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Qi L, Yang J, Niu Q, Li J. Exploring pesticide risk in autism via integrative machine learning and network toxicology. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2025; 297:118233. [PMID: 40280042 DOI: 10.1016/j.ecoenv.2025.118233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 04/09/2025] [Accepted: 04/22/2025] [Indexed: 04/29/2025]
Abstract
Autism Spectrum Disorder (ASD) is a prevalent neurodevelopmental condition influenced by both genetic and environmental factors, including pesticide exposure. This study aims to investigate the pathogenic mechanisms of ASD and identify potential causative pesticides by integrating bioinformatics, machine learning, network toxicology, and molecular docking approaches. A total of 156 differentially expressed genes (128 upregulated and 28 downregulated) were identified from ASD-related transcriptomic datasets. Using the LASSO algorithm, 23 key targets were initially selected. Each combination of 1-23 targets was used to construct predictive models using eight different machine learning algorithms. The Stochastic Gradient Descent (SGD) model demonstrated the best predictive performance for 20 features, which were defined as hub targets. These targets were subsequently used in a network toxicology framework to screen for associated environmental toxicants. Three pesticide candidates-epoxiconazole, flusilazole, and DEET-were identified as strongly interacting with these core targets. Molecular docking analysis further validated stable binding affinities between these pesticides and the hub targets. Functional enrichment analysis revealed significant involvement of glycosylation-related pathways, including mucin-type O-glycan biosynthesis, implicating potential mechanisms in ASD pathogenesis. Collectively, our findings highlight novel biomolecular links between pesticide exposure and ASD risk, and propose a set of candidate biomarkers and toxicants for further experimental validation and regulatory consideration.
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Affiliation(s)
- Ling Qi
- Department of Occupational and Environmental Health, College of Public Health, Xuzhou Medical University, 209 Tongshan Road, Yun Long District, Xuzhou 221000, China
| | - Jingran Yang
- Department of Occupational and Environmental Health, College of Public Health, Xuzhou Medical University, 209 Tongshan Road, Yun Long District, Xuzhou 221000, China
| | - Qiao Niu
- Department of Occupational and Environmental Health, College of Public Health, Xuzhou Medical University, 209 Tongshan Road, Yun Long District, Xuzhou 221000, China; Department of Occupational Health, College of Public Health, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
| | - Jianan Li
- Department of Occupational and Environmental Health, College of Public Health, Xuzhou Medical University, 209 Tongshan Road, Yun Long District, Xuzhou 221000, China.
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Yurumez E, Cikili-Uytun M, Kaymak B, Dogan O, Ozturk HH, Baysar-Kanoglu BN, Oztop DB. Neurodegeneration in Autism: A Study of Clusterin, Very Long-Chain Fatty Acids, and Carnitine. J Mol Neurosci 2025; 75:18. [PMID: 39932645 DOI: 10.1007/s12031-024-02303-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 12/17/2024] [Indexed: 04/02/2025]
Abstract
The clinical identification of regression phenomena in ASD lacks specific biological or laboratory criteria and is often based on family history and highly subjective observations by clinicians. The present study aimed to investigate the potential role of plasma clusterin (CLU), very long-chain fatty acids (VLCFA), and carnitine as biomarkers of neurodegeneration in children with autism spectrum disorder (ASD) with and without regression. By exploring these biomarkers, we sought to provide insights into mitochondrial dysfunction, glial activation, and lipid metabolism, which may contribute to the pathophysiology of ASD and aid in the early diagnosis and intervention of regression phenomena in ASD. Ninety children aged 2-6 years were included: 30 with autism spectrum disorder (ASD), 30 with regressive ASD, and 30 healthy controls. Psychiatric assessments were conducted using DSM-5 criteria, CARS, ABC, RBS-R, and ASSQ scales. Regression in ASD was evaluated retrospectively using a modified ADI-R questionnaire. Fasting blood samples were collected, and plasma clusterin (CLU), VLCFA, and carnitine levels were measured. Statistical analyses were performed using MANOVA to assess the effect of group differences on dependent biochemical variables. Serum clusterin and carnitine levels showed no significant differences between groups. However, C22 VLCFA levels were significantly higher in both autism groups compared to controls (p = 0.04), with post hoc analysis indicating the difference between the non-regressive and control groups (p = 0.02). Serum carnitine was positively correlated with stereotypic behaviors subscale scores (r = 0.37, p = 0.004) and total scores (r = 0.35, p = 0.006) of RBS-R. Our study provides insights into the complexities of biomarker research in autism spectrum disorder (ASD), highlighting the challenges in identifying consistent biological markers for regression and non-regression phenotypes. Although no significant findings were observed, further biomarker studies are essential to distinguish possible endophenotypes, improve early diagnosis, and uncover potential therapeutic targets in ASD.
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Affiliation(s)
- Esra Yurumez
- Department of Child and Adolescent Psychiatry, Faculty of Medicine, Ankara University, Ankara, 06620, Mamak, Turkey
- Autism Intervention and Research Center, Ankara University, Ankara, Turkey
| | - Merve Cikili-Uytun
- Department of Child and Adolescent Psychiatry, Faculty of Medicine, Ankara University, Ankara, 06620, Mamak, Turkey
- Autism Intervention and Research Center, Ankara University, Ankara, Turkey
| | - Banu Kaymak
- Department of Child and Adolescent Psychiatry, Faculty of Medicine, Ankara University, Ankara, 06620, Mamak, Turkey.
- Autism Intervention and Research Center, Ankara University, Ankara, Turkey.
| | - Ozlem Dogan
- Department of Biochemistry, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Humeyra Hilal Ozturk
- Department of Child and Adolescent Psychiatry, Bayburt State Hospital, Bayburt, Turkey
| | | | - Didem Behice Oztop
- Department of Child and Adolescent Psychiatry, Faculty of Medicine, Ankara University, Ankara, 06620, Mamak, Turkey
- Autism Intervention and Research Center, Ankara University, Ankara, Turkey
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Jiang Z, Sullivan PF, Li T, Zhao B, Wang X, Luo T, Huang S, Guan PY, Chen J, Yang Y, Stein JL, Li Y, Liu D, Sun L, Zhu H. The X chromosome's influences on the human brain. SCIENCE ADVANCES 2025; 11:eadq5360. [PMID: 39854466 PMCID: PMC11759047 DOI: 10.1126/sciadv.adq5360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Accepted: 12/23/2024] [Indexed: 01/26/2025]
Abstract
Genes on the X chromosome are extensively expressed in the human brain. However, little is known for the X chromosome's impact on the brain anatomy, microstructure, and functional networks. We examined 1045 complex brain imaging traits from 38,529 participants in the UK Biobank. We unveiled potential autosome-X chromosome interactions while proposing an atlas outlining dosage compensation for brain imaging traits. Through extensive association studies, we identified 72 genome-wide significant trait-locus pairs (including 29 new associations) that share genetic architectures with brain-related disorders, notably schizophrenia. Furthermore, we found unique sex-specific associations and assessed variations in genetic effects between sexes. Our research offers critical insights into the X chromosome's role in the human brain, underscoring its contribution to the differences observed in brain structure and functionality between sexes.
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Affiliation(s)
- Zhiwen Jiang
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Patrick F. Sullivan
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Tengfei Li
- Department of Radiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Biomedical Research Imaging Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Bingxin Zhao
- Department of Statistics and Data Science, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Xifeng Wang
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Tianyou Luo
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Shuai Huang
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Peter Y. Guan
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Jie Chen
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Yue Yang
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Jason L. Stein
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Yun Li
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Dajiang Liu
- Department of Public Health Sciences, Penn State University, Hershey, PA 17033, USA
- Department of Biochemistry and Molecular Biology, Penn State University, Hershey, PA 17033, USA
| | - Lei Sun
- Department of Statistical Sciences, University of Toronto, Toronto, ON M5G 1Z5, Canada
- Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada
| | - Hongtu Zhu
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Biomedical Research Imaging Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Department of Statistics and Operations Research, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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Verhoeven WMA, Pfundt R, Engelke UFH, Kluijtmans LAJ, Egger JIM. X-Linked Autism Type 9 Caused by a Hemizygote Pathogenic Variant in the TMLHE Gene: Etiological Diagnosis in an Adult Male with Moderate Intellectual Disability. Int Med Case Rep J 2025; 18:111-116. [PMID: 39845198 PMCID: PMC11753900 DOI: 10.2147/imcrj.s506204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 01/06/2025] [Indexed: 01/24/2025] Open
Abstract
Introduction Levocarnitine is essential for brain functioning and fatty acid metabolism and stems largely from dietary sources. The Epsilon-Trimethyllysine Hydroxylase (TMLHE) gene encodes the enzyme N-Trimethyllysine hydroxylase (TMLH) which catalyses the first step in the biosynthesis of carnitine. Lack of TMLH enzyme activity is associated with developmental delay and autistic behaviours described as X-linked recessive autism, type 6 (OMIM#300872). Patient and Methods Here, an institutionalized adult male patient with intellectual disability, autism, and challenging behaviours is presented in whom genetic analysis disclosed a novel pathogenic variant in the TMLHE gene. Extensive somatic, neurological, psychiatric, and neuropsychological investigations were performed next to examination of hematological and biochemical parameters including plasma carnitine status. Also, Whole Exome Sequencing (WES) and Next-Generation Metabolic Screening (NGMS) were performed. Results Moderate intellectual disability along with obsessive and aggressive behaviour in the context of autism spectrum disorders was established as well as symptoms from the catatonic spectrum. With WES, a novel variant in the TMHLE gene was identified and using NGMS, increased concentration of trimethyllysine and decreased concentration of γ-butyrobetaine were found resulting in a significantly decreased BB/TML ratio, confirming the pathogenicity of this variant. Conclusion X-linked autism type 6 is characterized by moderate intellectual disability and symptoms from the autism spectrum in the absence of any dysmorphisms. To prevent regressive autistic episodes in young children, it is highly recommended to consider next-generation sequencing techniques as the first step in the differential diagnostic process of autism.
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Affiliation(s)
- Willem M A Verhoeven
- Department of Psychiatry, Erasmus University Medical Center, Rotterdam, The Netherlands
- Centre for Consultation and Expertise, Utrecht, The Netherlands
- Vincent van Gogh Centre of Excellence for Neuropsychiatry, Venray, The Netherlands
| | - Rolph Pfundt
- Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands
- Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands
| | - Udo F H Engelke
- Department of Human Genetics, Translational Metabolic Laboratory, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Leo A J Kluijtmans
- Department of Human Genetics, Translational Metabolic Laboratory, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Jos I M Egger
- Vincent van Gogh Centre of Excellence for Neuropsychiatry, Venray, The Netherlands
- Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands
- Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands
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Demarquoy J. Revisiting the Role of Carnitine in Heart Disease Through the Lens of the Gut Microbiota. Nutrients 2024; 16:4244. [PMID: 39683637 PMCID: PMC11644639 DOI: 10.3390/nu16234244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 11/30/2024] [Accepted: 12/06/2024] [Indexed: 12/18/2024] Open
Abstract
L-Carnitine, sourced from red meat, dairy, and endogenous synthesis, plays a vital role in fatty acid metabolism and energy production. While beneficial for cardiovascular, muscular, and neural health, its interaction with the gut microbiota and conversion into trimethylamine (TMA) and trimethylamine N-oxide (TMAO) raise concerns about heart health. TMAO, produced through the gut-microbial metabolism of L-carnitine and subsequent liver oxidation, is associated with cardiovascular risks, including atherosclerosis, heart attacks, and stroke. It contributes to cholesterol deposition, vascular dysfunction, and platelet aggregation. Omnivorous diets, rich in L-carnitine, are associated with higher TMAO levels compared to plant-based diets, which are linked to lower cardiovascular disease risks. Dietary interventions, such as increasing fiber, polyphenols, and probiotics, can modulate the gut microbiota to reduce TMAO production. These strategies seek to balance L-carnitine's benefits with its potential risks related to TMAO production. Future research should focus on personalized approaches to optimize L-carnitine use while mitigating its cardiovascular impacts, exploring microbial modulation and dietary strategies to minimize the TMAO levels and associated risks.
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Affiliation(s)
- Jean Demarquoy
- Unité Mixte de Recherche Procédés Alimentaires et Microbiologiques (UMR PAM), Institut Agro, Institut National de Recherche Pour L'agriculture, L'alimentation et L'environnement (INRAE), Université de Bourgogne, 21000 Dijon, France
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Mazza T, Scalise M, Console L, Galluccio M, Giangregorio N, Tonazzi A, Pochini L, Indiveri C. Carnitine traffic and human fertility. Biochem Pharmacol 2024; 230:116565. [PMID: 39368751 DOI: 10.1016/j.bcp.2024.116565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 09/18/2024] [Accepted: 10/01/2024] [Indexed: 10/07/2024]
Abstract
Carnitine is a vital molecule in human metabolism, prominently involved in fatty acid β-oxidation within mitochondria. Predominantly sourced from dietary intake, carnitine also derives from endogenous synthesis. This review delves into the complex network of carnitine transport and distribution, emphasizing its pivotal role in human fertility. Together with its role in fatty acid oxidation, carnitine modulates the acety-CoA/CoA ratio, influencing carbohydrate metabolism, lipid biosynthesis, and gene expression. The intricate regulation of carnitine homeostasis involves a network of membrane transporters, notably OCTN2, which is central in its absorption, reabsorption, and distribution. OCTN2 dysfunction, results in Primary Carnitine Deficiency (PCD), characterized by systemic carnitine depletion and severe clinical manifestations, including fertility issues. In the male reproductive system, carnitine is crucial for sperm maturation and motility. In the female reproductive system, carnitine supports mitochondrial function necessary for oocyte quality, folliculogenesis, and embryonic development. Indeed, deficiencies in carnitine or its transporters have been linked to asthenozoospermia, reduced sperm quality, and suboptimal fertility outcomes in couples. Moreover, the antioxidant properties of carnitine protect spermatozoa from oxidative stress and help in managing conditions like polycystic ovary syndrome (PCOS) and endometriosis, enhancing sperm viability and fertilization potential of oocytes. This review summarizes the key role of membrane transporters in guaranteeing carnitine homeostasis with a special focus on the implications in fertility and possible treatments of infertility and other related disorders.
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Affiliation(s)
- Tiziano Mazza
- Department DiBEST (Biologia, Ecologia, Scienze della Terra) Unit of Biochemistry and Molecular Biotechnology, University of Calabria, Via P. Bucci 4C, Arcavacata di Rende 87036, Italy
| | - Mariafrancesca Scalise
- Department DiBEST (Biologia, Ecologia, Scienze della Terra) Unit of Biochemistry and Molecular Biotechnology, University of Calabria, Via P. Bucci 4C, Arcavacata di Rende 87036, Italy
| | - Lara Console
- Department DiBEST (Biologia, Ecologia, Scienze della Terra) Unit of Biochemistry and Molecular Biotechnology, University of Calabria, Via P. Bucci 4C, Arcavacata di Rende 87036, Italy
| | - Michele Galluccio
- Department DiBEST (Biologia, Ecologia, Scienze della Terra) Unit of Biochemistry and Molecular Biotechnology, University of Calabria, Via P. Bucci 4C, Arcavacata di Rende 87036, Italy
| | - Nicola Giangregorio
- CNR Institute of Biomembranes, Bioenergetics and Molecular Biotechnology (IBIOM), via Amendola 122/O, Bari 70126, Italy
| | - Annamaria Tonazzi
- CNR Institute of Biomembranes, Bioenergetics and Molecular Biotechnology (IBIOM), via Amendola 122/O, Bari 70126, Italy
| | - Lorena Pochini
- Department DiBEST (Biologia, Ecologia, Scienze della Terra) Unit of Biochemistry and Molecular Biotechnology, University of Calabria, Via P. Bucci 4C, Arcavacata di Rende 87036, Italy; CNR Institute of Biomembranes, Bioenergetics and Molecular Biotechnology (IBIOM), via Amendola 122/O, Bari 70126, Italy.
| | - Cesare Indiveri
- Department DiBEST (Biologia, Ecologia, Scienze della Terra) Unit of Biochemistry and Molecular Biotechnology, University of Calabria, Via P. Bucci 4C, Arcavacata di Rende 87036, Italy; CNR Institute of Biomembranes, Bioenergetics and Molecular Biotechnology (IBIOM), via Amendola 122/O, Bari 70126, Italy.
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Li Z, Li Y, Tang X, Xing A, Lin J, Li J, Ji J, Cai T, Zheng K, Lingampelly SS, Li K. Causal Metabolomic and Lipidomic Analysis of Circulating Plasma Metabolites in Autism: A Comprehensive Mendelian Randomization Study with Independent Cohort Validation. Metabolites 2024; 14:557. [PMID: 39452938 PMCID: PMC11509474 DOI: 10.3390/metabo14100557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Revised: 09/23/2024] [Accepted: 09/27/2024] [Indexed: 10/26/2024] Open
Abstract
BACKGROUND The increasing prevalence of autism spectrum disorder (ASD) highlights the need for objective diagnostic markers and a better understanding of its pathogenesis. Metabolic differences have been observed between individuals with and without ASD, but their causal relevance remains unclear. METHODS Bidirectional two-sample Mendelian randomization (MR) was used to assess causal associations between circulating plasma metabolites and ASD using large-scale genome-wide association study (GWAS) datasets-comprising 1091 metabolites, 309 ratios, and 179 lipids-and three European autism datasets (PGC 2015: n = 10,610 and 10,263; 2017: n = 46,351). Inverse-variance weighted (IVW) and weighted median methods were employed, along with robust sensitivity and power analyses followed by independent cohort validation. RESULTS Higher genetically predicted levels of sphingomyelin (SM) (d17:1/16:0) (OR, 1.129; 95% CI, 1.024-1.245; p = 0.015) were causally linked to increased ASD risk. Additionally, ASD children had higher plasma creatine/carnitine ratios. These MR findings were validated in an independent US autism cohort using machine learning analysis. CONCLUSION Utilizing large datasets, two MR approaches, robust sensitivity analyses, and independent validation, our novel findings provide evidence for the potential roles of metabolomics and circulating metabolites in ASD diagnosis and etiology.
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Affiliation(s)
- Zhifan Li
- Big Data and Internet of Things Program, Faculty of Applied Sciences, Macao Polytechnic University, Macao 999078, China; (Z.L.); (J.L.); (T.C.); (K.Z.)
| | - Yanrong Li
- Center for Artificial Intelligence-Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macao 999078, China; (Y.L.); (A.X.); (J.L.); (J.J.)
| | - Xinrong Tang
- Yantai Special Education School, Yantai 264001, China;
| | - Abao Xing
- Center for Artificial Intelligence-Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macao 999078, China; (Y.L.); (A.X.); (J.L.); (J.J.)
| | - Jianlin Lin
- Center for Artificial Intelligence-Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macao 999078, China; (Y.L.); (A.X.); (J.L.); (J.J.)
| | - Junrong Li
- Big Data and Internet of Things Program, Faculty of Applied Sciences, Macao Polytechnic University, Macao 999078, China; (Z.L.); (J.L.); (T.C.); (K.Z.)
| | - Junjun Ji
- Center for Artificial Intelligence-Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macao 999078, China; (Y.L.); (A.X.); (J.L.); (J.J.)
| | - Tiantian Cai
- Big Data and Internet of Things Program, Faculty of Applied Sciences, Macao Polytechnic University, Macao 999078, China; (Z.L.); (J.L.); (T.C.); (K.Z.)
| | - Ke Zheng
- Big Data and Internet of Things Program, Faculty of Applied Sciences, Macao Polytechnic University, Macao 999078, China; (Z.L.); (J.L.); (T.C.); (K.Z.)
| | - Sai Sachin Lingampelly
- Department of Medicine, University of California, San Diego School of Medicine, San Diego, CA 92103-8467, USA;
| | - Kefeng Li
- Center for Artificial Intelligence-Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macao 999078, China; (Y.L.); (A.X.); (J.L.); (J.J.)
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Ottosson F, Russo F, Abrahamsson A, MacSween N, Courraud J, Skogstrand K, Melander O, Ericson U, Orho-Melander M, Cohen AS, Grove J, Mortensen PB, Hougaard DM, Ernst M. Unraveling the metabolomic architecture of autism in a large Danish population-based cohort. BMC Med 2024; 22:302. [PMID: 39026322 PMCID: PMC11264881 DOI: 10.1186/s12916-024-03516-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 07/02/2024] [Indexed: 07/20/2024] Open
Abstract
BACKGROUND The prevalence of autism in Denmark has been increasing, reaching 1.65% among 10-year-old children, and similar trends are seen elsewhere. Although there are several factors associated with autism, including genetic, environmental, and prenatal factors, the molecular etiology of autism is largely unknown. Here, we use untargeted metabolomics to characterize the neonatal metabolome from dried blood spots collected shortly after birth. METHODS We analyze the metabolomic profiles of a subset of a large Danish population-based cohort (iPSYCH2015) consisting of over 1400 newborns, who later are diagnosed with autism and matching controls and in two Swedish population-based cohorts comprising over 7000 adult participants. Mass spectrometry analysis was performed by a timsTOF Pro operated in QTOF mode, using data-dependent acquisition. By applying an untargeted metabolomics approach, we could reproducibly measure over 800 metabolite features. RESULTS We detected underlying molecular perturbations across several metabolite classes that precede autism. In particular, the cyclic dipeptide cyclo-leucine-proline (FDR-adjusted p = 0.003) and the carnitine-related 5-aminovaleric acid betaine (5-AVAB) (FDR-adjusted p = 0.03), were associated with an increased probability for autism, independently of known prenatal and genetic risk factors. Analysis of genetic and dietary data in adults revealed that 5-AVAB was associated with increased habitual dietary intake of dairy (FDR-adjusted p < 0.05) and with variants near SLC22A4 and SLC22A5 (p < 5.0e - 8), coding for a transmembrane carnitine transporter protein involved in controlling intracellular carnitine levels. CONCLUSIONS Cyclo-leucine-proline and 5-AVAB are associated with future diagnosis of autism in Danish neonates, both representing novel early biomarkers for autism. 5-AVAB is potentially modifiable and may influence carnitine homeostasis.
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Affiliation(s)
- Filip Ottosson
- Section for Clinical Mass Spectrometry, Danish Center for Neonatal Screening, Department of Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark.
| | - Francesco Russo
- Section for Clinical Mass Spectrometry, Danish Center for Neonatal Screening, Department of Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark
| | - Anna Abrahamsson
- Section for Clinical Mass Spectrometry, Danish Center for Neonatal Screening, Department of Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark
| | - Nadia MacSween
- Section for Clinical Mass Spectrometry, Danish Center for Neonatal Screening, Department of Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark
| | - Julie Courraud
- Section for Clinical Mass Spectrometry, Danish Center for Neonatal Screening, Department of Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark
- Laboratory of Analytical Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, 15771, Panepistimiopolis, ZografouAthens, Greece
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Alexandra Hospital, 11528, Athens, Greece
| | - Kristin Skogstrand
- Section for Clinical Mass Spectrometry, Danish Center for Neonatal Screening, Department of Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark
| | - Olle Melander
- Department of Clinical Sciences, Lund University, Malmö, Sweden
| | - Ulrika Ericson
- Department of Clinical Sciences, Lund University, Malmö, Sweden
| | | | - Arieh S Cohen
- Section for Clinical Mass Spectrometry, Danish Center for Neonatal Screening, Department of Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark
- Testcenter Denmark, Statens Serum Institut, Copenhagen, Denmark
| | - Jakob Grove
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark
- Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, Denmark
- Bioinformatics Research Center, Aarhus University, Aarhus, Denmark
- Center for Genomics and Personalized Medicine, Aarhus, Denmark
| | - Preben Bo Mortensen
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark
- NCRR - National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark
- CIRRAU - Centre for Integrated Registerbased Research at Aarhus University, Aarhus, Denmark
| | - David M Hougaard
- Section for Clinical Mass Spectrometry, Danish Center for Neonatal Screening, Department of Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark
| | - Madeleine Ernst
- Section for Clinical Mass Spectrometry, Danish Center for Neonatal Screening, Department of Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark.
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Jiang Z, Sullivan PF, Li T, Zhao B, Wang X, Luo T, Huang S, Guan PY, Chen J, Yang Y, Stein JL, Li Y, Liu D, Sun L, Zhu H. The pivotal role of the X-chromosome in the genetic architecture of the human brain. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2023.08.30.23294848. [PMID: 37693466 PMCID: PMC10491353 DOI: 10.1101/2023.08.30.23294848] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/12/2023]
Abstract
Genes on the X-chromosome are extensively expressed in the human brain. However, little is known for the X-chromosome's impact on the brain anatomy, microstructure, and functional network. We examined 1,045 complex brain imaging traits from 38,529 participants in the UK Biobank. We unveiled potential autosome-X-chromosome interactions, while proposing an atlas outlining dosage compensation (DC) for brain imaging traits. Through extensive association studies, we identified 72 genome-wide significant trait-locus pairs (including 29 new associations) that share genetic architectures with brain-related disorders, notably schizophrenia. Furthermore, we discovered unique sex-specific associations and assessed variations in genetic effects between sexes. Our research offers critical insights into the X-chromosome's role in the human brain, underscoring its contribution to the differences observed in brain structure and functionality between sexes.
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10
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Chen Q, Wu C, Xu J, Ye C, Chen X, Tian H, Zong N, Zhang S, Li L, Gao Y, Zhao D, Lv X, Yang Q, Wang L, Cui J, Lin Z, Lu J, Yang R, Yin F, Qin N, Li N, Xu Q, Qin H. Donor-recipient intermicrobial interactions impact transfer of subspecies and fecal microbiota transplantation outcome. Cell Host Microbe 2024; 32:349-365.e4. [PMID: 38367621 DOI: 10.1016/j.chom.2024.01.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 12/08/2023] [Accepted: 01/25/2024] [Indexed: 02/19/2024]
Abstract
Studies on fecal microbiota transplantation (FMT) have reported inconsistent connections between clinical outcomes and donor strain engraftment. Analyses of subspecies-level crosstalk and its influences on lineage transfer in metagenomic FMT datasets have proved challenging, as single-nucleotide polymorphisms (SNPs) are generally not linked and are often absent. Here, we utilized species genome bin (SGB), which employs co-abundance binning, to investigate subspecies-level microbiome dynamics in patients with autism spectrum disorder (ASD) who had gastrointestinal comorbidities and underwent encapsulated FMT (Chinese Clinical Trial: 2100043906). We found that interactions between donor and recipient microbes, which were overwhelmingly phylogenetically divergent, were important for subspecies transfer and positive clinical outcomes. Additionally, a donor-recipient SGB match was indicative of a high likelihood of strain transfer. Importantly, these ecodynamics were shared across FMT datasets encompassing multiple diseases. Collectively, these findings provide detailed insight into specific microbial interactions and dynamics that determine FMT success.
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Affiliation(s)
- Qiyi Chen
- Department of Colorectal Disease, Intestinal Microenvironment Treatment Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China; Institute of Gut Microbiota Research and Engineering Development, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Chunyan Wu
- Institute of Gut Microbiota Research and Engineering Development, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China; Realbio Genomics Institute, Shanghai 200050, China
| | - Jinfeng Xu
- Institute of Gut Microbiota Research and Engineering Development, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Chen Ye
- Department of Colorectal Disease, Intestinal Microenvironment Treatment Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Xiang Chen
- Realbio Genomics Institute, Shanghai 200050, China
| | - Hongliang Tian
- Department of Colorectal Disease, Intestinal Microenvironment Treatment Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Naixin Zong
- Institute of Gut Microbiota Research and Engineering Development, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Shaoyi Zhang
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Long Li
- Department of Colorectal Disease, Intestinal Microenvironment Treatment Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Yuan Gao
- Institute of Gut Microbiota Research and Engineering Development, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Di Zhao
- Department of Colorectal Disease, Intestinal Microenvironment Treatment Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Xiaoqiong Lv
- Department of Colorectal Disease, Intestinal Microenvironment Treatment Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Qilin Yang
- Institute of Intestinal Diseases, Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Le Wang
- Department of Colorectal Disease, Intestinal Microenvironment Treatment Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Jiaqu Cui
- Department of Colorectal Disease, Intestinal Microenvironment Treatment Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Zhiliang Lin
- Department of Colorectal Disease, Intestinal Microenvironment Treatment Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Jubao Lu
- Department of Colorectal Disease, Intestinal Microenvironment Treatment Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Rong Yang
- Department of Pediatrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Fang Yin
- Institute of Gut Microbiota Research and Engineering Development, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Nan Qin
- Institute of Gut Microbiota Research and Engineering Development, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China; Realbio Genomics Institute, Shanghai 200050, China
| | - Ning Li
- Department of Colorectal Disease, Intestinal Microenvironment Treatment Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
| | - Qian Xu
- Institute of Gut Microbiota Research and Engineering Development, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China; Institute of Intestinal Diseases, Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
| | - Huanlong Qin
- Department of Colorectal Disease, Intestinal Microenvironment Treatment Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China; Institute of Gut Microbiota Research and Engineering Development, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China; Institute of Intestinal Diseases, Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
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11
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Smith AM, Donley ELR, Ney DM, Amaral DG, Burrier RE, Natowicz MR. Metabolomic biomarkers in autism: identification of complex dysregulations of cellular bioenergetics. Front Psychiatry 2023; 14:1249578. [PMID: 37928922 PMCID: PMC10622772 DOI: 10.3389/fpsyt.2023.1249578] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 08/30/2023] [Indexed: 11/07/2023] Open
Abstract
Autism Spectrum Disorder (ASD or autism) is a phenotypically and etiologically heterogeneous condition. Identifying biomarkers of clinically significant metabolic subtypes of autism could improve understanding of its underlying pathophysiology and potentially lead to more targeted interventions. We hypothesized that the application of metabolite-based biomarker techniques using decision thresholds derived from quantitative measurements could identify autism-associated subpopulations. Metabolomic profiling was carried out in a case-control study of 499 autistic and 209 typically developing (TYP) children, ages 18-48 months, enrolled in the Children's Autism Metabolome Project (CAMP; ClinicalTrials.gov Identifier: NCT02548442). Fifty-four metabolites, associated with amino acid, organic acid, acylcarnitine and purine metabolism as well as microbiome-associated metabolites, were quantified using liquid chromatography-tandem mass spectrometry. Using quantitative thresholds, the concentrations of 4 metabolites and 149 ratios of metabolites were identified as biomarkers, each identifying subpopulations of 4.5-11% of the CAMP autistic population. A subset of 42 biomarkers could identify CAMP autistic individuals with 72% sensitivity and 90% specificity. Many participants were identified by several metabolic biomarkers. Using hierarchical clustering, 30 clusters of biomarkers were created based on participants' biomarker profiles. Metabolic changes associated with the clusters suggest that altered regulation of cellular metabolism, especially of mitochondrial bioenergetics, were common metabolic phenotypes in this cohort of autistic participants. Autism severity and cognitive and developmental impairment were associated with increased lactate, many lactate containing ratios, and the number of biomarker clusters a participant displayed. These studies provide evidence that metabolic phenotyping is feasible and that defined autistic subgroups can lead to enhanced understanding of the underlying pathophysiology and potentially suggest pathways for targeted metabolic treatments.
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Affiliation(s)
- Alan M. Smith
- Stemina Biomarker Discovery, Inc, Madison, WI, United States
| | | | - Denise M. Ney
- Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, United States
| | - David G. Amaral
- Department of Psychiatry and Behavioral Sciences, The MIND Institute, University of California, Davis, Davis, CA, United States
| | | | - Marvin R. Natowicz
- Pathology and Laboratory Medicine, Genomic Medicine, Neurological and Pediatrics Institutes, Cleveland Clinic, Cleveland, OH, United States
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12
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Cao C, Li Q, Chen Y, Zou M, Sun C, Li X, Wu L. Untargeted Metabolomic Analysis Reveals the Metabolic Disturbances and Exacerbation of Oxidative Stress in the Cerebral Cortex of a BTBR Mouse Model of Autism. J Mol Neurosci 2023; 73:15-27. [PMID: 36574152 DOI: 10.1007/s12031-022-02096-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 12/09/2022] [Indexed: 12/28/2022]
Abstract
The etiology and pathology of autism spectrum disorders (ASDs) are still poorly understood, which largely limit the treatment and diagnosis of ASDs. Emerging evidence supports that abnormal metabolites in the cerebral cortex of a BTBR mouse model of autism are involved in the pathogenesis of autism. However, systematic study on global metabolites in the cerebral cortex of BTBR mice has not been conducted. The current study aims to characterize metabolic changes in the cerebral cortex of BTBR mice by using an untargeted metabolomic approach based on UPLC-Q-TOF/MS. C57BL/6 J mice were used as a control group. A total of 14 differential metabolites were identified. Compared with the control group, the intensities of PI(16:0/22:5(4Z,7Z,10Z,13Z,16Z)), PC(22:6(4Z,7Z,10Z,13Z,16Z,19Z)/18:1(9Z)), PA(16:0/18:1(11Z)), 17-beta-estradiol-3-glucuronide, and N6,N6,N6-trimethyl-L-lysine decreased significantly (p < 0.01) and the intensities of 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline, LysoPC(20:4(5Z,8Z,11Z,14Z)/0:0), adenosine monophosphate, adenosine-5'-phosphosulfate, LacCer(d18:1/12:0),3-dehydro-L-gulonate, N-(1-deoxy-1-fructosyl)tryptophan, homovanillic acid, and LPA(0:0/18:1(9Z)) increased significantly (p < 0.01) in the BTBR group. These changes in metabolites were closely related to perturbations in lipid metabolism, energy metabolism, purine metabolism, sulfur metabolism, amino acid metabolism, and carnitine biosynthesis. Notably, exacerbation of the oxidative stress response caused by differential prooxidant metabolites led to alteration of antioxidative systems in the cerebral cortex and resulted in mitochondrial dysfunction, further leading to abnormal energy metabolism as an etiological mechanism of autism. A central role of abnormal metabolites in neurological functions associated with behavioral outcomes and disturbance of sulfur metabolism and carnitine biosynthesis were found in the cerebral cortex of BTBR mice, which helped increase our understanding for exploring the pathological mechanism of autism.
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Affiliation(s)
- Can Cao
- Department of Children's and Adolescent Health, Public Health College of Harbin Medical University, Harbin, Heilongjiang, 150081, China
| | - Qi Li
- Department of Children's and Adolescent Health, Public Health College of Harbin Medical University, Harbin, Heilongjiang, 150081, China
| | - Yanping Chen
- Department of Children's and Adolescent Health, Public Health College of Harbin Medical University, Harbin, Heilongjiang, 150081, China
| | - Mingyang Zou
- Department of Children's and Adolescent Health, Public Health College of Harbin Medical University, Harbin, Heilongjiang, 150081, China
| | - Caihong Sun
- Department of Children's and Adolescent Health, Public Health College of Harbin Medical University, Harbin, Heilongjiang, 150081, China
| | - Xiangning Li
- Department of Children's and Adolescent Health, Public Health College of Harbin Medical University, Harbin, Heilongjiang, 150081, China
| | - Lijie Wu
- Department of Children's and Adolescent Health, Public Health College of Harbin Medical University, Harbin, Heilongjiang, 150081, China.
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13
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Nabi SU, Rehman MU, Arafah A, Taifa S, Khan IS, Khan A, Rashid S, Jan F, Wani HA, Ahmad SF. Treatment of Autism Spectrum Disorders by Mitochondrial-targeted Drug: Future of Neurological Diseases Therapeutics. Curr Neuropharmacol 2023; 21:1042-1064. [PMID: 36411568 PMCID: PMC10286588 DOI: 10.2174/1570159x21666221121095618] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 10/09/2022] [Accepted: 10/11/2022] [Indexed: 11/23/2022] Open
Abstract
Autism is a neurodevelopmental disorder with a complex etiology that might involve environmental and genetic variables. Recently, some epidemiological studies conducted in various parts of the world have estimated a significant increase in the prevalence of autism, with 1 in every 59 children having some degree of autism. Since autism has been associated with other clinical abnormalities, there is every possibility that a sub-cellular component may be involved in the progression of autism. The organelle remains a focus based on mitochondria's functionality and metabolic role in cells. Furthermore, the mitochondrial genome is inherited maternally and has its DNA and organelle that remain actively involved during embryonic development; these characteristics have linked mitochondrial dysfunction to autism. Although rapid stride has been made in autism research, there are limited studies that have made particular emphasis on mitochondrial dysfunction and autism. Accumulating evidence from studies conducted at cellular and sub-cellular levels has indicated that mitochondrial dysfunction's role in autism is more than expected. The present review has attempted to describe the risk factors of autism, the role of mitochondria in the progression of the disease, oxidative damage as a trigger point to initiate mitochondrial damage, genetic determinants of the disease, possible pathogenic pathways and therapeutic regimen in vogue and the developmental stage. Furthermore, in the present review, an attempt has been made to include the novel therapeutic regimens under investigation at different clinical trial stages and their potential possibility to emerge as promising drugs against ASD.
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Affiliation(s)
- Showkat Ul Nabi
- Large Animal Diagnostic Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Faculty of Veterinary Sciences and Animal Husbandry, Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST-K), Srinagar J&K, 190006, India
| | - Muneeb U. Rehman
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Azher Arafah
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Syed Taifa
- Large Animal Diagnostic Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Faculty of Veterinary Sciences and Animal Husbandry, Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST-K), Srinagar J&K, 190006, India
| | - Iqra Shafi Khan
- Large Animal Diagnostic Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Faculty of Veterinary Sciences and Animal Husbandry, Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST-K), Srinagar J&K, 190006, India
| | - Andleeb Khan
- Department of Pharmacology and Toxicology, College of Pharmacy, Jazan University, Jazan, 45142, Saudi Arabia
| | - Summya Rashid
- Department of Pharmacology & Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, P.O. Box 173, Al-Kharj, 11942, Saudi Arabia
| | - Fatimah Jan
- Department of Pharmaceutical Sciences, CT University, Ludhiana, Ferozepur Road, Punjab, 142024, India
| | - Hilal Ahmad Wani
- Department of Biochemistry, Government Degree College Sumbal, Bandipora, J&K, India
| | - Sheikh Fayaz Ahmad
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia
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14
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Wang X, Bao L, Jiang M, Li D, Xu L, Bai M. Toxic mechanism of the Mongolian medicine "Hunqile-7" based on metabonomics and the metabolism of intestinal flora. Toxicol Res (Camb) 2022; 12:49-61. [PMID: 36866222 PMCID: PMC9972816 DOI: 10.1093/toxres/tfac081] [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: 07/04/2022] [Revised: 11/04/2022] [Accepted: 11/18/2022] [Indexed: 12/27/2022] Open
Abstract
The traditional Mongolian medicine Hunqile-7 (HQL-7), which is mainly used to relieve pain in clinic, has certain toxicity. Therefore, toxicological investigation of HQL-7 is of great significance to its safety assessment. In this study, the toxic mechanism of HQL-7 was explored based on a combination of metabolomics and intestinal flora metabolism. UHPLC-MS was used to analyze the serum, liver and kidney samples of rats after intragastric administration of HQL-7. The decision tree and K Nearest Neighbor (KNN) model were established based on the bootstrap aggregation (bagging) algorithm to classify the omics data. After samples were extracted from rat feces, the high-throughput sequencing platform was used to analyze the 16s rRNA V3-V4 region of bacteria. The experimental results confirm that the bagging algorithm improved the classification accuracy. The toxic dose, toxic intensity, and toxic target organ of HQL-7 were determined in toxicity tests. Seventeen biomarkers were identified and the metabolism dysregulation of these biomarkers may be responsible for the toxicity of HQL-7 in vivo. Several kinds of bacteria was demonstrated to be closely related to the physiological indices of renal and liver function, indicating liver and kidney damage induced by HQL-7 may be related to the disturbance of these intestinal bacteria. Overall, the toxic mechanism of HQL-7 was revealed in vivo, which not only provides a scientific basis for the safe and rational clinical use of HQL-7, but also opens up a new field of research on big data for Mongolian medicine.
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Affiliation(s)
- Xiye Wang
- College of Chemistry and Materials Science, Inner Mongolia Minzu University, Tongliao 028000, China,Inner Mongolia Key Laboratory of Chemistry for Natural Products Chemistry and Synthesis for Functional Molecules, Inner Mongolia Minzu University, Tongliao 028000, China
| | - Leer Bao
- Inner Mongolia Autonomous Region Drug Inspection Center, Hohhot 010000, China
| | - Mingyang Jiang
- College of Computer Science and Technology, Inner Mongolia Minzu University, Tongliao 028000, China
| | - Dan Li
- College of Chemistry and Materials Science, Inner Mongolia Minzu University, Tongliao 028000, China,Inner Mongolia Key Laboratory of Chemistry for Natural Products Chemistry and Synthesis for Functional Molecules, Inner Mongolia Minzu University, Tongliao 028000, China
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15
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Perfilyeva A, Bespalova K, Perfilyeva Y, Skvortsova L, Musralina L, Zhunussova G, Khussainova E, Iskakova U, Bekmanov B, Djansugurova L. Integrative Functional Genomic Analysis in Multiplex Autism Families from Kazakhstan. DISEASE MARKERS 2022; 2022:1509994. [PMID: 36199823 PMCID: PMC9529466 DOI: 10.1155/2022/1509994] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 08/21/2022] [Accepted: 09/06/2022] [Indexed: 12/14/2022]
Abstract
The study of extended pedigrees containing autism spectrum disorder- (ASD-) related broader autism phenotypes (BAP) offers a promising approach to the search for ASD candidate variants. Here, a total of 650,000 genetic markers were tested in four Kazakhstani multiplex families with ASD and BAP to obtain data on de novo mutations (DNMs), common, and rare inherited variants that may contribute to the genetic risk for developing autistic traits. The variants were analyzed in the context of gene networks and pathways. Several previously well-described enriched pathways were identified, including ion channel activity, regulation of synaptic function, and membrane depolarization. Perhaps these pathways are crucial not only for the development of ASD but also for ВАР. The results also point to several additional biological pathways (circadian entrainment, NCAM and BTN family interactions, and interaction between L1 and Ankyrins) and hub genes (CFTR, NOD2, PPP2R2B, and TTR). The obtained results suggest that further exploration of PPI networks combining ASD and BAP risk genes can be used to identify novel or overlooked ASD molecular mechanisms.
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Affiliation(s)
| | - Kira Bespalova
- Institute of Genetics and Physiology, 93 Al-Farabi Ave., Almaty 050060, Kazakhstan
- Al-Farabi Kazakh National University, 71 Al-Farabi Ave., Almaty 050040, Kazakhstan
| | - Yuliya Perfilyeva
- M.A. Aitkhozhin's Institute of Molecular Biology and Biochemistry, 86 Dosmukhamedov St., Almaty 050012, Kazakhstan
- Branch of the National Center for Biotechnology, 14 Zhahanger St., Almaty 050054, Kazakhstan
| | - Liliya Skvortsova
- Institute of Genetics and Physiology, 93 Al-Farabi Ave., Almaty 050060, Kazakhstan
| | - Lyazzat Musralina
- Institute of Genetics and Physiology, 93 Al-Farabi Ave., Almaty 050060, Kazakhstan
| | - Gulnur Zhunussova
- Institute of Genetics and Physiology, 93 Al-Farabi Ave., Almaty 050060, Kazakhstan
| | - Elmira Khussainova
- Institute of Genetics and Physiology, 93 Al-Farabi Ave., Almaty 050060, Kazakhstan
| | - Ulzhan Iskakova
- Kazakh National Medical University, 94 Tole Bi St., Almaty 050000, Kazakhstan
| | - Bakhytzhan Bekmanov
- Institute of Genetics and Physiology, 93 Al-Farabi Ave., Almaty 050060, Kazakhstan
| | - Leyla Djansugurova
- Institute of Genetics and Physiology, 93 Al-Farabi Ave., Almaty 050060, Kazakhstan
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16
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Vernocchi P, Ristori MV, Guerrera S, Guarrasi V, Conte F, Russo A, Lupi E, Albitar-Nehme S, Gardini S, Paci P, Ianiro G, Vicari S, Gasbarrini A, Putignani L. Gut Microbiota Ecology and Inferred Functions in Children With ASD Compared to Neurotypical Subjects. Front Microbiol 2022; 13:871086. [PMID: 35756062 PMCID: PMC9218677 DOI: 10.3389/fmicb.2022.871086] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 04/19/2022] [Indexed: 12/28/2022] Open
Abstract
Autism spectrum disorders (ASDs) is a multifactorial neurodevelopmental disorder. The communication between the gastrointestinal (GI) tract and the central nervous system seems driven by gut microbiota (GM). Herein, we provide GM profiling, considering GI functional symptoms, neurological impairment, and dietary habits. Forty-one and 35 fecal samples collected from ASD and neurotypical children (CTRLs), respectively, (age range, 3–15 years) were analyzed by 16S targeted-metagenomics (the V3–V4 region) and inflammation and permeability markers (i.e., sIgA, zonulin lysozyme), and then correlated with subjects’ metadata. Our ASD cohort was characterized as follows: 30/41 (73%) with GI functional symptoms; 24/41 (58%) picky eaters (PEs), with one or more dietary needs, including 10/41 (24%) with food selectivity (FS); 36/41 (88%) presenting high and medium autism severity symptoms (HMASSs). Among the cohort with GI symptoms, 28/30 (93%) showed HMASSs, 17/30 (57%) were picky eaters and only 8/30 (27%) with food selectivity. The remaining 11/41 (27%) ASDs without GI symptoms that were characterized by HMASS for 8/11 (72%) and 7/11 (63%) were picky eaters. GM ecology was investigated for the overall ASD cohort versus CTRLs; ASDs with GI and without GI, respectively, versus CTRLs; ASD with GI versus ASD without GI; ASDs with HMASS versus low ASSs; PEs versus no-PEs; and FS versus absence of FS. In particular, the GM of ASDs, compared to CTRLs, was characterized by the increase of Proteobacteria, Bacteroidetes, Rikenellaceae, Pasteurellaceae, Klebsiella, Bacteroides, Roseburia, Lactobacillus, Prevotella, Sutterella, Staphylococcus, and Haemophilus. Moreover, Sutterella, Roseburia and Fusobacterium were associated to ASD with GI symptoms compared to CTRLs. Interestingly, ASD with GI symptoms showed higher value of zonulin and lower levels of lysozyme, which were also characterized by differentially expressed predicted functional pathways. Multiple machine learning models classified correctly 80% overall ASDs, compared with CTRLs, based on Bacteroides, Lactobacillus, Prevotella, Staphylococcus, Sutterella, and Haemophilus features. In conclusion, in our patient cohort, regardless of the evaluation of many factors potentially modulating the GM profile, the major phenotypic determinant affecting the GM was represented by GI hallmarks and patients’ age.
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Affiliation(s)
- Pamela Vernocchi
- Multimodal Laboratory Medicine Research Area, Unit of Human Microbiome, Bambino Gesù Children's Hospital, Scientific Institute for Research, Hospitalization and Healthcare, Rome, Italy
| | - Maria Vittoria Ristori
- Multimodal Laboratory Medicine Research Area, Unit of Human Microbiome, Bambino Gesù Children's Hospital, Scientific Institute for Research, Hospitalization and Healthcare, Rome, Italy
| | - Silvia Guerrera
- Child and Adolescent Neuropsychiatry Unit, Department of Neuroscience, Bambino Gesù Children's Hospital, Scientific Institute for Research, Hospitalization and Healthcare, Rome, Italy
| | | | - Federica Conte
- Institute for Systems Analysis and Computer Science "Antonio Ruberti," National Research Council, Rome, Italy
| | - Alessandra Russo
- Department of Diagnostics and Laboratory Medicine, Unit of Microbiology and Diagnostic Immunology, Unit of Microbiomics, Bambino Gesù Children's Hospital, Scientific Institute for Research, Hospitalization and Healthcare, Rome, Italy
| | - Elisabetta Lupi
- Child and Adolescent Neuropsychiatry Unit, Department of Neuroscience, Bambino Gesù Children's Hospital, Scientific Institute for Research, Hospitalization and Healthcare, Rome, Italy
| | - Sami Albitar-Nehme
- Department of Diagnostic and Laboratory Medicine, Unit of Microbiology and Diagnostic Immunology, Bambino Gesù Children's Hospital, Scientific Institute for Research, Hospitalization and Healthcare, Rome, Italy
| | | | - Paola Paci
- Department of Computer, Control and Management Engineering, Sapienza University of Rome, Rome, Italy
| | - Gianluca Ianiro
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario "A. Gemelli" Scientific Institute for Research, Hospitalization and Healthcare, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Stefano Vicari
- Child and Adolescent Neuropsychiatry Unit, Department of Neuroscience, Bambino Gesù Children's Hospital, Scientific Institute for Research, Hospitalization and Healthcare, Rome, Italy
| | - Antonio Gasbarrini
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario "A. Gemelli" Scientific Institute for Research, Hospitalization and Healthcare, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Lorenza Putignani
- Department of Diagnostics and Laboratory Medicine, Unit of Microbiology and Diagnostic Immunology, Unit of Microbiomics, and Multimodal Laboratory Medicine Research Area, Unit of Human Microbiome, Bambino Gesù Children's Hospital, Scientific Institute for Research, Hospitalization and Healthcare, Rome, Italy
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17
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Comprehensive assessment of the effectiveness of l-carnitine and transresveratrol in rats with diet-induced obesity. Nutrition 2021; 95:111561. [PMID: 34999386 DOI: 10.1016/j.nut.2021.111561] [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: 04/07/2021] [Revised: 11/05/2021] [Accepted: 11/28/2021] [Indexed: 11/24/2022]
Abstract
OBJECTIVES Transresveratrol (Res) and l-carnitine (l-Car) are proposed to alleviate metabolic and immune disorders and increase physical activity in obese individuals. This study aims to estimate the effect of Res and l-Car in rats with diet-induced obesity. METHODS Male Wistar rats were fed a diet with excess fat and fructose (high-fat high-carbohydrate diet [HFCD]) supplemented with Res and l-Car at doses of 25 and 300 mg/kg of body weight, respectively, for 63 d. An assessment of grip strength, behavioral reactions, as well as biochemical, morphological, and immunological parameters, was performed. RESULTS Res supplementation did not affect energy consumption, but l-Car increased when animals had free access to feed. Body weight gains were the highest in animals fed the HFCD, lowest in rats receiving the control balanced diet, and intermediate in animals receiving Res and l-Car. Feeding with Res and l-Car canceled the decrease in long-term memory in rats fed the HFCD, as well as reduced anxiety and increased mobility. With both supplements, bilirubin, triglycerides, and low-density lipoprotein levels in the blood plasma returned to normal values, but only l-Car increased the ratio of aspartic and alanine transaminases. In addition, l-Car lowered the levels of leptin and ghrelin and increased transforming growth factor beta 1 in the blood plasma, and consumption of Res was accompanied by a decrease in interleukin-17A and increase in interferon gamma in spleen lysates. Moreover, l-Car reduced the number of cells with lipid inclusions in the liver. CONCLUSIONS The consumption of Res and l-Car leads to a significant reduction in dyslipidemia and inflammation with potentially favorable changes in behavioral responses.
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18
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An mtDNA mutant mouse demonstrates that mitochondrial deficiency can result in autism endophenotypes. Proc Natl Acad Sci U S A 2021; 118:2021429118. [PMID: 33536343 PMCID: PMC8017921 DOI: 10.1073/pnas.2021429118] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Autism spectrum disorders (ASDs) have increasingly been associated with mitochondrial dysfunction, corroborated by mitochondrial DNA (mtDNA) germline and somatic variants being found in ASD patients. If mitochondrial defects can generate ASD, then specific mtDNA mutations should induce ASD endophenotypes in mice. We tested this prediction by introduction of an mtDNA ND6 gene missense mutation (ND6P25L) into the mouse germline and found ASD endophenotypes. The ND6P25L mice exhibit impaired social interaction, compulsive behavior, and increased anxiety. They have reduced electroencephalographic delta and theta wave power, increased predilection to seizures, but without diminution of hippocampal interneurons. These endophenotypes correlate with impaired cortical and hippocampal mitochondrial respiration and increased reactive oxygen species production. Thus, mitochondrial defects can be sufficient to produce ASD phenotypes. Autism spectrum disorders (ASDs) are characterized by a deficit in social communication, pathologic repetitive behaviors, restricted interests, and electroencephalogram (EEG) aberrations. While exhaustive analysis of nuclear DNA (nDNA) variation has revealed hundreds of copy number variants (CNVs) and loss-of-function (LOF) mutations, no unifying hypothesis as to the pathophysiology of ASD has yet emerged. Based on biochemical and physiological analyses, it has been hypothesized that ASD may be the result of a systemic mitochondrial deficiency with brain-specific manifestations. This proposal has been supported by recent mitochondrial DNA (mtDNA) analyses identifying both germline and somatic mtDNA variants in ASD. If mitochondrial defects do predispose to ASD, then mice with certain mtDNA mutations should present with autism endophenotypes. To test this prediction, we examined a mouse strain harboring an mtDNA ND6 gene missense mutation (P25L). This mouse manifests impaired social interactions, increased repetitive behaviors and anxiety, EEG alterations, and a decreased seizure threshold, in the absence of reduced hippocampal interneuron numbers. EEG aberrations were most pronounced in the cortex followed by the hippocampus. Aberrations in mitochondrial respiratory function and reactive oxygen species (ROS) levels were also most pronounced in the cortex followed by the hippocampus, but absent in the olfactory bulb. These data demonstrate that mild systemic mitochondrial defects can result in ASD without apparent neuroanatomical defects and that systemic mitochondrial mutations can cause tissue-specific brain defects accompanied by regional neurophysiological alterations.
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19
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Potential Role of L-Carnitine in Autism Spectrum Disorder. J Clin Med 2021; 10:jcm10061202. [PMID: 33805796 PMCID: PMC8000371 DOI: 10.3390/jcm10061202] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 03/12/2021] [Accepted: 03/12/2021] [Indexed: 12/17/2022] Open
Abstract
L-carnitine plays an important role in the functioning of the central nervous system, and especially in the mitochondrial metabolism of fatty acids. Altered carnitine metabolism, abnormal fatty acid metabolism in patients with autism spectrum disorder (ASD) has been documented. ASD is a complex heterogeneous neurodevelopmental condition that is usually diagnosed in early childhood. Patients with ASD require careful classification as this heterogeneous clinical category may include patients with an intellectual disability or high functioning, epilepsy, language impairments, or associated Mendelian genetic conditions. L-carnitine participates in the long-chain oxidation of fatty acids in the brain, stimulates acetylcholine synthesis (donor of the acyl groups), stimulates expression of growth-associated protein-43, prevents cell apoptosis and neuron damage and stimulates neurotransmission. Determination of L-carnitine in serum/plasma and analysis of acylcarnitines in a dried blood spot may be useful in ASD diagnosis and treatment. Changes in the acylcarnitine profiles may indicate potential mitochondrial dysfunctions and abnormal fatty acid metabolism in ASD children. L-carnitine deficiency or deregulation of L-carnitine metabolism in ASD is accompanied by disturbances of other metabolic pathways, e.g., Krebs cycle, the activity of respiratory chain complexes, indicative of mitochondrial dysfunction. Supplementation of L-carnitine may be beneficial to alleviate behavioral and cognitive symptoms in ASD patients.
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20
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Singh RS, Singh KK, Singh SM. Origin of Sex-Biased Mental Disorders: An Evolutionary Perspective. J Mol Evol 2021; 89:195-213. [PMID: 33630117 PMCID: PMC8116267 DOI: 10.1007/s00239-021-09999-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 02/06/2021] [Indexed: 12/12/2022]
Abstract
Sexual dimorphism or sex bias in diseases and mental disorders have two biological causes: sexual selection and sex hormones. We review the role of sexual selection theory and bring together decades of molecular studies on the variation and evolution of sex-biased genes and provide a theoretical basis for the causes of sex bias in disease and health. We present a Sexual Selection-Sex Hormone theory and show that male-driven evolution, including sexual selection, leads to: (1) increased male vulnerability due to negative pleiotropic effects associated with male-driven sexual selection and evolution; (2) increased rates of male-driven mutations and epimutations in response to early fitness gains and at the cost of late fitness; and (3) enhanced female immunity due to antagonistic responses to mutations that are beneficial to males but harmful to females, reducing female vulnerability to diseases and increasing the thresholds for disorders such as autism. Female-driven evolution, such as reproduction-related fluctuation in female sex hormones in association with stress and social condition, has been shown to be associated with increased risk of certain mental disorders such as major depression disorder in women. Bodies have history, cells have memories. An evolutionary framework, such as the Sexual Selection–Sex Hormone theory, provides a historical perspective for understanding how the differences in the sex-biased diseases and mental disorders have evolved over time. It has the potential to direct the development of novel preventive and treatment strategies.
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Affiliation(s)
- Rama S Singh
- Department of Biology, McMaster University, Hamilton, Canada.
| | - Karun K Singh
- Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Canada.,Krembil Research Institute, University Health Network, Toronto, Canada
| | - Shiva M Singh
- Department of Biology, University of Western Ontario, London, Canada
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21
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El-Ansary A, Chirumbolo S, Bhat RS, Dadar M, Ibrahim EM, Bjørklund G. The Role of Lipidomics in Autism Spectrum Disorder. Mol Diagn Ther 2021; 24:31-48. [PMID: 31691195 DOI: 10.1007/s40291-019-00430-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Autism spectrum disorder (ASD) is a complex neurodevelopmental syndrome commonly diagnosed in early childhood; it is usually characterized by impairment in reciprocal communication and speech, repetitive behaviors, and social withdrawal with loss in communication skills. Its development may be affected by a variety of environmental and genetic factors. Trained physicians diagnose and evaluate the severity of ASD based on clinical evaluations of observed behaviors. As such, this approach is inevitably dependent on the expertise and subjective assessment of those administering the clinical evaluations. There is a need to identify objective biological markers associated with diagnosis or clinical severity of the disorder. Several important issues and concerns exist regarding the diagnostic competence of the many abnormal plasma metabolites produced in the different biochemical pathways evaluated in individuals with ASD. The search for high-performing bio-analytes to diagnose and follow-up ASD development is still a major target in medicine. Dysregulation in the oxidative stress response and proinflammatory processes are major etiological causes of ASD pathogenesis. Furthermore, dicarboxylic acid metabolites, cholesterol-related metabolites, phospholipid-related metabolites, and lipid transporters and mediators are impaired in different pathological conditions that have a role in the ASD etiology. A mechanism may exist by which pro-oxidant environmental stressors and abnormal metabolites regulate clinical manifestations and development of ASD.
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Affiliation(s)
- Afaf El-Ansary
- Central Laboratory, Female Centre for Scientific and Medical Studies, King Saud University, Riyadh, Saudi Arabia.,Autism Research and Treatment Center, Riyadh, Saudi Arabia.,CONEM Saudi Autism Research Group, King Saud University, Riyadh, Saudi Arabia.,Therapeutic Chemistry Department, National Research Centre, Giza, Egypt
| | - Salvatore Chirumbolo
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.,CONEM Scientific Secretary, Verona, Italy
| | - Ramesa Shafi Bhat
- Biochemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Maryam Dadar
- Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran
| | - Eiman M Ibrahim
- Central Laboratory, Female Centre for Scientific and Medical Studies, King Saud University, Riyadh, Saudi Arabia
| | - Geir Bjørklund
- Council for Nutritional and Environmental Medicine (CONEM), Toften 24, 8610, Mo i Rana, Norway.
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22
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Langlois PH, Canfield MA, Rutenberg GW, Mandell DJ, Hua F, Reilly B, Ruktanonchai DJ, Jackson JF, Hunt P, Freedenberg D, Lee R, Villanacci JF. The association between newborn screening analytes as measured on a second screen and childhood autism in a Texas Medicaid population. Am J Med Genet B Neuropsychiatr Genet 2020; 183:331-340. [PMID: 32657040 DOI: 10.1002/ajmg.b.32804] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 03/31/2020] [Accepted: 04/08/2020] [Indexed: 12/12/2022]
Abstract
Autism (or autism spectrum disorder [ASD]) is an often disabling childhood neurologic condition of mostly unknown cause. We previously explored whether there was an association of ASD with any analyte measured in the first newborn screening blood test. Here we explore the second screen. Our matched case-control study examined data on 3-5 year-old patients with any ASD diagnosis in the Texas Medicaid system in 2010-2012. Subjects were linked to their 2007-2009 newborn screening blood test data, which included values for 36 analytes or analyte ratios. Data were available for 3,005 cases and 6,212 controls. The most compelling associations were evident for fatty acid oxidation analytes octanoylcarnitine (C8) and octanoylcarnitine/acetylcarnitine (C8/C2). Their adjusted odds ratios comparing 10th versus first analyte deciles were between 1.42 and 1.54 in total births, term births, and males. C8 was consistent with first screen results. Adipylcarnitine (C6DC), an organic acid analyte, showed opposite results in the two screens. Several other analytes exhibiting significant associations in the first screen did not in the second. Our results provide evidence that abnormal newborn blood levels of some carnitines may be associated with risk of later ASD, possibly related to their involvement with mitochondrial function in the developing brain.
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Affiliation(s)
- Peter H Langlois
- Birth Defects Epidemiology and Surveillance Branch, Texas Department of State Health Services, Austin, Texas, USA
| | - Mark A Canfield
- Birth Defects Epidemiology and Surveillance Branch, Texas Department of State Health Services, Austin, Texas, USA
| | - Gary W Rutenberg
- Center for Analytics and Decision Support, Texas Health and Human Services Commission, Austin, Texas, USA
| | - Dorothy J Mandell
- School of Community and Rural Health, University of Texas Health Science Center, Tyler, Texas, USA.,Population Health, Office of Health Affairs, UT System, Austin, Texas, USA
| | - Fei Hua
- Center for Health Statistics, Texas Department of State Health Services, Austin, Texas, USA
| | - Brendan Reilly
- Biochemistry and Genetics Branch, Laboratory Services Section, Texas Department of State Health Services, Austin, Texas, USA
| | - Duke J Ruktanonchai
- Children's Institute of Pittsburgh, Pittsburgh, Pennsylvania, USA.,Wesley Family Services, Pittsburgh, Pennsylvania, USA
| | - Janice F Jackson
- Center for Analytics and Decision Support, Texas Health and Human Services Commission, Austin, Texas, USA
| | - Patricia Hunt
- Biochemistry and Genetics Branch, Laboratory Services Section, Texas Department of State Health Services, Austin, Texas, USA
| | - Debra Freedenberg
- Newborn Screening and Genetics Unit, Texas Department of State Health Services, Austin, Texas, USA
| | - Rachel Lee
- Biochemistry and Genetics Branch, Laboratory Services Section, Texas Department of State Health Services, Austin, Texas, USA
| | - John F Villanacci
- Environmental Epidemiology and Disease Registries Section, Texas Department of State Health Services, Austin, Texas, USA
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23
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Kreiman BL, Boles RG. State of the Art of Genetic Testing for Patients With Autism: A Practical Guide for Clinicians. Semin Pediatr Neurol 2020; 34:100804. [PMID: 32446438 DOI: 10.1016/j.spen.2020.100804] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The explosion in knowledge, technology, and clinical capabilities regarding genetics and genetic testing has expanded greatly in recent years, and these gains have rapidly been applied to individuals with autism spectrum disorder (ASD). However, most clinicians are unaware or confused in regards to whom to test, what tests to order, and how testing might alter management and improve outcomes. This review will address these issues. Research shows that ASD is highly genetic, and while monogenic cases are common, most patients have multiple genes interacting in disease pathogenesis. However, as genetics dictates disease risk, not outcomes, this does not exclude environmental factors. Clinically actionable genetics test results can be found across the phenotypically-heterogeneous ASD spectrum; thus recommendations are to test everyone. As ASD is also highly genetically heterogeneous, testing should address a wide range of variant types, including both large (historically detected by microarray) and small (detected by sequencing), at least across all genes (exome). Additional specialized testing important in ASD diagnostics includes fragile X, mitochondrial DNA, and pharmacogenetics; the latter often informative for which drug to order, at which dose. Recently, whole genome sequencing has emerged as a favorite since all of the above testing, and more, can be performed at a lower total cost than individual test orders. Trio (child plus parents) sequencing is often indicated, especially in more "severe" cases in order to find new (de novo) variants not present in either parent. Additionally, Angelman syndrome testing should be considered in appropriate cases. Current testing provides a precise diagnosis in many cases with ASD. Beyond diagnosis, genetic testing can oftentimes help elucidate potentially treatable risk factors that predispose the individual patient to develop disease. In this clinician's experience (RGB), this information leads to improved outcomes in as many as one-half of cases. Clinical improvement can occur in common associated ASD symptoms (attention, behavior, and anxiety) and/or in general systemtic symptoms (nausea, fatigue, pain), as demonstrated in brief case reports. Practical guidance is provided regarding assisting clinicians to choose the appropriate test(s) and laboratory, as well as how to get testing paid for. Recent cost reductions now allow for most families to benefit from genetic testing.
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Affiliation(s)
- Bracha L Kreiman
- The Center for Neurological and Neurodevelopmental Health, Voorhees, NJ; Molecular and Mitochondrial Medicine, Pasadena, CA
| | - Richard G Boles
- The Center for Neurological and Neurodevelopmental Health, Voorhees, NJ; Molecular and Mitochondrial Medicine, Pasadena, CA.
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24
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Jargin SV. Scientific Papers and Patents on Substances with Unproven Effects. ACTA ACUST UNITED AC 2020; 13:37-45. [PMID: 30848224 DOI: 10.2174/1872211313666190307162041] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Revised: 02/26/2019] [Accepted: 02/26/2019] [Indexed: 01/22/2023]
Abstract
It is evident from reviewing scientific literature that the quality of argumentation in some areas of medical research has deteriorated during the last decades. Publication of a series of questionable reliability has continued without making references to the published criticism; examples are discussed in this review. Another tendency is that drugs without proven efficiency are advertised, corresponding products patented and marketed as evidence-based medications. Professional publications are required to register drugs and dietary supplements to obtain permissions for the practical use; and such papers appeared, sometimes being of questionable reliability. Several examples are discussed in this review when substances without proven effects were patented and introduced into practice being supported by publications of questionable reliability. Some of the topics are not entirely clear; and the arguments provided here can induce a constructive discussion.
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Affiliation(s)
- Sergei V Jargin
- Peoples' Friendship University of Russia, Clementovski per 6-82, 115184 Moscow, Russian Federation
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25
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Ahmadabadi F, Nemati H, Abdolmohammadzadeh A, Ahadi A. Autistic feature as a presentation of Inborn Errors of Metabolism. IRANIAN JOURNAL OF CHILD NEUROLOGY 2020; 14:17-28. [PMID: 33193781 PMCID: PMC7660030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 08/20/2020] [Indexed: 11/30/2022]
Abstract
Autism spectrum disorder (ASD) is a category of neurodevelopmental disorders characterized by social and communication impairment and restricted or repetitive behaviors. The pathogenesis of ASD is not well understood and it's proved that genetic is strongly associated with ASD in 5 to 25% of cases. Inborn errors of metabolism(IEMs), defined by a vast array of disorders that are caused by specific enzyme deficiencies or transport protein defects, is as frequent as in 1 in 800 births. IEMs can manifest several psychiatric or behavioral manifestations such as self-injuriesincreased activity and aggression, personality changes, paranoia, depression, catatonia, and psychosis. IEMs underlie autistic symptoms in less than 5% of cases. The literature on the association between ASD and respiratory chain abnormalities is growing, including complex III/IV deficiency and MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) syndrome, as well as glucose-6-phosphate dehydrogenase deficiency. Google Scholar, Pubmed, and SCOPUS databases were searched using a combination of the following keywords: "autism spectrum disorder", "autism spectrum", "autistic feature" and "inborn error of metabolism", " IEM", "congenital error of metabolism". Initially, 655 articles were found and our expert and methodologist altogether selected 187 articles based on the titles, relevance, and text language. After reading full texts, 37 studies were selected for review. We think it's best to consider IEMs in children with syndromic ASD and/or if there is a strong familial history of autism or parental consanguineous marriage.
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Affiliation(s)
- Farzad Ahmadabadi
- Department of Pediatrics,Faculty of Medicine,Ardebil University of Medical Sciences, Ardebil, Iran
| | - Hamid Nemati
- Shiraz Neuroscience Research Center,Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Adel Ahadi
- Department of Pediatrics,Faculty of Medicine,Ardebil University of Medical Sciences, Ardebil, Iran
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26
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Malaguarnera M, Cauli O. Effects of l-Carnitine in Patients with Autism Spectrum Disorders: Review of Clinical Studies. Molecules 2019; 24:molecules24234262. [PMID: 31766743 PMCID: PMC6930613 DOI: 10.3390/molecules24234262] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 11/21/2019] [Accepted: 11/21/2019] [Indexed: 12/27/2022] Open
Abstract
Carnitine is an amino acid derivative, which plays several important roles in human physiology, in the central nervous system, and for mitochondrial metabolism, in particular. Altered carnitine metabolic routes have been associated with a subgroup of patients with autism spectrum disorders (ASD) and could add to the pathophysiology associated with these disorders. We review the current evidence about the clinical effects of carnitine administration in ASD in both non-syndromic forms and ASD associated with genetic disorders. Two randomized clinical trials and one open-label prospective trial suggest that carnitine administration could be useful for treating symptoms in non-syndromic ASD. The effect of carnitine administration in ASD associated with genetic disorders is not conclusive because of a lack of clinical trials and objectives in ASD evaluation, but beneficial effects have also been reported for other comorbid disorders, such as intellectual disability and muscular strength. Side effects observed with a dose of 200 mg/kg/day consisted of gastro-intestinal symptoms and a strong, heavy skin odor. Doses of about 50–100 mg/kg/day are generally well tolerated. Further clinical trials with the identification of the subgroup of ASD patients that would benefit from carnitine administration are warranted.
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Affiliation(s)
- Michele Malaguarnera
- Research Center “The Great Senescence”, University of Catania, 95100 Catania, Italy;
- Department of Nursing, University of Valencia, 46010 Valencia, Spain
| | - Omar Cauli
- Department of Nursing, University of Valencia, 46010 Valencia, Spain
- Frailty and Cognitive Impairment Group (FROG), University of Valencia, 46010 Valencia, Spain
- Correspondence:
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27
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Bankaitis VA, Xie Z. The neural stem cell/carnitine malnutrition hypothesis: new prospects for effective reduction of autism risk? J Biol Chem 2019; 294:19424-19435. [PMID: 31699893 DOI: 10.1074/jbc.aw119.008137] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Autism spectrum disorders (ASDs) are developmental neuropsychiatric disorders with heterogeneous etiologies. As the incidence of these disorders is rising, such disorders represent a major human health problem with escalating social cost. Although recent years witnessed advances in our understanding of the genetic basis of some dysmorphic ASDs, little progress has been made in translating the improved understanding into effective strategies for ASD management or minimization of general ASD risk. Here we explore the idea, described in terms of the neural stem cell (NSC)/carnitine malnutrition hypothesis, that an unappreciated risk factor for ASD is diminished capacity for carnitine-dependent long-chain fatty acid β-oxidation in neural stem cells of the developing mammalian brain. The basic premise is that fetal carnitine status is a significant metabolic component in determining NSC vulnerability to derangements in their self-renewal program and, therefore, to fetal ASD risk. As fetal carnitine status exhibits a genetic component that relates to de novo carnitine biosynthesis and is sensitive to environmental and behavioral factors that affect maternal circulating carnitine levels, to which the fetus is exposed, we propose that reduced carnitine availability during gestation is a common risk factor that lurks beneath the genetically complex ASD horizon. One major prediction of the NSC/carnitine malnutrition hypothesis is that a significant component of ASD risk might be effectively managed from a public policy perspective by implementing a carnitine surveillance and dietary supplementation strategy for women planning pregnancies and for women in their first trimester of pregnancy. We argue that this prediction deserves serious clinical interrogation.
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Affiliation(s)
- Vytas A Bankaitis
- Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, College Station, Texas 77843-1114 .,Department of Biochemistry and Biophysics, Texas A&M University Health Science Center, College Station, Texas 77843-1114.,Department of Chemistry, Texas A&M University Health Science Center, College Station, Texas 77843-1114
| | - Zhigang Xie
- Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, College Station, Texas 77843-1114
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28
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Glinton KE, Elsea SH. Untargeted Metabolomics for Autism Spectrum Disorders: Current Status and Future Directions. Front Psychiatry 2019; 10:647. [PMID: 31551836 PMCID: PMC6746843 DOI: 10.3389/fpsyt.2019.00647] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 08/12/2019] [Indexed: 12/20/2022] Open
Abstract
Autism spectrum disorders (ASDs) are a group of neurodevelopment disorders characterized by childhood onset deficits in social communication and interaction. Although the exact etiology of most cases of ASDs is unknown, a portion has been proposed to be associated with various metabolic abnormalities including mitochondrial dysfunction, disorders of cholesterol metabolism, and folate abnormalities. Targeted biochemical testing like plasma amino acid and acylcarnitine profiles have demonstrated limited utility in helping to diagnose and manage such patients. Untargeted metabolomics has emerged, however, as a promising tool in screening for underlying biochemical abnormalities and managing treatment and as a means of investigating possible novel biomarkers for the disorder. Here, we review the principles and methodology behind untargeted metabolomics, recent pilot studies utilizing this technology, and areas in which it may be integrated into the care of children with this disorder in the future.
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Affiliation(s)
- Kevin E. Glinton
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
| | - Sarah H. Elsea
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
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29
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Almannai M, Alfadhel M, El-Hattab AW. Carnitine Inborn Errors of Metabolism. Molecules 2019; 24:molecules24183251. [PMID: 31500110 PMCID: PMC6766900 DOI: 10.3390/molecules24183251] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 08/29/2019] [Accepted: 09/04/2019] [Indexed: 12/21/2022] Open
Abstract
Carnitine plays essential roles in intermediary metabolism. In non-vegetarians, most of carnitine sources (~75%) are obtained from diet whereas endogenous synthesis accounts for around 25%. Renal carnitine reabsorption along with dietary intake and endogenous production maintain carnitine homeostasis. The precursors for carnitine biosynthesis are lysine and methionine. The biosynthetic pathway involves four enzymes: 6-N-trimethyllysine dioxygenase (TMLD), 3-hydroxy-6-N-trimethyllysine aldolase (HTMLA), 4-N-trimethylaminobutyraldehyde dehydrogenase (TMABADH), and γ-butyrobetaine dioxygenase (BBD). OCTN2 (organic cation/carnitine transporter novel type 2) transports carnitine into the cells. One of the major functions of carnitine is shuttling long-chain fatty acids across the mitochondrial membrane from the cytosol into the mitochondrial matrix for β-oxidation. This transport is achieved by mitochondrial carnitine–acylcarnitine cycle, which consists of three enzymes: carnitine palmitoyltransferase I (CPT I), carnitine-acylcarnitine translocase (CACT), and carnitine palmitoyltransferase II (CPT II). Carnitine inborn errors of metabolism could result from defects in carnitine biosynthesis, carnitine transport, or mitochondrial carnitine–acylcarnitine cycle. The presentation of these disorders is variable but common findings include hypoketotic hypoglycemia, cardio(myopathy), and liver disease. In this review, the metabolism and homeostasis of carnitine are discussed. Then we present details of different inborn errors of carnitine metabolism, including clinical presentation, diagnosis, and treatment options. At the end, we discuss some of the causes of secondary carnitine deficiency.
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Affiliation(s)
- Mohammed Almannai
- Section of Medical Genetics, Children's Hospital, King Fahad Medical City, Riyadh 11525, Saudi Arabia.
| | - Majid Alfadhel
- Division of Genetics, Department of Pediatrics, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (MNGHA), Riyadh 11426, Saudi Arabia.
- King Abdullah International Medical Research Center (KAIMRC), Riyadh 11426, Saudi Arabia.
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh 11426, Saudi Arabia.
| | - Ayman W El-Hattab
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, UAE.
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30
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Xu M, Xu X, Li J, Li F. Association Between Gut Microbiota and Autism Spectrum Disorder: A Systematic Review and Meta-Analysis. Front Psychiatry 2019; 10:473. [PMID: 31404299 PMCID: PMC6673757 DOI: 10.3389/fpsyt.2019.00473] [Citation(s) in RCA: 162] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2018] [Accepted: 06/13/2019] [Indexed: 12/12/2022] Open
Abstract
Autism spectrum disorder (ASD) is characterized by stereotyped behavior and deficits in communication and social interactions. Gastrointestinal (GI) dysfunction is an ASD-associated comorbidity, implying a potential role of the gut microbiota in ASD GI pathophysiology. Several recent studies found that autistic individuals harbor an altered bacterial gut microbiota. In some cases, remodeling the gut microbiota by antibiotic administration and microbiota transfer therapy reportedly alleviated the symptoms of ASD. However, there is little consensus on specific bacterial species that are similarly altered across individual studies. The aim of this study is to summarize previously published data and analyze the alteration of the relative abundance of bacterial genera in the gut microbiota in controls and individuals with ASD using meta-analysis. We analyzed nine studies, including 254 patients with ASD, and found that children with ASD had lower percentages of Akkermansia, Bacteroides, Bifidobacterium, and Parabacteroides and a higher percentage of Faecalibacterium in the total detected microflora compared to controls. In contrast, children with ASD had lower abundance of Enterococcus, Escherichia coli, Bacteroides, and Bifidobacterium and higher abundance of Lactobacillus. This meta-analysis suggests an association between ASD and alteration of microbiota composition and warrants additional prospective cohort studies to evaluate the association of bacterial changes with ASD symptoms, which would provide further evidence for the precise microbiological treatment of ASD.
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Affiliation(s)
- Mingyu Xu
- Developmental and Behavioral Pediatric & Child Primary Care Department, Ministry of Education-Shanghai Key Laboratory of Children’s Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xuefeng Xu
- Department of Pulmonology, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jijun Li
- Department of Integrative Medicine on Pediatrics, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fei Li
- Developmental and Behavioral Pediatric & Child Primary Care Department, Ministry of Education-Shanghai Key Laboratory of Children’s Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Pediatric Research, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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31
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Canfield MA, Langlois PH, Rutenberg GW, Mandell DJ, Hua F, Reilly B, Ruktanonchai DJ, Jackson JF, Hunt P, Freedenberg D, Lee R, Villanacci JF. The association between newborn screening analytes and childhood autism in a Texas Medicaid population, 2010-2012. Am J Med Genet B Neuropsychiatr Genet 2019; 180:291-304. [PMID: 31016859 DOI: 10.1002/ajmg.b.32728] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 01/28/2019] [Accepted: 04/01/2019] [Indexed: 12/27/2022]
Abstract
Autism (or autism spectrum disorder [ASD]) is an often disabling childhood neurologic condition of mostly unknown cause. It is commonly diagnosed at 3 or 4 years of age. We explored whether there was an association of any analytes measured by newborn screening tests with a later diagnosis of ASD. A database was compiled of 3-5 year-old patients with any ASD diagnosis in the Texas Medicaid system in 2010-2012. Two controls (without any ASD diagnosis) were matched to each case by infant sex and birth year/month. All study subjects were linked to their 2007-2009 birth and newborn screening laboratory records, including values for 36 analytes or analyte ratios. We examined the association of analytes/ratios with a later diagnosis of ASD. Among 3,258 cases and 6,838 controls, seven analytes (e.g., 17-hydroxyprogesterone, acylcarnitines) were associated with a later ASD diagnosis. In this exploratory study, an ASD diagnosis was associated with 7 of 36 newborn screening analytes/ratios. These findings should be replicated in other population-based datasets.
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Affiliation(s)
- Mark A Canfield
- Birth Defects Epidemiology and Surveillance Branch, Texas Department of State Health Services, Austin, Texas
| | - Peter H Langlois
- Birth Defects Epidemiology and Surveillance Branch, Texas Department of State Health Services, Austin, Texas
| | - Gary W Rutenberg
- Center for Analytics and Decision Support, Texas Health and Human Services Commission, Austin, Texas
| | - Dorothy J Mandell
- School of Community and Rural Health, University of Texas Health Science Center, Tyler, Texas.,Population Health, Office of Health Affairs, UT System, Austin, Texas
| | - Fei Hua
- Center for Health Statistics, Texas Department of State Health Services, Austin, Texas
| | - Brendan Reilly
- Biochemistry and Genetics Branch, Laboratory Services Section, Texas Department of State Health Services, Austin, Texas
| | - Duke J Ruktanonchai
- Department of Psychiatry, Children's Institute of Pittsburgh, Pittsburgh, Pennsylvania.,Department of Psychiatry, Wesley Family Services, Pittsburgh, Pennsylvania
| | - Janice F Jackson
- Center for Analytics and Decision Support, Texas Health and Human Services Commission, Austin, Texas
| | - Patricia Hunt
- Biochemistry and Genetics Branch, Laboratory Services Section, Texas Department of State Health Services, Austin, Texas
| | - Debra Freedenberg
- Newborn Screening and Genetics Unit, Texas Department of State Health Services, Austin, Texas
| | - Rachel Lee
- Biochemistry and Genetics Branch, Laboratory Services Section, Texas Department of State Health Services, Austin, Texas
| | - John F Villanacci
- Environmental Epidemiology and Disease Registries Section, Texas Department of State Health Services, Austin, Texas
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Ning Z, Williams JM, Kumari R, Baranov PV, Moore T. Opposite Expression Patterns of Spry3 and p75NTR in Cerebellar Vermis Suggest a Male-Specific Mechanism of Autism Pathogenesis. Front Psychiatry 2019; 10:416. [PMID: 31275178 PMCID: PMC6591651 DOI: 10.3389/fpsyt.2019.00416] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 05/24/2019] [Indexed: 12/22/2022] Open
Abstract
Autism is a genetically complex neurobehavioral disorder with a population prevalence of more than 1%. Cerebellar abnormalities, including Purkinje cell deficits in the vermis, are consistently reported, and rodent models of cerebellar dysfunction exhibit features analogous to human autism. We previously analyzed the regulation and expression of the pseudoautosomal region 2 gene SPRY3, which is adjacent to X chromosome-linked TMLHE, a known autism susceptibility gene. SPRY3 is a regulator of branching morphogenesis and is strongly expressed in Purkinje cells. We previously showed that mouse Spry3 is not expressed in cerebellar vermis lobules VI-VII and X, regions which exhibit significant Purkinje cell loss or abnormalities in autism. However, these lobules have relatively high expression of p75NTR, which encodes a neurotrophin receptor implicated in autism. We propose a mechanism whereby inappropriate SPRY3 expression in these lobules could interact with TrkB and p75NTR signaling pathways resulting in Purkinje cell pathology. We report preliminary characterization of X and Y chromosome-linked regulatory sequences upstream of SPRY3, which are polymorphic in the general population. We suggest that an OREG-annotated region on chromosome Yq12 ∼60 kb from SPRY3 acts as a silencer of Y-linked SPRY3 expression. Deletion of a β-satellite repeat, or alterations in chromatin structure in this region due to trans-acting factors, could affect the proposed silencing function, leading to reactivation and inappropriate expression of Y-linked SPRY3. This proposed male-specific mechanism could contribute to the male bias in autism prevalence.
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Affiliation(s)
| | | | | | | | - Tom Moore
- School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland
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Guevara-Campos J, González-Guevara L, Guevara-González J, Cauli O. First Case Report of Primary Carnitine Deficiency Manifested as Intellectual Disability and Autism Spectrum Disorder. Brain Sci 2019; 9:brainsci9060137. [PMID: 31200524 PMCID: PMC6628273 DOI: 10.3390/brainsci9060137] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 06/12/2019] [Accepted: 06/12/2019] [Indexed: 12/26/2022] Open
Abstract
Systemic primary carnitine deficiency (PCD) is a genetic disorder caused by decreased or absent organic cation transporter type 2 (OCTN2) carnitine transporter activity, resulting in low serum carnitine levels and decreased carnitine accumulation inside cells. In early life, PCD is usually diagnosed as a metabolic decompensation, presenting as hypoketotic hypoglycemia, Reye syndrome, or sudden infant death; in childhood, PCD presents with skeletal or cardiac myopathy. However, the clinical presentation of PCD characterized by autism spectrum disorder (ASD) with intellectual disability (ID) has seldom been reported in the literature. In this report, we describe the clinical features of a seven-year-old girl diagnosed with PCD who presented atypical features of the disease, including a developmental delay involving language skills, concentration, and attention span, as well as autistic features and brain alterations apparent in magnetic resonance imaging. We aim to highlight the difficulties related to the diagnostic and therapeutic approaches used to diagnose such patients. The case reported here presented typical signs of PCD, including frequent episodes of hypoglycemia, generalized muscle weakness, decreased muscle mass, and physical growth deficits. A molecular genetic study confirmed the definitive diagnosis of the disease (c.1345T>G (p.Y449D)) in gene SLC22A5, located in exon 8. PCD can be accompanied by less common clinical signs, which may delay its diagnosis because the resulting global clinical picture can closely resemble other metabolic disorders. In this case, the patient was prescribed a carnitine-enriched diet, as well as oral carnitine at a dose of 100 mg/kg/day. PCD has a better prognosis if it is diagnosed and treated early; however, a high level of clinical suspicion is required for its timely and accurate diagnosis.
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Affiliation(s)
- José Guevara-Campos
- "Felipe Guevara Rojas" Hospital, Pediatrics Service, University of Oriente, El Tigre-Anzoátegui 6034, Venezuela.
| | - Lucía González-Guevara
- "Felipe Guevara Rojas" Hospital, Epilepsy and Encephalography Unit, El Tigre-Anzoátegui 6034, Venezuela.
| | | | - Omar Cauli
- Department of Nursing, University of Valencia, 46010 Valencia, Spain.
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Goin-Kochel RP, Scaglia F, Schaaf CP, Berry LN, Dang D, Nowel KP, Laakman AL, Dowell LR, Minard CG, Loh A, Beaudet AL. Side Effects and Behavioral Outcomes Following High-Dose Carnitine Supplementation Among Young Males With Autism Spectrum Disorder: A Pilot Study. Glob Pediatr Health 2019; 6:2333794X19830696. [PMID: 30815516 PMCID: PMC6381434 DOI: 10.1177/2333794x19830696] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Revised: 12/10/2018] [Accepted: 12/18/2018] [Indexed: 12/18/2022] Open
Affiliation(s)
| | | | | | | | - Dianne Dang
- Baylor College of Medicine, Houston, TX, USA
| | | | | | | | | | - Alvin Loh
- Surrey Place Centre, Toronto, Ontario, Canada
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35
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Duis J, van Wattum PJ, Scheimann A, Salehi P, Brokamp E, Fairbrother L, Childers A, Shelton AR, Bingham NC, Shoemaker AH, Miller JL. A multidisciplinary approach to the clinical management of Prader-Willi syndrome. Mol Genet Genomic Med 2019; 7:e514. [PMID: 30697974 PMCID: PMC6418440 DOI: 10.1002/mgg3.514] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 10/16/2018] [Accepted: 10/22/2018] [Indexed: 12/14/2022] Open
Abstract
Background Prader–Willi syndrome (PWS) is a complex neuroendocrine disorder affecting approximately 1/15,000–1/30,000 people. Unmet medical needs of individuals with PWS make it a rare disease that models the importance of multidisciplinary approaches to care with collaboration between academic centers, medical homes, industry, and parent organizations. Multidisciplinary clinics support comprehensive, patient‐centered care for individuals with complex genetic disorders and their families. Value comes from improved communication and focuses on quality family‐centered care. Methods Interviews with medical professionals, scientists, managed care experts, parents, and individuals with PWS were conducted from July 1 to December 1, 2016. Review of the literature was used to provide support. Results Data are presented based on consensus from these interviews by specialty focusing on unique aspects of care, research, and management. We have also defined the Center of Excellence beyond the multidisciplinary clinic. Conclusion Establishment of clinics motivates collaboration to provide evidence‐based new standards of care, increases the knowledge base including through randomized controlled trials, and offers an additional resource for the community. They have a role in global telemedicine, including to rural areas with few resources, and create opportunities for clinical work to inform basic and translational research. As a care team, we are currently charged with understanding the molecular basis of PWS beyond the known genetic cause; developing appropriate clinical outcome measures and biomarkers; bringing new therapies to change the natural history of disease; improving daily patient struggles, access to care, and caregiver burden; and decreasing healthcare load. Based on experience to date with a PWS multidisciplinary clinic, we propose a design for this approach and emphasize the development of “Centers of Excellence.” We highlight the dearth of evidence for management approaches creating huge gaps in care practices as a means to illustrate the importance of the collaborative environment and translational approaches.
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Affiliation(s)
- Jessica Duis
- Division of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Pieter J van Wattum
- Department of Psychiatry, Child Study Center, Yale School of Medicine, New Haven, Connecticut.,Clifford Beers Clinic, New Haven, Connecticut
| | - Ann Scheimann
- Pediatric Gastroenterology, Johns Hopkins Children's Center, Baltimore, Maryland
| | - Parisa Salehi
- Division of Endocrinology and Diabetes, Seattle Children's, University of Washington, Seattle, Washington
| | - Elly Brokamp
- Division of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Laura Fairbrother
- Division of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Anna Childers
- Division of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Althea Robinson Shelton
- Neuro-Sleep Division, Department of Neurology, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Nathan C Bingham
- Division of Pediatric Endocrinology, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Ashley H Shoemaker
- Division of Pediatric Endocrinology, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Jennifer L Miller
- Pediatric Endocrinology, University of Florida, Gainesville, Florida
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Demarquoy C, Demarquoy J. Autism and carnitine: A possible link. World J Biol Chem 2019; 10:7-16. [PMID: 30622681 PMCID: PMC6314880 DOI: 10.4331/wjbc.v10.i1.7] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 10/26/2018] [Accepted: 11/26/2018] [Indexed: 02/05/2023] Open
Abstract
Patients with autism spectrum disorders (ASD) present deficits in social interactions and communication, they also show limited and stereotypical patterns of behaviors and interests. The pathophysiological bases of ASD have not been defined yet. Many factors seem to be involved in the onset of this disorder. These include genetic and environmental factors, but autism is not linked to a single origin, only. Autism onset can be connected with various factors such as metabolic disorders: including carnitine deficiency. Carnitine is a derivative of two amino acid lysine and methionine. Carnitine is a cofactor for a large family of enzymes: the carnitine acyltransferases. Through their action these enzymes (and L-carnitine) are involved in energy production and metabolic homeostasis. Some people with autism (less than 20%) seem to have L-carnitine metabolism disorders and for these patients, a dietary supplementation with L-carnitine is beneficial. This review summarizes the available information on this topic.
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Affiliation(s)
- Caroline Demarquoy
- DATSA 71 - Foyer Marie-José Marchand, 5 allée du Carrouge, Sennecey-le-Grand 71240, France
| | - Jean Demarquoy
- Université de Bourgogne-Agrosup Dijon, UMR PAM, 6 blvd Gabriel, Dijon 21000, France
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Abstract
West syndrome (WS) is an early life epileptic encephalopathy associated with infantile spasms, interictal electroencephalography (EEG) abnormalities including high amplitude, disorganized background with multifocal epileptic spikes (hypsarrhythmia), and often neurodevelopmental impairments. Approximately 64% of the patients have structural, metabolic, genetic, or infectious etiologies and, in the rest, the etiology is unknown. Here we review the contribution of etiologies due to various metabolic disorders in the pathology of WS. These may include metabolic errors in organic molecules involved in amino acid and glucose metabolism, fatty acid oxidation, metal metabolism, pyridoxine deficiency or dependency, or acidurias in organelles such as mitochondria and lysosomes. We discuss the biochemical, clinical, and EEG features of these disorders as well as the evidence of how they may be implicated in the pathogenesis and treatment of WS. The early recognition of these etiologies in some cases may permit early interventions that may improve the course of the disease.
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Affiliation(s)
- Seda Salar
- Laboratory of Developmental EpilepsySaul R. Korey Department of NeurologyMontefiore/Einstein Epilepsy CenterAlbert Einstein College of MedicineBronxNew YorkU.S.A.
| | - Solomon L. Moshé
- Laboratory of Developmental EpilepsySaul R. Korey Department of NeurologyMontefiore/Einstein Epilepsy CenterAlbert Einstein College of MedicineBronxNew YorkU.S.A.
- Dominick P. Purpura Department of NeuroscienceMontefiore/Einstein Epilepsy CenterAlbert Einstein College of MedicineBronxNew YorkU.S.A.
- Department of PediatricsMontefiore/Einstein Epilepsy CenterAlbert Einstein College of MedicineBronxNew YorkU.S.A.
| | - Aristea S. Galanopoulou
- Laboratory of Developmental EpilepsySaul R. Korey Department of NeurologyMontefiore/Einstein Epilepsy CenterAlbert Einstein College of MedicineBronxNew YorkU.S.A.
- Dominick P. Purpura Department of NeuroscienceMontefiore/Einstein Epilepsy CenterAlbert Einstein College of MedicineBronxNew YorkU.S.A.
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38
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Fluegge K. Gene and environment interactions in autism risk: Reflections on the carnitine deficiency hypothesis by Beaudet (Comment on DOI 10.1002/bies.201700012). Bioessays 2017; 39. [PMID: 28833341 DOI: 10.1002/bies.201700127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Affiliation(s)
- Keith Fluegge
- Institute of Health and Environmental Research, Cleveland, OH, USA
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