Autism and Environmental Links

Presented by Laura Lott RNC-NIC, MPH Student at Walden University

PUBH 6165-6Instructor: Dr Robert Marino

Spring Quarter, 2010

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AGENDA

• I. Welcome.

• II. What is Autism?• definitions of autism• prevalence of Autism

• III. Causes of Autism?. Genetics. Environmental Factors. Genetic-Environmental Factors

•

• IV. Genetic Susceptibility, Autoimmune Diseases, Autism and Environmental Triggers

• infectious agents as environmental triggers for autoimmune diseases/autism

. Microbes associated with specific autoimmune disease

. Vaccines associated with autoimmune disorders

. Autoimmune Diseases, Environmental triggers, and Autism.

Are they Linked?

AGENDA• V. Shared Characteristics of

Autoimmune Diseases and Autism

• VI. Autoimmune Diseases, Infectious Triggers and the Hygiene Hypothesis

• VII. Autism, Autoimmune Diseases, Dyslexia, ADHD, Hyperlexia

• are they all connected?• are they all part of a major subgroup on the autism spectrum?

VIII. Summary

. where do we go from here?

Solutions

XI. Questions?

Learning Objectives

By the end of this conference participants will be able to:

• Define, describe and understand autism as part of a spectrum of disorders

• Describe autism spectrum disorders as polygenic and multi-causal• Identify associated environmental triggers• Understand and describe the links between ASD, autoimmune

diseases and environmental triggers• Explain the mechanism of environmental triggers in relation to genetic

susceptibility, autoimmune diseases and autism spectrum disorders.http://www.cdc.gov/ncbddd/autism/index.htmlHertz-Piciotto, J. et al (2006). The Charge Study: An Epidemiologic Investigation of Genetic and Environmental Factors Contributing to Autism, Environmental Health

Perspectives, 114 (7)Comi, A. et al. (1999). Familial Clustering of Autoimmune Disorders and Evaluation of Medical Risk Factors in Autism, Journal of Child Neurology, 14:388Atladottir, HO., et al (2009). Association of Family History of Autoimmune Diseases and Autism Spectrum Disorders, Pediatrics, 124(2), 687-694Molina, V. & Schoenfeld, Y. (2005). Infection, Vaccines and Other Environmental Triggers of Autoimmunity, Autoimmunity, 38(3), 235-245

What is Autism?

• Definition under the year 2000 statistical manual of mental disorders (DSM): Autism is one of five disorders under the category of Pervasive Developmental Disorders (PDD).

• Pervasive Developmental Disorders are also known as Autism Spectrum Disorders or ASD. The CDC (2009) defines ASD as a group of developmental disabilities that can cause significant social, communication, and behavioral challenges.

http://www.cdc.gov/ncbddd/autism/index.html

Prevalence of Autism Spectrum Disorders

According to the CDC (2009):. the current prevalence of ASD in the US averages 1 in 110 children.. Between 2002-2006 there was an average increase in prevalence of 57% across 10 surveillance sites through the Autism and Developmental Disabilities Monitoring (ADDM) Network.

http://www.cdc.gov/ncbddd/autism/addm.html http://www.cdc.gov/mmwr/preview/mmwrhtml/ss58101l.htm

Causes of Autism Spectrum Disorders?

• A. Genetic Cause

• B. Environmental Cause

• C. Genetic-Environmental Cause

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A. Genetics

• Strong Familial Tendency – if one sibling has an ASD there is a 10-20 fold increased risk of other siblings also having the disorder (Hertz-Picciotto, I., et al. 2006).

• Autism is associated with several distinct genetic syndromes such as:

Angelman Syndrome; tuberous sclerosis; phenylketonuria; Joubert Syndrome; Mobius Syndrome and chromosomal abnormalities such as Fragile X (Hertz-Picciotto, I., et al. 2006)

Hertz-Piciotto, I., et al (2006) The Charge Study: An Epidemiologic Investigation of Genetic and Environmental Factors Contributing to Autism, Environmental Health Perspectives, 114(7)

http://media-2.web.britannica.com/eb-media/46/59346-004-9EC58E43.jpg

• Genetics alone cannot explain the increased prevalence in autism spectrum disorders

• Although autism is associated with several known genetic disorders, the majority of autism cases (90%) are not linked to them.

• No single gene has been identified with autism

• Most likely polygenic involvement• A minimum of 40% of autism cases likely

associated with environmental causesHertz-Picciotto,I. et al (2006) The charge Study: An Epidemiologic Investigation of Genetic and Environmental Factors Contributing to Autism, Environmental Health Perspectives, 114(7)

B. Environmental Causes

• Chemical Exposures

Chemicals known to be associated with development of autism include: Thalidomide; Valproic Acid; and Lead Poisoning.

Other environmental chemicals are known to produce autism-like behaviors in animal studies including Trimethyl tin (TMT) and organomercurials such as methylmercury, both of which can cause limbic damage in susceptible animal models (Lathe, R. 2008)

Lathe,R. (2008) Environmental Factors and Limbic vulnerability in Childhood Autism, American Journal of Biochemistry and Biotechnology

• GABR Blockers• Chlorinated hydrocarbon insecticides (including: heptachlor,

chlordane, dieldrin and toxaphene). Use in the US was discontinued between 1987-1990 however, these chemicals are persistent in the environment and human tissues.

• Several uses of Lindane continue for example in the control of head lice and scabies.

• New class of GABR antagonists are in use for domestic and agricultural applications.

• 30-35% of children with autism have seizures. An altered GABAA receptor (GABR) system is found fairly frequently in people with autism and this has been proposed as a major underlying cause of seizure susceptibility. Do children with GABR deficiencies have a heightened susceptibility to adverse responses when exposed to environmental GABR blockers?

Pessah,I. (2006) Can Exposure to Environmental Toxicants Influence Autism Susceptibility?, Autism Society of America

Bioaccumulation of Environmental Chemicals

• Example: Methyl-mercury

http://health.state.tn.us/images/mercury3.jpg

Maternal Environmental Exposures

• 1. Infectious agents:

Rubella, CMV, Herpes, Measles and Mumps (Hertz-Picciotto, I. 2006)

• 2. Maternal Risk Factors

Advanced Maternal age and cumulative effect of environmental toxins

. 3. Air Pollutants

• 4. Obstetric Complications Breech, traumatic delivery, low 5 min apgar score, low birth weight, RDS, rhesus incompatibility, c-section, resuscitation, severe fetal/ neonatal infection, pre-eclampsia, pre-term delivery

5. Assistive Reproductive Technology

6. Chronic Diseases in Mother Hypertension, IDDM, Auto immune disorders

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C. Genetic-Environmental Causes

• Genetic Susceptibility • Environmental Triggers

• Heavy metal exposure/bioaccumulation

• Air pollution

• Infections

• vaccines

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Genetic Susceptibility, Autoimmune Diseases, Autism and

Environmental Triggers

• Environmental Triggers:

• 1. Infections

• 2. Vaccines

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Infections as Environmental Triggers for Autoimmune

Disorders/Autism• Infectious Triggers include bacteria, viruses,

and parasites

• How? Mainly by molecular mimicry

• Genetic susceptibility triggered by microbial antigens can lead to development of autoimmune diseases.

Molina,V., & Shoenfeld, Y. (2005) Infection, vaccines and other environmental triggers of autoimmunity, Autoimmunity, 38(3), 235-245

Molecular Mimicry

http://www.bcm.edu/.../images/ms-infect1(345x530).jpg

Examples of microbes associated with specific autoimmune disorders• Epstein Barr Virus – Multiple Sclerosis• Human Parvovirus B19 – Rheumatoid Arthritis

and Lupus (SLE)• Measles and Mumps infection after age 15yrs

associated with MS• Campylobacter jejuni associated with Gullian

Barre Syndrome (GBS)• Streptococcal Infections associated with

PANDAS (pediatric autoimmune neuropsychiatric disorders)

Molina,v. & Shoenfeld, Y (2005) Infection, vaccines and other environmental triggers of autoimmunity, Autoimmunity, 38(3) 235-245

Vaccines as Environmental Triggers of Autoimmune Disorders

• Examples of vaccines associated with autoimmune diseases

• Diphtheria and Tetanus toxoid, polio and measles vaccines – GBS

• MMR vaccines – Thrombocytopenia (ITP) and IBD• Rubella vaccine – acute and chronic arthritis in adult

women• Hepatitis B Vaccine – has been connected with MS• Flu vaccine – associated with GBS• Measles Vaccine – most commonly associated with

Autism

Three major neurological autoimmune disorders have been addressed in association with vaccination:GBS, MS and Autism

Molina, V., & Shoenfeld, Y. (2005) Infection, vaccines and other environmental triggers of autoimmunity, Autoimmunity, 38(3), 235-245

How Do Vaccines Trigger Autoimmune Diseases?

• Two Types of Vaccines: Active (live microbe) and Passive (inactivated).

• It has been proposed that the same mechanism that triggers autoimmune diseases by microbes also occurs in genetically susceptible people through vaccinations

• Much debate has focused on thimerosal in childhood vaccines prior to 1999 causing a cumulative exposure to ethylmercury and being a possible trigger for autism.

• However, the prevalence of autism continues to grow despite the removal of thimerosal from childhood vaccines suggesting that this is not a trigger.

Molina,V., & Shoenfeld,Y. (2005) Infection, vaccines and other environmental triggers of autoimmunity, Autoimmunity, 38(3), 235-345Schecter,R. & Grether, J. (2008) Continuing Increases in Autism Reported to California’s Developmental Services System, Arch Gen Psychiatry, 65(1), 19-24

Autoimmune Diseases, Environmental Triggers and

Autism: Are they linked?

• A study by Comi,A., et al (1999) reports an increased incidence of autoimmune diseases in mothers and first-degree relatives of children with autism.

• The most common autoimmune disorders associated with autism were Type I diabetes, Rheumatoid Arthritis, Hypothyroidism, and Systemic Lupus Erythematosus (SLE).

Comi,A., et al (1999) Familial Clustering of Autoimmune Disorders and Evaluation of Medical Risk Factors in Autism, Journal of Child Neurology, 14; 388

Shared Characteristics of Autoimmune Disorders and Autism

• Familial Predisposition

• Associated Immune Abnormalities

• A relationship with viruses (or other environmental triggers)

• A sex preponderance

Autism ratio of boys to girls is

about 4:1

Autoimmune Disorders ratio is about 3:1 with women affected more than men.

incidence and prevalence of autism and auto immune disorders is increasing.

The world wide prevalence of rheumatoid arthritis is estimated to be about 1-2% with auto-immune disorders affecting about 8% of the US population Fairweather, D. & Rose, NR (2004). Approximately 1% of children in the US are affected by autism spectrum disorders (CDC, 2006).

Fai

Fairweather, D. & Rose, NR (2004) Women and autoimmune diseases, Emerging Infectious Disease, available from http://www.cdc.gov/ncidod/EID/vol10no11/04-0367.htmCDC (2006) ADDM, MMWR Surveillance Summary, 58 (SS-10)

Increased Incidence and Prevalence of ASD

• Changes in Prevalence of ASDs Among

• Children 8 yrs old, 2002-2006

• New Cases ASD per 10,000 child-years

CDC (2006) New Autism Data available from http://www.cdc.gov/mmwr/preview/mmwrhtml/225810a1.htm http://www.environmentalhealthnews.org/ehs/images/2009/january/2009-0109autism.png

Autoimmune Diseases, Infectious Triggers and the Hygiene

Hypothesis• Autoimmune diseases can be triggered by infectious

agents and vaccines as already discussed.

• In addition to vaccines can autoimmune diseases also be triggered by other environmental agents such as antibiotics and antiseptic cleaning agents?

• The Hygiene Hypothesis proposes autoimmune disorders can also be triggered by the above agents and are also contributing to increases in asthma and allergies.

Moore, E. (2007) Infection and Autoimmune Disease, General Medicine available from http://autoimmunedisease.suite101.com/article.cfm/infection_and_autoimmune_disease

Antibiotic Use, Autism and Autoimmune Diseases

• Under the Hygiene Hypothesis is the use of antibiotics contributing to the increase in autism spectrum disorders, autoimmune disorders, and other chronic diseases such as asthma and allergies?

• In addition to the above connection, is it possible that antibiotics have led to an increase in these disorders because they contributed to the survival of infants and children with immune system dysfunctions who would not have survived infancy or childhood prior to their use?

Association Between Autoimmune Diseases and Autism Confirmed

• A recent study by Atladottir, HO, et al (2009) confirms an association between autism and autoimmune disorders.

• Associations between Type I Diabetes and Infantile Autism

• Associations between Rheumatoid Arthritis and ASD

• Association between maternal Celiac Disease and ASD

Atladottir, HO., et al (2009) Association of Family History of Autoimmune Diseases and Autism Spectrum Disorders, Pediatrics, 124(2), 687-694

How Big is the Public Health Crisis if Autoimmune diseases and Autism Spectrum Disorders are linked?

• How to identify and develop prevention measures for autoimmune diseases and ASD.

• Identification of genetic biomarkers in

women?

Autism, Dyslexia, ADHD, Hyperlexia, Autoimmune Diseases.

• Currently we know the causes of less than 25% of all neuro-developmental disabilities, including dyslexia, ADHD, and Autism. (Weiss, B., & Landrigan, P. 2000).

• Are they all linked?

• Are they just different expressions of a common genetic predisposition, and triggered by environmental factors?

• Can an autoimmune disease or a genetic susceptibility to an autoimmune disease in a mother be manifested as autism in a son? Is the gene located on the X chromosome? Is this a distinct subgroup within the autism spectrum? Growing evidence would suggest the answer is yes. Are Dyslexia and ADHD a lesser expression of the same disorder within this subgroup?

Comi,A. et al (1999) Familial Clustering of Autoimmune Disorders and Evaluation of Medical Risk Factors in Autism, Journal of Child Psychology, 14, 388-394

Weiss,B. & Landrigan, P. (2000) The Developing Brain and the Environment: An Introduction, Environmental Health Perspectives, 108(3)

Summary of Causes of Autism

• 1. Approximately 10% of all cases of autism are associated with known genetic syndromes.

• 2. Some cases of autism have been linked to adverse birth outcomes such as pre-term delivery

• 3. A minimum of 40% of all cases of autism are thought to be linked to environmental exposures

• 4. Autism has been linked with autoimmune disorders and mounting evidence suggests a genetic predisposition with environmental triggers.

Hertz-Picciotto,I et al (2006) The CHARGE Study: An Epidemiologic Investigation of Genetic and Environmental Factors Contributing to Autism, Environmental HealthPerspectives, 114(7)

Where to Go From Here?

• Autism is likely polygenic and multi-causal. There is a need to separate and distinguish between the different causes.

• Are there other distinct genetic syndromes within the Autism Spectrum that have not yet been classified?

• Autoimmune Diseases, environmental triggers, and autism. Finding the common link.

• Environmental Causes? Viruses, Bacteria and What Else?

Hertz-Picciotto, I. et al (2006) The CHARGE Study: An Epidemiologic Investigation of Genetic and Environmental Factors Contributing to Autism, Environmental HealthPerspectives, 114(7)

Solutions?

Separate out distinct sub-groups of populations on the autism spectrum

a. specific genetic syndromes b. maternal risk factors/preterm birth c. environmental exposures d. autoimmune diseases and environmental triggers – identify specific genetic biomarkers

Atladottir, HO., et al. (2009). Association of Familial History of Autoimmune Diseases and Autism Spectrum Disorders, Pediatrics, 124(2), 687-694Comi, AM., et al. (1999). Familial clustering of Autoimmune Disorders and Evaluation of Medical Risk Factors in Autism, Journal of Child Neurology, 14(388)Fairweather, D. & Rose, NR.(2004). Women and Autoimmune Diseases, Emerging Infectious Diseases, 10(11)Hertz-Picciotto, I., et al. (2006). The Charge Study: An Epidemiologic Investigation of Genetic and Environmental Factors Contributing to Autism, Environmental HealthPerspectives, 114(7)Lathe, R. (2008). Environmental Factors and Limbic Vulnerability in Childhood Autism, American Journal of Biochemistry and Biotechnology, 4(2), 183-197March of Dimes. (2010). Preterm Birth, available from http://www.marchofdimes.orgMolina, V. & Schoenfeld, Y. (2005). Infection, Vaccines, and Other Environmental Triggers of Autoimmunity, Autoimmunity, 38(3), 235-245

QUESTIONS?

References• Atladottir, HO., Et al. (2009). Association of Family History of Autoimmune Diseases and Autism Spectrum Disorders,

Pediatrics, 124(2), 687-694• Buchmayer, S., et al (2009). Can Association Between Preterm Birth and Autism be Explained by Maternal or

Neonatal Morbidity? Pediatrics, 124(5), e817-e825• CDC (2009.) Prevalence of the Autism Spectrum Disorders (ASDs) in Multiple Areas of the United States, 2004 and

2006, MMWR Surveillance Summary, 58(SS-10_• Comi, AM., et al. (1999). Familial Clustering of Autoimmune Disorders and Evaluation of Medical Risk Factors in

Autism, Journal Child Neurology, 14(388)• Fairweather, D. & Rose, NR. (2004). Women and Autoimmune Diseases, Emerging Infectious Diseases, 10(11)• Hertz-Picciotto, I., et al. (2006). The CHARGE Study: An Epidemiolgic Investigation of Genetic and Environmental

Factors Contributing to Autism, Environmental Health Perspectives, 114(7)• Hughes, D. (2007) Increased Autism Risk May Be Linked to Assisted Reproductive Technology, Neuropsychiatry,

8(12)• Juul-Dam, N., Townsend, J., & Courchesne, E. (2001). Prenatal, Perinatal, and Neonatal Factors in Autism,

Pervasive Developmental Disorder-Not Otherwise Specified, and the General Population, Pediatrics, 107(4), e63• Lathe, R. (2008). Environmental Factors and Limbic Vulnerability in Childhood Autism, American Journal of

Biochemistry and Biotechnology, 4(2), 183-197• March of Dimes (2010) Preterm Birth, available from http://www.marchofdimes.org• Molina, V. & Shoenfeld, Y. (2005). Infection, vaccines and other environmental triggers of autoimmunity,

Autoimmunity, 38(3), 235-245• Moore, E. (2007). Infection and Autoimmune Disease, General Medicine• Paoloni-Giacobino, A. & Chaillet, JR. (2004) Genomic Imprinting and assisted reproduction, Reproductive Health,

1(6)• Schechter, R. & Grether, J. (2008). Continuing Increases in Autism Reported to California’s Developmental Services

System, Arch Gen Psychiatry, 65(1)• Pessah, IN. (2006). Can Exposure to Environmental Toxicants Influence Autism Susceptibility? Autism Society of

America• Weiss, B. & Landrigan, P. (2000). The Developing Brain and the Environment: An Introduction, Environmental Health

Perspectives, 108(3)• Windham, G. et al. (2006). Autism Spectrum Disorders in Relation to Distribution of Hazardous Air Pollutants in the

San Francisco Bay Area, Environmental Health Perspectives, 114(9)• Wu, J. et al. (2009) Association between Local Traffic-Generated Air Pollution and Preeclampsia and Preterm

Delivery in the South Coast Air Basin of California, Environmental Health Perspectives, 117(11), 1773-1779

Resources/Further Reading• Autism Society of America. www.autism-society.org• Blaxill, M. (2004). What’s Going On? The Question of Time Trends in Autism, Public Health Reports, 119• CDC (2010). Facts About ADS, available from http://www.cdc.gov/ncbddd/autism/facts.html• Folstein, S. & Mankoski, R. (2000). Chromosome 7q: where Autism Meets Language Disorder? American Journal

of Human Genetics, 67, 278-281• Garvey, M., Giedd, J. & Swedo, S. (1998). PANDAS: The Search for Environmental Triggers of Pediatric

Neuropsychiatric Disorders. Lessons From Rheumatic Fever, Journal Child Neurology, 13, 413-423• Healy, J. & Aram, D. (1986). Hyperlexia and Dyslexia: A family study, Annals of Dyslexia, 36(1), 237-252• Herbert, MR. et al. (2006). Autism and Environmental Genomics, Neurotoxicology, 27, 671-684• Kinney, DK, et al. (2010). Environmental risk factors for autism: do they help cause de novo genetic mutations

that contribute to the disorder? Medical Hypotheses, 74, 102-106• Maimburg, RD. & Vaeth, M. (2006). Perinatal Risk Factors and infantile autism, Acta Psychiatr Scand 114, 257-

264• Morse, SM, et al. (2009). Early School Age Outcomes of Late Preterm Infants, Pediatrics, 123(4), e622-e629• O’Connor, S. et al. (2004). Infectious Etiologies of Chronic Diseases: Focus on Women, Emerging Infectious

Diseases, 10(11)• Petrini, J. et al. (2009). Increased Risk of Adverse Neurological Development for Late Preterm Infants, The

Journal of Pediatrics, 154(2), 169-176.e3• Schettler, T. (2004). Autism: Do Environmental Factors Play a Role in Causation? Science and Environmental

Health Network• Stone, J. et al. (2004). Evidence for Sex-Specific Risk Allelles in Autism Spectrum Disorder, American Society of

Human Genetics, 75(6), 1117-1123• Szpir, M. (2006). Tracing the Origins of Autism, Environmental Health Perspectives, 114(7)