Autism genes and the leukocyte transcriptome in autistic toddlers relate to pathogen interactomes, infection and the immune system. A role for excess neurotrophic sAPPα and reduced antimicrobial Aβ - ScienceDirect

Prenatal and early childhood infections have been implicated in autism.
Many autism susceptibility genes (206 Autworks genes) are localised in
the immune system and are related to immune/infection pathways. They are
enriched in the host/pathogen interactomes of 18 separate microbes
(bacteria/viruses and fungi) and to the genes regulated by bacterial
toxins, mycotoxins and Toll-like receptor ligands. This enrichment was
also observed for misregulated genes from a microarray study of
leukocytes from autistic toddlers. The upregulated genes from this
leukocyte study also matched the expression profiles in response to
numerous infectious agents from the Broad Institute molecular signatures
database. They also matched genes related to sudden infant death
syndrome and autism comorbid conditions (autoimmune disease, systemic
lupus erythematosus, diabetes, epilepsy and cardiomyopathy) as well as
to estrogen and thyrotropin responses and to those upregulated by
different types of stressors including oxidative stress, hypoxia,
endoplasmic reticulum stress, ultraviolet radiation or
2,4-dinitrofluorobenzene, a hapten used to develop allergic skin
reactions in animal models. The oxidative/integrated stress response is
also upregulated in the autism brain and may contribute to myelination
problems. There was also a marked similarity between the expression
signatures of autism and Alzheimer's disease, and 44 shared
autism/Alzheimer's disease genes are almost exclusively expressed in the
blood-brain barrier. However, in contrast to Alzheimer's disease,
levels of the antimicrobial peptide beta-amyloid are decreased and the
levels of the neurotrophic/myelinotrophic soluble APP alpha are
increased in autism, together with an increased activity of α-secretase.
sAPPα induces an increase in glutamatergic and a decrease in GABA-ergic
synapses creating and excitatory/inhibitory imbalance that has also
been observed in autism. A literature survey showed that multiple autism
genes converge on APP processing and that many are able to increase
sAPPalpha at the expense of beta-amyloid production. A genetically
programmed tilt of this axis towards an overproduction of
neurotrophic/gliotrophic sAPPalpha and underproduction of antimicrobial
beta-amyloid may explain the brain overgrowth and myelination
dysfunction, as well as the involvement of pathogens in autism.

Israeli research links acetaminophen during pregnancy to autism, ADHD |

An extensive Israeli study has found that mothers who continuously
use a popular pain relief medication during their pregnancy face an
increased risk of the newborn suffering from autism or ADHD.


The meta-analysis by a team of researchers from the Hebrew
University of Jerusalem, published Tuesday in the American Journal of
Epidemiology, showed that prolonged exposure to acetaminophen — also
known as paracetamol — during pregnancy is associated with a 30 percent
increase in relative risk for attention deficit hyperactivity disorder
(ADHD) and a 20% increase in relative risk for autistic spectrum
disorder (ASD), compared with those who did not take acetaminophen
during pregnancy.

Brain development disorders in children linked to common environmental toxin exposures -- ScienceDaily

Exposures of pregnant women and children to common
thyroid-hormone-disrupting toxins may be linked to the increased
incidence of brain development disorders, according to a review
published in Endocrine Connections. The review describes how
numerous, common chemicals can interfere with normal thyroid hormone
actions, which are essential for normal brain development in foetuses
and young children, and suggests a need for greater public health
intervention.



Here's the paper from "Endocrine connections":-

Thyroid disrupting chemicals and brain development: an update

What does the environment have to do with autism? | Ensia

Studies help explain link between autism, severe infection during pregnancy

 "Mothers who experience an infection severe enough to require hospitalization during pregnancy are at higher risk of having a child with autism. Two new studies from MIT and the University of Massachusetts Medical School shed more light on this phenomenon and identify possible approaches to preventing it.

In research on mice, the researchers found that the composition of bacterial populations in the mother's digestive tract can influence whether maternal infection leads to autistic-like behaviors in offspring. They also discovered the specific brain changes that produce these behaviors."



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Folic acid may mitigate autism risk from pesticides

 "In the paper, which used data from the Childhood Autism Risks from Genetics and the Environment (CHARGE) study, researchers looked at 296 children between 2 and 5 who had been diagnosed with ASD and 220 who had developed typically. Mothers were interviewed about their household pesticide exposure during pregnancy, as well as their folic acid and B vitamin intake. The team also linked data from California Pesticide Use reports, which provide important details about agricultural spraying, with the mothers' addresses.
Mothers who took less than 800 micrograms and encountered household pesticides had a much higher estimated risk of having a child who developed an ASD than moms who took 800 micrograms of folic acid or more and were not exposed to pesticides. The associated risk increased for women exposed repeatedly. Women with low folic acid intake who were exposed to agricultural pesticides during a window from three months before conception to three months afterward also were at higher estimated risk."



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Autism Linked to Mitochondrial DNA Variation, Possible Cause Gains Traction | GEN

 : "Looking beyond the nuclear genome, researchers have found further evidence that the nearby mitochondrial genome, often overlooked, could be an underlying cause of autism spectrum disorder (ASD). The study reported an association between ancient mitochondrial DNA (mtDNA) variants and ASD and was published August 23 in JAMA Psychiatry.

“What we discovered is that a very significant proportion of the risk of developing autism correlates with the mitochondrial DNA variants, not the nuclear variants, so that implies then that mitochondrial energetics might be the cause, or a major factor, in the etiology of this disease,” senior study author Douglas Wallace, Ph.D., told GEN. Wallace is the director of the Center for Mitochondrial and Epigenomic Medicine at The Children’s Hospital of Philadelphia Research Institute.

Wallace continued, explaining, “The brain uses 20% of all the energy that our body generates but is only 2% to 3% of our body’s weight; therefore, subtle changes in mitochondrial energy production should have a disproportionate effect on the brain.”"

Here's the paper

Association Between Mitochondrial DNA Haplogroup Variation and Autism Spectrum Disorders

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Study on the Association among Mycotoxins and other Variables in Children with Autism.

 Environmental factors and genetic susceptibility are implicated in the increased risk of autism spectrum disorder (ASD). Mycotoxins are agricultural contaminants of fungal origin that represent real risk factors for human health and especially for children. Thus, the main hypothesis of this work is that the deterioration of the clinical manifestation of autism in children may result from the exposure to mycotoxins through the consumption of contaminated food. Within a cross-sectional study, a group of autistic children (n = 172) and a group of controls (n = 61) (siblings and non-parental) were recruited in North and South Italy. All children had blood and urine samples taken, for testing some mycotoxins by a LC-MS/MS validated method. Blood samples were also tested for assessing specific IgG against food and fungal antigens and cytokines. The analyses outputs highlighted statistically significant differences comparing mycotoxins levels between (i) children groups both in urine (deoxynivalenol and de-epoxydeoxynivalenol, p = 0.0141 and p = 0.0259, respectively) and serum (aflatoxin M1, ochratoxin A and fumonisin B1, p = 0.0072, p = 0.0141 and p = 0.0061, respectively); (ii) a group of selected fungal IgGs, and IgGs against wheat and gluten and (iii) cytokines. These results suggest the need for a deeper examination of the role that mycotoxins may have on the etiology of ASD."



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The joint effect of air pollution exposure and copy number variation on risk for autism - Kim - 2017 - Autism Research - Wiley Online Library

 Autism spectrum disorder is a complex trait with a high degree of heritability as well as documented susceptibility from environmental factors. In this study the contributions of copy number variation, exposure to air pollutants, and the interaction between the two on autism risk, were evaluated in the population-based case-control Childhood Autism Risks from Genetics and Environment (CHARGE) Study. For the current investigation, we included only those CHARGE children (a) who met criteria for autism or typical development and (b) for whom our team had conducted both genetic evaluation of copy number burden and determination of environmental air pollution exposures based on mapping addresses from the pregnancy and early childhood. This sample consisted of 158 cases of children with autism and 147 controls with typical development. Multiple logistic regression models were fit with and without environmental variable-copy number burden interactions. We found no correlation between average air pollution exposure from conception to age 2 years and the child's CNV burden. We found a significant interaction in which a 1SD increase in duplication burden combined with a 1SD increase in ozone exposure was associated with an elevated autism risk (OR 3.4, P < 0.005) much greater than the increased risks associated with either genomic duplication (OR 1.85, 95% CI 1.25–2.73) or ozone (OR 1.20, 95% CI 0.93–1.54) alone. Similar results were obtained when CNV and ozone were dichotomized to compare those in the top quartile relative to those having a smaller CNV burden and lower exposure to ozone, and when exposures were assessed separately for pregnancy, the first year of life, and the second year of life. No interactions were observed for other air pollutants, even those that demonstrated main effects; ozone tends to be negatively correlated with the other pollutants examined. While earlier work has demonstrated interactions between the presence of a pathogenic CNV and an environmental exposure [Webb et al., 2016], these findings appear to be the first indication that global copy number variation may increase susceptibility to certain environmental factors, and underscore the need to consider both genomics and environmental exposures as well as the mechanisms by which each may amplify the risks for autism associated with the other.



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Prenatal fever and autism risk. - PubMed - NCBI

 Some studies suggest that prenatal infection increases risk of autism spectrum disorders (ASDs). This study was undertaken in a prospective cohort in Norway to examine whether we could find evidence to support an association of the prenatal occurrence of fever, a common manifestation of infection, with ASD risk. Prospective questionnaires provided maternal exposure data; case status was established from clinical assessments and registry linkages. In a large, prospectively ascertained cohort of pregnant mothers and their offspring, we examined infants born ⩾32 weeks for associations between fever exposure in each trimester and ASD risk using logistic regression. Maternal exposure to second-trimester fever was associated with increased ASD risk, adjusting for presence of fever in other trimesters and confounders (adjusted odds ratio (aOR), 1.40; 95% confidence interval, 1.09-1.79), with a similar, but nonsignificant, point estimate in the first trimester. Risk increased markedly with exposure to three or more fever episodes after 12 weeks' gestation (aOR, 3.12; 1.28-7.63). ASD risk appears to increase with maternal fever, particularly in the second trimester. Risk magnified dose dependently with exposure to multiple fevers after 12 weeks' gestation. Our findings support a role for gestational maternal infection and innate immune responses to infection in the pathogenesis of at least some cases of ASD"



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Fetal and postnatal metal dysregulation in autism : Nature Communications

 Genetic and environmental factors contribute to the etiologies of autism spectrum disorder (ASD), but evidence of specific environmental exposures and susceptibility windows is limited. Here we study monozygotic and dizygotic twins discordant for ASD to test whether fetal and postnatal metal dysregulation increases ASD risk. Using validated tooth-matrix biomarkers, we estimate pre- and post-natal exposure profiles of essential and toxic elements. Significant divergences are apparent in metal uptake between ASD cases and their control siblings, but only during discrete developmental periods. Cases have reduced uptake of essential elements manganese and zinc, and higher uptake of the neurotoxin lead. Manganese and lead are also correlated with ASD severity and autistic traits. Our study suggests that metal toxicant uptake and essential element deficiency during specific developmental windows increases ASD risk and severity, supporting the hypothesis of systemic elemental dysregulation in ASD. Independent replication in population-based studies is needed to extend these findings."



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Suramin and Autism - UC San Diego Health

 "Suramin is a 100-year-old drug developed to treat African sleeping sickness and river blindness. Though it has been investigated for other diseases, including cancer, it is not approved for any therapeutic use in the United States.
However, a small, randomized clinical trial conducted by Robert Naviaux, MD, PhD, professor of medicine, pediatrics and pathology, and colleagues at University of California San Diego School of Medicine have found that a single intravenous dose of suramin produced dramatic, but transient, improvement of core symptoms of autism spectrum disorder (ASD). Currently, there are no drugs approved for treating the core symptoms of ASD.
More broadly, the trial findings support the “cell danger response theory,” which posits that autism and other chronic conditions are fundamentally driven by metabolic dysfunction—and thus treatable. Naviaux and his co-authors propose larger, longer clinical trials to assess suramin (or similar drugs) as an ASD treatment."



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Aerial spraying to combat mosquitos linked to increased risk of autism in children

 Researchers who will present the abstract, "Aerial Pesticide Exposure Increases the Risk of Developmental Delay and Autism Spectrum Disorder," identified a swampy region in central New York where health officials use airplanes to spray pyrethroid pesticides each summer. The pesticides target mosquitos that carry the eastern equine encephalitis virus, which can cause swelling of the brain and spinal cord. They found that children living in ZIP codes in which aerial pesticide spraying has taken place each summer since 2003 were approximately 25 percent more likely to have an autism diagnosis or documented developmental delay compared to those in ZIP codes with other methods of pesticide distribution, such as manually spreading granules or using hoses or controlled droplet applicators."

Effects of bumetanide on neurobehavioral function in children and adolescents with autism spectrum disorders

 In animal models of autism spectrum disorder (ASD), the NKCC1 chloride-importer inhibitor bumetanide restores physiological (Cl−)i levels, enhances GABAergic inhibition and attenuates electrical and behavioral symptoms of ASD. In an earlier phase 2 trial; bumetanide reduced the severity of ASD in children and adolescents (3–11 years old). Here we report the results of a multicenter phase 2B study primarily to assess dose/response and safety effects of bumetanide. Efficacy outcome measures included the Childhood Autism Rating Scale (CARS), the Social Responsive Scale (SRS) and the Clinical Global Impressions (CGI) Improvement scale (CGI-I). Eighty-eight patients with ASD spanning across the entire pediatric population (2–18 years old) were subdivided in four age groups and randomized to receive bumetanide (0.5, 1.0 or 2.0 mg twice daily) or placebo for 3 months. The mean CARS value was significantly improved in the completers group (P: 0.015). Also, 23 treated children had more than a six-point improvement in the CARS compared with only one placebo-treated individual. Bumetanide significantly improved CGI (P: 0.0043) and the SRS score by more than 10 points (P: 0.02). The most frequent adverse events were hypokalemia, increased urine elimination, loss of appetite, dehydration and asthenia. Hypokalemia occurred mainly at the beginning of the treatment at 1.0 and 2.0 mg twice-daily doses and improved gradually with oral potassium supplements. The frequency and incidence of adverse event were directly correlated with the dose of bumetanide. Therefore, bumetanide improves the core symptoms of ASD and presents a favorable benefit/risk ratio particularly at 1.0 mg twice daily."



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Molecular Psychiatry - Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder

 Maternal immune activation (MIA) via infection during pregnancy is known to increase risk for autism spectrum disorder (ASD). However, it is unclear how MIA disrupts fetal brain gene expression in ways that may explain this increased risk. Here we examine how MIA dysregulates rat fetal brain gene expression (at a time point analogous to the end of the first trimester of human gestation) in ways relevant to ASD-associated pathophysiology. MIA downregulates expression of ASD-associated genes, with the largest enrichments in genes known to harbor rare highly penetrant mutations. MIA also downregulates expression of many genes also known to be persistently downregulated in the ASD cortex later in life and which are canonically known for roles in affecting prenatally late developmental processes at the synapse. Transcriptional and translational programs that are downstream targets of highly ASD-penetrant FMR1 and CHD8 genes are also heavily affected by MIA. MIA strongly upregulates expression of a large number of genes involved in translation initiation, cell cycle, DNA damage and proteolysis processes that affect multiple key neural developmental functions. Upregulation of translation initiation is common to and preserved in gene network structure with the ASD cortical transcriptome throughout life and has downstream impact on cell cycle processes. The cap-dependent translation initiation gene, EIF4E, is one of the most MIA-dysregulated of all ASD-associated genes and targeted network analyses demonstrate prominent MIA-induced transcriptional dysregulation of mTOR and EIF4E-dependent signaling. This dysregulation of translation initiation via alteration of the Tsc2–mTor–Eif4e axis was further validated across MIA rodent models. MIA may confer increased risk for ASD by dysregulating key aspects of fetal brain gene expression that are highly relevant to pathophysiology affecting ASD.



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World's largest autism genome database shines new light on many 'autisms'

Through its research platform on the Google Cloud, Autism Speaks is making all of MSSNG's fully sequenced genomes directly available to researchers free of charge, along with analytic tools. In the coming weeks, the MSSNG team will be uploading an additional 2,000 fully sequenced autism genomes, bringing the total over 7,000.
Currently, more than 90 investigators at 40 academic and medical institutions are using the MSSNG database to advance autism research around the world."



Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder, Nature Neuroscience (2017). DOI: 10.1038/nn.4524 

Autism risk linked to herpes infection during pregnancy

Women actively infected with genital herpes ( HSV-2) during early pregnancy had twice the odds of giving birth to a child later diagnosed with autism spectrum disorder (ASD), according to a study by scientists at the Center for Infection and Immunity at Columbia University's Mailman School of Public Health and the Norwegian Institute of Public Health."



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Detection of Clostridium perfringens toxin genes in the gut microbiota of autistic children. - PubMed - NCBI

We studied stool specimens from 33 autistic children aged 2-9 years with gastrointestinal (GI) abnormalities and 13 control children without autism and without GI symptoms. We performed quantitative comparison of all Clostridium species and Clostridium perfringens strains from the fecal microbiota by conventional, selective anaerobic culture methods. We isolated C. perfringens strains and performed PCR analysis for the main C. perfringens toxin genes, alpha, beta, beta2, epsilon, iota and C. perfringens enterotoxin gene. Our results indicate that autistic subjects with gastrointestinal disease harbor statistically significantly (p = 0.031) higher counts of C. perfringens in their gut compared to control children. Autistic subjects also harbor statistically significantly (p = 0.015) higher counts of beta2-toxin gene-producing C. perfringens in their gut compared to control children, and the incidence of beta2-toxin gene-producing C. perfringens is significantly higher in autistic subjects compared to control children (p = 0.014). Alpha toxin gene was detected in all C. perfringens strains studied. C. perfringens enterotoxin gene was detected from three autistic and one control subject. Beta, epsilon, and iota toxin genes were not detected from autistic or control subjects."



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ASU gut microbe study shows promise as a potential treatment for autism | EurekAlert! Science News

"The key to fighting autism might lie not in the mind, but in the gut.

A team led by Arizona State University researchers is taking a novel approach the search for effective autism treatments by focusing on improving the gut microbiome through fecal microbial transplants.

Early results are promising, but additional testing is required before an FDA-approved therapy would be available or recommended to the public.

The team -- including collaborators from Northern Arizona University, Ohio State University and the University of Minnesota -- completed a study involving 18 participants with autism spectrum disorders who ranged in age from 7 to 16 years old. The results were recently published in the journal Microbiome.

Participants underwent a 10-week treatment program involving antibiotics, a bowel cleanse and daily fecal microbial transplants over eight weeks.

Past ASU research has shown ties between autism symptoms and the composition and diversity of a person's gut microbes.

The treatment program showed long-term benefits, including an average 80 percent improvement of gastrointestinal symptoms associated with autism spectrum disorders and 20-25 percent improvement in autism behaviors, including improved social skills and better sleep habits."



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Changes in blood-brain barrier, intestinal permeability found in individuals with autism

The group analyzed postmortem cerebral cortex and cerebellum tissues from 33 individuals - 8 with ASD, 10 with schizophrenia and 15 healthy controls. Altered expression of genes associated with blood-brain-barrier integrity and function and with inflammation was detected in ASD tissue samples, supporting the hypothesis that an impaired blood-brain barrier associated with neuroinflammation contributes to ASD.
In keeping with the hypothesis that the interplay within the gut-brain axis is a crucial component in the development of neurodevelopmental disorders, the group also analyzed intestinal epithelial tissue from 12 individuals with ASD and 9 without such disorders. That analysis revealed that 75 percent of the individuals affected by ASD had reduced expression of barrier-forming cellular components, compared with controls, and 66 percent showed a higher expression of molecules that increase intestinal permeability."


See also:-

The barrier, airway particle clearance, placental and detoxification functions of autism susceptibility genes.Pubmed