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Aishworiya R, Chin HL, Savulescu J. Should newborn genetic testing for autism be introduced? JOURNAL OF MEDICAL ETHICS 2024:jme-2024-110166. [PMID: 39626956 DOI: 10.1136/jme-2024-110166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 11/11/2024] [Indexed: 01/12/2025]
Abstract
This manuscript provides a review of the potential role of newborn genetic testing for autism, and whether the state has an inherent responsibility to facilitate and subsidise this. This is situated within the broader construct of benefits and limitations of genetic testing currently. Potential benefits of such presymptomatic genetic testing include facilitating earlier diagnosis and access to appropriate intervention which can improve the treatment outcome for the child and indirectly benefit caregivers and society by reducing the care needs of the child and adult in future. However, there are several limitations to newborn genetic testing including the variable penetrance of 'autism-risk' genes, marked phenotypic heterogeneity of autism, real-world limitations in access to treatment, potential psychological harm to caregivers and financial considerations. We hence argue for facilitation of diagnostic genetic testing instead, especially for parents who seek to have greater understanding of recurrence likelihoods, related to reproductive decision-making. Facilitation of such testing can be in the form of both financial subsidies and infrastructural elements including availability of testing facilities and trained healthcare personnel for individualised pregenetic and postgenetic test counselling.
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Affiliation(s)
- Ramkumar Aishworiya
- Division of Developmental and Behavioural Paediatrics, Department of Paediatrics, Khoo Teck Puat - National University Children's Medical Institute, National University Hospital, Singapore
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Hui-Lin Chin
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Division of Genetics and Metabolism, Department of Paediatrics, Khoo Teck Puat - National University Children's Medical Institute, National University Hospital, Singapore
| | - Julian Savulescu
- Centre for Biomedical Ethics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Oxford Uehiro Centre for Practical Ethics, Faculty of Philosophy, University of Oxford, Oxford, UK
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Ciolino A, Ferreira ML, Loyacono N. Groups and Subgroups in Autism Spectrum Disorder (ASD) Considering an Advanced Integrative Model (AIM). J Pers Med 2024; 14:1031. [PMID: 39452538 PMCID: PMC11508306 DOI: 10.3390/jpm14101031] [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: 08/01/2024] [Revised: 09/09/2024] [Accepted: 09/23/2024] [Indexed: 10/26/2024] Open
Abstract
BACKGROUND Autism spectrum disorder (ASD) is related to social communication difficulties, repetitive behaviors, and highly restricted interests beginning early in life. Currently, ASD is more diagnosed than in the past, and new models are needed. The Advanced Integrative Model (AIM) is a new model in which genes and concomitant medical problems to diagnosis (CMPD) and the impact of their rigorous and adequate treatment are considered. METHODS The role of a dynamic encephalopathy from which the individual response, susceptibilities in the brain and outside the brain, gut barrier and brain-blood-barrier permeabilities, and the plastic nature of the brain is proposed as a tool for diagnosis. The concomitant medical problems (CMP) are those at and outside the brain. The individual response to treatments of CMP is analyzed. RESULTS The AIM allows for classification into 3 main groups and 24 subgroups. CONCLUSIONS The groups and subgroups in ASD are obtained taking into account CMPD treatments and individual response.
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Affiliation(s)
- Andrés Ciolino
- Planta Piloto de Ingeniería Química–PLAPIQUI (UNS–CONICET), Camino La Carrindanga Km 7, CC 717, Bahía Blanca 8000, Argentina;
- Departamento de Ingeniería Química, Universidad Nacional del Sur (UNS), Avda. Alem 1253, Cuerpo C’-Primer Piso, Bahía Blanca 8000, Argentina
| | - María Luján Ferreira
- Planta Piloto de Ingeniería Química–PLAPIQUI (UNS–CONICET), Camino La Carrindanga Km 7, CC 717, Bahía Blanca 8000, Argentina;
- Departamento de Química, Universidad Nacional del Sur (UNS), Avda. Alem 1253, Bahía Blanca 8000, Argentina
| | - Nicolás Loyacono
- Sociedad Argentina de Neurodesarrollo y Trastornos Asociados (SANyTA), Migueletes 681, Piso 2, Departamento 2, Ciudad Autónoma de Buenos Aires C1426BUE, Argentina;
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Serangeli I, Diamanti T, De Jaco A, Miranda E. Role of mitochondria-endoplasmic reticulum contacts in neurodegenerative, neurodevelopmental and neuropsychiatric conditions. Eur J Neurosci 2024; 60:5040-5068. [PMID: 39099373 DOI: 10.1111/ejn.16485] [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: 07/17/2023] [Revised: 04/15/2024] [Accepted: 07/15/2024] [Indexed: 08/06/2024]
Abstract
Mitochondria-endoplasmic reticulum contacts (MERCs) mediate a close and continuous communication between both organelles that is essential for the transfer of calcium and lipids to mitochondria, necessary for cellular signalling and metabolic pathways. Their structural and molecular characterisation has shown the involvement of many proteins that bridge the membranes of the two organelles and maintain the structural stability and function of these contacts. The crosstalk between the two organelles is fundamental for proper neuronal function and is now recognised as a component of many neurological disorders. In fact, an increasing proportion of MERC proteins take part in the molecular and cellular basis of pathologies affecting the nervous system. Here we review the alterations in MERCs that have been reported for these pathologies, from neurodevelopmental and neuropsychiatric disorders to neurodegenerative diseases. Although mitochondrial abnormalities in these debilitating conditions have been extensively attributed to the high energy demand of neurons, a distinct role for MERCs is emerging as a new field of research. Understanding the molecular details of such alterations may open the way to new paths of therapeutic intervention.
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Affiliation(s)
- Ilaria Serangeli
- Department of Biology and Biotechnologies 'Charles Darwin', Sapienza University of Rome, Rome, Italy
| | - Tamara Diamanti
- Department of Biology and Biotechnologies 'Charles Darwin', Sapienza University of Rome, Rome, Italy
| | - Antonella De Jaco
- Department of Biology and Biotechnologies 'Charles Darwin', Sapienza University of Rome, Rome, Italy
| | - Elena Miranda
- Department of Biology and Biotechnologies 'Charles Darwin', Sapienza University of Rome, Rome, Italy
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Pereira AC, Leonard A, Velthuis H, Wong NML, Ponteduro FM, Dimitrov M, Ellis CL, Kowalewski L, Lythgoe DJ, Rotaru DG, Edden RAE, Ivin G, Pretzsch CM, Daly E, Murphy DGM, McAlonan GM. Frontal and occipital brain glutathione levels are unchanged in autistic adults. PLoS One 2024; 19:e0308792. [PMID: 39146282 PMCID: PMC11326623 DOI: 10.1371/journal.pone.0308792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 07/30/2024] [Indexed: 08/17/2024] Open
Abstract
BACKGROUND The neurobiological underpinnings of Autism Spectrum Disorder (ASD) are diverse and likely multifactorial. One possible mechanism is increased oxidative stress leading to altered neurodevelopment and brain function. However, this hypothesis has mostly been tested in post-mortem studies. So far, available in vivo studies in autistic individuals have reported no differences in glutathione (GSH) levels in frontal, occipital, and subcortical regions. However, these studies were limited by the technically challenging quantification of GSH, the main brain antioxidant molecule. This study aimed to overcome previous studies' limitations by using a GSH-tailored spectroscopy sequence and optimised quantification methodology to provide clarity on GSH levels in autistic adults. METHODS We used spectral editing proton-magnetic resonance spectroscopy (1H-MRS) combined with linear combination model fitting to quantify GSH in the dorsomedial prefrontal cortex (DMPFC) and medial occipital cortex (mOCC) of autistic and non-autistic adults (male and female). We compared GSH levels between groups. We also examined correlations between GSH and current autism symptoms, measured using the Autism Quotient (AQ). RESULTS Data were available from 31 adult autistic participants (24 males, 7 females) and 40 non-autistic participants (21 males, 16 females); the largest sample to date. The GSH levels did not differ between groups in either region. No correlations with AQ were observed. CONCLUSION GSH levels as measured using 1H-MRS are unaltered in the DMPFC and mOCC regions of autistic adults, suggesting that oxidative stress in these cortical regions is not a marked neurobiological signature of ASD.
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Affiliation(s)
- Andreia C Pereira
- Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
- Institute for Nuclear Sciences Applied to Health (ICNAS), Coimbra Institute for Biomedical Imaging and Translational Research (CIBIT), University of Coimbra, Portugal, Coimbra, Portugal
| | - Alison Leonard
- Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
- Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Hester Velthuis
- Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
| | - Nichol M L Wong
- Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
- Department of Psychology, The Education University of Hong Kong, Hong Kong, China
| | - Francesca M Ponteduro
- Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
| | - Mihail Dimitrov
- Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
| | - Claire L Ellis
- Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
| | - Lukasz Kowalewski
- Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
| | - David J Lythgoe
- Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
| | - Diana-Georgina Rotaru
- Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
| | - Richard A E Edden
- Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, Maryland, United States of America
| | - Glynis Ivin
- South London and Maudsley NHS Foundation Trust Pharmacy, London, United Kingdom
| | - Charlotte M Pretzsch
- Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
| | - Eileen Daly
- Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
| | - Declan G M Murphy
- Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
- MRC Centre for Neurodevelopmental Disorders, King's College London, London, United Kingdom
| | - Gráinne M McAlonan
- Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
- MRC Centre for Neurodevelopmental Disorders, King's College London, London, United Kingdom
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Al-Beltagi M, Saeed NK, Bediwy AS, Elbeltagi R. Metabolomic changes in children with autism. World J Clin Pediatr 2024; 13:92737. [PMID: 38947988 PMCID: PMC11212761 DOI: 10.5409/wjcp.v13.i2.92737] [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: 02/04/2024] [Revised: 04/23/2024] [Accepted: 05/06/2024] [Indexed: 06/07/2024] Open
Abstract
BACKGROUND Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication and repetitive behaviors. Metabolomic profiling has emerged as a valuable tool for understanding the underlying metabolic dysregulations associated with ASD. AIM To comprehensively explore metabolomic changes in children with ASD, integrating findings from various research articles, reviews, systematic reviews, meta-analyses, case reports, editorials, and a book chapter. METHODS A systematic search was conducted in electronic databases, including PubMed, PubMed Central, Cochrane Library, Embase, Web of Science, CINAHL, Scopus, LISA, and NLM catalog up until January 2024. Inclusion criteria encompassed research articles (83), review articles (145), meta-analyses (6), systematic reviews (6), case reports (2), editorials (2), and a book chapter (1) related to metabolomic changes in children with ASD. Exclusion criteria were applied to ensure the relevance and quality of included studies. RESULTS The systematic review identified specific metabolites and metabolic pathways showing consistent differences in children with ASD compared to typically developing individuals. These metabolic biomarkers may serve as objective measures to support clinical assessments, improve diagnostic accuracy, and inform personalized treatment approaches. Metabolomic profiling also offers insights into the metabolic alterations associated with comorbid conditions commonly observed in individuals with ASD. CONCLUSION Integration of metabolomic changes in children with ASD holds promise for enhancing diagnostic accuracy, guiding personalized treatment approaches, monitoring treatment response, and improving outcomes. Further research is needed to validate findings, establish standardized protocols, and overcome technical challenges in metabolomic analysis. By advancing our understanding of metabolic dysregulations in ASD, clinicians can improve the lives of affected individuals and their families.
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Affiliation(s)
- Mohammed Al-Beltagi
- Department of Pediatric, Faculty of Medicine, Tanta University, Tanta 31511, Alghrabia, Egypt
- Department of Pediatric, University Medical Center, King Abdulla Medical City, Arabian Gulf University, Manama 26671, Bahrain
- Department of Pediatric, University Medical Center, Dr. Sulaiman Al Habib Medical Group, Manama, Bahrain, Manama 26671, Bahrain
| | - Nermin Kamal Saeed
- Medical Microbiology Section, Department of Pathology, Salmaniya Medical Complex, Ministry of Health, Kingdom of Bahrain, Manama 12, Bahrain
- Medical Microbiology Section, Department of Pathology, Irish Royal College of Surgeon, Bahrain, Busaiteen 15503, Muharraq, Bahrain
| | - Adel Salah Bediwy
- Department of Pulmonology, Faculty of Medicine, Tanta University, Tanta 31527, Alghrabia, Egypt
- Department of Chest Disease, University Medical Center, King Abdulla Medical City, Arabian Gulf University, Manama 26671, Bahrain
- Department of Chest Disease, University Medical Center, Dr. Sulaiman Al Habib Medical Group, Manama, Manama 26671, Bahrain
| | - Reem Elbeltagi
- Department of Medicine, The Royal College of Surgeons in Ireland - Bahrain, Busiateen 15503, Muharraq, Bahrain
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Carson L, Parlatini V, Safa T, Baig B, Shetty H, Phillips-Owen J, Prasad V, Downs J. The association between early childhood onset epilepsy and attention-deficit hyperactivity disorder (ADHD) in 3237 children and adolescents with Autism Spectrum Disorder (ASD): a historical longitudinal cohort data linkage study. Eur Child Adolesc Psychiatry 2023; 32:2129-2138. [PMID: 35927526 PMCID: PMC10576710 DOI: 10.1007/s00787-022-02041-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 06/25/2022] [Indexed: 11/03/2022]
Abstract
Children and young people with Autism Spectrum Disorder (ASD) have an increased risk of comorbidities, such as epilepsy and Attention-Deficit/Hyperactivity Disorder (ADHD). However, little is known about the relationship between early childhood epilepsy (below age 7) and later ADHD diagnosis (at age 7 or above) in ASD. In this historical cohort study, we examined this relationship using an innovative data source, which included linked data from routinely collected acute hospital paediatric records and childhood community and inpatient psychiatric records. In a large sample of children and young people with ASD (N = 3237), we conducted a longitudinal analysis to examine early childhood epilepsy as a risk factor for ADHD diagnosis while adjusting for potential confounders, including socio-demographic characteristics, intellectual disability, family history of epilepsy and associated physical conditions. We found that ASD children and young people diagnosed with early childhood epilepsy had nearly a twofold increase in risk of developing ADHD later in life, an association which persisted after adjusting for potential confounders (adjusted OR = 1.72, CI95% = 1.13-2.62). This study suggests that sensitive monitoring of ADHD symptoms in children with ASD who have a history of childhood epilepsy may be important to promote early detection and treatment. It also highlights how linked electronic health records can be used to examine potential risk factors over time for multimorbidity in neurodevelopmental conditions.
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Affiliation(s)
- Lauren Carson
- Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Valeria Parlatini
- Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
| | - Tara Safa
- National Institute for Health Research (NIHR) Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, London, UK
| | - Benjamin Baig
- Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Hitesh Shetty
- National Institute for Health Research (NIHR) Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, London, UK
| | - Jacqueline Phillips-Owen
- Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Vibhore Prasad
- School of Population Health and Environmental Sciences, King's College London, London, UK
| | - Johnny Downs
- Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
- National Institute for Health Research (NIHR) Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, London, UK
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Tang X, Feng C, Zhao Y, Zhang H, Gao Y, Cao X, Hong Q, Lin J, Zhuang H, Feng Y, Wang H, Shen L. A study of genetic heterogeneity in autism spectrum disorders based on plasma proteomic and metabolomic analysis: multiomics study of autism heterogeneity. MedComm (Beijing) 2023; 4:e380. [PMID: 37752942 PMCID: PMC10518435 DOI: 10.1002/mco2.380] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 08/04/2023] [Accepted: 08/24/2023] [Indexed: 09/28/2023] Open
Abstract
Genetic heterogeneity poses a challenge to research and clinical translation of autism spectrum disorder (ASD). In this study, we conducted a plasma proteomic and metabolomic study of children with ASD with and without risk genes (de novo mutation) and controls to explore the impact of genetic heterogeneity on the search for biomarkers for ASD. In terms of the proteomic and metabolomic profiles, the groups of children with ASD carrying and those not carrying de novo mutation tended to cluster and overlap, and integrating them yielded differentially expressed proteins and differential metabolites that effectively distinguished ASD from controls. The mechanisms associated with them focus on several common and previously reported mechanisms. Proteomics results highlight the role of complement, inflammation and immunity, and cell adhesion. The main pathways of metabolic perturbations include amino acid, vitamin, glycerophospholipid, tryptophan, and glutamates metabolic pathways and solute carriers-related pathways. Integrating the two omics analyses revealed that L-glutamic acid and malate dehydrogenase may play key roles in the pathogenesis of ASD. These results suggest that children with ASD may have important underlying common mechanisms. They are not only potential therapeutic targets for ASD but also important contributors to the study of biomarkers for the disease.
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Affiliation(s)
- Xiaoxiao Tang
- College of Life Science and OceanographyShenzhen UniversityShenzhenP. R. China
| | - Chengyun Feng
- Maternal and Child Health Hospital of BaoanShenzhenP. R. China
| | - Yuxi Zhao
- College of Life Science and OceanographyShenzhen UniversityShenzhenP. R. China
| | - Huajie Zhang
- College of Life Science and OceanographyShenzhen UniversityShenzhenP. R. China
| | - Yan Gao
- Maternal and Child Health Hospital of BaoanShenzhenP. R. China
| | - Xueshan Cao
- College of Life Science and OceanographyShenzhen UniversityShenzhenP. R. China
| | - Qi Hong
- Maternal and Child Health Hospital of BaoanShenzhenP. R. China
| | - Jing Lin
- College of Life Science and OceanographyShenzhen UniversityShenzhenP. R. China
| | - Hongbin Zhuang
- College of Life Science and OceanographyShenzhen UniversityShenzhenP. R. China
| | - Yuying Feng
- College of Life Science and OceanographyShenzhen UniversityShenzhenP. R. China
| | - Hanghang Wang
- College of Life Science and OceanographyShenzhen UniversityShenzhenP. R. China
| | - Liming Shen
- College of Life Science and OceanographyShenzhen UniversityShenzhenP. R. China
- Shenzhen‐Hong Kong Institute of Brain Science‐Shenzhen Fundamental Research InstitutionsShenzhenP. R. China
- Shenzhen Key Laboratory of Marine Biotechnology and EcologyShenzhenP. R. China
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Gaitanis J, Nie D, Hou T, Frye R. Developmental Regression Followed by Epilepsy and Aggression: A New Syndrome in Autism Spectrum Disorder? J Pers Med 2023; 13:1049. [PMID: 37511662 PMCID: PMC10381960 DOI: 10.3390/jpm13071049] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 06/20/2023] [Accepted: 06/22/2023] [Indexed: 07/30/2023] Open
Abstract
Autism spectrum disorder (ASD) with regression (ASD-R) involves the loss of previously attained developmental milestones, typically during the first or second year of life. As children age, it is not uncommon for them to develop comorbid conditions such as aggressive behaviors or epilepsy, which can inhibit habilitation in language and social function. In this paper, we hypothesize that aggressive behaviors and epilepsy more commonly develop in patients with ASD-R than in those without a history of regression (ASD-NR). We conducted a retrospective review of non-syndromic patients with ASD over 12 years of age and compared the rates of epilepsy and aggression between ASD-R and ASD-NR patients. Patients with ASD-R, as compared to ASD-NR patients, demonstrated non-significantly higher rates of epilepsy (51.8% vs. 38.1%, p = 0.1335) and aggressive behaviors (73.2% vs. 57.1%, p = 0.0673) when evaluated separately. The rates for combined epilepsy and aggression, however, were statistically significant when comparing ASD-R versus ASD patients (44.5% vs. 23.8%, p = 0.0163). These results suggest that epilepsy with aggression is more common in ASD-R as compared to ASD-NR patients. When considering the impact of epilepsy and aggression on quality of life, these co-morbidities effectively cause a second regression in patients who experienced an earlier regression as toddlers. A larger, prospective trial is recommended to confirm these associations and further define the timeline in which these characteristics develop from early childhood to adolescence.
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Affiliation(s)
- John Gaitanis
- Hasbro Children's Hospital, The Warren Alpert Medical School of Brown University, Providence, RI 02903, USA
| | - Duyu Nie
- Hasbro Children's Hospital, The Warren Alpert Medical School of Brown University, Providence, RI 02903, USA
| | - Tao Hou
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
| | - Richard Frye
- Autism Discovery and Treatment Foundation, Phoenix, AZ 85050, USA
- Rossignol Medical Center, Phoenix, AZ 85050, USA
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Moravej H, Inaloo S, Nahid S, Mazloumi S, Nemati H, Moosavian T, Nasiri J, Ghasemi F, Alaei MR, Dalili S, Aminzadeh M, Katibeh P, Amirhakimi A, Yazdani N, Ilkhanipoor H, Afshar Z, Hadipour F, Hadipour Z. Inborn Errors of Metabolism Associated With Autism Among Children: A Multicenter Study from Iran. Indian Pediatr 2023. [PMID: 36604934 DOI: 10.1007/s13312-023-2833-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/31/2023]
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10
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Indika NLR, Frye RE, Rossignol DA, Owens SC, Senarathne UD, Grabrucker AM, Perera R, Engelen MPKJ, Deutz NEP. The Rationale for Vitamin, Mineral, and Cofactor Treatment in the Precision Medical Care of Autism Spectrum Disorder. J Pers Med 2023; 13:252. [PMID: 36836486 PMCID: PMC9964499 DOI: 10.3390/jpm13020252] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/27/2023] [Accepted: 01/28/2023] [Indexed: 01/31/2023] Open
Abstract
Children with autism spectrum disorder may exhibit nutritional deficiencies due to reduced intake, genetic variants, autoantibodies interfering with vitamin transport, and the accumulation of toxic compounds that consume vitamins. Importantly, vitamins and metal ions are essential for several metabolic pathways and for neurotransmitter functioning. The therapeutic benefits of supplementing vitamins, minerals (Zinc, Magnesium, Molybdenum, and Selenium), and other cofactors (coenzyme Q10, alpha-lipoic acid, and tetrahydrobiopterin) are mediated through their cofactor as well as non-cofactor functions. Interestingly, some vitamins can be safely administered at levels far above the dose typically used to correct the deficiency and exert effects beyond their functional role as enzyme cofactors. Moreover, the interrelationships between these nutrients can be leveraged to obtain synergistic effects using combinations. The present review discusses the current evidence for using vitamins, minerals, and cofactors in autism spectrum disorder, the rationale behind their use, and the prospects for future use.
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Affiliation(s)
- Neluwa-Liyanage R. Indika
- Department of Biochemistry, Faculty of Medical Sciences, University of Sri Jayewardenepura, Nugegoda 10250, Sri Lanka
| | - Richard E. Frye
- Autism Discovery and Research Foundation, Phoenix, AZ 85050, USA
- Rossignol Medical Center, Phoenix, AZ 85050, USA
| | - Daniel A. Rossignol
- Rossignol Medical Center, Phoenix, AZ 85050, USA
- Rossignol Medical Center, Aliso Viejo, CA 92656, USA
| | - Susan C. Owens
- Autism Oxalate Project at the Autism Research Institute, San Diego, CA 92116, USA
| | - Udara D. Senarathne
- Department of Biochemistry, Faculty of Medical Sciences, University of Sri Jayewardenepura, Nugegoda 10250, Sri Lanka
| | - Andreas M. Grabrucker
- Department of Biological Sciences, University of Limerick, V94 T9PX Limerick, Ireland
- Bernal Institute, University of Limerick, V94 T9PX Limerick, Ireland
- Health Research Institute (HRI), University of Limerick, V94 T9PX Limerick, Ireland
| | - Rasika Perera
- Department of Biochemistry, Faculty of Medical Sciences, University of Sri Jayewardenepura, Nugegoda 10250, Sri Lanka
| | - Marielle P. K. J. Engelen
- Center for Translational Research in Aging & Longevity, Texas A&M University, College Station, TX 77843, USA
| | - Nicolaas E. P. Deutz
- Center for Translational Research in Aging & Longevity, Texas A&M University, College Station, TX 77843, USA
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Muacevic A, Adler JR, Lacasse BM, Beggs J, Lou J, Motta FC, Nemzer LR, Worth R, Cravens GD. A Literature Review of Similarities Between and Among Patients With Autism Spectrum Disorder and Epilepsy. Cureus 2023; 15:e33946. [PMID: 36819340 PMCID: PMC9937677 DOI: 10.7759/cureus.33946] [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: 08/11/2022] [Accepted: 01/18/2023] [Indexed: 01/20/2023] Open
Abstract
Autism spectrum disorder (ASD) has been shown to be associated with various other conditions, and most commonly, ASD has been demonstrated to be linked to epilepsy. ASD and epilepsy have been observed to exhibit high rates of comorbidity, even when compared to the co-occurrence of other disorders with similar pathologies. At present, nearly one-half of the individuals diagnosed with ASD also have been diagnosed with comorbid epilepsy. Research suggests that both conditions likely share similarities in their underlying disease pathophysiology, possibly associated with disturbances in the central nervous system (CNS), and may be linked to an imbalance between excitation and inhibition in the brain. Meanwhile, it remains unclear whether one condition is the consequence of the other, as the pathologies of both disorders are commonly linked to many different underlying signal transduction mechanisms. In this review, we aim to investigate the co-occurrence of ASD and epilepsy, with the intent of gaining insights into the similarities in pathophysiology that both conditions present with. Elucidating the underlying disease pathophysiology as a result of both disorders could lead to a better understanding of the underlying mechanism of disease activity that drives co-occurrence, as well as provide insight into the underlying mechanisms of each condition individually.
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12
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Indika NLR, Owens SC, Senarathne UD, Grabrucker AM, Lam NSK, Louati K, McGuinness G, Frye RE. Metabolic Approaches to the Treatment of Autism Spectrum Disorders. NEUROBIOLOGY OF AUTISM SPECTRUM DISORDERS 2023:291-312. [DOI: 10.1007/978-3-031-42383-3_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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13
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Yu R, Zhang M, Ahmed T, Wu Z, Lv L, Zhou G, Li B. Metabolic and Proteomic Profiles Reveal the Response of the ASD-Associated Resistant Strain 6-1 of Lactobacillus plantarum to Propionic Acid. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:17020. [PMID: 36554909 PMCID: PMC9779356 DOI: 10.3390/ijerph192417020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 11/26/2022] [Accepted: 12/15/2022] [Indexed: 06/17/2023]
Abstract
Autism spectrum disorder (ASD) seriously affects children's health. In our previous study, we isolated and identified a bacterium (Lactobacillus plantarum strain 6-1) that is resistant to propionic acid (PA), which has been reported to play a significant role in the formation of ASD. In order to elucidate the mechanism of the resistance to PA, this study investigated the change in the metabolic and proteomic profile of L. plantarum strain 6-1 in the presence and absence of PA. The results show that 967 and 1078 proteins were specifically identified in the absence and the presence of PA, respectively, while 616 proteins were found under both conditions. Gene ontology enrichment analysis of 130 differentially expressed proteins accumulated in the presence and absence of PA indicated that most of the proteins belong to biological processes, cellular components, and molecular functions. Pathway enrichment analysis showed a great reduction in the metabolic pathway-related proteins when this resistant bacterium was exposed to PA compared to the control. Furthermore, there was an obvious difference in protein-protein interaction networks in the presence and the absence of propionic acid. In addition, there was a change in the metabolic profile of L. plantarum strain 6-1 when this bacterium was exposed to PA compared to the control, while six peaks at 696.46, 1543.022, 1905.241, 2004.277, 2037.374, and 2069.348 m/z disappeared. Overall, the results could help us to understand the mechanism of the resistance of gut bacteria to PA, which will provide a new insight for us to use PA-resistant bacteria to prevent the development of ASD in children.
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Affiliation(s)
- Rongrong Yu
- College of Education, Zhejiang University of Technology, Hangzhou 310032, China
| | - Muchen Zhang
- Institute of Biotechnology, Zhejiang University, Hangzhou 310058, China
| | - Temoor Ahmed
- Institute of Biotechnology, Zhejiang University, Hangzhou 310058, China
| | - Zhifeng Wu
- Institute of Biotechnology, Zhejiang University, Hangzhou 310058, China
| | - Luqiong Lv
- Institute of Biotechnology, Zhejiang University, Hangzhou 310058, China
| | - Guoling Zhou
- Hangzhou Seventh People’s Hospital (HSPH), Hangzhou 310013, China
| | - Bin Li
- Institute of Biotechnology, Zhejiang University, Hangzhou 310058, China
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14
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Boktor JC, Adame MD, Rose DR, Schumann CM, Murray KD, Bauman MD, Careaga M, Mazmanian SK, Ashwood P, Needham BD. Global metabolic profiles in a non-human primate model of maternal immune activation: implications for neurodevelopmental disorders. Mol Psychiatry 2022; 27:4959-4973. [PMID: 36028571 PMCID: PMC9772216 DOI: 10.1038/s41380-022-01752-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 08/02/2022] [Accepted: 08/12/2022] [Indexed: 01/14/2023]
Abstract
Epidemiological evidence implicates severe maternal infections as risk factors for neurodevelopmental disorders, such as ASD and schizophrenia. Accordingly, animal models mimicking infection during pregnancy, including the maternal immune activation (MIA) model, result in offspring with neurobiological, behavioral, and metabolic phenotypes relevant to human neurodevelopmental disorders. Most of these studies have been performed in rodents. We sought to better understand the molecular signatures characterizing the MIA model in an organism more closely related to humans, rhesus monkeys (Macaca mulatta), by evaluating changes in global metabolic profiles in MIA-exposed offspring. Herein, we present the global metabolome in six peripheral tissues (plasma, cerebrospinal fluid, three regions of intestinal mucosa scrapings, and feces) from 13 MIA and 10 control offspring that were confirmed to display atypical neurodevelopment, elevated immune profiles, and neuropathology. Differences in lipid, amino acid, and nucleotide metabolism discriminated these MIA and control samples, with correlations of specific metabolites to behavior scores as well as to cytokine levels in plasma, intestinal, and brain tissues. We also observed modest changes in fecal and intestinal microbial profiles, and identify differential metabolomic profiles within males and females. These findings support a connection between maternal immune activation and the metabolism, microbiota, and behavioral traits of offspring, and may further the translational applications of the MIA model and the advancement of biomarkers for neurodevelopmental disorders such as ASD or schizophrenia.
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Affiliation(s)
- Joseph C Boktor
- Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA
| | - Mark D Adame
- Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA
| | - Destanie R Rose
- Department of Medical Microbiology and Immunology, University of California Davis, Davis, CA, 95616, USA
- The M.I.N.D. Institute, University of California, Davis, Sacramento, CA, 95817, USA
| | - Cynthia M Schumann
- The M.I.N.D. Institute, University of California, Davis, Sacramento, CA, 95817, USA
| | - Karl D Murray
- The M.I.N.D. Institute, University of California, Davis, Sacramento, CA, 95817, USA
| | - Melissa D Bauman
- The M.I.N.D. Institute, University of California, Davis, Sacramento, CA, 95817, USA
| | - Milo Careaga
- Department of Medical Microbiology and Immunology, University of California Davis, Davis, CA, 95616, USA
- The M.I.N.D. Institute, University of California, Davis, Sacramento, CA, 95817, USA
| | - Sarkis K Mazmanian
- Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA
| | - Paul Ashwood
- Department of Medical Microbiology and Immunology, University of California Davis, Davis, CA, 95616, USA.
- The M.I.N.D. Institute, University of California, Davis, Sacramento, CA, 95817, USA.
| | - Brittany D Needham
- Department of Anatomy, Cell Biology & Physiology, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
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15
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Sun Q. Quantitation of Purine in Urine by Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry. Methods Mol Biol 2022; 2546:421-430. [PMID: 36127609 DOI: 10.1007/978-1-0716-2565-1_37] [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: 10/14/2022]
Abstract
Inborn errors of purine metabolism, either deficiencies of synthesis or catabolism pathways, lead to a wide spectrum of clinical presentations: urolithiasis (adenine phosphoribosyltransferase), primary immune deficiency (adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency), severe intellectual disability, and other neurological symptoms (Lesch-Nyhan disease, adenylosuccinase deficiency, and molybdenum cofactor deficiency). A rapid quantitative purine assay was developed using UPLC-MS/MS to determine purine nucleoside and base concentrations in urine. Taking advantages of ultra-performance liquid chromatography, we achieved satisfactory analyte separation and recovery with a polar T3 column in a short run time with no requirement of time-consuming sample preparation or derivatization. This targeted assay is intended for diagnosis and management of purine diseases, newborn screening follow-up of SCID, and evaluation of autism spectrum disorders.
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Affiliation(s)
- Qin Sun
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. .,Baylor Genetics, Houston, TX, USA.
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16
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Chakraborty S, Parayil R, Mishra S, Nongthomba U, Clement JP. Epilepsy Characteristics in Neurodevelopmental Disorders: Research from Patient Cohorts and Animal Models Focusing on Autism Spectrum Disorder. Int J Mol Sci 2022; 23:ijms231810807. [PMID: 36142719 PMCID: PMC9501968 DOI: 10.3390/ijms231810807] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 08/31/2022] [Accepted: 09/05/2022] [Indexed: 11/24/2022] Open
Abstract
Epilepsy, a heterogeneous group of brain-related diseases, has continued to significantly burden society and families. Epilepsy comorbid with neurodevelopmental disorders (NDDs) is believed to occur due to multifaceted pathophysiological mechanisms involving disruptions in the excitation and inhibition (E/I) balance impeding widespread functional neuronal circuitry. Although the field has received much attention from the scientific community recently, the research has not yet translated into actionable therapeutics to completely cure epilepsy, particularly those comorbid with NDDs. In this review, we sought to elucidate the basic causes underlying epilepsy as well as those contributing to the association of epilepsy with NDDs. Comprehensive emphasis is put on some key neurodevelopmental genes implicated in epilepsy, such as MeCP2, SYNGAP1, FMR1, SHANK1-3 and TSC1, along with a few others, and the main electrophysiological and behavioral deficits are highlighted. For these genes, the progress made in developing appropriate and valid rodent models to accelerate basic research is also detailed. Further, we discuss the recent development in the therapeutic management of epilepsy and provide a briefing on the challenges and caveats in identifying and testing species-specific epilepsy models.
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Affiliation(s)
- Sukanya Chakraborty
- Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru 560064, India
| | - Rrejusha Parayil
- Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru 560064, India
| | - Shefali Mishra
- Molecular Reproduction, Development and Genetics (MRDG), Indian Institute of Science, Bengaluru 560012, India
| | - Upendra Nongthomba
- Molecular Reproduction, Development and Genetics (MRDG), Indian Institute of Science, Bengaluru 560012, India
| | - James P. Clement
- Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru 560064, India
- Correspondence: ; Tel.: +91-08-2208-2613
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17
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Kwon CS, Wirrell EC, Jetté N. Autism Spectrum Disorder and Epilepsy. Neurol Clin 2022; 40:831-847. [DOI: 10.1016/j.ncl.2022.03.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
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18
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A Personalized Multidisciplinary Approach to Evaluating and Treating Autism Spectrum Disorder. J Pers Med 2022; 12:jpm12030464. [PMID: 35330464 PMCID: PMC8949394 DOI: 10.3390/jpm12030464] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 03/09/2022] [Accepted: 03/10/2022] [Indexed: 02/06/2023] Open
Abstract
Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder without a known cure. Current standard-of-care treatments focus on addressing core symptoms directly but have provided limited benefits. In many cases, individuals with ASD have abnormalities in multiple organs, including the brain, immune and gastrointestinal system, and multiple physiological systems including redox and metabolic systems. Additionally, multiple aspects of the environment can adversely affect children with ASD including the sensory environment, psychosocial stress, dietary limitations and exposures to allergens and toxicants. Although it is not clear whether these medical abnormalities and environmental factors are related to the etiology of ASD, there is evidence that many of these factors can modulate ASD symptoms, making them a potential treatment target for improving core and associated ASD-related symptoms and improving functional limitation. Additionally, addressing underlying biological disturbances that drive pathophysiology has the potential to be disease modifying. This article describes a systematic approach using clinical history and biomarkers to personalize medical treatment for children with ASD. This approach is medically comprehensive, making it attractive for a multidisciplinary approach. By concentrating on treatable conditions in ASD, it is possible to improve functional ability and quality of life, thus providing optimal outcomes.
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19
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Al Dera H. Cellular and molecular mechanisms underlying autism spectrum disorders and associated comorbidities: A pathophysiological review. Biomed Pharmacother 2022; 148:112688. [PMID: 35149383 DOI: 10.1016/j.biopha.2022.112688] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/25/2022] [Accepted: 02/01/2022] [Indexed: 12/31/2022] Open
Abstract
Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders that develop in early life due to interaction between several genetic and environmental factors and lead to alterations in brain function and structure. During the last decades, several mechanisms have been placed to explain the pathogenesis of autism. Unfortunately, these are reported in several studies and reviews which make it difficult to follow by the reader. In addition, some recent molecular mechanisms related to ASD have been unrevealed. This paper revises and highlights the major common molecular mechanisms responsible for the clinical symptoms seen in people with ASD, including the roles of common genetic factors and disorders, neuroinflammation, GABAergic signaling, and alterations in Ca+2 signaling. Besides, it covers the major molecular mechanisms and signaling pathways involved in initiating the epileptic seizure, including the alterations in the GABAergic and glutamate signaling, vitamin and mineral deficiency, disorders of metabolism, and autoimmunity. Finally, this review also discusses sleep disorder patterns and the molecular mechanisms underlying them.
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Affiliation(s)
- Hussain Al Dera
- Department of Basic Medical Sciences, College of Medicine at King Saud, Abdulaziz University for Health Sciences (KSAU-HS), Riyadh, Saudi Arabia; King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia.
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20
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Wang Y, Huo X, Li W, Xiao L, Li M, Wang C, Sun Y, Sun T. Knowledge Atlas of the Co-Occurrence of Epilepsy and Autism: A Bibliometric Analysis and Visualization Using VOSviewer and CiteSpace. Neuropsychiatr Dis Treat 2022; 18:2107-2119. [PMID: 36157199 PMCID: PMC9507454 DOI: 10.2147/ndt.s378372] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 09/14/2022] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE This study aimed to analyze research on epilepsy in autism and autism in epilepsy using VOSviewer and CiteSpace to identify research hotspots and future directions. METHODS We searched the Web of Science Core Collection (WoSCC) for relevant studies about epilepsy in autism and autism in epilepsy published from inception to 31 May 2022. VOSviewer and CiteSpace were used to analyze the authors, institutions, countries, publishing journals, reference co-citation patterns, keyword co-occurrence, keyword clustering, keywords with citation bursts, and other aspects to construct a knowledge atlas. RESULTS A total of 473 publications related to epilepsy/autism were retrieved. The number of publications about epilepsy/ASD has generally increased over time, with some fluctuations. The USA (202 papers) and University of California-Los Angeles (15 papers) were the leading country and institution, respectively, in this field. Frye, Richard E. was the most published author (9 papers). Notably, collaboration between institutions, countries, and authors does not appear to be active. Hot topics and research frontiers include intellectual disability and exploring the mechanism of epilepsy/ASD from a genetics perspective. CONCLUSION This analysis identified the most influential publications, authors, journals, institutions, and countries in the field of epilepsy/ASD research. Using co-occurrence and evolution analyses, the status of the field was identified and future trends were predicted.
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Affiliation(s)
- Yangyang Wang
- Ningxia Key Laboratory of Cerebrocranial Disease, Ningxia Medical University, Yinchuan, People's Republic of China
| | - Xianhao Huo
- Ningxia Key Laboratory of Cerebrocranial Disease, Ningxia Medical University, Yinchuan, People's Republic of China
| | - Wenchao Li
- Ningxia Key Laboratory of Cerebrocranial Disease, Ningxia Medical University, Yinchuan, People's Republic of China
| | - Lifei Xiao
- Ningxia Key Laboratory of Cerebrocranial Disease, Ningxia Medical University, Yinchuan, People's Republic of China
| | - Mei Li
- Ningxia Key Laboratory of Cerebrocranial Disease, Ningxia Medical University, Yinchuan, People's Republic of China
| | - Chaofan Wang
- Ningxia Key Laboratory of Cerebrocranial Disease, Ningxia Medical University, Yinchuan, People's Republic of China
| | - Yangyang Sun
- Ningxia Key Laboratory of Cerebrocranial Disease, Ningxia Medical University, Yinchuan, People's Republic of China
| | - Tao Sun
- Ningxia Key Laboratory of Cerebrocranial Disease, Ningxia Medical University, Yinchuan, People's Republic of China
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21
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Seidel M, Buono S, Città S, Trubia G, Zagaria T, Zingale M, Bertelli MO, Elia M. Disorders Due to Brain Damage and Dysfunction and to Physical Diseases (Excluding Neurocognitive Disorders). TEXTBOOK OF PSYCHIATRY FOR INTELLECTUAL DISABILITY AND AUTISM SPECTRUM DISORDER 2022:757-782. [DOI: 10.1007/978-3-319-95720-3_29] [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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22
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Likhitweerawong N, Thonusin C, Boonchooduang N, Louthrenoo O, Nookaew I, Chattipakorn N, Chattipakorn SC. Profiles of urine and blood metabolomics in autism spectrum disorders. Metab Brain Dis 2021; 36:1641-1671. [PMID: 34338974 PMCID: PMC8502415 DOI: 10.1007/s11011-021-00788-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 07/01/2021] [Indexed: 01/06/2023]
Abstract
Early diagnosis and treatment for autism spectrum disorder (ASD) pose challenges. The current diagnostic approach for ASD is mainly clinical assessment of patient behaviors. Biomarkers-based identification of ASD would be useful for pediatricians. Currently, there is no specific treatment for ASD, and evidence for the efficacy of alternative treatments remains inconclusive. The prevalence of ASD is increasing, and it is becoming more urgent to find the pathogenesis of such disorder. Metabolomic studies have been used to deeply investigate the alteration of metabolic pathways, including those associated with ASD. Metabolomics is a promising tool for identifying potential biomarkers and possible pathogenesis of ASD. This review comprehensively summarizes and discusses the abnormal metabolic pathways in ASD children, as indicated by evidence from metabolomic studies in urine and blood. In addition, the targeted interventions that could correct the metabolomic profiles relating to the improvement of autistic behaviors in affected animals and humans have been included. The results revealed that the possible underlying pathophysiology of ASD were alterations of amino acids, reactive oxidative stress, neurotransmitters, and microbiota-gut-brain axis. The potential common pathways shared by animal and human studies related to the improvement of ASD symptoms after pharmacological interventions were mammalian-microbial co-metabolite, purine metabolism, and fatty acid oxidation. The content of this review may contribute to novel biomarkers for the early diagnosis of ASD and possible therapeutic paradigms.
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Affiliation(s)
- Narueporn Likhitweerawong
- Division of Growth and Development, Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Chanisa Thonusin
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, 110 Inthawarorot Road, Sriphum, Muang, Chiang Mai 50200, Thailand
- Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand
| | - Nonglak Boonchooduang
- Division of Growth and Development, Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Orawan Louthrenoo
- Division of Growth and Development, Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Intawat Nookaew
- Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Arkanasa, USA
| | - Nipon Chattipakorn
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, 110 Inthawarorot Road, Sriphum, Muang, Chiang Mai 50200, Thailand
- Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand
| | - Siriporn C. Chattipakorn
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, 110 Inthawarorot Road, Sriphum, Muang, Chiang Mai 50200, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand
- Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand
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23
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Impact of Zinc Oxide Nanoparticles on the Composition of Gut Microbiota in Healthy and Autism Spectrum Disorder Children. MATERIALS 2021; 14:ma14195488. [PMID: 34639886 PMCID: PMC8509275 DOI: 10.3390/ma14195488] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/09/2021] [Accepted: 09/14/2021] [Indexed: 01/25/2023]
Abstract
Autism spectrum disorder (ASD) seriously affects children’s health, while the gut microbiome has been widely hypothesized to be involved in the regulation of ASD behavior. This study investigated and compared the number, diversity, and population structure of gut microbiota between healthy and ASD children and their susceptibility to zinc oxide nanoparticles (ZnONPs) based on the measurement of live cell number, living/dead bacterial staining test, flow cytometry observation and bacterial community analysis using 16S rRNA gene amplicon sequencing. The result of this present study revealed that ASD children not only significantly reduced the live cell number and the community diversity of gut bacteria, but also changed the gut bacterial community composition compared to the healthy children. In addition, this result revealed that ZnONPs significantly reduced the number of live bacterial cells in the gut of healthy children, but not in that of ASD children. In contrast, ZnONPs generally increased the gut bacterial community diversity in both ASD and healthy children, while a greater increase was found in ASD children than that of healthy children. Furthermore, this study successfully isolated and identified some representative nanoparticle-resistant bacteria based on the color, shape, and edge of colony as well as the 16S rDNA sequence analysis. The community of nanoparticle-resistant bacteria differed in between healthy and ASD children. Indeed, the representative strains 6-1, 6-2, 6-3 and 6-4 from healthy children were identified as Bacillus anthracis, Escherichia coli, Bacillus cereus and Escherichia coli with sequence similarity of 97.86%, 99.86%, 99.03% and 99.65%, respectively, while the representative strains 8-1, 8-2 and 8-3 from ASD children were identified as Bacillus cereus, with sequence similarities of 99.58%, 99.72% and 99.72%, respectively. Overall, this study demonstrated that ZnONPs caused a change in number, diversity, and species composition of gut bacteria, but differed in healthy and ASD children.
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24
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Stanton JE, Malijauskaite S, McGourty K, Grabrucker AM. The Metallome as a Link Between the "Omes" in Autism Spectrum Disorders. Front Mol Neurosci 2021; 14:695873. [PMID: 34290588 PMCID: PMC8289253 DOI: 10.3389/fnmol.2021.695873] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 06/14/2021] [Indexed: 12/26/2022] Open
Abstract
Metal dyshomeostasis plays a significant role in various neurological diseases such as Alzheimer's disease, Parkinson's disease, Autism Spectrum Disorders (ASD), and many more. Like studies investigating the proteome, transcriptome, epigenome, microbiome, etc., for years, metallomics studies have focused on data from their domain, i.e., trace metal composition, only. Still, few have considered the links between other "omes," which may together result in an individual's specific pathologies. In particular, ASD have been reported to have multitudes of possible causal effects. Metallomics data focusing on metal deficiencies and dyshomeostasis can be linked to functions of metalloenzymes, metal transporters, and transcription factors, thus affecting the proteome and transcriptome. Furthermore, recent studies in ASD have emphasized the gut-brain axis, with alterations in the microbiome being linked to changes in the metabolome and inflammatory processes. However, the microbiome and other "omes" are heavily influenced by the metallome. Thus, here, we will summarize the known implications of a changed metallome for other "omes" in the body in the context of "omics" studies in ASD. We will highlight possible connections and propose a model that may explain the so far independently reported pathologies in ASD.
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Affiliation(s)
- Janelle E Stanton
- Department of Biological Sciences, University of Limerick, Limerick, Ireland.,Bernal Institute, University of Limerick, Limerick, Ireland
| | - Sigita Malijauskaite
- Bernal Institute, University of Limerick, Limerick, Ireland.,Department of Chemical Sciences, University of Limerick, Limerick, Ireland
| | - Kieran McGourty
- Bernal Institute, University of Limerick, Limerick, Ireland.,Department of Chemical Sciences, University of Limerick, Limerick, Ireland.,Health Research Institute, University of Limerick, Limerick, Ireland
| | - Andreas M Grabrucker
- Department of Biological Sciences, University of Limerick, Limerick, Ireland.,Bernal Institute, University of Limerick, Limerick, Ireland.,Health Research Institute, University of Limerick, Limerick, Ireland
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25
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Sodium phenylbutyrate reduces repetitive self-grooming behavior and rescues social and cognitive deficits in mouse models of autism. Psychopharmacology (Berl) 2021; 238:1833-1845. [PMID: 33723660 DOI: 10.1007/s00213-021-05812-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 03/01/2021] [Indexed: 12/11/2022]
Abstract
Autism spectrum disorder (ASD) is a neurodevelopment disorder characterized by deficits in social interaction and restrictive, repetitive, and stereotypical patterns of behavior. However, there is no pharmacological drug that is currently used to target these core ASD symptoms. Sodium phenylbutyrate (NaPB) is a well-known long-term treatment of urea cycle disorders in children. In this study, we assessed the therapeutic effects of NaPB, which is a chemical chaperone as well as histone deacetylase inhibitor on a BTBR T + Itpr3tf/J (BTBR) mice model of ASD. We found that acute and chronic treatment of NaPB remarkably improved, not only core ASD symptoms, including repetitive behaviors and sociability deficit, but also cognitive impairment in the BTBR mice. NaPB substantially induced histone acetylation in the brain of the BTBR mice. Intriguingly, the therapeutic effects of NaPB on autistic-like behaviors, such as repetitive behaviors, impaired sociability, and cognitive deficit also showed in the valproic acid (VPA)-induced mouse model of autism. In addition, pentylenetetrazole (PTZ)-induced seizure was significantly attenuated by NaPB treatment in C57BL/6J and BTBR mice. These findings suggest that NaPB may provide a novel therapeutic approach for the treatment of patients with ASD.
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26
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Ferreira ML, Loyacono N. Rationale of an Advanced Integrative Approach Applied to Autism Spectrum Disorder: Review, Discussion and Proposal. J Pers Med 2021; 11:jpm11060514. [PMID: 34199906 PMCID: PMC8230111 DOI: 10.3390/jpm11060514] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 05/22/2021] [Accepted: 05/27/2021] [Indexed: 12/14/2022] Open
Abstract
The rationale of an Advanced Integrative Model and an Advanced Integrative Approach is presented. In the context of Allopathic Medicine, this model introduces the evaluation, clinical exploration, diagnosis, and treatment of concomitant medical problems to the diagnosis of Autism Spectrum Disorder. These may be outside or inside the brain. The concepts of static or chronic, dynamic encephalopathy and condition for Autism Spectrum Disorder are defined in this model, which looks at the response to the treatments of concomitant medical problemsto the diagnosis of Autism Spectrum Disorder. (1) Background: Antecedents and rationale of an Advanced Integrative Model and of an Advanced Integrative Approach are presented; (2) Methods: Concomitant medical problems to the diagnosis of Autism Spectrum Disorder and a discussion of the known responses of their treatments are presented; (3) Results: Groups in Autism are defined and explained, related to the responses of the treatments of the concomitant medical problems to ASD and (4) Conclusions: The analysis in the framework of an Advanced Integrative Model of three groups including the concepts of static encephalopathy; chronic, dynamic encephalopathy and condition for Autism Spectrum Disorder explains findings in the field, previously not understood.
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Affiliation(s)
| | - Nicolás Loyacono
- TEA-Enfoque Integrador Group, Bahía Blanca 8000, Argentina;
- SANyTA (Sociedad Argentina de Neurodesarrollo y Trastornos Asociados), Migueletes 681, Piso 2, Departamento 2, BUE-Ciudad Autónoma de Buenos Aires C1426, Argentina
- Correspondence: ; Tel.: +54-911-5825-5209
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Žigman T, Petković Ramadža D, Šimić G, Barić I. Inborn Errors of Metabolism Associated With Autism Spectrum Disorders: Approaches to Intervention. Front Neurosci 2021; 15:673600. [PMID: 34121999 PMCID: PMC8193223 DOI: 10.3389/fnins.2021.673600] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Accepted: 05/03/2021] [Indexed: 12/13/2022] Open
Abstract
Increasing evidence suggests that the autism spectrum disorder (ASD) may be associated with inborn errors of metabolism, such as disorders of amino acid metabolism and transport [phenylketonuria, homocystinuria, S-adenosylhomocysteine hydrolase deficiency, branched-chain α-keto acid dehydrogenase kinase deficiency, urea cycle disorders (UCD), Hartnup disease], organic acidurias (propionic aciduria, L-2 hydroxyglutaric aciduria), cholesterol biosynthesis defects (Smith-Lemli-Opitz syndrome), mitochondrial disorders (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes-MELAS syndrome), neurotransmitter disorders (succinic semialdehyde dehydrogenase deficiency), disorders of purine metabolism [adenylosuccinate lyase (ADSL) deficiency, Lesch-Nyhan syndrome], cerebral creatine deficiency syndromes (CCDSs), disorders of folate transport and metabolism (cerebral folate deficiency, methylenetetrahydrofolate reductase deficiency), lysosomal storage disorders [Sanfilippo syndrome, neuronal ceroid lipofuscinoses (NCL), Niemann-Pick disease type C], cerebrotendinous xanthomatosis (CTX), disorders of copper metabolism (Wilson disease), disorders of haem biosynthesis [acute intermittent porphyria (AIP)] and brain iron accumulation diseases. In this review, we briefly describe etiology, clinical presentation, and therapeutic principles, if they exist, for these conditions. Additionally, we suggest the primary and elective laboratory work-up for their successful early diagnosis.
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Affiliation(s)
- Tamara Žigman
- Department of Paediatrics, University Hospital Center Zagreb and University of Zagreb School of Medicine, Zagreb, Croatia
| | - Danijela Petković Ramadža
- Department of Paediatrics, University Hospital Center Zagreb and University of Zagreb School of Medicine, Zagreb, Croatia
| | - Goran Šimić
- Department of Neuroscience, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Ivo Barić
- Department of Paediatrics, University Hospital Center Zagreb and University of Zagreb School of Medicine, Zagreb, Croatia
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28
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Abstract
Epilepsy and autism frequently co-occur. Epilepsy confers an increased risk of autism and autism confers an increased risk of epilepsy. Specific epilepsy syndromes, intellectual disability, and female gender present a particular risk of autism in individuals with epilepsy. Epilepsy and autism are likely to share common etiologies, which predispose individuals to either or both conditions. Genetic factors, metabolic disorders, mitochondrial disorders, and immune dysfunction all can be implicated.
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Affiliation(s)
- Frank M C Besag
- East London NHS Foundation Trust, 5-7 Rush Court, Bedford MK40 3JT, UK; University College London, London, UK; King's College London, London, UK.
| | - Michael J Vasey
- East London NHS Foundation Trust, 5-7 Rush Court, Bedford MK40 3JT, UK
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29
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Rontani P, Perche O, Greetham L, Jullien N, Gepner B, Féron F, Nivet E, Erard-Garcia M. Impaired expression of the COSMOC/MOCOS gene unit in ASD patient stem cells. Mol Psychiatry 2021; 26:1606-1618. [PMID: 32327736 PMCID: PMC8159765 DOI: 10.1038/s41380-020-0728-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Revised: 03/17/2020] [Accepted: 04/03/2020] [Indexed: 12/16/2022]
Abstract
Autism spectrum disorders (ASD) are complex neurodevelopmental disorders with a very large number of risk loci detected in the genome. However, at best, each of them explains rare cases, the majority being idiopathic. Genomic data on ASD derive mostly from post-mortem brain analyses or cell lines derived from blood or patient-specific induced pluripotent stem cells (iPSCS). Therefore, the transcriptional and regulatory architecture of the nervous system, particularly during early developmental periods, remains highly incomplete. To access the critical disturbances that may have occurred during pregnancy or early childhood, we recently isolated stem cells from the nasal cavity of anesthetized patients diagnosed for ASD and compared them to stem cells from gender-matched control individuals without neuropsychiatric disorders. This allowed us to discover MOCOS, a non-mutated molybdenum cofactor sulfurase-coding gene that was under-expressed in the stem cells of most ASD patients of our cohort, disturbing redox homeostasis and synaptogenesis. We now report that a divergent transcription upstream of MOCOS generates an antisense long noncoding RNA, to which we coined the name COSMOC. Surprisingly, COSMOC is strongly under-expressed in all ASD patients of our cohort with the exception of a patient affected by Asperger syndrome. Knockdown studies indicate that loss of COSMOC reduces MOCOS expression, destabilizes lipid and energy metabolisms of stem cells, but also affects neuronal maturation and splicing of synaptic genes. Impaired expression of the COSMOC/MOCOS bidirectional unit might shed new lights on the origins of ASD that could be of importance for future translational studies.
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Affiliation(s)
- Pauline Rontani
- grid.5399.60000 0001 2176 4817Aix Marseille University, CNRS, INP, UMR 7051 Marseille, France
| | - Olivier Perche
- grid.112485.b0000 0001 0217 6921Orléans University, CNRS, INEM, UMR 7355 Orleans, France ,Department of Genetics, Regional Hospital, Orleans, France
| | - Louise Greetham
- grid.5399.60000 0001 2176 4817Aix Marseille University, CNRS, INP, UMR 7051 Marseille, France
| | - Nicolas Jullien
- grid.5399.60000 0001 2176 4817Aix Marseille University, CNRS, INP, UMR 7051 Marseille, France
| | - Bruno Gepner
- grid.5399.60000 0001 2176 4817Aix Marseille University, CNRS, INP, UMR 7051 Marseille, France
| | - François Féron
- grid.5399.60000 0001 2176 4817Aix Marseille University, CNRS, INP, UMR 7051 Marseille, France
| | - Emmanuel Nivet
- grid.5399.60000 0001 2176 4817Aix Marseille University, CNRS, INP, UMR 7051 Marseille, France
| | - Madeleine Erard-Garcia
- Aix Marseille University, CNRS, INP, UMR 7051, Marseille, France. .,Orléans University, CNRS, INEM, UMR 7355, Orleans, France.
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30
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Yao F, Zhang K, Feng C, Gao Y, Shen L, Liu X, Ni J. Protein Biomarkers of Autism Spectrum Disorder Identified by Computational and Experimental Methods. Front Psychiatry 2021; 12:554621. [PMID: 33716802 PMCID: PMC7947305 DOI: 10.3389/fpsyt.2021.554621] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 01/19/2021] [Indexed: 12/27/2022] Open
Abstract
Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that affects millions of people worldwide. However, there are currently no reliable biomarkers for ASD diagnosis. Materials and Methods: The strategy of computational prediction combined with experimental verification was used to identify blood protein biomarkers for ASD. First, brain tissue-based transcriptome data of ASD were collected from Gene Expression Omnibus database and analyzed to find ASD-related genes by bioinformatics method of significance analysis of microarrays. Then, a prediction program of blood-secretory proteins was applied on these genes to predict ASD-related proteins in blood. Furthermore, ELISA was used to verify these proteins in plasma samples of ASD patients. Results: A total of 364 genes were identified differentially expressed in brain tissue of ASD, among which 59 genes were predicted to encode ASD-related blood-secretory proteins. After functional analysis and literature survey, six proteins were chosen for experimental verification and five were successfully validated. Receiver operating characteristic curve analyses showed that the area under the curve of SLC25A12, LIMK1, and RARS was larger than 0.85, indicating that they are more powerful in discriminating ASD cases from controls. Conclusion: SLC25A12, LIMK1, and RARS might serve as new potential blood protein biomarkers for ASD. Our findings provide new insights into the pathogenesis and diagnosis of ASD.
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Affiliation(s)
- Fang Yao
- College of Life Science and Oceanography, Shenzhen University, Shenzhen, China
| | - Kaoyuan Zhang
- College of Life Science and Oceanography, Shenzhen University, Shenzhen, China.,Department of Dermatology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Chengyun Feng
- Department of Child Healthcare, Maternal and Child Health Hospital of Baoan, Shenzhen, China
| | - Yan Gao
- Department of Child Healthcare, Maternal and Child Health Hospital of Baoan, Shenzhen, China
| | - Liming Shen
- College of Life Science and Oceanography, Shenzhen University, Shenzhen, China
| | - Xukun Liu
- College of Life Science and Oceanography, Shenzhen University, Shenzhen, China
| | - Jiazuan Ni
- College of Life Science and Oceanography, Shenzhen University, Shenzhen, China
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31
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Abstract
Food containing gluten and casein could play a role in autism spectrum disorders (ASD) symptoms. The present review aimed to update the evidence about the role of the gluten- and casein-free diet (GCFD) on the management of ASD. Web of Science, Science Direct, Google Scholar, and PubMed databases were used to search for randomized controlled trials (RCT) conducted between January 2000 and February 2020. In total, 9 RCT were included (521 participants) with age range between 2 to 18 years. Four of these studies did not show a significant improvement regarding the symptoms of ASD. The rest of these studies (n=5) showed improvement in communication, stereotyped movements, aggressiveness, language, hyperactivity, tantrums, and signs of attention deficit hyperactivity disorder compared to control group. Hence, the data remains insu cient to support the use of GCFD to improve the symptoms of ASD in children.
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Affiliation(s)
- Eman S Alamri
- Department of Nutrition and Food Science, Faculty of Home Economics, University of Tabuk, Tabuk, Kingdom of Saudi Arabia. E-mail.
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32
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Yu R, Wu Z, Wang S, Zhang M, Zhou G, Li B. Isolation, identification and characterization of propionic acid bacteria associated with autistic spectrum disorder. Microb Pathog 2020; 147:104371. [PMID: 32634613 DOI: 10.1016/j.micpath.2020.104371] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Revised: 06/28/2020] [Accepted: 06/29/2020] [Indexed: 01/25/2023]
Abstract
Autism spectrum disorder (ASD) seriously affects children's health. Recently, propionic acid (PA) has been reported to play a significant role in the formation of ASD. In this study, we investigated the community structure of PA-related bacteria in healthy and ASD children by isolation and culture, while a group of representative PA-related bacteria were identified and characterized based on colony morphological observation, physiological and biochemical tests, as well as living/dead cells staining analysis and 16S rRNA gene sequencing. The results showed that the number of PA-related bacteria in healthy children was >100-fold higher than that in ASD children, while compared to healthy children, greater diversity was found in PA-associated bacteria from ASD children. The sensitivity of the representative strains to PA was affected by bacterial species, PA concentration and incubation time. The decrease of pH value was found in PA-resistant Lactobacillus plantarum strain 6-1 but not in PA-sensitive Enterococcus lactis strain 4-1, while biofilm formation of both strains were unaffected by PA. Furthermore, PA inhibited the propagation of the two selected bacteria rather than killed them, while the greater inhibitory effect was observed on strain 4-1. Overall, the result is of great significance for revealing the role of PA-related bacteria in development of ASD.
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Affiliation(s)
- Rongrong Yu
- College of Education, Zhejiang University of Technology, Hangzhou, 310032, China.
| | - Zhifeng Wu
- Institute of Biotechnology, Zhejiang University, Hangzhou, 310058, China.
| | - Shuhui Wang
- College of Education, Zhejiang University of Technology, Hangzhou, 310032, China.
| | - Muchen Zhang
- Institute of Biotechnology, Zhejiang University, Hangzhou, 310058, China.
| | - Guoling Zhou
- Hangzhou Seventh People's Hospital (HSPH), Hangzhou, 310013, China.
| | - Bin Li
- Institute of Biotechnology, Zhejiang University, Hangzhou, 310058, China.
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33
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Abstract
Epilepsy and autism frequently co-occur. Epilepsy confers an increased risk of autism and autism confers an increased risk of epilepsy. Specific epilepsy syndromes, intellectual disability, and female gender present a particular risk of autism in individuals with epilepsy. Epilepsy and autism are likely to share common etiologies, which predispose individuals to either or both conditions. Genetic factors, metabolic disorders, mitochondrial disorders, and immune dysfunction all can be implicated.
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Affiliation(s)
- Frank M C Besag
- East London NHS Foundation Trust, 5-7 Rush Court, Bedford MK40 3JT, UK; University College London, London, UK; King's College London, London, UK.
| | - Michael J Vasey
- East London NHS Foundation Trust, 5-7 Rush Court, Bedford MK40 3JT, UK
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34
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Propionic acid induced behavioural effects of relevance to autism spectrum disorder evaluated in the hole board test with rats. Prog Neuropsychopharmacol Biol Psychiatry 2020; 97:109794. [PMID: 31639413 DOI: 10.1016/j.pnpbp.2019.109794] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 10/11/2019] [Accepted: 10/17/2019] [Indexed: 12/20/2022]
Abstract
Autism spectrum disorders (ASD) are a set of neurodevelopmental disorders characterized by abnormal social interactions, impaired language, and stereotypic and repetitive behaviours. Among genetically susceptible subpopulations, gut and dietary influences may play a role in etiology. Propionic acid (PPA), produced by enteric gut bacteria, crosses both the gut-blood and the blood-brain barrier. Previous research has demonstrated that repeated intracerebroventricular (ICV) infusions of PPA in adult rats produce behavioural and neuropathological changes similar to those seen in ASD patients, including hyperactivity, stereotypy, and repetitive movements. The current study examined dose and time related changes of exploratory and repetitive behaviours with the use of the hole-board task. Adult male Long-Evans rats received ICV infusions twice a day, 4 h apart, of either buffered PPA (low dose 0.052 M or high dose 0.26 M, pH 7.5, 4 μL/infusion) or phosphate buffered saline (PBS, 0.1 M) for 7 consecutive days. Locomotor activity and hole-poke behaviour were recorded daily in an automated open field apparatus (Versamax), equipped with 16 open wells, for 30 min immediately after the second infusion. In a dose dependent manner PPA infused rats displayed significantly more locomotor activity, stereotypic behaviour and nose-pokes than PBS infused rats. Low-dose PPA animals showed locomotor activity levels similar to those of PBS animals at the start of the infusion schedule, but gradually increased to levels comparable to those of high-dose PPA animals by the end of the infusion schedule, demonstrating a dose and time dependent effect of the PPA treatments.
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35
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Higher Levels of Low Molecular Weight Sulfur Compounds and Homocysteine Thiolactone in the Urine of Autistic Children. Molecules 2020; 25:molecules25040973. [PMID: 32098164 PMCID: PMC7070266 DOI: 10.3390/molecules25040973] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 02/17/2020] [Accepted: 02/19/2020] [Indexed: 12/23/2022] Open
Abstract
In this study, the levels of concentration of homocysteine thiolactone (HTL), cysteine (Cys), and cysteinylglycine (CysGly) in the urine of autistic and non-autistic children were investigated and compared. HTL has never been analyzed in autistic children. The levels of low molecular weight sulfur compounds in the urine of both groups were determined by validated methods based on high-performance liquid chromatography with spectrofluorometric and diode-array detectors. The statistical data show a significant difference between the examined groups. Children with autism were characterized by a significantly higher level of HTL (p = 5.86 × 10−8), Cys (p = 1.49 × 10−10) and CysGly (p = 1.06 × 10−8) in urine compared with the control group. A difference in the p-value of <0.05 is statistically significant. Higher levels of HTL, Cys, and CysGly in the urine of 41 children with autism, aged 3 to 17, were observed. The obtained results may indicate disturbances in the metabolism of methionine, Cys, and glutathione in some autistic patients. These preliminary results suggest that further research with more rigorous designs and a large number of subjects is needed.
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36
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Mierau SB, Neumeyer AM. Metabolic interventions in Autism Spectrum Disorder. Neurobiol Dis 2019; 132:104544. [PMID: 31351171 DOI: 10.1016/j.nbd.2019.104544] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Revised: 06/08/2019] [Accepted: 07/23/2019] [Indexed: 10/26/2022] Open
Abstract
Metabolic interventions including special diets and supplements are commonly used in Autism Spectrum Disorder (ASD). Yet little is known about how these interventions, typically initiated by caregivers, may affect metabolic function or the core symptoms of ASD. This review examines possible direct and indirect roles for metabolism in the core symptoms of ASD as well as evidence for metabolic dysfunction and nutritional deficiencies. We also discuss some of the most popular diets and supplements used in our patient population and suggest strategies for discussing the utility of these interventions with patients, families, and caregivers.
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Affiliation(s)
- Susanna B Mierau
- Dept. of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
| | - Ann M Neumeyer
- Lurie Center for Autism, Massachusetts General Hospital, Lexington, MA, USA; Harvard Medical School, Boston, MA USA.
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37
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Vargason T, Frye RE, McGuinness DL, Hahn J. Clustering of co-occurring conditions in autism spectrum disorder during early childhood: A retrospective analysis of medical claims data. Autism Res 2019; 12:1272-1285. [PMID: 31149786 DOI: 10.1002/aur.2128] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 03/20/2019] [Accepted: 05/05/2019] [Indexed: 12/18/2022]
Abstract
Individuals with autism spectrum disorder (ASD) are frequently affected by co-occurring medical conditions (COCs), which vary in severity, age of onset, and pathophysiological characteristics. The presence of COCs contributes to significant heterogeneity in the clinical presentation of ASD between individuals and a better understanding of COCs may offer greater insight into the etiology of ASD in specific subgroups while also providing guidance for diagnostic and treatment protocols. This study retrospectively analyzed medical claims data from a private United States health plan between years 2000 and 2015 to investigate patterns of COC diagnoses in a cohort of 3,278 children with ASD throughout their first 5 years of enrollment compared to 279,693 children from the general population without ASD diagnoses (POP cohort). Three subgroups of children with ASD were identified by k-means clustering using these COC patterns. The first cluster was characterized by generally high rates of COC diagnosis and comprised 23.7% (n = 776) of the cohort. Diagnoses of developmental delays were dominant in the second cluster containing 26.5% (n = 870) of the cohort. Children in the third cluster, making up 49.8% (n = 1,632) of the cohort, had the lowest rates of COC diagnosis, which were slightly higher than rates observed in the POP cohort. A secondary analysis using these data found that gastrointestinal and immune disorders showed similar longitudinal patterns of prevalence, as did seizure and sleep disorders. These findings may help to better inform the development of diagnostic workup and treatment protocols for COCs in children with ASD. Autism Res 2019, 12: 1272-1285. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Medical conditions that co-occur with autism spectrum disorder (ASD) vary significantly from person to person. This study analyzed patterns in diagnosis of co-occurring conditions from medical claims data and observed three subtypes of children with ASD. These results may aid with screening for co-occurring conditions in children with ASD and with understanding ASD subtypes.
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Affiliation(s)
- Troy Vargason
- Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, New York.,Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York.,OptumLabs Visiting Fellow, Cambridge, Massachusetts
| | - Richard E Frye
- Department of Child Health, University of Arizona College of Medicine, Phoenix, Arizona.,Phoenix Children's Hospital, Phoenix, Arizona
| | - Deborah L McGuinness
- Department of Computer Science, Rensselaer Polytechnic Institute, Troy, New York.,Department of Cognitive Science, Rensselaer Polytechnic Institute, Troy, New York
| | - Juergen Hahn
- Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, New York.,Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York.,Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, New York
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38
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Abstract
INTRODUCTION Epilepsy is a prominent feature of myoclonic epilepsy with ragged-red fibers (MERRF)-syndrome. The most frequent seizure type is myoclonic seizures, of which the treatment is challenging and empiric. AREAS COVERED Herein, the author summarises and discusses previous and recent findings of antiepileptic drug (AED) treatment in MERRF-syndrome. EXPERT OPINION MERRF-syndrome is a predominantly maternally inherited, multisystem mitochondrial disorder caused by pathogenic variants predominantly of the mitochondrial DNA (mtDNA). Canonical clinical features of MERRF include myoclonus, epilepsy, ataxia, and myopathy. Additionally, other manifestations in the CNS, peripheral nerves, eyes, ears, heart, gastrointestinal tract, and endocrine organs may occur (MERRF-plus). Today, MERRF is considered rather as myoclonic ataxia than as myoclonic epilepsy. Genotypically, MERRF is due to mutations in 13 mtDNA-located genes and 1 nDNA-located gene. According to the modified Smith-score, the strongest gene-disease relationship exists for MT-TK, MT-TL1, and POLG1. Epilepsy is the second most frequent phenotypic feature of MERRF. Seizure-types associated with MERRF include focal myoclonic, focal clonic, and focal atonic seizures, generalized myoclonic, tonic-clonic, atonic, and myoclonic-atonic seizures, or typical absences. Treatment of myoclonic epilepsy relies on expert judgments recommending levetiracetam, together with clonazepam, or topiramate, zonisamide, or piracetam in monotherapy as the first line AEDs.
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Affiliation(s)
- Josef Finsterer
- a Krankenanstalt Rudolfstiftung , Messerli Institute , Vienna , Austria
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39
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Reduced levels of modified nucleosides in the urine of autistic children. Preliminary studies. Anal Biochem 2019; 571:62-67. [PMID: 30771338 DOI: 10.1016/j.ab.2019.02.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 02/11/2019] [Accepted: 02/12/2019] [Indexed: 12/31/2022]
Abstract
The aim of this study was to investigate and compare the levels of concentration of modified nucleosides in the urine of autistic and healthy children. The compounds have never been analyzed before. The levels of nucleosides in the urine of both groups were determined by validated high performance liquid chromatography coupled to mass spectrometry (LC-MS/MS) method using multiple reaction monitoring (MRM) mode. Chromatographic separation was achieved with HILIC column and tubercidin was used as the internal standard for the quantification of urinary nucleosides. The within run accuracy and precision ranged from 89 to 106% and from 0.8% to 4.9%, respectively. Lower levels of O-methylguanosine, 7-methylguanosine, 1-methyladenosine, 1-methylguanine, 7-methylguanine and 3-methyladenine in the urine of 22 children with autism, aged 3 to 16 were observed. The differences were not observed in 20 healthy volunteers, in a similar age group. These findings show that modified nucleosides there are metabolic disturbances and nutritional deficiencies in autistic children.
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40
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Abstract
It is proposed that proteins/enzymes be classified into two classes according to their essentiality for immediate survival/reproduction and their function in long-term health: that is, survival proteins versus longevity proteins. As proposed by the triage theory, a modest deficiency of one of the nutrients/cofactors triggers a built-in rationing mechanism that favors the proteins needed for immediate survival and reproduction (survival proteins) while sacrificing those needed to protect against future damage (longevity proteins). Impairment of the function of longevity proteins results in an insidious acceleration of the risk of diseases associated with aging. I also propose that nutrients required for the function of longevity proteins constitute a class of vitamins that are here named "longevity vitamins." I suggest that many such nutrients play a dual role for both survival and longevity. The evidence for classifying taurine as a conditional vitamin, and the following 10 compounds as putative longevity vitamins, is reviewed: the fungal antioxidant ergothioneine; the bacterial metabolites pyrroloquinoline quinone (PQQ) and queuine; and the plant antioxidant carotenoids lutein, zeaxanthin, lycopene, α- and β-carotene, β-cryptoxanthin, and the marine carotenoid astaxanthin. Because nutrient deficiencies are highly prevalent in the United States (and elsewhere), appropriate supplementation and/or an improved diet could reduce much of the consequent risk of chronic disease and premature aging.
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Affiliation(s)
- Bruce N Ames
- Nutrition and Metabolism Center, Children's Hospital Oakland Research Institute (CHORI), Oakland, CA 94609-1809
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Frye RE. Social Skills Deficits in Autism Spectrum Disorder: Potential Biological Origins and Progress in Developing Therapeutic Agents. CNS Drugs 2018; 32:713-734. [PMID: 30105528 PMCID: PMC6105175 DOI: 10.1007/s40263-018-0556-y] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Autism spectrum disorder is defined by two core symptoms: a deficit in social communication and the presence of repetitive behaviors and/or restricted interests. Currently, there is no US Food and Drug Administration-approved drug for these core symptoms. This article reviews the biological origins of the social function deficit associated with autism spectrum disorder and the drug therapies with the potential to treat this deficit. A review of the history of autism demonstrates that a deficit in social interaction has been the defining feature of the concept of autism from its conception. Abnormalities identified in early social skill development and an overview of the pathophysiology abnormalities associated with autism spectrum disorder are discussed as are the abnormalities in brain circuits associated with the social function deficit. Previous and ongoing clinical trials examining agents that have the potential to improve social deficits associated with autism spectrum disorder are discussed in detail. This discussion reveals that agents such as oxytocin and propranolol are particularly promising and undergoing active investigation, while other agents such as vasopressin agonists and antagonists are being activity investigated but have limited published evidence at this time. In addition, agents such as bumetanide and manipulation of the enteric microbiome using microbiota transfer therapy appear to have promising effects on core autism spectrum disorder symptoms including social function. Other pertinent issues associated with developing treatments in autism spectrum disorder, such as disease heterogeneity, high placebo response rates, trial design, and the most appropriate way of assessing effects on social skills (outcome measures), are also discussed.
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Affiliation(s)
- Richard E Frye
- Division of Neurodevelopmental Disorders, Department of Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, 1919 E Thomas St, Phoenix, AZ, 85016, USA.
- Department of Child Health, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, 85004, USA.
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Bitar T, Mavel S, Emond P, Nadal-Desbarats L, Lefèvre A, Mattar H, Soufia M, Blasco H, Vourc’h P, Hleihel W, Andres CR. Identification of metabolic pathway disturbances using multimodal metabolomics in autistic disorders in a Middle Eastern population. J Pharm Biomed Anal 2018; 152:57-65. [DOI: 10.1016/j.jpba.2018.01.007] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Revised: 12/17/2017] [Accepted: 01/06/2018] [Indexed: 12/21/2022]
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Diallo FB, Fombonne É, Kisely S, Rochette L, Vasiliadis HM, Vanasse A, Noiseux M, Pelletier É, Renaud J, St-Laurent D, Lesage A. Prevalence and Correlates of Autism Spectrum Disorders in Quebec: Prévalence et corrélats des troubles du spectre de l'autisme au Québec. CANADIAN JOURNAL OF PSYCHIATRY. REVUE CANADIENNE DE PSYCHIATRIE 2018; 63:231-239. [PMID: 29056086 PMCID: PMC5894913 DOI: 10.1177/0706743717737031] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
OBJECTIVE To estimate the prevalence, comorbidities, and service use of people with autism spectrum disorders (ASDs) based on data from Quebec Integrated Chronic Diseases Surveillance System (QICDSS). METHODS We included all residents up to age 24 eligible for health plan coverage who were in Quebec for at least 1 day from January 1, 1996, to March 31, 2015. To be considered as having an ASD, an individual had to have had at least 1 physician claim or hospital discharge abstract from 2000 to 2015 indicating one of the following ASD diagnosis codes: ICD-9 codes 299.0 to 299.9 or their ICD-10 equivalents. RESULTS The QICDSS shows that the prevalence of ASD has risen steadily over the past decade to approximately 1.2% ( n = 16,940) of children and youths aged 1 to 17 years in 2014 to 2015. The same prevalence was obtained using Ministry of Education data. Common medical comorbidities included congenital abnormalities of the nervous system, particularly in the first year of life. Psychiatric comorbidity was much more highly prevalent, especially common mental disorders like anxiety and attention-deficit/hyperactivity disorder. Children and youths with ASDs made on average 2.3 medical visits per year compared with 0.2 in the general population. Between 18 and 24 years old, the mental health needs of individuals with ASDs were met less by medical specialists and more by general practitioners. CONCLUSION Information derived from this database could support and monitor development of better medical services coordination and shared care to meet the continuous and changing needs of patients and families over time.
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Affiliation(s)
- Fatoumata Binta Diallo
- 1 Quebec's Public Health Institute (Bureau d'information et d'études en santé des populations, Institut national de santé publique du Québec), Quebec, Quebec
| | - Éric Fombonne
- 2 Department of Psychiatry, Oregon Health Sciences University, Portland, Oregon, USA
| | - Steve Kisely
- 3 Departments of Community Health and Epidemiology, Dalhousie University, Halifax, Nova Scotia.,4 School of Medicine, University of Queensland, Queensland, Australia
| | - Louis Rochette
- 1 Quebec's Public Health Institute (Bureau d'information et d'études en santé des populations, Institut national de santé publique du Québec), Quebec, Quebec
| | | | - Alain Vanasse
- 6 Department of Family Medicine, University of Sherbrooke, Sherbrooke, Quebec
| | - Manon Noiseux
- 7 Department of Public Health, Health and Social Services Centre of Montérégie-Centre, Montérégie, Quebec
| | - Éric Pelletier
- 1 Quebec's Public Health Institute (Bureau d'information et d'études en santé des populations, Institut national de santé publique du Québec), Quebec, Quebec
| | - Johanne Renaud
- 8 Department of Psychiatry, McGill University, Montreal, Quebec
| | - Danielle St-Laurent
- 1 Quebec's Public Health Institute (Bureau d'information et d'études en santé des populations, Institut national de santé publique du Québec), Quebec, Quebec
| | - Alain Lesage
- 1 Quebec's Public Health Institute (Bureau d'information et d'études en santé des populations, Institut national de santé publique du Québec), Quebec, Quebec.,9 Department of Psychiatry, Research Centre of the Montreal Mental Health University Institute, University of Montreal, Montreal, Quebec
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Brain responses to auditory oddball task in children with benign childhood epilepsy with centrotemporal spikes: Quantitative analysis and correlation with neuropsychological assessment scores. Epilepsy Behav 2018; 80:272-279. [PMID: 29398625 DOI: 10.1016/j.yebeh.2018.01.017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Revised: 01/06/2018] [Accepted: 01/12/2018] [Indexed: 11/23/2022]
Abstract
OBJECTIVE Variable degrees of cognitive dysfunction have been reported in children with benign childhood epilepsy with centrotemporal spikes (BCECTS). Our aim was to perform quantitative analyses of the brain responses to cognitive tasks using event-related desynchronization (ERD) and event-related synchronization (ERS) and correlating the results with the scores of neuropsychological tests in patients with BCECTS. METHODS This case control study included 30 patients with BCECTS and 20 controls. Clinical assessment, neuropsychological tests, the Positive wave at 300 msec (P300) parameters recording, and quantitative electroencephalography (EEG) analysis were carried out for both groups. Alpha power ERD and ERS were measured in six different brain regions during an auditory oddball paradigm. RESULTS Children with epilepsy showed a statistically significant poorer performance in verbal intelligence quotient (IQ), performance IQ, and total scale IQ and lower number of correct responses. Moreover, both groups showed diffuse alpha power attenuation in response to the target tones. After summation of the alpha power ERD over all brain regions to get the net diffuse ERD, the patients' group showed a statistically significant smaller net alpha ERD compared with that of the control group (P=0.001). No significant correlations between the alpha ERD percentage, recorded P300 parameters, and neuropsychological tests scores were found. CONCLUSIONS Children with BCECTS have subtle cognitive dysfunction proved by significantly lower scores of verbal IQ and performance IQ subtests. The significantly smaller net diffuse alpha power ERD detected in children with epilepsy may be an electrophysiological indicator of disruptive brain activation in relation to cognitive attentional tasks; however, its correlation with neuropsychological tests was insignificant.
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Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial. Mol Psychiatry 2018; 23:247-256. [PMID: 27752075 PMCID: PMC5794882 DOI: 10.1038/mp.2016.168] [Citation(s) in RCA: 108] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Revised: 08/01/2016] [Accepted: 08/03/2016] [Indexed: 02/07/2023]
Abstract
We sought to determine whether high-dose folinic acid improves verbal communication in children with non-syndromic autism spectrum disorder (ASD) and language impairment in a double-blind placebo control setting. Forty-eight children (mean age 7 years 4 months; 82% male) with ASD and language impairment were randomized to receive 12 weeks of high-dose folinic acid (2 mg kg-1 per day, maximum 50 mg per day; n=23) or placebo (n=25). Children were subtyped by glutathione and folate receptor-α autoantibody (FRAA) status. Improvement in verbal communication, as measured by a ability-appropriate standardized instrument, was significantly greater in participants receiving folinic acid as compared with those receiving placebo, resulting in an effect of 5.7 (1.0,10.4) standardized points with a medium-to-large effect size (Cohen's d=0.70). FRAA status was predictive of response to treatment. For FRAA-positive participants, improvement in verbal communication was significantly greater in those receiving folinic acid as compared with those receiving placebo, resulting in an effect of 7.3 (1.4,13.2) standardized points with a large effect size (Cohen's d=0.91), indicating that folinic acid treatment may be more efficacious in children with ASD who are FRAA positive. Improvements in subscales of the Vineland Adaptive Behavior Scale, the Aberrant Behavior Checklist, the Autism Symptom Questionnaire and the Behavioral Assessment System for Children were significantly greater in the folinic acid group as compared with the placebo group. There was no significant difference in adverse effects between treatment groups. Thus, in this small trial of children with non-syndromic ASD and language impairment, treatment with high-dose folinic acid for 12 weeks resulted in improvement in verbal communication as compared with placebo, particularly in those participants who were positive for FRAAs.
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Benke PJ, Duchowny M, McKnight D. Biotin and Acetazolamide for Treatment of an Unusual Child With Autism Plus Lack of Nail and Hair Growth. Pediatr Neurol 2018; 79:61-64. [PMID: 29413639 DOI: 10.1016/j.pediatrneurol.2017.10.013] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Revised: 10/13/2017] [Accepted: 10/14/2017] [Indexed: 11/27/2022]
Abstract
BACKGROUND Patients with autism spectrum disorder and developmental delay or encephalopathy rarely demonstrate no or negligible hair and nail growth, suggesting a biotin-responsive clinical disorder. METHODS A ten-year-old girl presented with features of autism spectrum disorder, isolated headaches, and episodes of headaches and limb shaking. Her medical history revealed that her hair and nails did not grow. Administration of biotin restored her nail and hair growth and improved intellectual ability and school performance. Her episodes of headaches, single limb shaking, and loss of consciousness responded to administration of acetazolamide, and her school performance and social skills further improved. RESULTS A de novo c.1091 C > T, p.T364M pathogenic variant was found in the ATP1A2 gene by whole-exome sequencing, but a genetic etiology in the biotin-responsive metabolic pathways was not identified. CONCLUSIONS The combination of biotin and acetazolamide treatment was successful in restoring normal mental function and school performance. Poor or no clinical nail and hair growth in any child with a developmental delay-autism spectrum disorder presentation should be considered as evidence for a biotin-responsive genetic disorder even when exome testing is negative.
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Affiliation(s)
- Paul J Benke
- Genetics Division, Joe DiMaggio Children's Hospital, and Charles E. Schmidt College of Medicine, Hollywood, Florida.
| | - Michael Duchowny
- Neurology Division, Nicklaus Children's Hospital, Miami, Florida
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McCammon JM, Blaker-Lee A, Chen X, Sive H. The 16p11.2 homologs fam57ba and doc2a generate certain brain and body phenotypes. Hum Mol Genet 2018; 26:3699-3712. [PMID: 28934389 PMCID: PMC5886277 DOI: 10.1093/hmg/ddx255] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Accepted: 06/29/2017] [Indexed: 01/28/2023] Open
Abstract
Deletion of the 16p11.2 CNV affects 25 core genes and is associated with multiple symptoms affecting brain and body, including seizures, hyperactivity, macrocephaly, and obesity. Available data suggest that most symptoms are controlled by haploinsufficiency of two or more 16p11.2 genes. To identify interacting 16p11.2 genes, we used a pairwise partial loss of function antisense screen for embryonic brain morphology, using the accessible zebrafish model. fam57ba, encoding a ceramide synthase, was identified as interacting with the doc2a gene, encoding a calcium-sensitive exocytosis regulator, a genetic interaction not previously described. Using genetic mutants, we demonstrated that doc2a+/− fam57ba+/− double heterozygotes show hyperactivity and increased seizure susceptibility relative to wild-type or single doc2a−/− or fam57ba−/− mutants. Additionally, doc2a+/− fam57ba+/− double heterozygotes demonstrate the increased body length and head size. Single doc2a+/− and fam57ba+/− heterozygotes do not show a body size increase; however, fam57ba−/− homozygous mutants show a strongly increased head size and body length, suggesting a greater contribution from fam57ba to the haploinsufficient interaction between doc2a and fam57ba. The doc2a+/− fam57ba+/− interaction has not been reported before, nor has any 16p11.2 gene previously been linked to increased body size. These findings demonstrate that one pair of 16p11.2 homologs can regulate both brain and body phenotypes that are reflective of those in people with 16p11.2 deletion. Together, these findings suggest that dysregulation of ceramide pathways and calcium sensitive exocytosis underlies seizures and large body size associated with 16p11.2 homologs in zebrafish. The data inform consideration of mechanisms underlying human 16p11.2 deletion symptoms.
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Affiliation(s)
| | - Alicia Blaker-Lee
- Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
| | - Xiao Chen
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Hazel Sive
- Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.,Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
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Abstract
Autism is more common in people with epilepsy, approximately 20%, and epilepsy is more common in people with autism with reported rates of approximately 20%. However, these figures are likely to be affected by the current broader criteria for autism spectrum disorder (ASD), which have contributed to an increased prevalence of autism, with the result that the rate for ASD in epilepsy is likely to be higher and the figure for epilepsy in ASD is likely to be lower. Some evidence suggests that there are two peaks of epilepsy onset in autism, in infancy and adolescence. The rate of autism in epilepsy is much higher in those with intellectual disability. In conditions such as the Landau-Kleffner syndrome and nonconvulsive status epilepticus, the epilepsy itself may present with autistic features. There is no plausible mechanism for autism causing epilepsy, however. The co-occurrence of autism and epilepsy is almost certainly the result of underlying factors predisposing to both conditions, including both genetic and environmental factors. Conditions such as attention deficit hyperactivity disorder, anxiety and sleep disorders are common in both epilepsy and autism. Epilepsy is generally not a contraindication to treating these conditions with suitable medication, but it is important to take account of relevant drug interactions. One of the greatest challenges in autism is to determine why early childhood regression occurs in perhaps 25%. Further research should focus on finding the cause for such regression. Whether epilepsy plays a role in the regression of a subgroup of children with autism who lose skills remains to be determined.
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Affiliation(s)
- Frank Mc Besag
- Neurodevelopmental Team, East London Foundation NHS Trust, Family Consultation Clinic, Bedford, UK
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O'Sullivan A, Henrick B, Dixon B, Barile D, Zivkovic A, Smilowitz J, Lemay D, Martin W, German JB, Schaefer SE. 21st century toolkit for optimizing population health through precision nutrition. Crit Rev Food Sci Nutr 2017; 58:3004-3015. [PMID: 28678528 DOI: 10.1080/10408398.2017.1348335] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Scientific, technological, and economic progress over the last 100 years all but eradicated problems of widespread food shortage and nutrient deficiency in developed nations. But now society is faced with a new set of nutrition problems related to energy imbalance and metabolic disease, which require new kinds of solutions. Recent developments in the area of new analytical tools enable us to systematically study large quantities of detailed and multidimensional metabolic and health data, providing the opportunity to address current nutrition problems through an approach called Precision Nutrition. This approach integrates different kinds of "big data" to expand our understanding of the complexity and diversity of human metabolism in response to diet. With these tools, we can more fully elucidate each individual's unique phenotype, or the current state of health, as determined by the interactions among biology, environment, and behavior. The tools of precision nutrition include genomics, metabolomics, microbiomics, phenotyping, high-throughput analytical chemistry techniques, longitudinal tracking with body sensors, informatics, data science, and sophisticated educational and behavioral interventions. These tools are enabling the development of more personalized and predictive dietary guidance and interventions that have the potential to transform how the public makes food choices and greatly improve population health.
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Affiliation(s)
| | - Bethany Henrick
- b Foods for Health Institute , University of California , Davis , USA
| | - Bonnie Dixon
- b Foods for Health Institute , University of California , Davis , USA
| | - Daniela Barile
- c Food Science and Technology , University of California , Davis , USA
| | - Angela Zivkovic
- d Department of Nutrition , University of California , Davis , USA
| | - Jennifer Smilowitz
- b Foods for Health Institute , University of California , Davis , USA.,e USDA-ARS Western Human Nutrition Research Center , Davis , USA
| | - Danielle Lemay
- f Nutritional Biology , University of California , Davis , USA
| | | | - J Bruce German
- h Department of Food Science and Technology , University of California , Davis , USA
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Finsterer J, Zarrouk-Mahjoub S. Management of epilepsy in MERRF syndrome. Seizure 2017; 50:166-170. [DOI: 10.1016/j.seizure.2017.06.010] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Revised: 05/26/2017] [Accepted: 06/13/2017] [Indexed: 11/28/2022] Open
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