Author: envgencauses

The Environmental and Genetic Causes of Autism

The Environmental and Genetic Causes of Autism

Praise for “Causes”

Chapter 1. Background and Concepts 5

Chapter 2. Symptoms and Diagnosis of Autism 69

Chapter 3. Evidence of Genetic and Epigenetic Risk Components of Autism and Autism Spectrum Disorder 87

Chapter 4. Speech, Language, and Communication Phenotypes in ASD 116

Chapter 5. Genetic and Environmental Factors That Influence Social Cognitive Skills in ASD 134

Chapter 6. Cognitive Phenotypes in ASD 153

Chapter 7. Repetitive Motor Behaviors and Seizure Phenotypes 159

Chapter 8. Sensory Phenotypes and Sensory Processing Disorder 165

Chapter 9. Immunological Factors in Autism and ASD 169

Chapter 10. Gastrointestinal and Renal Phenotypes 192

Chapter 11. Neurotoxin-Induced Autoimmune-Mediated Neurological Damage in Autism 200

Chapter 12. Vaccine-Autism Studies Ignored by the CDC 217

Chapter 13. Concepts of Comorbidity in Autism and Autism Research 230

Chapter 14. Study Designs for Meaningful Future Causal Research in Autism 241

Chapter 15. Biological Pathways and Networks Views of Autism 253

Chapter 16. Toward a Multidimensional Matrix Risk Model for Autism 260

Chapter 17. The Logic of Prevention in Autism and Gene-Informed Treatment 271

Chapter 18. Injecting Objective Association and Causal Inference into Clinical Trials, Prevention, Diagnosis, and Treatment of ASD 292

“Causes” Acronym List

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Chapter 18. Injecting Objective Association and Causal Inference into Clinical Trials, Prevention, Diagnosis and Treatment of ASD

CDC, 2014. Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years — Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2010 Morbid. Mort. Weekly Rprt March 28, 2014. http://www.cdc.gov/mmwr/pdf/ss/ss6302.pdf

Rosman NP et al., 2013. Childhood disintegrative disorder: distinction from autistic disorder and predictors of outcome. J Child Neurol. 28(12):1587-98. doi: 10.1177/0883073812472391.

Tuchman R et al.. 2002. Epilepsy in autism. Lancet Neurol 1: 352–358.

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Chapter 17. The Logic of Prevention in Autism and Gene-Informed Treatment

Ahn Y et al., 2014. The ketogenic diet modifies social and metabolic alterations identified in the prenatal valproic acid model of autism spectrum disorder. Dev Neurosci. 36(5):371-80. doi: 10.1159/000362645.

Amiet C et al., 2014. Are there cultural differences in parental interest in early diagnosis and genetic risk assessment for autism spectrum disorder? Front Pediatr. 2:32. doi: 10.3389/fped.2014.00032.

Auyeung B et al., 2015. Oxytocin increases eye contact during a real-time, naturalistic social interaction in males with and without autism. Transl Psychiatry. 5:e507. doi: 10.1038/tp.2014.146.

Avella-Garcia CB et al., 2016. Acetaminophen use in pregnancy and neurodevelopment: attention function and autism spectrum symptoms. Int J Epidemiol. Jun 28. pii: dyw115.

Barua S 2015. High gestational folic acid supplementation alters expression of imprinted and candidate autism susceptibility genes in a sex-specific manner in mouse offspring. J Mol Neurosci. 58(2):277-86. doi: 10.1007/s12031-015-0673-8.

Bradstreet JJ et al., 2010. Biomarker-guided interventions of clinically relevant conditions associated with autism spectrum disorders and attention deficit hyperactivity disorder. Altern Med Rev. 15(1):15-32.

Brandenburg LO et al., 2010. Sulforaphane suppresses LPS-induced inflammation in primary rat microglia. Inflamm Res. 59(6):443-50. doi: 10.1007/s00011-009-0116-5.

Burrows EL et al., 2015. A neuroligin-3 mutation implicated in autism causes abnormal aggression and increases repetitive behavior in mice. Mol Autism. 14:6:62.

Chen PS, 2006. Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes. Mol Psychiatry. 11(12):1116-25.

Chen PS et al., 2007. Valproic acid and other histone deacetylase inhibitors induce microglial apoptosis and attenuate lipopolysaccharide-induced dopaminergic neurotoxicity. Neuroscience. 149(1):203-12.

Chez MG et al., 2004. Memantine as add-on therapy in pediatric epileptic patients: Effects on cognitive development and seizure frequency. Epilepsia. 45(Suppl. 7):152.

Chez MG et al. 2007. Memantine as adjunctive therapy in children diagnosed with autistic spectrum disorders: an observation of initial clinical response and maintenance tolerability. J Child Neurol. 22(5):574-9.

Dragunow M et al., 2006. Valproic acid induces caspase 3-mediated apoptosis in microglial cells. Neuroscience. 140(4):1149-56.

Erickson CA et al. 2009. Open-label memantine in fragile X syndrome. J Autism Dev Disord. 39(12):1629-35.

Faber S. et al., 2015. b. A cleanroom sleeping environment’s impact on markers of oxidative stress, immune dysregulation, and behavior in children with autism spectrum disorders. BMC Complement Altern Med. 2015; 15: 71. doi: 10.1186/s12906-015-0564-0

Feng J et al., 2016. Clinical improvement following vitamin D3 supplementation in Autism Spectrum Disorder. Nutr Neurosci. 2016 Jan 18. [Epub ahead of print] doi: 10.1080/1028415X.2015.1123847

Frühauf PK et al., 2015. Spermine reverses lipopolysaccharide-induced memory deficit in mice. J Neuroinflammation. 12:3. doi: 10.1186/s12974-014-0220-5.

Frye RE et al., 2010. Tetrahydrobiopterin as a novel therapeutic intervention for autism. Neurotherapeutics. 7(3):241-9. doi: 10.1016/j.nurt.2010.05.004.

Frye RE, Rossignol DA 2014. Treatments for biomedical abnormalities associated with autism spectrum disorder. Front Pediatr. 2:66. doi: 10.3389/fped.2014.00066.

Gozes I. 2015. The cytoskeleton as a drug target for neuroprotection: the case of the autism- mutated ADNP. Biol Chem. pii: /j/bchm.ahead-of-print/hsz-2015-0152/hsz-2015-0152.xml. doi: 10.1515/hsz-2015-0152.

Gozes I et al.,2011. Microtubules, schizophrenia and cognitive behavior: Preclinical development of davunetide (NAP) as a peptide-drug candidate. Peptides. 32:428–431.

Handrigan GR. 2013. Deletions in 16q24.2 are associated with autism spectrum disorder, intellectual disability and congenital renal malformation. J Med Genet. 50(3):163-73. doi: 10.1136/jmedgenet-2012-101288.

Hultman CM et al., 2011. Advancing paternal age and risk of autism: new evidence from a population-based study and a meta-analysis of epidemiological studies. Mol Psychiatry. 16(12):1203-12. doi: 10.1038/mp.2010.121.

Kanne SM et al., 2011. The role of adaptive behavior in autism spectrum disorders: implications for functional outcome. J Autism Dev Disord. 41(8):1007-18. doi: 10.1007/s10803-010-1126-4.

Klaiman C et al., 2013. Tetrahydrobiopterin as a treatment for autism spectrum disorders: a double-blind, placebo-controlled trial. J Child Adolesc Psychopharmacol. 23(5):320-8. doi: 10.1089/cap.2012.0127.

Kloss CU et al., 1997. Proliferation of ramified microglia on an astrocyte monolayer: characterization of stimulatory and inhibitory cytokines. J Neurosci Res. 49(2):248-54.

Lai MC et al., 2014. Autism. Lancet. 383(9920):896-910. doi: 10.1016/S0140-6736(13)61539-1.

Lee JC and JB Tomblin. 2012. Reinforcement learning in young adults with developmental language impairment. Brain Lang. 123(3):154-63. doi: 10.1016/j.bandl.2012.07.009.

May ME et al., 2012. Moderating effects of autism on parent views of genetic screening for aggression. Intellect Dev Disabil. 50(5):415-25. doi: 10.1352/1934-9556-50.5.415.

Napoli E et al., 2014. Potential therapeutic use of the ketogenic diet in autism spectrum disorders. Front Pediatr. 2:69. doi: 10.3389/fped.2014.00069.

Pagan C et al., 2014. The serotonin-N-acetylserotonin-melatonin pathway as a biomarker for autism spectrum disorders. Transl Psychiatry. 4:e479. doi: 10.1038/tp.2014.120.

Rosi S et al., 2006. Memantine protects against LPS-induced neuroinflammation, restores behaviorally-induced gene expression and spatial learning in the rat. Neuroscience 142(4):1303–15. doi:10.1016/j.neuroscience.2006.08.017.

Ruskin DN et al., 2013. Ketogenic diet improves core symptoms of autism in BTBR mice. PLoS One. 8(6):e65021. doi: 10.1371/journal.pone.0065021.

Segura M et al., 2015 Neurotrophin blood-based gene expression and social cognition analysis in patients with autism spectrum disorder. Neurogenetics. 16(2):123-31. doi: 10.1007/s10048-014-0434-9.

Singh K et al., 2014. Sulforaphane treatment of autism spectrum disorder (ASD). Proc Natl Acad Sci U S A. 111(43):15550-5. doi: 10.1073/pnas.1416940111.

Suda S et al., 2013. Valproic acid attenuates ischemia-reperfusion injury in the rat brain through inhibition of oxidative stress and inflammation. Eur J Pharmacol 707(1-3):26-31. doi: 10.1016/j.ejphar.2013.03.020.

Surén P et al., 2013. Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children. JAMA. 309(6):570-7. doi: 10.1001/jama.2012.155925.

Stutzman D and J Dopheide. 2015. Acetylcysteine for treatment of autism spectrum disorder symptoms. Am J Health Syst Pharm. 72(22):1956-9. doi: 10.2146/ajhp150072.

Takesada M et al., 1990. An open clinical study of aprpterin hydrochloride(R-tetrahydrobiopterin, R-THBP) in infantile autism – clinical effects and long-term follow-up. International Symposium on Neurobiology of Infantile Autism; Tokyo, Japan. 1990.

Tsilioni I et al., 2015. Children with autism spectrum disorders, who improved with a luteolin-containing dietary formulation, show reduced serum levels of TNF and IL-6. Transl Psychiatry. 5:e647. doi: 10.1038/tp.2015.142.

Vulih-Shultzman I, et al., 2007. Activity dependent neuroprotective protein snippet NAP reduces tau hyper-phosphorylation and enhances learning in a novel transgenic mouse model. J Pharmacol Exp Ther 323:438–449.

Wei H et al. 2012. The therapeutic effect of memantine through the stimulation of synapse formation and dendritic spine maturation in autism and fragile X syndrome. PLoS One. 7(5):e36981. doi: 10.1371/journal.pone.0036981.

Wu HM et al., 2009. Novel neuroprotective mechanisms of memantine: increase in neurotrophic factor release from astroglia and anti-inflammation by preventing microglial activation. Neuropsychopharmacology. 34(10):2344-57. doi: 10.1038/npp.2009.64.

Xuan A et al., 2012. Neuroprotective effects of valproic acid following transient global ischemia in rats. Life Sci. 90(11-12):463-8. doi: 10.1016/j.lfs.2012.01.001.

Zhang XY et al., 2015. Deferoxamine attenuates lipopolysaccharide-induced neuroinflammation and memory impairment in mice. J Neuroinflammation.;12:20. doi: 10.1186/s12974-015-0238-3.

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Chapter 16. Toward a Multidimensional Matrix Risk Model for Autism

Abraham A, et al., 2008. Minds, persons and space: an fMRI investigation into the relational complexity of higher-order intentionality. Conscious Cogn. 17(2):438-50. doi: 10.1016/j.concog.2008.03.011.

Belgard TG et al., 2014. Population structure confounds autism genetic classifier. Mol Psychiatry. 19(4):405-7. doi: 10.1038/mp.2013.34.

Felleman DJ and Van Essen DC. 1991. Distributed hierarchical processing in the primate cerebral cortex. Cereb Cortex. 1(1):1-47.

Gergely, G. and JS Watson. 1999. Contingency perception and the social-feedback model. in: Philippe Rochat, Ed. Early Social Cognition (Hillsdale, NJ: Erlbaum, 1999).

Kontaris et al., 2009. Dissociation of extrastriate body and biological-motion selective areas by manipulation of visual-motor congruency. Neuropsychologia. 47(14): 3118–3124. doi: 10.1016/j.neuropsychologia.2009.07.012.

Milne E et al., 2009. Independent component analysis reveals atypical electroencephalographic activity during visual perception in individuals with autism. Biol Psychiatry. 65(1):22-30. doi: 10.1016/j.biopsych.2008.07.017.

Mountcastle VB et al., 1997. The columnar organization of the neocortex. Brain. 1120 ( Pt 4):701-22.

Nevison CD. 2014. A comparison of temporal trends in United States autism prevalence to trends in suspected environmental factors. Environ Health. 13:73. doi: 10.1186/1476-069X-13-73.

Okamoto Y et al., 2014. Attenuation of the contingency detection effect in the extrastriate body area in autism spectrum disorder. Neurosci Res. 87:66-76. doi: 10.1016/j.neures.2014.06.012.

Robinson EB et al., 2014. Response to ‘Predicting the diagnosis of autism spectrum disorder using gene pathway analysis’. Mol Psychiatry19(8):859-61. doi: 10.1038/mp.2013.125.

Skafidas E et al., 2014. Response to Belgard et al. Mol Psychiatry. 19(4):407-9. doi: 10.1038/mp.2013.186.

Skafidas E et al., 2014. Predicting the diagnosis of autism spectrum disorder using gene pathway analysis. Mol Psychiatry. 19(4):504-10. doi: 10.1038/mp.2012.126.

Schroeder JC et al., 2015. Genetic animal models for autism spectrum disorder. Curr Top Behav Neurosci. 2015 Nov 25 pp 1-14.

Talkvik I et al., 2015. Clinical Phenotype of De Novo GNAO1 Mutation. Child Neurology, 2:2 doi: 10.1177/2329048X15583717

Theoharides TC et al., 2013. Focal brain inflammation and autism. J Neuroinflammation. 10:46. doi: 10.1186/1742-2094-10-46.

Uddin M et al., 2014. Brain-expressed exons under purifying selection are enriched for de novo mutations in autism spectrum disorder. Nat Genet. 46(7):742-7. doi: 10.1038/ng.2980.

Veenstra-VanderWeele J, Blakely RD, 2012. Networking in autism: leveraging genetic, biomarker and model system findings in the search for new treatments. Neuropsychopharmacology. 37(1):196-212. doi: 10.1038/npp.2011.185.

Weiner et al., 2011. Not one extrastriate body area: Using anatomical landmarks, hMT+ and visual field maps to parcellate limb-selective activations in human lateral occipitotemporal cortex. Neuroimage. 56(4): 2183–2199. doi: 10.1016/j.neuroimage.2011.03.041

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Chapter 14. Study Designs for Meaningful Future Causal Research in Autism

Barr, K. 2015. Vaccine Whistleblower: Exposing Autism Research Fraud in the CDC. Skyhorse Publishing, New York.

Curtis B, et al., 2015. Examination of the safety of pediatric vaccine schedules in a non-human primate model: assessments of neurodevelopment, learning and social behavior. Environ Health Perspect. 123(6):579-89. doi: 10.1289/ehp.1408257.

Fine PE and RT Chen. 1992. Confounding in studies of adverse reactions to vaccines. Am J Epidemiol. 136(2):121-35.

Gadad BS et al., 2015. Administration of Thimerosal-containing vaccines to infant rhesus macaques does not result in autism-like behavior or neuropathology. Proc Natl Acad Sci U S A. 112(40):12498-503. doi: 10.1073/pnas.1500968112.

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Wahlund, S. 1928. Zusammensetzung von Population und Korrelationserscheinung vom Standpunkt der Vererbungslehre aus betrachtet. Hereditas 11:65–106.

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Chapter 13. Concepts of Comorbidity in Autism and Autism Research

Abbeduto, L. et al., 2015. Chapter 8. Neurodevelopmental Disorders, The American Psychiatric Publishing Textbook of Psychiatry (6 ed.). Arlington, VA: American Psychiatric Publishing. ISBN 978-1-58562-444-7.

Amiet C, et al., 2013. Epilepsy in simplex autism pedigrees is much lower than the rate in multiplex autism pedigrees. Biol Psychiatry. 74(3):e3-4. doi: 10.1016/j.biopsych.2013.01.037.

Bilder DA, 2016. Brief Report: the prevalence of Neurofibromatosis Type 1 among children with autism spectrum disorder identified by the autism and developmental disabilities monitoring network. J Autism Dev Disord. 2016 Jul 27.

Bird G, R Cook. 2013. Mixed emotions: the contribution of alexithymia to the emotional symptoms of autism. Transl Psychiatry3:e285. doi: 10.1038/tp.2013.61.

Cook R et al. 2013. Alexithymia, not autism, predicts poor recognition of emotional facial expressions. Psychol Sci. 24(5):723-32. doi: 10.1177/0956797612463582.

Crespi, B et al. 2010. Comparative genomics of autism and schizophrenia. PNAS 107:1736-1741.

Frye RE and DA Rossignol. 2016. Identification and treatment of pathophysiological comorbidities of autism spectrum disorder to achieve optimal outcomes. Clin Med Insights Pediatr. 2016 Jun 15;10:43-56. doi: 10.4137/CMPed.S38337. eCollection 2016.

Griffin C et al., 2015. Alexithymia in children with and without autism spectrum disorders. Autism Res. doi: 10.1002/aur.1569.

La Malfa G et al. 2004. Autism and intellectual disability: a study of prevalence on a sample of the Italian population. J Intellect Disabil Res. 48:262–7.

LaFrance Jr WC et al., 2008. Psychiatric comorbidities in epilepsy. Int Rev Neurobiol. 83:347–83.

Iverson JM and RH Wozniak. 2007. Variation in vocal-motor development in infant siblings of children with autism. J Autism Dev Disord. 37(1):158-70.

Silani, G et al.2007. Levels of emotional awareness and autism: An fMRI study. Social Neuroscience 3:97-112.

Tuchman R et al.. 2002. Epilepsy in autism. Lancet Neurol 1: 352–358.

Wang Q et al., 2015. Pervasive pleiotropy between psychiatric disorders and immune disorders revealed by integrative analysis of multiple GWAS. Hum Genet.134(11-12):1195-209. doi: 10.1007/s00439-015-1596-8.

Zerbo O. 2015. Immune mediated conditions in autism spectrum disorders. Brain Behav Immun. 46:232-6. doi: 10.1016/j.bbi.2015.02.001.

Zerbo O et al. 2016. Maternal mid-pregnancy C-reactive protein and risk of autism spectrum disorders: the early markers for autism study. Transl Psychiatry. 6:e783. doi: 10.1038/tp.2016.46.

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