{"id":17868,"date":"2024-03-30T16:13:45","date_gmt":"2024-03-30T21:13:45","guid":{"rendered":"https:\/\/autism.org\/?p=17868"},"modified":"2024-09-23T15:39:35","modified_gmt":"2024-09-23T20:39:35","slug":"biomarkers-and-pathophysiology","status":"publish","type":"post","link":"https:\/\/autism.org\/biomarkers-and-pathophysiology\/","title":{"rendered":"Biomarkers start telling us a story: Autism pathophysiology revisited"},"content":{"rendered":"<p><div class=\"fusion-fullwidth fullwidth-box fusion-builder-row-1 nonhundred-percent-fullwidth non-hundred-percent-height-scrolling\" style=\"--awb-border-radius-top-left:0px;--awb-border-radius-top-right:0px;--awb-border-radius-bottom-right:0px;--awb-border-radius-bottom-left:0px;--awb-flex-wrap:wrap;\" ><div class=\"fusion-builder-row fusion-row\"><div class=\"fusion-layout-column fusion_builder_column fusion-builder-column-0 fusion_builder_column_1_6 1_6 fusion-one-sixth fusion-column-first\" style=\"--awb-padding-top:80px;--awb-bg-size:cover;width:13.3333%; margin-right: 4%;\"><div class=\"fusion-column-wrapper fusion-flex-column-wrapper-legacy\"><div class=\"fusion-sep-clear\"><\/div><div class=\"fusion-separator fusion-full-width-sep\" style=\"margin-left: auto;margin-right: auto;margin-top:40px;width:100%;\"><\/div><div class=\"fusion-sep-clear\"><\/div><div class=\"fusion-clearfix\"><\/div><\/div><\/div><div class=\"fusion-layout-column fusion_builder_column fusion-builder-column-1 fusion_builder_column_2_3 2_3 fusion-two-third\" style=\"--awb-padding-top:80px;--awb-bg-size:cover;width:65.3333%; margin-right: 4%;\"><div class=\"fusion-column-wrapper fusion-flex-column-wrapper-legacy\"><div class=\"fusion-sep-clear\"><\/div><div class=\"fusion-separator fusion-full-width-sep\" style=\"margin-left: auto;margin-right: auto;margin-top:40px;width:100%;\"><\/div><div class=\"fusion-sep-clear\"><\/div><div class=\"fusion-image-element fusion-image-align-center in-legacy-container\" style=\"text-align:center;--awb-caption-title-font-family:var(--h2_typography-font-family);--awb-caption-title-font-weight:var(--h2_typography-font-weight);--awb-caption-title-font-style:var(--h2_typography-font-style);--awb-caption-title-size:var(--h2_typography-font-size);--awb-caption-title-transform:var(--h2_typography-text-transform);--awb-caption-title-line-height:var(--h2_typography-line-height);--awb-caption-title-letter-spacing:var(--h2_typography-letter-spacing);\"><div class=\"imageframe-align-center\"><span class=\" fusion-imageframe imageframe-none imageframe-1 hover-type-none\"><img decoding=\"async\" width=\"2560\" height=\"619\" alt=\"World Autism Org Collab image\" title=\"World Autism Org Collab_Horizontal\" src=\"https:\/\/autism.org\/wp-content\/uploads\/2023\/09\/World-Autism-Org-Collab_Horizontal-1.png\" data-orig-src=\"https:\/\/autism.org\/wp-content\/uploads\/2023\/09\/World-Autism-Org-Collab_Horizontal-1.png\" class=\"lazyload img-responsive wp-image-19541\" srcset=\"data:image\/svg+xml,%3Csvg%20xmlns%3D%27http%3A%2F%2Fwww.w3.org%2F2000%2Fsvg%27%20width%3D%272560%27%20height%3D%27619%27%20viewBox%3D%270%200%202560%20619%27%3E%3Crect%20width%3D%272560%27%20height%3D%27619%27%20fill-opacity%3D%220%22%2F%3E%3C%2Fsvg%3E\" data-srcset=\"https:\/\/autism.org\/wp-content\/uploads\/2023\/09\/World-Autism-Org-Collab_Horizontal-1-200x48.png 200w, https:\/\/autism.org\/wp-content\/uploads\/2023\/09\/World-Autism-Org-Collab_Horizontal-1-400x97.png 400w, https:\/\/autism.org\/wp-content\/uploads\/2023\/09\/World-Autism-Org-Collab_Horizontal-1-600x145.png 600w, https:\/\/autism.org\/wp-content\/uploads\/2023\/09\/World-Autism-Org-Collab_Horizontal-1-800x193.png 800w, https:\/\/autism.org\/wp-content\/uploads\/2023\/09\/World-Autism-Org-Collab_Horizontal-1-1200x290.png 1200w, https:\/\/autism.org\/wp-content\/uploads\/2023\/09\/World-Autism-Org-Collab_Horizontal-1.png 2560w\" data-sizes=\"auto\" data-orig-sizes=\"(max-width: 800px) 100vw, 800px\" \/><\/span><\/div><\/div><div class=\"fusion-sep-clear\"><\/div><div class=\"fusion-separator fusion-full-width-sep\" style=\"margin-left: auto;margin-right: auto;margin-top:40px;width:100%;\"><\/div><div class=\"fusion-sep-clear\"><\/div><div class=\"fusion-text fusion-text-1\" style=\"--awb-text-transform:none;\"><p style=\"text-align: center;\"><strong>This is a joint presentation with the World Autism Organisation.<\/strong><\/p>\n<\/div><div class=\"fusion-text fusion-text-2\" style=\"--awb-text-transform:none;\"><p><span style=\"font-weight: 400;\"><a href=\"#jump\">Antonio Persico, MD<\/a>, a recent <a href=\"https:\/\/autism.org\/ari-funded-research-studies-2022\/\">ARI Research Grant recipient<\/a>, explores the role of biomarkers in understanding autism pathophysiology. He discusses the complexity inherent to neurodevelopmental conditions and emphasizes the need to combine information from multiple fields of investigation. The presenter discusses contemporary autism research on genomics, methylomics, transcriptomics, proteomics, metabolomics, and functional brain imaging. He highlights the implications of protein transcription regulation and how it appears across groups and generations. Persico reiterates the complexities of neurodevelopmental conditions and the need for interdisciplinary research and understanding before the Q&amp;A. <\/span><\/p>\n<p>This is a joint presentation with the World Autism Organisation.<\/p>\n<\/div><div class=\"fusion-sep-clear\"><\/div><div class=\"fusion-separator fusion-full-width-sep\" style=\"margin-left: auto;margin-right: auto;margin-top:40px;width:100%;\"><\/div><div class=\"fusion-sep-clear\"><\/div><div class=\"fusion-video fusion-youtube fusion-aligncenter\" style=\"--awb-max-width:600px;--awb-max-height:360px;--awb-width:100%;\"><div class=\"video-shortcode\"><div class=\"fluid-width-video-wrapper\" style=\"padding-top:60%;\" ><iframe title=\"YouTube video player 1\" src=\"https:\/\/www.youtube.com\/embed\/6NOSGcGSQJQ?wmode=transparent&autoplay=0\" width=\"600\" height=\"360\" allowfullscreen allow=\"autoplay; fullscreen\"><\/iframe><\/div><\/div><\/div><div class=\"fusion-sep-clear\"><\/div><div class=\"fusion-separator fusion-full-width-sep\" style=\"margin-left: auto;margin-right: auto;margin-top:40px;width:100%;\"><\/div><div class=\"fusion-sep-clear\"><\/div><div class=\"fusion-text fusion-text-3\" style=\"--awb-text-transform:none;\"><h2>In this webinar:<\/h2>\n<p><strong>0:30 &#8211; 6:30<\/strong> &#8211; Organization introductions<br \/>\n<strong>8:10 &#8211;<\/strong> Presentation introduction<br \/>\n<strong>12:25 &#8211;<\/strong> Genomics<br \/>\n<strong>16:00 &#8211;<\/strong> Interaction of rare and common gene variants<br \/>\n<strong>18:00 &#8211;<\/strong> Functional analysis of genetic pathways<br \/>\n<strong>21:15 &#8211;<\/strong> Neurodevelopmental genes<br \/>\n<strong>26:00 &#8211;<\/strong> Methylomics<br \/>\n<strong>30:00 &#8211;<\/strong> Genomic and epigenetic overlap<br \/>\n<strong>34:40 &#8211;<\/strong> Generational methylation and pathophysiology<br \/>\n<strong>41:00 &#8211;<\/strong> Transcriptomics<br \/>\n<strong>46:30 &#8211;<\/strong> Proteomics<br \/>\n<strong>50:30 &#8211;<\/strong> Metabolomics<br \/>\n<strong>55:00 &#8211;<\/strong> Functional brain imaging<br \/>\n<strong>59:55 &#8211;<\/strong> Summary and conclusion<br \/>\n<strong>1:03:00 &#8211;<\/strong> Q&amp;A<\/p>\n<h2><b>The complexity of autism pathophysiology<\/b><\/h2>\n<p><span style=\"font-weight: 400;\">Persico considers classic approaches to biomarker research and how they inform diagnosis, risk assessments, and developmental trajectories for neurodevelopmental conditions<\/span><b> (8:10)<\/b><span style=\"font-weight: 400;\">. However, focusing on biomarkers alone neglects the complexity of autism pathogenesis. He explains that while genomics closely analyzes the biological mechanisms of autism, it cannot inform brain structure and behavior <\/span><b>(12:25)<\/b><span style=\"font-weight: 400;\">. To understand the drivers of autism, the speaker asserts that we must combine knowledge from genetics, methylomics, metabolomics, movement kinetics, and more <\/span><b>(11:20)<\/b><span style=\"font-weight: 400;\">. He presents on a variety of these aspects.\u00a0<\/span><\/p>\n<h2><b>Genomics<\/b><\/h2>\n<p><span style=\"font-weight: 400;\">The speaker explains how high-effect genes (rare variants) are enough to push beyond the autism risk threshold on their own. Contrastingly, low-to-moderate-effect genes (common variants) must occur in combination with other mutations to reach the genetic threshold <\/span><b>(14:15)<\/b><span style=\"font-weight: 400;\">. Persico outlines a recent study revealing only one in five people with autism had a causal gene mutation, rebutting previously held assumptions that rare causal genes are the most common genetic drivers of autism <\/span><b>(12:25)<\/b><span style=\"font-weight: 400;\">. He asserts that it is very rare for a single gene to cause autism and notes the increasing number of known common variant genes present in the general population <\/span><b>(16:00)<\/b><span style=\"font-weight: 400;\">. Persico states that autism genetics is beginning to resemble that of epilepsy, type 2 diabetes, and other conditions with strong familiality and complex underlying biology <\/span><b>(17:35)<\/b><span style=\"font-weight: 400;\">.\u00a0<\/span><\/p>\n<ul>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><a href=\"https:\/\/doi.org\/10.3389\/fped.2021.526779\"><i><span style=\"font-weight: 400;\">Genetic Testing in Neurodevelopmental Disorders<\/span><\/i><\/a><span style=\"font-weight: 400;\"> (Savatt &amp; Myers, 2021)<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><a href=\"https:\/\/doi.org\/10.1146\/annurev-genom-083115-022647\"><i><span style=\"font-weight: 400;\">The Yin and Yang of autism genetics: how rare de novo and common variations affect liability<\/span><\/i><\/a><span style=\"font-weight: 400;\"> (<\/span><span style=\"font-weight: 400;\">Chaste et al., 2017)<\/span><\/li>\n<\/ul>\n<h3><b>Genetic pathways and protein function<\/b><\/h3>\n<p><span style=\"font-weight: 400;\">The speaker explains how analyzing the function of proteins encoded by common variants\/candidate genes can help us understand autism pathogenesis <\/span><b>(18:00)<\/b><span style=\"font-weight: 400;\">. He outlines two recent exome sequencing studies that show autism-related genes are generally linked to expression regulation (expressed during gestation) and neuronal communication (expressed in early life) pathways <\/span><b>(19:15)<\/b><span style=\"font-weight: 400;\">. These findings are replicated in Italian and Tunisian cohorts <\/span><b>(20:15)<\/b><span style=\"font-weight: 400;\">.<\/span><\/p>\n<ul>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><a href=\"https:\/\/doi.org\/10.1016\/j.cell.2019.12.036\"><i><span style=\"font-weight: 400;\">Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism<\/span><\/i><\/a><span style=\"font-weight: 400;\"> (Satterstrom et al., 2020)<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><a href=\"https:\/\/doi.org\/10.1038\/nature13772\"><i><span style=\"font-weight: 400;\">Synaptic, transcriptional and chromatin genes disrupted in autism<\/span><\/i><\/a><span style=\"font-weight: 400;\"> (De Rubeis et al., 2014)<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><a href=\"https:\/\/doi.org\/10.1002\/mgg3.2182\"><i><span style=\"font-weight: 400;\">Diagnostic yield and clinical impact of chromosomal microarray analysis in autism spectrum disorder<\/span><\/i><\/a><span style=\"font-weight: 400;\"> (Cucinotta et al., 2023)<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><a href=\"https:\/\/doi.org\/10.1002\/mgg3.1939\"><i><span style=\"font-weight: 400;\">Yield of array\u2010CGH analysis in Tunisian children with autism spectrum disorder<\/span><\/i><\/a><span style=\"font-weight: 400;\"> (Chehbani et al., 2022)<\/span><\/li>\n<\/ul>\n<h3><b>Neurodevelopmental gene pathways<\/b><\/h3>\n<p><span style=\"font-weight: 400;\">Persico states that there is <\/span><i><span style=\"font-weight: 400;\">no such thing as an autism gene<\/span><\/i><span style=\"font-weight: 400;\"> because, depending on the affected pathways and protein functions, candidate genes could result in a variety of neurodevelopmental conditions <\/span><b>(21:15)<\/b><span style=\"font-weight: 400;\">. He discusses pleiotropy and outlines two studies illustrating the variability in gene expression among supposedly homogenous genetic symptoms <\/span><b>(22:00)<\/b><span style=\"font-weight: 400;\">. Another recent investigation found that nearly half of the siblings with a pathogenic\/rare variant gene did not evolve toward autism. The speaker asserts that, due to the variability in neurodevelopmental gene pathways and expression, genetics alone is not often sufficient to predict autism. Persico reasserts the need for interdisciplinary research in unraveling the pathophysiology of autism and other neurodevelopmental conditions<\/span><b> (24:00)<\/b><span style=\"font-weight: 400;\">.\u00a0<\/span><\/p>\n<ul>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><a href=\"https:\/\/doi.org\/10.1016\/j.ajhg.2020.04.004\"><i><span style=\"font-weight: 400;\">Insufficient evidence for \u201cautism-specific\u201d genes<\/span><\/i><\/a><span style=\"font-weight: 400;\"> (Myers et al., 2020)<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><a href=\"https:\/\/doi.org\/10.1038\/s41467-019-13380-2\"><i><span style=\"font-weight: 400;\">Predictive impact of rare genomic copy number variations in siblings of individuals with autism spectrum disorders<\/span><\/i><\/a><span style=\"font-weight: 400;\"> (D\u2019Abate et al., 2019)<\/span><\/li>\n<\/ul>\n<h2><b>Methylomics<\/b><\/h2>\n<p><span style=\"font-weight: 400;\">Methylomics is an epigenetic mechanism that alters gene expression via transcription pathway regulation. The presenter describes how DNA strands coil themselves around histones to create RNA transcription sites and how, if wrapped too tightly, those transcription regions are repressed <\/span><b>(26:00)<\/b><span style=\"font-weight: 400;\">. Persico explains that both transcription pathway repression and gene deletion lead to gene silencing, making it challenging to pinpoint causal mechanisms <\/span><b>(27:50)<\/b><span style=\"font-weight: 400;\">. He outlines two studies that illustrate this variability in genetics and methylation across sibling pairs <\/span><b>(28:25)<\/b><span style=\"font-weight: 400;\">.\u00a0<\/span><\/p>\n<p><span style=\"font-weight: 400;\">A 2017 investigation combining data from genetics and epigenetics found that a significant number of common autism-related variants are associated with methylation <\/span><b>(39:00)<\/b><span style=\"font-weight: 400;\">. The presenter reminds viewers that methylation influences immune-related pathways, which can affect individuals much later in development <\/span><b>(40:22)<\/b><span style=\"font-weight: 400;\">. He underscores the importance of epigenetics, noting a study that used methylomic biomarkers to distinguish between autistic and unaffected siblings with 99.7% accuracy <\/span><b>(32:45)<\/b><span style=\"font-weight: 400;\">. He affirms that, although this study may not be replicable, contemporary evidence clearly suggests different patterns of methylation in autistic children and their siblings <\/span><b>(33:40)<\/b><span style=\"font-weight: 400;\">.\u00a0<\/span><\/p>\n<ul>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><a href=\"https:\/\/doi.org\/10.1038\/mp.2013.41\"><i><span style=\"font-weight: 400;\">Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traits<\/span><\/i><\/a><span style=\"font-weight: 400;\"> (Wong et al., 2014)\u00a0<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><a href=\"https:\/\/doi.org\/10.1186\/1741-7015-7-62\"><i><span style=\"font-weight: 400;\">Genomic and epigenetic evidence for oxytocin receptor deficiency in autism<\/span><\/i><\/a><span style=\"font-weight: 400;\"> (Gregory et al., 2009)<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><a href=\"https:\/\/doi.org\/10.1038\/s41467-017-00868-y\"><i><span style=\"font-weight: 400;\">Cross-tissue integration of genetic and epigenetic data offers insight into autism spectrum disorder<\/span><\/i><\/a><span style=\"font-weight: 400;\">(Andrews et al., 2017)<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><a href=\"https:\/\/www.sciencedirect.com\/science\/article\/abs\/pii\/S0969996108000247\"><i><span style=\"font-weight: 400;\">Immune transcriptome alterations in the temporal cortex of subjects with autism<\/span><\/i><\/a><span style=\"font-weight: 400;\"> (Garbett et al., 2008)<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><a href=\"https:\/\/doi.org\/10.1007\/s12539-019-00328-9\"><i><span style=\"font-weight: 400;\">Detecting Methylomic Biomarkers of Pediatric Autism in the Peripheral Blood Leukocytes<\/span><\/i><\/a><span style=\"font-weight: 400;\"> (Feng et al., 2019)<\/span><\/li>\n<\/ul>\n<h3><b>Generational methylation and pathophysiology<\/b><\/h3>\n<p><span style=\"font-weight: 400;\">A 2020 genome sequencing study found sex-specific differentially methylated genes in the cord blood of newborns who later received an autism diagnosis <\/span><b>(34:40)<\/b><span style=\"font-weight: 400;\">. Researchers have also recorded methylome differences in the sperm genome of fathers of autistic children <\/span><b>(35:57)<\/b><span style=\"font-weight: 400;\">. Persico asserts that these findings suggest that differential methylation and potential autism biomarkers are present before birth. The speaker describes early embryo demethylation, highlighting how some parental methylation sites are maintained through at least early childhood <\/span><b>(37:15)<\/b><span style=\"font-weight: 400;\">. He considers how these findings may help broaden the focus of biomarker research to encompass intergenerational drivers and patterns <\/span><b>(38:00)<\/b><span style=\"font-weight: 400;\">.\u00a0<\/span><\/p>\n<ul>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><a href=\"https:\/\/doi.org\/10.1186\/s13073-020-00785-8\"><i><span style=\"font-weight: 400;\">Cord blood DNA methylome in newborns later diagnosed with autism spectrum disorder reflects early dysregulation of neurodevelopmental and X-linked genes<\/span><\/i><\/a><span style=\"font-weight: 400;\"> (Mordaunt et al., 2020)<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><a href=\"https:\/\/doi.org\/10.1093\/ije\/dyv028\"><i><span style=\"font-weight: 400;\">Paternal sperm DNA methylation associated with early signs of autism risk in an autism-enriched cohort<\/span><\/i><\/a><span style=\"font-weight: 400;\"> (Feinberg et al., 2015)<\/span><\/li>\n<\/ul>\n<h2><b>Transcriptomics<\/b><\/h2>\n<p><span style=\"font-weight: 400;\">Transcriptomics studies the structure, function, and evolution of genome-wide RNA (transcriptome). The speaker outlines brain imaging studies showing significant overexpression of immune genes and underexpression of neuronal genes across ages and brain regions in autistic participants <\/span><b>(41:00)<\/b><span style=\"font-weight: 400;\">. Similarly, a 2023 RNA sequencing analysis found specific co-expressed genes that are regulated differently in autistic siblings of typically developing children <\/span><b>(43:15)<\/b><span style=\"font-weight: 400;\">. Persico discusses RACK1 and its role in the translational control of neuroinflammation and neurodevelopment. He asserts that evidence is beginning to point toward specific and significantly different neurodevelopment pathways and reiterates the advantages of combining information from multiple fields <\/span><b>(45:00)<\/b><span style=\"font-weight: 400;\">.\u00a0<\/span><\/p>\n<ul>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/16806505\/\"><i><span style=\"font-weight: 400;\">Autism, the superior temporal sulcus and social perception<\/span><\/i><\/a><span style=\"font-weight: 400;\"> (Zilbovicius et al., 2006)<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><a href=\"https:\/\/doi.org\/10.1038\/s41598-023-27378-w\"><i><span style=\"font-weight: 400;\">RNA sequencing of blood from sex- and age-matched discordant siblings supports immune and transcriptional dysregulation in autism spectrum disorder<\/span><\/i><\/a><span style=\"font-weight: 400;\"> (Tomaiuolo et al., 2023)<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><a href=\"https:\/\/doi.org\/10.1038\/nature10110\"><i><span style=\"font-weight: 400;\">Transcriptomic analysis of autistic brain reveals convergent molecular pathology<\/span><\/i><\/a><span style=\"font-weight: 400;\"> (Voineagu et al., 2011)\u00a0<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><a href=\"https:\/\/doi.org\/10.1016\/j.cellsig.2017.01.026\"><i><span style=\"font-weight: 400;\">Structural analysis of ribosomal RACK1 and its role in translational control. Cellular Signalling<\/span><\/i><\/a><span style=\"font-weight: 400;\"> (Nielsen et al., 2017)<\/span><\/li>\n<\/ul>\n<h2><b>Proteomics<\/b><\/h2>\n<p><span style=\"font-weight: 400;\">Proteomics is the large-scale study of protein expression in the body and is relatively understudied in autism. Findings to date suggest the presence of inflammation in the periphery and central tissue of autistic participants <\/span><b>(46:30)<\/b><span style=\"font-weight: 400;\">. Persico uses a diagram to explain alternative splicing, the mechanism by which proteins are expressed slightly differently across the body. When this process is deranged, expression is incomplete or disrupted in alternatively spliced proteins <\/span><b>(47:00)<\/b><span style=\"font-weight: 400;\">. The speaker asks why abnormal alternative splicing and inflammation are common in autism and asserts that adding another level of investigation may provide some answers <\/span><b>(50:00)<\/b><span style=\"font-weight: 400;\">.\u00a0<\/span><\/p>\n<ul>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><a href=\"https:\/\/doi.org\/10.1002\/aur.1803\"><i><span style=\"font-weight: 400;\">Proteomic explorations of autism spectrum disorder<\/span><\/i><\/a><span style=\"font-weight: 400;\"> (Szoko et al., 2017)<\/span><\/li>\n<\/ul>\n<h2><b>Metabolomics<\/b><\/h2>\n<p><span style=\"font-weight: 400;\">Metabolomics is the large-scale study of small molecules in cells and tissues, including the microbiome. Gut health is a critical aspect of overall health and autism risk. Extant literature shows microbiome profiles specific to autism with high levels of inflammatory bacteria and non-human compounds <\/span><b>(50:30)<\/b><span style=\"font-weight: 400;\">. Persico outlines an animal model where the offspring of mice colonized with autistic gut bacteria displayed autism-like behaviors <\/span><b>(52:08)<\/b><span style=\"font-weight: 400;\">. The offspring microbiome induced abnormal alternative splicing involving at least 52 of the known autism genes. These data, Persico claims, show that offspring are affected by parental microbiome content, further solidifying the intergenerational aspect and complexity of autism pathogenesis <\/span><b>(52:20)<\/b><span style=\"font-weight: 400;\">.\u00a0<\/span><\/p>\n<ul>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><a href=\"https:\/\/doi.org\/10.1186\/s13229-016-0109-5\"><i><span style=\"font-weight: 400;\">Urinary metabolomics of young Italian autistic children supports abnormal tryptophan and purine metabolism<\/span><\/i><\/a><span style=\"font-weight: 400;\"> (Gevi et al., 2016)<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><a href=\"https:\/\/doi.org\/10.1038\/s41598-018-32219-2\"><i><span style=\"font-weight: 400;\">Analysis of gut microbiota profiles and microbe-disease associations in children with autism spectrum disorders in China<\/span><\/i><\/a><span style=\"font-weight: 400;\"> (Zhang et al., 2018)<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><a href=\"https:\/\/doi.org\/10.1016\/j.cell.2019.05.004\"><i><span style=\"font-weight: 400;\">Human gut microbiota from autism spectrum disorder promote behavioral symptoms in mice<\/span><\/i><\/a><span style=\"font-weight: 400;\"> (Sharon et al., 2019)<\/span><\/li>\n<\/ul>\n<h2><b>Functional brain imaging<\/b><\/h2>\n<p><span style=\"font-weight: 400;\">Autism is described by altered behavior stemming from differences in brain connectivity. The speaker describes instances of reduced connectivity and hyperconnectivity across brain regions observed in autism, noting the interplay of brain structure and function <\/span><b>(55:00)<\/b><span style=\"font-weight: 400;\">. A neurogenetics study of 647 autistic individuals found that brain connectivity varies across individuals, with most experiencing a mixture of hyper and reduced connectivity <\/span><b>(57:20)<\/b><span style=\"font-weight: 400;\">. Persico notes that hyperconnected brain regions are linked to genes exhibiting excitation, which demonstrates the relationship between genetics and other fields of investigation <\/span><b>(58:35)<\/b><span style=\"font-weight: 400;\">.\u00a0<\/span><\/p>\n<ul>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><a href=\"https:\/\/doi.org\/10.1093\/brain\/awv051\"><i><span style=\"font-weight: 400;\">Autism: reduced connectivity between cortical areas involved in face expression, theory of mind, and the sense of self<\/span><\/i><\/a><span style=\"font-weight: 400;\"> (Cheng et al., 2015)<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><a href=\"https:\/\/doi.org\/10.1038\/nn.3919\"><i><span style=\"font-weight: 400;\">The idiosyncratic brain: distortion of spontaneous connectivity patterns in autism spectrum disorder<\/span><\/i><\/a><span style=\"font-weight: 400;\"> (Hahamy et al., 2015)<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><a href=\"https:\/\/doi.org\/10.1016\/j.biopsych.2023.04.014\"><i><span style=\"font-weight: 400;\">The neurogenetics of functional connectivity alterations in autism: Insights from subtyping in 657 individuals<\/span><\/i><\/a><span style=\"font-weight: 400;\"> (Rasero et al., 2023)<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><a href=\"https:\/\/doi.org\/10.1038\/s41467-021-26131-z\"><i><span style=\"font-weight: 400;\">mTOR-related synaptic pathology causes autism spectrum disorder-associated functional hyperconnectivity<\/span><\/i><\/a><span style=\"font-weight: 400;\"> (Pagani et al., 2021)<\/span><\/li>\n<\/ul>\n<h2><b>Conclusion<\/b><\/h2>\n<p><span style=\"font-weight: 400;\">The speaker discusses the mTOR pathway in autism, noting the implications of immune activation and inflammation associated with hyperconnectivity. Epigenetics and the gut microbiome also contribute to candidate gene regulation via mTOR, beginning in the parental gut and sperm cells <\/span><b>(59:55)<\/b><span style=\"font-weight: 400;\">. Persico therefore claims that altered brain connectivity can be due to genetics, epigenetics, neuroinflammation, microbiome composition, and\/or altered protein expression. He reiterates that we cannot use biomarker research alone if we want to understand complex conditions. Researchers and clinicians must respect the complexities of neurodevelopment and assemble information to unravel autism pathophysiology and inform proper care <\/span><b>(1:02:30)<\/b><span style=\"font-weight: 400;\">. He provides thanks and acknowledgments before the Q&amp;A <\/span><b>(1:03:00)<\/b><span style=\"font-weight: 400;\">.\u00a0<\/span><\/p>\n<ul>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><a href=\"https:\/\/doi.org\/10.1038\/nrm2672\"><i><span style=\"font-weight: 400;\">Molecular mechanisms of mTOR-mediated translational control<\/span><\/i><\/a><span style=\"font-weight: 400;\"> (Ma &amp; Blenis, 2009)<\/span><\/li>\n<\/ul>\n<p>Learn more about the mTOR and other signaling pathways in <a href=\"https:\/\/autism.org\/molecular-and-celluar-mechanisms\/\">this webinar<\/a><br \/>\n<i><\/i><\/p>\n<p><strong><em>Originally published March 26, 2024<\/em><\/strong><\/p>\n<\/div><div class=\"fusion-sep-clear\"><\/div><div class=\"fusion-separator fusion-full-width-sep\" style=\"margin-left: auto;margin-right: auto;margin-top:40px;width:100%;\"><\/div><div class=\"fusion-sep-clear\"><\/div><div class=\"fusion-clearfix\"><\/div><\/div><\/div><div class=\"fusion-layout-column fusion_builder_column fusion-builder-column-2 fusion_builder_column_1_6 1_6 fusion-one-sixth fusion-column-last\" style=\"--awb-padding-top:80px;--awb-bg-size:cover;width:13.3333%;\"><div class=\"fusion-column-wrapper fusion-flex-column-wrapper-legacy\"><div class=\"fusion-sep-clear\"><\/div><div class=\"fusion-separator fusion-full-width-sep\" style=\"margin-left: auto;margin-right: auto;margin-top:40px;width:100%;\"><\/div><div class=\"fusion-sep-clear\"><\/div><div class=\"fusion-clearfix\"><\/div><\/div><\/div><\/div><\/div><div id=\"#jump\" class=\"fusion-container-anchor\"><div class=\"fusion-fullwidth fullwidth-box fusion-builder-row-2 has-pattern-background has-mask-background nonhundred-percent-fullwidth non-hundred-percent-height-scrolling\" style=\"--awb-border-radius-top-left:0px;--awb-border-radius-top-right:0px;--awb-border-radius-bottom-right:0px;--awb-border-radius-bottom-left:0px;--awb-flex-wrap:wrap;\" ><div class=\"fusion-builder-row fusion-row\"><div class=\"fusion-layout-column fusion_builder_column fusion-builder-column-3 fusion_builder_column_1_3 1_3 fusion-one-third fusion-column-first\" style=\"--awb-bg-size:cover;width:33.333333333333%;width:calc(33.333333333333% - ( ( 4% ) * 0.33333333333333 ) );margin-right: 4%;\"><div class=\"fusion-column-wrapper fusion-column-has-shadow fusion-flex-column-wrapper-legacy\"><div class=\"fusion-text fusion-text-4\" style=\"--awb-text-transform:none;\"><h3>The speaker:<\/h3>\n<p><b><img decoding=\"async\" class=\"lazyload size-full wp-image-17869 alignleft\" src=\"data:image\/svg+xml,%3Csvg%20xmlns%3D%27http%3A%2F%2Fwww.w3.org%2F2000%2Fsvg%27%20width%3D%27100%27%20height%3D%27138%27%20viewBox%3D%270%200%20100%20138%27%3E%3Crect%20width%3D%27100%27%20height%3D%27138%27%20fill-opacity%3D%220%22%2F%3E%3C%2Fsvg%3E\" data-orig-src=\"https:\/\/autism.org\/wp-content\/uploads\/2024\/02\/persico_small.jpg\" alt=\"\" width=\"100\" height=\"138\" \/><\/b> <strong>Antonio Persico, MD,<\/strong> studied Psychiatry at the Catholic University of the Sacred Heart (Rome, Italy) in 1990 and worked as Visiting Foreign Fellow at the Natl. Inst. on Drug Abuse (Baltimore, MD) between 1991 and 1994, with a focus on the genetics of drug addiction. Starting in 1995, at University \u201cCampus Bio-Medico\u201d (Rome, Italy), Dr. Persico began exploring the role of serotonin in neurodevelopment and the genetics of autism. Since then, autism and neurodevelopmental disorders have been his primary focus. In 2010, he started the clinical Unit of Child &amp; Adolescent Neuropsychiatry at UCBM, then becoming in 2015 Full Professor of Child and Adolescent Neuropsychiatry at the University of Messina (Italy). Here he directed the Interdepartmental Program \u201cAutism 0-90\u201d at the \u201cG. Martino\u201d University Hospital. Dr. Persico&#8217;s overarching target is to &#8220;link clinical phenomena to their genetic, epigenetic and neurobiological underpinnings in neurodevelopmental disorders.&#8221; His specific research interests are thus primarily translational: clustering autistic patients in biologically meaningful ways, identifying biomarkers for early diagnosis and to predict response\/non-response to specific forms of therapies, developing novel evidence-based pharmacological, behavioral and occupational interventions. Dr. Persico&#8217;s goal is to &#8220;improve as much as possible the long-term trajectory and the quality of life of autistic individuals and their families at all ages.&#8221; Currently, Dr. Persico is at Universit\u00e0 di Modena e Reggio Emilia.<\/p>\n<\/div><div class=\"fusion-clearfix\"><\/div><\/div><\/div><div class=\"fusion-layout-column fusion_builder_column fusion-builder-column-4 fusion_builder_column_2_3 2_3 fusion-two-third fusion-column-last\" style=\"--awb-bg-size:cover;width:66.666666666667%;width:calc(66.666666666667% - ( ( 4% ) * 0.66666666666667 ) );\"><div class=\"fusion-column-wrapper fusion-column-has-shadow fusion-flex-column-wrapper-legacy\"><div class=\"fusion-text fusion-text-5\"><h4>Take the knowledge quiz<\/h4>\n<p>Can&#8217;t see the quiz below? Take it online <a href=\"https:\/\/www.classmarker.com\/online-test\/start\/?quiz=np666034e13da3ee\">HERE<\/a><\/p>\n<\/div><div class=\"fusion-text fusion-text-6\"><p><script src=\"https:\/\/www.classmarker.com\/public\/js\/embed-classmarker-1.0.0.js?quiz=np666034e13da3ee\" data-quiz=\"np666034e13da3ee\" data-width=\"700\" data-height=\"800\" ><\/script><\/p>\n<\/div><div class=\"fusion-clearfix\"><\/div><\/div><\/div><\/div><\/div><\/div><div class=\"fusion-fullwidth fullwidth-box fusion-builder-row-3 nonhundred-percent-fullwidth non-hundred-percent-height-scrolling\" style=\"--awb-border-radius-top-left:0px;--awb-border-radius-top-right:0px;--awb-border-radius-bottom-right:0px;--awb-border-radius-bottom-left:0px;--awb-flex-wrap:wrap;\" ><div class=\"fusion-builder-row fusion-row\"><div class=\"fusion-layout-column fusion_builder_column fusion-builder-column-5 fusion_builder_column_1_1 1_1 fusion-one-full fusion-column-first fusion-column-last\" style=\"--awb-bg-size:cover;\"><div class=\"fusion-column-wrapper fusion-column-has-shadow fusion-flex-column-wrapper-legacy\"><div class=\"fusion-sep-clear\"><\/div><div class=\"fusion-separator fusion-full-width-sep\" style=\"margin-left: auto;margin-right: auto;margin-top:30px;width:100%;\"><\/div><div class=\"fusion-sep-clear\"><\/div><div class=\"fusion-sep-clear\"><\/div><div class=\"fusion-separator fusion-full-width-sep\" style=\"margin-left: auto;margin-right: auto;margin-top:30px;width:100%;\"><\/div><div class=\"fusion-sep-clear\"><\/div><div class=\"fusion-text fusion-text-7\" style=\"--awb-text-transform:none;\"><h4 style=\"text-align: left;\">Free webinar at 3 p.m. Eastern time (US), Wednesday, March 27, 2024<\/h4>\n<\/div><div class=\"fusion-sep-clear\"><\/div><div class=\"fusion-separator fusion-full-width-sep\" style=\"margin-left: auto;margin-right: auto;margin-top:30px;width:100%;\"><\/div><div class=\"fusion-sep-clear\"><\/div><div class=\"fusion-sep-clear\"><\/div><div class=\"fusion-separator 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