Etiology of Autism

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Etiology of Autism

• Institute of Medicine
• Immunization Safety Review Committee
• National Academy of Sciences
• Washington, D.C.
• March 8, 2001

Marie Bristol-Power, Ph.D., NICHD/NIH
NAS/IOM March 8, 2001
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Marie Bristol-Power, Ph.D.

• Special Assistant for Autism
• Office of the Director
• National Institute for Child Health Human
  Development (NICHD)
• The National Institutes of Health (NIH)

Marie Bristol-Power, Ph.D., NICHD/NIH
NAS/IOM March 8, 2001
3
No Single Cause No Single Cure

• Genetic
• Infectious
• Neurologic
• Metabolic
• Immunologic
• Environmental

Marie Bristol-Power, Ph.D., NICHD/NIH
NAS/IOM March 8, 2001
4
Etiological Hypotheses

• No single cause no single cure
• Early onset autism vs regressive autism
• Regression in other disorders
• Retts syndrome
• Glutaric Aciduria

Marie Bristol-Power, Ph.D., NICHD/NIH
NAS/IOM March 8, 2001
5
Some Possible Mechanisms for Immune Developmental
Disorders

• Inadequate protection against viral or other
  pathogens results in fetal/child infection
• Maternal immune defect results in inadequate
  protection or autoimmune attack of developing
  fetal brain
• Pre or postnatal genetic immune defect in child
  plus antigenic trigger result in autoimmune
  attack of brain

Marie Bristol-Power, Ph.D., NICHD/NIH
NAS/IOM March 8, 2001
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Immune findings in autismWarren et al.

• C4B null allele
• 25/50 subjects vs. 17/85 controls
• Extended HLA haplotype B44-S30-DR4
• 14/50 subjects vs. 2/85 controls
• HVR-3 sequence 1
• 17/50 subjects vs. 2/85 controls

Marie Bristol-Power, Ph.D., NICHD/NIH
NAS/IOM March 8, 2001
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Limitations in Immune Hypotheses of Autism

• No autopsy studies of brains from individuals
  with autism have demonstrated immune pathology
• Comparison across studies difficult autism
  assessment, control groups, and immune measures
  vary across studies

Marie Bristol-Power, Ph.D., NICHD/NIH
NAS/IOM March 8, 2001
8
Limitations in Immune Hypotheses of Autism

• No immune mechanism has been elaborated to
  explain how immune defects alter brain anatomy or
  physiology in a specific pathway that results in
  autism
• There is no immune animal model for autism
• Treatment studies do not support clinical use of
  IVIG

Marie Bristol-Power, Ph.D., NICHD/NIH
NAS/IOM March 8, 2001
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NICHD/NIDCD

• Network on the Neurobiology and Genetics of
  Autism
• Collaborative Programs of Excellence in Autism
  (CPEAs)

Marie Bristol-Power, Ph.D., NICHD/NIH
NAS/IOM March 8, 2001
10
CPEA Network

• 10 multidisciplinary programs
• Each a unique research program
• All study etiology, brain structure /or
  function, developmental course of autism
• Collaborate on studies that no single project can
  carry out alone
• Common diagnostic core measures

Marie Bristol-Power, Ph.D., NICHD/NIH
NAS/IOM March 8, 2001
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U. of Chicago Volkmar/Lord/Smalley
U. of Washington CPEA Dawson
U. of Rochester CPEA Rodier
Albert Einstein College of Medicine
CPEA Dunn/Rapin
E. Kennedy Shriver Ctr. NIDCD/CPEA Tager-Flusberg/
Folstein
Utah State McMahon
MGH/Harvard Tager-Flusberg/Folstein
U. of Utah CPEA McMahon
Brigham Young U. McMahon
Yale Child Study Ctr. CPEA Vokmar/Lord/Smalley
Johns Hopkins Rogers/Pennington
UCLA CPEA Sigman
U. of Pittsburgh/Carnegie Mellon
CPEA Minshew/Carpenter
UCLA Volkmar/Lord/Smalley
Case-Western Reserve U. Minshew/Carpenter
U.C. Irvine CPEA Spence/Filipek
U. of Colorado Health Sciences Ctr. U. of
Denver Rogers/Pennington
CPEA Main Site - Principal Investigator
CPEA Subcontract Site
Marie Bristol-Power, Ph.D., NICHD/NIH
NAS/IOM March 8, 2001
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Some CPEA Research Findings

• Genetic hotspots in autism (with international
  consortium), esp. Ch.7
• Hox A1 gene
• Chromosome 15

Marie Bristol-Power, Ph.D., NICHD/NIH
NAS/IOM March 8, 2001
13
Some CPEA findings

• Evidence of autism behaviors by 8 - 12
  mos
• Also evidence of subgroup with later regression
  after normal development
• Functional brain differences in processing social
  and auditory info
• Immune indicators, possible immune assay found in
  autism
• Differences in head circumference, children and
  adults

Marie Bristol-Power, Ph.D., NICHD/NIH
NAS/IOM March 8, 2001
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CPEA Autism Regression/ Vaccination Study

• Co-funded by Centers for Disease Control in
  Atlanta, National Immunization Program
• Assess temporal association between MMR
  vaccination and onset of autism (early onset vs
  regressive)
• Replicate studies of persistent measles infection
  in autism cases vs healthy controls

Marie Bristol-Power, Ph.D., NICHD/NIH
NAS/IOM March 8, 2001
15
CPEA Autism Regression/ Vaccination Study - Stage1

• 1600 well-diagnosed cases of autism
• 1250 healthy controls
• individual vaccination records
• records of onset of autism - ADI-R
• age of onset
• age of recognition
• age of diagnosis

Marie Bristol-Power, Ph.D., NICHD/NIH
NAS/IOM March 8, 2001
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CPEA Autism Regression/ Vaccination Study - Stage2

• Replicate findings re abnormal measles antibody
  titers and persistent measles infection

Marie Bristol-Power, Ph.D., NICHD/NIH
NAS/IOM March 8, 2001
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• 250 early onset autism cases
• 250 regressive autism cases
• 250 healthy controls matched to early onset
• 250 healthy controls matched to regressive cases

Marie Bristol-Power, Ph.D., NICHD/NIH
NAS/IOM March 8, 2001
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CPEA Autism Regression/ Vaccination Study

• http//www.nichd.nih.gov/autism/

Marie Bristol-Power, Ph.D., NICHD/NIH
NAS/IOM March 8, 2001
19
The Longitudinal Cohort Study of Environmental
Effects on Child Health and Development

• NICHD/NIH
• CDC
• EPA
• Other agencies

Marie Bristol-Power, Ph.D., NICHD/NIH
NAS/IOM March 8, 2001
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Children -- Increased Vulnerability to
Environmental Exposures

• Critical windows of vulnerability during
  development
• Children have immature mechanisms for
  detoxification
• Differences in metabolism and behavior may yield
  higher exposure in the same environment

Marie Bristol-Power, Ph.D., NICHD/NIH
NAS/IOM March 8, 2001
21
Children -- Increased Vulnerability to
Environmental Exposures

• Critical windows of vulnerability during
  development
• Children have immature mechanisms for
  detoxification
• Differences in metabolism and behavior may yield
  higher exposure in the same environment

Marie Bristol-Power, Ph.D., NICHD/NIH
NAS/IOM March 8, 2001
22
Why a longitudinal study?

• Links between many exposures and childrens
  health not adequately investigated (especially
  mixtures)
• Infers causality
• Life-stage effort
• Timing of exposures
• Timing of outcome
• Typical studies limited in size scope
• National resource for other studies

Marie Bristol-Power, Ph.D., NICHD/NIH
NAS/IOM March 8, 2001
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Aims

• Do environmental agents affect the health and
  development of children?
• How do environmental agents (timing, mixtures,
  interactions) affect childrens health and
  development?
• Are certain conditions exacerbated by
  environmental exposures?

Marie Bristol-Power, Ph.D., NICHD/NIH
NAS/IOM March 8, 2001
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Longitudinal Cohort Study

• http//www.nichd.nih.gov/despr/cohort/

Marie Bristol-Power, Ph.D., NICHD/NIH
NAS/IOM March 8, 2001