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As with all risk factors, these do not cause Autism: they add an element of risk and may act in synergy with other risk factors or susceptibility genes. Their risk promoting ability may be increased or decreased by these other factors. Nevertheless, autism is increasing at an alarming rate, a factor that is unlikely to be gene-related. These risk factors, and the genes, form the components of a puzzle, whose assembly will one day alow us to see the whole picture Autism books ... The Autism Birth Cohort project..... Autism genetic Ressource exchange Healing Thresholds Autism Therapy

Environmental risk factors and medical conditions associated with Autism

Ongoing clinical trails, worldwide, can be interrogated at ClinicalTrials.Gov a service of the US National Institutes of Health

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Risk Factor (Links to Wikipedia and Pubmed)

GWAS from Genome.Gov CDH9 CDH10 MACROD2 PARD3B PPP2R5C SEMA5A TAF1C TAS2R1

A noise-reduction GWAS analysis implicates altered regulation of neurite outgrowth and guidance in autism.Hussman et al, 2011 (Open access)

Rare mutations ASMT CHD8, DYRK1A, GRIN2B, KATNAL2, POGZ, and SCN2A, Buxbaum et al, 2012

KEGG pathway analysis of Autism susceptibility genes

Children with autism were more likely to have mitochondrial dysfunction, mtDNA overreplication, and mtDNA deletions Giulivi et al, 2010

Environmental factors

US autism rates from 1996 to 2006 from Wikimedia Commons

  • Susceptibility to autism has moderate genetic heritability and a substantial shared twin environmental component Hallmayer et al, 2011

Infectious agents

Vaccinations

  • For historical interest, the original MMR vaccine paper from Wakefield et al, 1998
  • Other papers on measles, mumps and rubella vaccines Refs
  • Hepatitis B vaccination of male neonates has been associated with an increased risk of autism Gallagher and Goodman
  • Thiomersal (organic mercury) in vaccines has been linked to autism and a comparison between organic mercury containing and non-containing vaccines using the Vaccine Adverse Event Reporting System suggested a number of associations with significantly increased odds ratios for autism (OR = 1.8, p < .05), mental retardation (OR = 2.6, p < .002), speech disorder (OR = 2.1, p < .02), personality disorders (OR = 2.6, p < .01), and thinking abnormality (OR = 8.2, p < .01) Geier and Geier, 2004.
    • Thimerosal has been shown to be more toxic in female mice Branch, 2009 and further research may be needed
  • A family history of Pink disease (infantile acrodynia), related to mercury poisoning has been linked to autism Shandley and Austin, 2011.

Autoimmunity Pubmed autoantibody search

  • Familial autoimmunity has been associated with autism: Notably Type 1 diabetes, rheumatoid arthritis, and coeliac disease Atladottir et al, 2009
  • Altered toll receptor responses in autism Jyonouchi et al, 2008
  • Autoantibodies (IgG isotype) to neuron-axon filament protein (NAFP) and glial fibrillary acidic protein (GFAP) are significantly increased in autistic patients (Singh et al., 1997)
  • Autoantibodies to GABAergic Golgi neurons of the cerebellum Rossi et al, 2011
  • Antibodies to a 45 kDa cerebellar protein and other cerebellar proteins raised maternally Goines et al, 2011
  • Autoantibodies to the voltage-dependent anion channel (VDAC) and hexokinase-I Gonzalez-Gronow et al, 2010
  • myelin basic protein (MBP) autoantibodies and elevated levels of antibodies to measles virus and measles-mumps-rubella (MMR) vaccine Singh, 2009.
  • anti-myelin basic protein (MBP) and anti-myelin-associated glycoprotein (MAG) auto-antibodies in some autistic children Mostafa and Al-Ayadhi, 2013
  • antinucleosome-specific antibodies increased in some autistic children Al-Ayadhi et al, 2014
  • anti-amygdala, anti-caudate nucleus, anti-cerebellum anti-brain stem, anti-hippocampus, anti-corpus callosum and anti-cortex antibodies Mora et al, 2009
  • anti-nuclear antibodies Mostafa and Kitchener, 2009
  • Folate receptor autoantibodies
    • Oral folinic acid supplements led to partial or complete clinical recovery after 12 months Ramaekers et al, 2007 .
  • Metallothionein autoantibodies Russo, 2008
  • Antibodies to gliadin, a component of gluten, and to cerebellar peptides have been observed Vojdani et al, 2004
  • Antibodies to casein, lactalbumin and beta-lactoglobulin have been found in autism where symptoms were improved by milk and wheat free diets Lucarelli et al 1995 see also Kawashti et al, 2006
  • Antibodies to brain elements, related to herpes viral infection have been decribed in autism , particularly Herpes virus HSV-2 Mora et al, 2009
  • Plasma concentrations of the cytokines IL1B, IL1RA, IL5, IL8, IL12, IL13, IL17 and GRO-alpha are higher in autism spectrum disorder subjects Suzuki et al, 2011
  • A humoral immunity profile, described by three binary variables, IgA < 0.97 g/l, IgE > 36 IU/ml, and IgG > 6.3 g/l, was able to identify children with autism Wasilewska et al, 2012.
  • maternal autoantibodies that target foetal brain proteins Braunschweig et al, 2008
  • Maternal autoantibodies associated with autism spectrum disorders may affect brain development Nordahl et al, 2013
  • Lactate dehydrogenase A and B (LDH), guanine deaminase (GDA/cypin) , stress-induced phosphoprotein 1 (STIP1), collapsin response mediator proteins 1 and 2 (CRMP1, CRMP2) and Y-box-binding protein described as the primary antigens of maternal autoantibody-related autism.Braunschweig et al, 2013
  • Autoantibodies to cardiolipin, ß 2-glycoprotein 1 ( apolipoprotein H APOH) , and phosphoserine Careaga et al, 2013

Prenatal factors and Birth related

  • Fever during pregnancy increases the risk of autism in the offspring - an effect reduced in those taking antipyretics Zerbo et al, 2012
  • Prenatal and perinatal paracetamol (acetaminophen) exposure heve been correlated with autism Bauer and Kriebel, 2013
  • Obstetric sub-optimality (prematurity, low Agpar scores, growth restriction, or macrosomia (large birth size)) was positively associated with autism Haglund and kallen, 2010
  • Associated with closely-spaced pregnancies Cheslack-Postava et al, 2011
  • Pre-pregnancy obesity or excessive weight gain during pregnancy may increase the risk of autism in the offspring Dodds et al, 2010
  • Maternal obesity (BMI =30) weakly associated with ASD risk : Paternal obesity associated with an increased risk of autistic disorder and Asperger disorder Surén et al, 2014.
  • Higher risks for autism among those conceived in winter months suggest the presence of environmental causes of autism that vary by season Zerbo et al, 2011.
  • Interactions between the 5-HTTLPR gene (serotonin transporter) or COMT (catechol-O-methyltransferase) maternal smoking and low birthweight have been associated with autism risk Nijmeijer et al, 2010
  • Nine risk factors showed significant association with autism: maternal second-hand smoke exposure, maternal chronic or acute medical conditions unrelated to pregnancy, maternal unhappy emotional state, gestational complications, edema, abnormal gestational age (<35 or >42 weeks), nuchal cord, Number of pregnancies >1, and advanced paternal age at delivery (>30 year-old)". Zhang et al, 2010
  • Increased concentrations of interferon-gamma, interleukins IL-4 and IL-5 in midgestation maternal serum has been associated with a 50% increased risk of autism in the offspring Goines et al, 2011
  • Breech presentation has been associated with autism Bilder et al, 2009
  • Prenatal exposure to valproic acid, ethanol, thalidomide and misoprostol has been shown to be associated with an increased incidence of autism Dufour-Rainfray et al, 2011
  • Birth defects are more common in autism Dawson et al, 2009
  • Prenatal exposure to serotonin uptake inhibitor antidepressants during the first trimester has been associated with autism Croehn et al, 2011
  • Exposure to valproic acid a drug used in Bipolar disorder, in pregnancy Ornoy, 2009
  • Associated with thalidomide embryopathy Stromland et al, 1994
  • The use of prenatal vitamins may reduce the risk of having children with autism, especially for genetically susceptible mothers and children Schmidt et al, 201
  • Higher parental age has been associated with Autism spectrum disorders. Ben Itzchak et al, 2011.
  • Periconceptional use of prenatal vitamins may reduce the risk of having children with autism ( an effect conditioned by genes in folate and one carbon metabolism pathways : MTHFR, CBS, COMT) Schmidt et al, 2011
  • Maternal diabetes and obesity have been associated with autism in the offspring Krakowiak et al, 2012
  • Prenatal Polycyclic Aromatic Hydrocarbon (PAH) Exposure has been associated with autism and related disorders Perera et al, 2012
  • Prenatal exposures to lacquer, varnish, or xylene have been associated with autism McCanlies et al, 2012
  • Parental exposure to night work, handling of solvents and/or electromagnetic fields has been associated with an increased incidence of autism in the children Pino-López and Romero-Ayuso , 2013
  • Placental trophoblast inclusions have been related to autism risk in the child Anderson et al, 2007. Walker et al, 2013
  • Severe, early gestation maternal hypothyroxinemia is associated with autistic symptoms in the offspring Román et al, 2013
  • Induced childbirth has been associated with autism in the offspring Gregory et al, 2013
  • Elevated progesterone, 17a-hydroxy-progesterone, androstenedione and testosterone as well as cortisol in utero related to autism in the offspring Baron-Cohen et al, 2014
  • Association with pre-eclampsia (related to reduced birth weight ) Mann et al, 2010 Walker et al, 2014
  • Maternal chemical intolerance associated with ADHD and autism in the offspring Heilbrun et al, 2015
Dietary factors
  • High fructose corn syrup has been linked to the development of autism and related disorders Dufault et al, 2012
  • Maternal Vitamin D deficiency has been linked with autism Grant and Soles, 2009
  • Autism is more common in areas of impaired UVB penetration away from the equator, urban areas, areas with high air pollution, and areas of high rainfall. Autism is more common in dark-skinned persons and severe maternal vitamin D deficiency is exceptionally common the dark-skinned.Cannell, 2008
  • Vitamin D treatment has been reported to ameliorate both autism and schizophrenia symptoms in some cases Humble et al, 2010
  • Low levels of vitamins A, B6 and vitamin C, folic acid, calcium, and zinc have been implicated in autism Xia et al, 2010
  • Low vitamin E and A plasma values indicate lower consumption of food rich in vitamin A and Vitamin E (e.g. whole-grain products, plant oils, oil seeds, nuts, fat spreads and dairy products).Krajcovicova-Kudlackova et al, 2009
  • High mercury levels have been implicated in autism Geier et al, 2010
  • Low levels of tryptophan have been observed in autism Kaluzna-Czaplinska et al, 2010
  • Low levels of cholesterol have been observed in autism Tierney et al, 2006
  • Dyslipidaemia has been observed in autism: High plasma triglyceride; low HDL-C Kim et al, 2010
  • Serum levels of Apolipoprotein B-100, Complement Factor H Related Protein (FHR1), Complement C1q and Fibronectin 1 (FN1) levels are elevaed in autism Corbett et al, 2007
  • Plasma fatty acid profiles show that docosahexaenoic acid (DHA, 22:6n-3) was significantly decreased in phosphatidylethanolamine. Dimethyl acetals were significantly decreased in phosphatidylethanolamine and phosphatidylcholine Wiest et al, 2009
  • Increased MCP-1, RANTES and eotaxin levels have been noted in autistic children's plasma Ashwood et al, 2011
  • Autism has been associated with toxic metal burden Adams et al, 2009
  • Low glutathione levels have been associated with autism James et al, 2009
  • Plasma-reduced glutathione, cysteine methionine and serum cystathionine and homocysteine are decreased in autism Geier and Geier, 2006. Low brain levels of glutathione have also been reported Chauhan et al, 2012
  • High plasma levels of thioredoxin , thioredoxin reductase and peroxiredoxins (PRDX1 and PRDX3) have been recorded in autistic children together with a reduction in plasma glutathione s transferase activity Al-Yafee et al, 2011 High levels of thioredoxin correlate with the autism score Zhang et al, 2014
  • High levels of urinary homocysteine have been reported in autism suggesting deficiencies of folic acid and vitamins B6 and B12 Kaluzna-Czaplinska et al, 2011
  • High fasting serum homocysteine and low folate and vitamin B12 levels could be used as clinical biomarkers for an early diagnosis and management of autism Ali et al, 2011.
  • Increased serum androstenedione in adults with autism spectrum conditions.Ruta et al, 2011
  • Increased urinary excretion of N-methyl-2-pyridone-5-carboxamide, N-methyl nicotinic acid, and N-methyl nicotinamide suggest malfunction of the tryptophan-nicotinic acid metabolic pathway.higher levels of urinary taurine and lower levels of urinary glutamate, indicate perturbation in sulfur and amino acid metabolism: Changes in mammalian-microbial cometabolites including dimethylamine, hippurate, and phenyacetylglutamine also observed Yap et al, 2010
  • Gluten- and casein-free diets can be of benefit in some sufferers Whiteley et al, 2010
  • Urinary concentrations of 3-methyl-cyclopentanone, 3-methyl-butanal, 2-methyl-butanal, and hexane under acid conditions, and 2-methyl-pyrazine, 2,3-dimethyl-pyrazine, and isoxazolo under alkaline pH had statistically higher levels from autistic children Cozzolino et al, 2014
Drugs and treatments Association with other diseases
  • Epilepsy and autism coexist in a substantial proportion of either types of patient Tuchman and Cuccaro, 2011
  • Autism is frequent in tuberous sclerosis complex ( a genetic disorder causing non-malignant brain tumours) Numis et al, 2011
  • Autism has been associated with neonatal jaundice Maimburg et al, 2010
  • Gastrointestinal problems are common in autism Casanova, 2008 Wang et al, 2011
  • Depression has been associated with autism Magnuson and Constantino, 2011
  • Intestinal permeability has been associated with autism D'Eufemie at al, 1996
  • Chronic inflammation of the gastrointestinal tract, dysbiosis, maldigestion, malabsorption, malnutrition, food intolerance, allergies, chronic viral, fungal and bacterial infections, impaired kidney function, impaired detoxification of endo- and exotoxins, disorders of metal ion transportation have been implicated in autism Cubala-Kucharska, 2010
  • Children with autism are at risk of developing oral diseases Stein et al, 2011
  • Immune conditions, gastrointestinal and sleep disorders, seizure, obesity, dyslipidemia, hypertension, and diabetes as well as stroke and Parkinson's disease, significantly more common among adults with autism Croen et al, 2005.
Others

Blood levels and other physiology

  • serum follicle-stimulating hormone levels are decreased in autistic patients Geier and Geier, 2006
  • Elevated copro- , hexacarboxyl- and pentacarboxyl- porphyrin concentrations have been associated with autism Woods et al, 2010
  • Children with autism had much lower levels of total short chain fatty acids including lower levels of acetate, proprionate, and valerate Adams et al, 2011
  • Plasma levels of chemokines involved in the T-helper cell immune system and hematopoiesis were lower in the children with Autism compared with unrelated siblings without Autism Manzardo et al, 2011
  • Plasma and urinary oxalate levels have been reported as increased in autism spectrum disorders Konstantynowicz et al, 2011
  • Low levels of plasma EGF Onore et al, 2012
  • Low plasma levels of platelet endothelial adhesion molecule-1 and P-selectin Onore et al, 2012
  • High plasma levels of complement factor 1 in autistic children Momeni et al, 2009
  • Glutathione imbalance and oxidative stress in peripheral immune cells Rose et al, 2012
  • In newborns who later develop autism, decreased levels of T helper-1(Th-1)-like cytokines (i.e. Iinterferon gamma) and Th-2like cytokines (i.e. IL-4, IL-10) suggest a depressed or hypoactive immune cell activity during the neonatal period Abdallah et al, 2012
  • Low plasma levels of immunoglobulins IgG and IgM Heuer et al, 2012
  • Urinary levels of several amino acids such as glycine, serine, threonine, alanine, histidine, glutamyl amino acids and taurine were significantly lower in ASD children. The levels of antioxidants such as carnosine were also reduced in ASD Ming et al, 2012
  • Activating killer-cell immune globulin-like receptor/HLA complexes are increased whereas inhibitory KIR/HLA complexes are reduced in autistic children; and more significant in their mothers suggesting immune activation Guerini et al, 2013.
  • Higher urinary levels of succinate and glycolate and lower levels of hippurate, 3-hydroxyphenylacetate, vanillylhydracrylate, 3-hydroxyhippurate, 4-hydroxyphenyl-2-hydroxyacetate, 1H-indole-3-acetate, phosphate, palmitate, stearate, and 3-methyladipate Emond et al, 2013.
  • Urinary levels of p-cresol ( a bacterial product derived from tyrosine) reported to be elevated in autistic children Altieri et al, 2011
  • Elevated plasma neopterin levels may be associated with autism severity Zhao et al, 2015

 

Toxins

  • Nickel pollution has been linked to autism Lewandowski et al, 2009
  • Traffic pollution (living near a freeway) has been linked to autism Volk et al, 2010
  • Industrial mercury pollution has been linked to autism Palmer et al, 2009
  • Maternal smoking; male gender; economic problems in the family; condensation on windows, a low ventilation rate in the home; PVC flooring (a source of airborne phthalates) : airway symptoms of wheezing and asthma have been associated with autism risk Larsson et al, 2009
  • The rate of autism is higher for schools near Superfund sites (those earmarked for pollution clean-up) DeSoto, 2009
  • DDT (the pesticide dichlorodiphenyltriichloroethene , has been associated with autism Audouze and Grandjean 2011
  • Organochlorine pesticide applications--specifically dicofol and endosulfan--occurring immediately before and during central nervous system embryogenesis have been associated with the subsequent development of autism spectrum disorders Roberts et al, 2007
  • A Finnish study has noted an association between prenatal exposure to persistent organic pollutants (Polychlorinated biphenyls and Dichlorodiphenyldichloroethylene related ) and autism (combined pollution level rather than any particular pollutant) Cheslack-Postava et al, 2013
  • Polybrominated diphenyl ether-28 or trans-nonachlor levels in maternal blood or urine during pregnancy associated with the subsequent development of autism in children Braun et al, 2014
  • 2,3,7,8-Tetrachlorodibenzo-p-dioxin, a contaminant of agent orange has been associated with autistic traits in Vietnam Nishijo et al, 2014
  • CHARGE study (Childhood Autism Risks from Genetics and the Environment) : Proximity to organophosphates at some point during gestation was associated with a 60% increased risk for autism spectrum disorders, higher for 3rd trimester exposures [Odds ratio (OR) = 2.0, 95% ], and 2nd trimester chlorpyrifos applications: OR = 3.3 Children of mothers residing near pyrethroid insecticide applications just prior to conception or during 3rd trimester were at greater risk for both ASD and developmental delay , with OR’s ranging from 1.7 to 2.3. Risk for developmental delay was increased in those near carbamate applications, but no specific vulnerable period was identified Shelton et al, 2014.
  • Sleeping in clean-room conditions has been reported to improve autism symptoms Faber et al, 2015
  • Higher urinary levels of bisphenol A in autistic children Stein et al, 2015

The microbiome and autism Pubmed

  • Bacteroidetes species exist at high levels in severely autistic children, while Firmicutes were more predominant in the control group. Smaller, but significant, differences also occurred in the Actinobacterium and Proteobacterium phyla. Desulfovibrio species and Bacteroides vulgatus are present in higher numbers in stools of severely autistic children Finegold et al, 2010
  • Children with autism had lower levels of species of Bifidobacter, higher levels of species of Lactobacillus , but similar levels of other bacteria and yeast Adams et al, 2011
  • Lower abundances of Prevotella, Coprococcus, and unclassified Veillonellaceae genera in autistic samples ( carbohydrate-degrading and/or fermenting bacteria) Kang et al, 2013
  • Enzyme-catalyzing reactions involved with glutamate under-represented in the autism microbiome Heberling and Dhurjati, 2015

Autism Maps

An article on the developmental toxicity of industrial chemicals Labie 2007

The National Children's study

Pesticides and disease database including childhood developmental disorders

DEVNERTOX Toxic threats to the developing nervous system: in vivo and in vitro studies on the effects of mixture of neurotoxic substances potentially contaminating food

HAZMAP A Relational Database of Hazardous Chemicals and Occupational Diseases

IVTIP In vitro testing industrial platform

Toxics Release Inventory (TRI) Program : USA environmental protection agency

Dangerous household chemicals

TOXNET - Databases on toxicology, hazardous chemicals, environmental health, and toxic releases.

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