre-conceptional and prenatal periods and the subsequent risk of autism spectrum disorder (ASD) in offspring. Methods A total of 6,049 toddlers aged 16-30 months were recruited from August 2016 to March 2017 for this cross-sectional study conducted in China. The parents of the enrolled toddlers provided information on maternal supplemental FA, socio-demographic information, and related covariates. Standard diagnostic procedures were implemented to identify toddlers with ASD. Results Among the 6,049 children included in the study, consisting of 3,364 boys with an average age of 22.7 ± 4.1 months, a total of 71 children (1.2%) were diagnosed with ASD. Mothers who did not consume FA supplements during the prenatal period were found to have a significantly increased risk of having offspring with ASD, in comparison to those who were exposed to FA supplements (odds ratio [OR] = 2.47). However, we did not find a similar association during the pre-conceptional period. Compared to mothers who consistently used FA supplements from pre-conception to the prenatal period, those who never used FA supplements were statistically significantly associated with a higher risk of ASD in their offspring (OR = 2.88). Conclusion This study indicated that providing continuous maternal FA supplementation during the pre-conceptional and prenatal periods may decrease the risk of ASD in offspring. The prenatal period is considered to be the most crucial time for intervention.
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Affiliation(s)
- Yan Jiang
- Department of Children Health Care, Dongguan Children's Hospital, Dongguan, Guangdong, China
| | - Cuihua Guo
- Department of Children Health Care, Dongguan Children's Hospital, Dongguan, Guangdong, China
| | - Min Kuang
- Department of Children Health Care, Dongguan Children's Hospital, Dongguan, Guangdong, China
| | - Lizi Lin
- Department of Occupational and Environmental Health, Guangdong Provincial Engineering Technology Research Center of Environmental Pollution and Health Risk Assessment, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Guifeng Xu
- The First Affiliated Hospital, University of Science and Technology of China, Hefei, Anhui, China
| | - Ning Pan
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education; Institute for Brain Research and Rehabilitation, and Guangdong Key Laboratory of Mental Health and Cognitive Science, South China Normal University, Guangzhou, Guangdong, China
| | - Xuchu Weng
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education; Institute for Brain Research and Rehabilitation, and Guangdong Key Laboratory of Mental Health and Cognitive Science, South China Normal University, Guangzhou, Guangdong, China
| | - Jin Jing
- Department of Maternal and Child Health, Research Center of Children and Adolescent Psychological and Behavioral Development, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Lei Shi
- JNU-HKUST Joint Laboratory for Neuroscience and Innovative Drug Research, College of Pharmacy, Jinan University, Guangzhou, Guangdong, China
| | - Quanying Yi
- Department of Children Health Care, Dongguan Children's Hospital, Dongguan, Guangdong, China
| | - Xin Wang
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education; Institute for Brain Research and Rehabilitation, and Guangdong Key Laboratory of Mental Health and Cognitive Science, South China Normal University, Guangzhou, Guangdong, China
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19
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Frye RE, McCarty PJ, Werner BA, Scheck AC, Collins HL, Adelman SJ, Rossignol DA, Quadros EV. Binding Folate Receptor Alpha Autoantibody Is a Biomarker for Leucovorin Treatment Response in Autism Spectrum Disorder. J Pers Med 2024; 14:62. [PMID: 38248763 PMCID: PMC10820361 DOI: 10.3390/jpm14010062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 12/27/2023] [Accepted: 12/31/2023] [Indexed: 01/23/2024] Open
Abstract
Autism spectrum disorder (ASD) affects up to 1 in 36 children in the United States. It is a heterogeneous neurodevelopmental disorder with life-long consequences. Patients with ASD and folate pathway abnormalities have demonstrated improved symptoms after treatment with leucovorin (folinic acid), a reduced form of folate. However, biomarkers for treatment response have not been well investigated and clinical trials are lacking. In this retrospective analysis, a cohort of prospectively collected data from 110 consecutive ASD clinic patients [mean (SD) age: 10.5 (6.2) years; 74% male] was examined. These patients all underwent testing for folate receptor alpha autoantibodies (FRAAs) and soluble folate binding proteins (sFBPs) biomarkers and were treated with leucovorin, if appropriate. Analyses examined whether these biomarkers could predict response to leucovorin treatment as well as the severity of ASD characteristics at baseline. The social responsiveness scale (SRS), a measure of core ASD symptoms, and the aberrant behavior checklist (ABC), a measure of disruptive behavior, were collected at each clinic visit. Those positive for sFBPs had more severe ASD symptoms, and higher binding FRAA titers were associated with greater ABC irritability. Treatment with leucovorin improved most SRS subscales with higher binding FRAA titers associated with greater response. Leucovorin treatment also improved ABC irritability. These results confirm and expand on previous studies, underscore the need for biomarkers to guide treatment of folate pathways in ASD, and suggest that leucovorin may be effective for children with ASD.
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Affiliation(s)
- Richard E. Frye
- Rossignol Medical Center, Phoenix, AZ 85050, USA
- Autism Discovery and Treatment Foundation, Phoenix, AZ 85050, USA;
| | | | | | - Adrienne C. Scheck
- Department of Child Health, University of Arizona College of Medicine—Phoenix, Phoenix, AZ 85004, USA;
| | - Heidi L. Collins
- Vascular Strategies LLC, Plymouth Meeting, PA 19462, USA; (H.L.C.); (S.J.A.)
| | - Steven J. Adelman
- Vascular Strategies LLC, Plymouth Meeting, PA 19462, USA; (H.L.C.); (S.J.A.)
| | - Daniel A. Rossignol
- Autism Discovery and Treatment Foundation, Phoenix, AZ 85050, USA;
- Rossignol Medical Center, Aliso Viejo, CA 92656, USA
| | - Edward V. Quadros
- Department of Medicine, State University of New York—Downstate, Brooklyn, NY 11203, USA;
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Al-Beltagi M. Pre-autism: What a paediatrician should know about early diagnosis of autism. World J Clin Pediatr 2023; 12:273-294. [PMID: 38178935 PMCID: PMC10762597 DOI: 10.5409/wjcp.v12.i5.273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 09/07/2023] [Accepted: 09/25/2023] [Indexed: 12/08/2023] Open
Abstract
Autism, also known as an autism spectrum disorder, is a complex neurodevelopmental disorder usually diagnosed in the first three years of a child's life. A range of symptoms characterizes it and can be diagnosed at any age, including adolescence and adulthood. However, early diagnosis is crucial for effective management, prognosis, and care. Unfortunately, there are no established fetal, prenatal, or newborn screening programs for autism, making early detection difficult. This review aims to shed light on the early detection of autism prenatally, natally, and early in life, during a stage we call as "pre-autism" when typical symptoms are not yet apparent. Some fetal, neonatal, and infant biomarkers may predict an increased risk of autism in the coming baby. By developing a biomarker array, we can create an objective diagnostic tool to diagnose and rank the severity of autism for each patient. These biomarkers could be genetic, immunological, hormonal, metabolic, amino acids, acute phase reactants, neonatal brainstem function biophysical activity, behavioral profile, body measurements, or radiological markers. However, every biomarker has its accuracy and limitations. Several factors can make early detection of autism a real challenge. To improve early detection, we need to overcome various challenges, such as raising community awareness of early signs of autism, improving access to diagnostic tools, reducing the stigma attached to the diagnosis of autism, and addressing various culturally sensitive concepts related to the disorder.
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Affiliation(s)
- Mohammed Al-Beltagi
- Department of Pediatric, Faculty of Medicine, Tanta University, Tanta 31511, Algahrbia, Egypt
- Department of Pediatric, University Medical Center, King Abdulla Medical City, Arabian Gulf University, Dr. Sulaiman Al Habib Medical Group, Manama 26671, Manama, Bahrain
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21
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Gusso D, Prauchner GRK, Rieder AS, Wyse ATS. Biological Pathways Associated with Vitamins in Autism Spectrum Disorder. Neurotox Res 2023; 41:730-740. [PMID: 37864660 DOI: 10.1007/s12640-023-00674-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 09/18/2023] [Accepted: 10/07/2023] [Indexed: 10/23/2023]
Abstract
Autism spectrum disorder (ASD) is characterized by early-appearing social communication deficits, with genetic and environmental factors potentially playing a role in its etiology, which remains largely unknown. During pregnancy, certain deficiencies in critical nutrients are mainly associated with central nervous system impairment. The vitamin B9 (folate) is primarily related to one-carbon and methionine metabolism, participating in methyl donor generation. In addition, supplementation with folic acid (FA) is recommended by the World Health Organization (WHO) in the first three gestational months to prevent neural tube defects. Vitamin B12 is related to folate regeneration, converting it into an active form. Deficiencies in this vitamin have a negative impact on cognitive function and brain development since it is involved in myelin synthesis. Vitamin D is intimately associated with Ca2+ levels, acting in bone development and calcium-dependent signaling. This vitamin is associated with ASD at several levels since it has a relation with ASD genes and oxidative stress environment. This review carries the recent literature about the role of folate, vitamin B12, and vitamin D in ASD. In addition, we discuss the possible impact of nutrient deficiency or hypersupplementation during fetal development. On the other hand, we explore the biases of vitamin supplementation studies such as the loss of participants in retrospective studies, as well as multiple variants that are not considered in the conclusion, like dietary intake or auto-medication during pregnancy. In this regard, we aim to contribute to the discussion about the role of vitamins in ASD currency, but also in pregnancy and fetal development as well. Furthermore, stress during pregnancy can be an ASD predisposition, with cortisol as a regulator. In this view, we propose that cortisol is the bridge of susceptibility between vitamin disorders and ASD prevalence.
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Affiliation(s)
- Darlan Gusso
- Neuroprotection and Neurometabolic Diseases Laboratory (Wyse's Lab), Graduate Program in Biological Sciences: Biochemistry, Department of Biochemistry, Federal University of Rio Grande Do Sul (UFRGS), Rua Ramiro Barcelos, 2600-Anexo, Zip Code 90035003, Porto Alegre, RS, Brazil.
| | - Gustavo Ricardo Krupp Prauchner
- Neuroprotection and Neurometabolic Diseases Laboratory (Wyse's Lab), Graduate Program in Biological Sciences: Biochemistry, Department of Biochemistry, Federal University of Rio Grande Do Sul (UFRGS), Rua Ramiro Barcelos, 2600-Anexo, Zip Code 90035003, Porto Alegre, RS, Brazil
| | - Alessandra Schmitt Rieder
- Neuroprotection and Neurometabolic Diseases Laboratory (Wyse's Lab), Graduate Program in Biological Sciences: Biochemistry, Department of Biochemistry, Federal University of Rio Grande Do Sul (UFRGS), Rua Ramiro Barcelos, 2600-Anexo, Zip Code 90035003, Porto Alegre, RS, Brazil
| | - Angela T S Wyse
- Neuroprotection and Neurometabolic Diseases Laboratory (Wyse's Lab), Graduate Program in Biological Sciences: Biochemistry, Department of Biochemistry, Federal University of Rio Grande Do Sul (UFRGS), Rua Ramiro Barcelos, 2600-Anexo, Zip Code 90035003, Porto Alegre, RS, Brazil
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22
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Miyake K, Horiuchi S, Shinohara R, Kushima M, Otawa S, Yui H, Akiyama Y, Ooka T, Kojima R, Yokomichi H, Mochizuki K, Yamagata Z. Maternal dietary fiber intake during pregnancy and child development: the Japan Environment and Children's Study. Front Nutr 2023; 10:1203669. [PMID: 37575329 PMCID: PMC10415901 DOI: 10.3389/fnut.2023.1203669] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 06/20/2023] [Indexed: 08/15/2023] Open
Abstract
Background Animal studies have shown that maternal low-fiber diets during pregnancy may impair brain development and function in offspring, but this has not been validated by epidemiological studies. The aim of this study was to investigate the link between maternal dietary fiber intake during pregnancy and neurodevelopmental delay in offspring using a large birth cohort. Methods A total of 76,207 mother-infant pairs were analyzed using data from the Japan Environment and Children's Study, a nationwide prospective cohort study. Maternal dietary fiber intake was estimated using the food frequency questionnaire in mid-pregnancy. Maternal dietary fiber intake was adjusted for energy and classified into quintiles. Developmental delay was assessed in five domains using the Japanese version of the Ages and Stages Questionnaire, Third Edition at the age of 3 years. The logistic regression analysis was performed to estimate the odds ratio (OR) and 95% confidence interval (CI) for the link between dietary fiber intake during pregnancy and developmental delay at the age of 3 years. Results The lowest intake group of total dietary fiber had a higher risk of delayed communication [adjusted OR (aOR), 1.51; 95% CI, 1.32-1.74], fine motor (aOR, 1.45; 95% CI, 1.32-1.61), problem-solving (aOR, 1.46; 95% CI, 1.32-1.61), and personal-social skills (aOR, 1.30; 95% CI, 1.12-1.50) than did the highest intake group. An analysis that excluded the effects of insufficient folic acid intake during pregnancy also showed a similar trend. Conclusion This study showed that maternal dietary fiber deficiency during pregnancy might influence an increased risk of neurodevelopmental delay in offspring.
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Affiliation(s)
- Kunio Miyake
- Department of Health Sciences, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Japan
| | - Sayaka Horiuchi
- Center for Birth Cohort Studies, University of Yamanashi, Chuo, Japan
| | - Ryoji Shinohara
- Center for Birth Cohort Studies, University of Yamanashi, Chuo, Japan
| | - Megumi Kushima
- Center for Birth Cohort Studies, University of Yamanashi, Chuo, Japan
| | - Sanae Otawa
- Center for Birth Cohort Studies, University of Yamanashi, Chuo, Japan
| | - Hideki Yui
- Department of Health Sciences, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Japan
| | - Yuka Akiyama
- Department of Health Sciences, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Japan
| | - Tadao Ooka
- Department of Health Sciences, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Japan
| | - Reiji Kojima
- Department of Health Sciences, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Japan
| | - Hiroshi Yokomichi
- Department of Health Sciences, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Japan
| | - Kazuki Mochizuki
- Department of Local Produce and Food Sciences, Faculty of Life and Environmental Sciences, University of Yamanashi, Kofu, Japan
| | - Zentaro Yamagata
- Department of Health Sciences, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Japan
- Center for Birth Cohort Studies, University of Yamanashi, Chuo, Japan
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Dorsey SG, Mocci E, Lane MV, Krueger BK. Rapid effects of valproic acid on the fetal brain transcriptome: Implications for brain development and autism. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.01.538959. [PMID: 37205520 PMCID: PMC10187231 DOI: 10.1101/2023.05.01.538959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
Abstract
There is an increased incidence of autism among the children of women who take the anti-epileptic, mood stabilizing drug, valproic acid (VPA) during pregnancy; moreover, exposure to VPA in utero causes autistic-like symptoms in rodents and non-human primates. Analysis of RNAseq data ob-tained from E12.5 fetal mouse brains 3 hours after VPA administration revealed that VPA significant-ly increased or decreased the expression of approximately 7,300 genes. No significant sex differ-ences in VPA-induced gene expression were observed. Expression of genes associated with neu-rodevelopmental disorders (NDDs) such as autism as well as neurogenesis, axon growth and syn-aptogenesis, GABAergic, glutaminergic and dopaminergic synaptic transmission, perineuronal nets, and circadian rhythms was dysregulated by VPA. Moreover, expression of 399 autism risk genes was significantly altered by VPA as was expression of 252 genes that have been reported to play fundamental roles in the development of the nervous system but are not otherwise linked to autism. The goal of this study was to identify mouse genes that are: (a) significantly up- or down-regulated by VPA in the fetal brain and (b) known to be associated with autism and/or to play a role in embryonic neurodevelopmental processes, perturbation of which has the potential to alter brain connectivity in the postnatal and adult brain. The set of genes meeting these criteria pro-vides potential targets for future hypothesis-driven approaches to elucidating the proximal underly-ing causes of defective brain connectivity in NDDs such as autism.
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Gevezova M, Sbirkov Y, Sarafian V, Plaimas K, Suratanee A, Maes M. Autistic spectrum disorder (ASD) - Gene, molecular and pathway signatures linking systemic inflammation, mitochondrial dysfunction, transsynaptic signalling, and neurodevelopment. Brain Behav Immun Health 2023; 30:100646. [PMID: 37334258 PMCID: PMC10275703 DOI: 10.1016/j.bbih.2023.100646] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 06/03/2023] [Indexed: 06/20/2023] Open
Abstract
Background Despite advances in autism spectrum disorder (ASD) research and the vast genomic, transcriptomic, and proteomic data available, there are still controversies regarding the pathways and molecular signatures underlying the neurodevelopmental disorders leading to ASD. Purpose To delineate these underpinning signatures, we examined the two largest gene expression meta-analysis datasets obtained from the brain and peripheral blood mononuclear cells (PBMCs) of 1355 ASD patients and 1110 controls. Methods We performed network, enrichment, and annotation analyses using the differentially expressed genes, transcripts, and proteins identified in ASD patients. Results Transcription factor network analyses in up- and down-regulated genes in brain tissue and PBMCs in ASD showed eight main transcription factors, namely: BCL3, CEBPB, IRF1, IRF8, KAT2A, NELFE, RELA, and TRIM28. The upregulated gene networks in PBMCs of ASD patients are strongly associated with activated immune-inflammatory pathways, including interferon-α signaling, and cellular responses to DNA repair. Enrichment analyses of the upregulated CNS gene networks indicate involvement of immune-inflammatory pathways, cytokine production, Toll-Like Receptor signalling, with a major involvement of the PI3K-Akt pathway. Analyses of the downregulated CNS genes suggest electron transport chain dysfunctions at multiple levels. Network topological analyses revealed that the consequent aberrations in axonogenesis, neurogenesis, synaptic transmission, and regulation of transsynaptic signalling affect neurodevelopment with subsequent impairments in social behaviours and neurocognition. The results suggest a defense response against viral infection. Conclusions Peripheral activation of immune-inflammatory pathways, most likely induced by viral infections, may result in CNS neuroinflammation and mitochondrial dysfunction, leading to abnormalities in transsynaptic transmission, and brain neurodevelopment.
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Affiliation(s)
- Maria Gevezova
- Department of Medical Biology, Medical University of Plovdiv, Bulgaria
- Research Institute at MU-Plovdiv, Bulgaria
| | - Yordan Sbirkov
- Department of Medical Biology, Medical University of Plovdiv, Bulgaria
- Research Institute at MU-Plovdiv, Bulgaria
| | - Victoria Sarafian
- Department of Medical Biology, Medical University of Plovdiv, Bulgaria
- Research Institute at MU-Plovdiv, Bulgaria
| | - Kitiporn Plaimas
- Advanced Virtual and Intelligent Computing (AVIC) Center, Department of Mathematics and Computer Science, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Apichat Suratanee
- Department of Mathematics, Faculty of Applied Science, King Mongkut's University of Technology North Bangkok, Bangkok, 10800, Thailand
| | - Michael Maes
- Research Institute at MU-Plovdiv, Bulgaria
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, Thailand
- Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, South Korea
- Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria
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25
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Sadigurschi N, Scrift G, Hirrlinger J, Golan HM. Genetic impairment of folate metabolism regulates cortical interneurons and social behavior. Front Neurosci 2023; 17:1203262. [PMID: 37449270 PMCID: PMC10338116 DOI: 10.3389/fnins.2023.1203262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 06/06/2023] [Indexed: 07/18/2023] Open
Abstract
Introduction The implications of folate deficiency in neuropsychiatric disorders were demonstrated in numerous studies. Genetic deficiency in a key folate metabolism enzyme, MTHFR, is an example of the interaction between genetic and environmental risk factors: the maternal MTHFR deficiency governs in-utero nutrient availability, and the embryo's Mthfr genotype influences its ability to metabolize folates. Here, we explore how the maternal and offspring Mthfr genotypes affect cortical interneuron densities and distributions, mouse social outcome, and the relation of the different interneuron patterns to cortical excitability. Methods Two experiments were conducted to examine the effects of maternal and offspring Mthfr-KO heterozygosity. Mice were tested for direct social interactions (DSIs), repetitive behavior and cortical laminar distribution of interneuron populations expressing glutamate-decarboxylase-65, parvalbumin and somatostatin. Susceptibility to seizure was tested by exposure to pentylenetetrazole (PTZ). Results Maternal Mthfr+/- genotype was associated with suppressed social activities and reduced interneuron densities in all layers of the retrosplenial cortex (RSC). Somatostatin density and the somatostatin/parvalbumin ratio in the RSC and frontal cortex positively correlated with social behavior in the mice. An interaction between maternal and offspring Mthfr genotypes resulted in higher susceptibility of wild-type offspring to PTZ induced seizure. Discussion Maternal folate metabolism was shown to be critical to interneuron ontogenesis. Our results demonstrate that interneurons have a specific susceptibility to folate deficiency that may mediate folate's involvement in neuropsychiatric disease. The relations between cortical somatostatin interneuron patterns and social behavior highlight this subpopulation of interneurons as a target for further research.
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Affiliation(s)
- Noa Sadigurschi
- Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - Gilad Scrift
- Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - Johannes Hirrlinger
- Carl-Ludwig-Institute for Physiology, University of Leipzig, Leipzig, Germany
- Department of Neurogenetics, Max-Planck-Institute for Multidisciplinary Sciences, Göttingen, Germany
| | - Hava M. Golan
- Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
- Azrieli National Center for Autism and Neurodevelopment Research, Ben-Gurion University of the Negev, Beer Sheva, Israel
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26
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Roufael M, Bitar T, Sacre Y, Andres C, Hleihel W. Folate-Methionine Cycle Disruptions in ASD Patients and Possible Interventions: A Systematic Review. Genes (Basel) 2023; 14:709. [PMID: 36980981 PMCID: PMC10048251 DOI: 10.3390/genes14030709] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 03/03/2023] [Accepted: 03/09/2023] [Indexed: 03/17/2023] Open
Abstract
Autism Spectrum Disorder (ASD) has become a major public health concern due to its rapidly rising incidence over the past few years. Disturbances in folate or methionine metabolism have been identified in many individuals with ASD, suggesting that the folate-methionine cycle may play an essential role in the pathogenesis of autism. Thus, changes in metabolite concentrations associated with this cycle could be used as potential biomarkers and therapeutic targets for ASD. The aim of this systematic review is to elucidate the perturbations of this cycle and the possible interventions that may be proposed in this context. Several studies have shown that high levels of homocysteine and low levels of vitamins B12 and folate are associated with ASD. These changes in serum metabolites are influenced by poor diet. In fact, children with ASD tend to eat selectively, which could compromise the quality of their diet and result in nutrient deficiencies. Moreover, these disturbances may also be caused by genetic predispositions such as polymorphisms of the MTHFR gene. Few studies have demonstrated the beneficial effects of the use of nutritional supplements in treating ASD children. Therefore, larger, well-structured studies are recommended to examine the impact of vitamin B12 and folate supplementation on homocysteine levels.
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Affiliation(s)
- Melissa Roufael
- Department of Biology, Faculty of Arts and Sciences, Holy Spirit University of Kaslik, Jounieh P.O. Box 446, Lebanon
- UMR Inserm 1253 Ibrain, Université de Tours, 37032 Tours, France
| | - Tania Bitar
- Department of Biology, Faculty of Arts and Sciences, Holy Spirit University of Kaslik, Jounieh P.O. Box 446, Lebanon
| | - Yonna Sacre
- Department of Nutrition and Food Sciences, Faculty of Arts and Sciences, Holy Spirit University of Kaslik, Jounieh P.O. Box 446, Lebanon
| | - Christian Andres
- UMR Inserm 1253 Ibrain, Université de Tours, 37032 Tours, France
| | - Walid Hleihel
- Department of Biology, Faculty of Arts and Sciences, Holy Spirit University of Kaslik, Jounieh P.O. Box 446, Lebanon
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Heland S, Fields N, Ellery SJ, Fahey M, Palmer KR. The role of nutrients in human neurodevelopment and their potential to prevent neurodevelopmental adversity. Front Nutr 2022; 9:992120. [PMID: 36483929 PMCID: PMC9722743 DOI: 10.3389/fnut.2022.992120] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 11/02/2022] [Indexed: 06/21/2024] Open
Abstract
Nutritional deficits or excesses affect a huge proportion of pregnant women worldwide. Maternal nutrition has a significant influence on the fetal environment and can dramatically impact fetal brain development. This paper reviews current nutritional supplements that can be used to optimise fetal neurodevelopment and prevent neurodevelopmental morbidities, including folate, iodine, vitamin B12, iron, and vitamin D. Interestingly, while correcting nutritional deficits can prevent neurodevelopmental adversity, overcorrecting them can in some cases be detrimental, so care needs to be taken when recommending supplementation in pregnancy. The potential benefits of using nutrition to prevent neurodiversity is shown by promising nutraceuticals, sulforaphane and creatine, both currently under investigation. They have the potential to promote improved neurodevelopmental outcomes through mitigation of pathological processes, including hypoxia, inflammation, and oxidative stress. Neurodevelopment is a complex process and whilst the role of micronutrients and macronutrients on the developing fetal brain is not completely understood, this review highlights the key findings thus far.
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Affiliation(s)
- Sarah Heland
- Monash Women’s and Newborn, Monash Health, Clayton, VIC, Australia
| | - Neville Fields
- Monash Women’s and Newborn, Monash Health, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
| | - Stacey Joan Ellery
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
| | - Michael Fahey
- Paediatric Neurology Unit, Monash Children’s Hospital, Clayton, VIC, Australia
- Department of Paediatrics, Monash University, Clayton, VIC, Australia
| | - Kirsten Rebecca Palmer
- Monash Women’s and Newborn, Monash Health, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
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28
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Ahmad AMR, Intikhab A, Abid J, Iqbal S. Dietary Approaches and Nutritional Complexities of Autism Spectrum Disorder. INTERNATIONAL JOURNAL OF NUTRITION, PHARMACOLOGY, NEUROLOGICAL DISEASES 2022; 12:221-241. [DOI: 10.4103/ijnpnd.ijnpnd_65_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
Abstract
Background:
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by poor social interaction, repetitive behavior, learning difficulties, cognitive issues, and unusual eating patterns. Different factors including genetic and environmental variables have been identified to increase the risk of developing ASD.
Objective:
The main objective of the present review is to investigate the dietary approaches and modifications to reduce the intricacies related to ASD.
Results:
Studies included in this review suggested that abnormalities in the gut microbiota are involved in the pathogenesis and severity of the disease. Medical nutrition therapy for ASD consists of excluding harmful food components such as gluten, casein, processed foods, and excessive sugars and increasing the consumption of omega-3 fats, vitamins and minerals, probiotics, and antioxidants. Furthermore, awareness regarding food labels might help to avoid food allergens in diet.
Conclusion:
Active dietary treatments including the use of dietary supplements and elimination of processed foods appear to reduce the complexities of ASD. Furthermore, support of health care professionals and adopting public health approaches might help to prevent adverse outcomes related to ASD. Future research is required to determine the prevalence of ASD and related outcomes in low/middle income countries as this area is highly neglected.
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Li B, Xu Y, Pang D, Zhao Q, Zhang L, Li M, Li W, Duan G, Zhu C. Interrelation between homocysteine metabolism and the development of autism spectrum disorder in children. Front Mol Neurosci 2022; 15:947513. [PMID: 36046711 PMCID: PMC9421079 DOI: 10.3389/fnmol.2022.947513] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 07/18/2022] [Indexed: 11/18/2022] Open
Abstract
Evidence is emerging that dysregulation of circulating concentrations of homocysteine, an important intermediate in folate and vitamin B12 metabolism, is associated with autism spectrum disorder (ASD), but comprehensive assessments and correlations with disease characteristics have not been reported. Multivariate ordinal regression and restricted cubic spline (RCS) models were used to estimate independent correlations between serum homocysteine, folate, and vitamin B12 levels and clinical outcomes and severity of children with ASD. After adjusting for confounding factors, serum homocysteine levels were significantly higher in children with ASD than in healthy controls (β: 0.370; 95% CI: 0.299~0.441, p < 0.001). Moreover, homocysteine had a good diagnostic ability for distinguishing children with ASD from healthy subjects (AUC: 0.899, p < 0.001). The RCS model indicated a positive and linear association between serum homocysteine and the risk of ASD. The lowest quartile of folate was positively associated with ASD severity (OR: 4.227, 95% CI: 1.022~17.488, p = 0.041) compared to the highest quartile, and serum folate showed a negative and linear association with ASD severity. In addition, decreased concentrations of folate and vitamin B12 were associated with poor adaptive behavior developmental quotients of the Gesell Developmental Schedules (p < 0.05). Overall, an increased homocysteine level was associated with ASD in a linear manner and is thus a novel diagnostic biomarker for ASD. Decreased concentrations of folate and vitamin B12 were associated with poor clinical profiles of children with ASD. These findings suggest that homocysteine-lowering interventions or folate and vitamin B12 supplementation might be a viable treatment strategy for ASD.
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Affiliation(s)
- Bingbing Li
- Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, Third Affiliated Hospital and Institute of Neuroscience, Zhengzhou University, Zhengzhou, China
| | - Yiran Xu
- Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, Third Affiliated Hospital and Institute of Neuroscience, Zhengzhou University, Zhengzhou, China
| | - Dizhou Pang
- Center for Child Behavioral Development, Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Qiang Zhao
- Key Clinical Laboratory of Henan Province, Department of Clinical Laboratory, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Lingling Zhang
- Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, Third Affiliated Hospital and Institute of Neuroscience, Zhengzhou University, Zhengzhou, China
| | - Ming Li
- Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, Third Affiliated Hospital and Institute of Neuroscience, Zhengzhou University, Zhengzhou, China
| | - Wenhua Li
- Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, Third Affiliated Hospital and Institute of Neuroscience, Zhengzhou University, Zhengzhou, China
| | - Guiqin Duan
- Center for Child Behavioral Development, Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Changlian Zhu
- Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, Third Affiliated Hospital and Institute of Neuroscience, Zhengzhou University, Zhengzhou, China
- Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Sahlgrenska Academy, Gothenburg, Sweden
- *Correspondence: Changlian Zhu ;
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30
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Carpita B, Migli L, Chiarantini I, Battaglini S, Montalbano C, Carmassi C, Cremone IM, Dell’Osso L. Autism Spectrum Disorder and Fetal Alcohol Spectrum Disorder: A Literature Review. Brain Sci 2022; 12:brainsci12060792. [PMID: 35741677 PMCID: PMC9221419 DOI: 10.3390/brainsci12060792] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 06/07/2022] [Accepted: 06/15/2022] [Indexed: 02/06/2023] Open
Abstract
Fetal alcohol spectrum disorders (FASD) are a group of conditions associated with the effects of prenatal alcohol exposure and characterized by somatic and neuropsychological alterations. On the other hand, autism spectrum disorder (ASD) is characterized by a multifaceted neurobehavioral syndrome. Since alcohol can affect every stage of brain development, some authors hypothesized that in utero alcohol exposure might be linked to an increased risk of ASD in subjects with genetic vulnerability. The present review aimed to summarize the available literature on the possible association between FASD and ASD, also focusing on the reported clinical overlaps and on the possible shared pathogenic mechanisms. Studies in this field have stressed similarities and differences between the two conditions, leading to controversial results. The available literature also highlighted that both the disorders are often misdiagnosed or underdiagnosed, stressing the need to broaden the perspective, paying specific attention to milder presentations and sub-syndromic traits.
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31
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Gallo R, Stoccoro A, Cagiano R, Nicolì V, Ricciardi R, Tancredi R, Trovato R, Santorelli FM, Calderoni S, Muratori F, Migliore L, Coppedè F. Correlation among maternal risk factors, gene methylation and disease severity in females with autism spectrum disorder. Epigenomics 2022; 14:175-185. [PMID: 35081728 DOI: 10.2217/epi-2021-0494] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Aim: To detect early-life environmental factors leading to DNA methylation changes of autism spectrum disorder (ASD)-related genes in young ASD females and reveal epigenetic biomarkers of disease severity. Materials & methods: We investigated blood methylation levels of MECP2, OXTR, BDNF, RELN, BCL2, EN2 and HTR1A genes in 42 ASD females. Results: Maternal gestational weight gain correlated with BDNF methylation levels (Bonferroni-corrected p = 0.034), and lack of folic acid supplementation at periconception resulted in higher disease severity in the ASD children (Bonferroni-corrected p = 0.048). RELN methylation levels were inversely correlated with disease severity (Bonferroni corrected p = 0.042). Conclusion: The present study revealed gene-environment interactions and potential epigenetic biomarkers of disease severity in ASD females.
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Affiliation(s)
- Roberta Gallo
- Department of Translational Research & of New Surgical & Medical Technologies, University of Pisa, Via Roma 55, Pisa, 56126, Italy
| | - Andrea Stoccoro
- Department of Translational Research & of New Surgical & Medical Technologies, University of Pisa, Via Roma 55, Pisa, 56126, Italy
| | - Romina Cagiano
- IRCCS Stella Maris Foundation, Calambrone, Pisa, 56128, Italy
| | - Vanessa Nicolì
- Department of Translational Research & of New Surgical & Medical Technologies, University of Pisa, Via Roma 55, Pisa, 56126, Italy
| | - Rosanna Ricciardi
- Department of Translational Research & of New Surgical & Medical Technologies, University of Pisa, Via Roma 55, Pisa, 56126, Italy
| | | | - Rosanna Trovato
- IRCCS Stella Maris Foundation, Calambrone, Pisa, 56128, Italy
| | | | - Sara Calderoni
- IRCCS Stella Maris Foundation, Calambrone, Pisa, 56128, Italy.,Department of Clinical & Experimental Medicine, University of Pisa, Via Roma 55, Pisa, 56126, Italy
| | - Filippo Muratori
- IRCCS Stella Maris Foundation, Calambrone, Pisa, 56128, Italy.,Department of Clinical & Experimental Medicine, University of Pisa, Via Roma 55, Pisa, 56126, Italy
| | - Lucia Migliore
- Department of Translational Research & of New Surgical & Medical Technologies, University of Pisa, Via Roma 55, Pisa, 56126, Italy
| | - Fabio Coppedè
- Department of Translational Research & of New Surgical & Medical Technologies, University of Pisa, Via Roma 55, Pisa, 56126, Italy
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