Beyond the Vaccine Controversy: How Do We Know What Autism IS NOT if We Do Not Know What Autism IS

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Beyond the Vaccine Controversy How Do We Know
What Autism IS NOT if WeDo Not Know What Autism
IS?

• Presented 5/2009 to CDC Maine
• By Jon S. Poling MD PhD
• Clinical Assistant Professor, Department of
  Neurology, Medical College of Georgia
• Managing Partner, Athens Neurological Associates

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Rosemary Poling April 2, 1925 to April 28, 2009
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Beyond the Vaccine Controversy

• On Anti-science
• How to Approach the Open Scientific Questions
• The Mito Piece of the Autism Puzzle
• Future Directions

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The MisdirectionOffit in NEJM 2008

• Vaccines and Autism Revisited The Hannah Poling
  Case Paul A. Offit, M.D.
• Jon Poling said that "the results in this case
  may well signify a landmark decision with
  children developing autism following
  vaccinations.
• Offit PA. Vaccines and autism revisited--the
  Hannah Poling case. N Engl J Med
  20083582089-91.

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The True Transcript

• The transcript reads, "Many in the autism
  community and their champions believe that the
  result in this case may well signify a landmark
  decision as it pertains to children developing
  autism following vaccinations. This still remains
  to be seen, but currently there are almost 5,000
  other cases pending."

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Letter to Paul Offit

• A strong, safe vaccination program is a
  cornerstone of public health. Misrepresenting
  Hannah Poling v. HHS to the medical profession
  does not improve confidence in the immunization
  program or advance science toward an
  understanding of how and why regressive
  encephalopathy with autistic features follows
  vaccination in susceptible children.
• Poling, Jon S., Vaccines and Autism Revisited N
  Engl J Med 2008 359 655-656

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The Retort

• Offit writes, Poling implies that by omitting
  his phrase many in the autism community and
  their champions, I unfairly attributed the
  notion that vaccines might cause autism to him
  alone. However, Dr. Poling's public announcement
  of the DHHS concession to the press and his
  subsequent appearances on national television and
  at autism conferences suggest that he is, at the
  very least, a vocal centerpiece of that
  community.

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Proper Approach to Autism Etiopathogenesis
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Step 1 What is Autism(s)?

• Classical School
• Genetic Disorder
• CNS
• Developmental/
• Preprogrammed
• Static Encephalopathy
• Disorganized Neural Network and Plasticity

• New Paradigm
• GeneEnvironment
• Systemic
• Neuroinflammatory/
• Metabolic
• Dynamic Encephalopathy
• Disorganized Neural Network and Plasticity

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Step 2 Define Endophenotypes and Develop
Biomarkers

• Mitochondrial myopathy/biochemical
• Glutathione/Oxidative Status
• Immune system biomarkers
• Impairments in Detoxification pathways
• Maternal-Fetal Antibodies
• Genetic Markers for subtypes

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Step 3 Design Properly Powered Epidemiology

• IOM 2004 Determining a specific cause (for
  autism) in the individual is impossible unless
  the etiology is known and there is a biological
  marker. Determining causality with
  population-based methods requires either a
  well-defined at-risk population or a large effect
  in the general population.
• Clarify which autism subpopulation is under
  investigation
• Estimate Effect Size and Power of your study so
  as to avoid Type II error (ie False Negative
  Result)

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Several Large Population Based Studies Support
No Link Between Vaccines and Autism

• The Science Shows

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Offit on Autism Epidemiology

• (S)cientists have not been afraid to test the
  hypothesis that vaccines might cause autism. Far
  from it the ill-founded notion that the
  measlesmumpsrubella (MMR) vaccine caused autism
  was tested in 10 epidemiologic studies.
  Unfortunately, the public airing of that
  hypothesis caused thousands of parents to avoid
  the MMR many children were hospitalized and
  several died from measles as a result.1,2,3,4
  Now, Poling and Healy are standard-bearers for
  the poorly conceived hypothesis that children
  receive too many vaccines too early. As a
  consequence, some parents are choosing to delay,
  withhold, or separate vaccines. The problem here
  is not a failure of scientists to consider
  hypotheses rather, it is a failure of the media
  and the public to distinguish hypotheses from
  scientific evidence.
• Offit PA. Vaccines and autism revisited. N Engl J
  Med 2008359 August 2008

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The Open Question of a Vaccine-Autism
Connection How Open ?
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Danish MMR Study

• Madsen et al. (NEJM, 2002) (Danish)
• Largest Study (2,129,864 person-years)
• 440,655 Vaccinated with MMR
• 96,648 Not vaccinated with MMR
• No Significant Difference in Autism Rates between
  the two groups
• Overall prevalence was about 11273 and
  1728(Note lower than current estimates)

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Since There is No Significant Difference in the
Autism Rate Between the Vaccinated and
Unvaccinated GroupsCan We Conclude That The
Rate is the Same in The Vaccinated and
Unvaccinated Groups? NO
Madsen et al. Study Conclusions
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Power Analysis/Madsen
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Statistical Leaps of Faith

• Select condition with poor case definition
  (i.e. a syndromic diagnosis like Autism).
• Make no attempt to calculate power of study
  (probability of Type II error) or effect size.
• Add in or neglect confounding variables.
• Choose population with lower disease prevalence
  to further reduce statistical power.
• Permit other scientists not involved in the study
  to spin the scientific conclusion that no link
  was found into the pseudoscientific statement
  good studies show that no link exists.

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Autism Epidemiology Faith Science

• Formerly, when religion was strong and science
  weak, men mistook magic for medicine now, when
  science is strong and religion weak, men mistake
  medicine for magic.
• Thomas Szasz, The Second Sin (1973) "Science and
  Scientism

Positive studies Scientific facts are always
stated with a healthy dose of faith
vs. Negative studies Absence of Evidence
is not evidence of absence
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Epidemiology To Date

• 2004 Institute of Medicine executive summary
  report regarding Autism and vaccines
  Determining a specific cause (for autism) in the
  individual is impossible unless the etiology is
  known and there is a biological marker.
  Determining causality with population-based
  methods requires either a well-defined at-risk
  population or a large effect in the general
  population.

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The solution to pollution is adequate dilution
anonymous
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Autism Mitochondrial Dysfunction
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Is this an important subgroup or are we nibbling
at the edges?
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New Or Redux?

• Dr. Mary Coleman, Georgetown U 1985
• 4 of 80 (5) of patients with lactic acidemia
• 1 of 4 pts with regression
• Propose primary defect in carbohydrate
  metabolism, pyruvate dehydrogenase
• Speculate that Ketogenic diet may be helpful

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Mitochondrial Dysfunction emerging as most common
medical condition associated with autism.

• Of 159 autism patients in one autism clinic, 38
  had non-specific biochemical abnormalities.
  Poling et al. Developmental regression and
  mitochondrial dysfunction in a child with autism.
  J Child Neurol, 2006. 21(2) p. 170-2.
• 7.2 of patients with Autism could be classified
  as having a definite mitochondrial respiratory
  chain disorder and 20 had elevated serum lactic
  acid Oliveira, G., et al., Mitochondrial
  dysfunction in autism spectrum disorders a
  population-based study. Dev Med Child Neurol,
  2005. 47(3) p. 185-9.
• 2nd study 4 Oliveira, G., et al., Epidemiology
  of autism spectrum disorder in Portugal
  prevalence, clinical characterization, and
  medical conditions. Dev Med Child Neurol, 2007.
  49(10) p. 726-33.

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Mitochondrial Dysfunction emerging as most common
medical condition associated with autism 2

• 36 of 100 autism patients have total carnitine
  levels 1SD below mean control, pattern suggestive
  mild mitochondrial dysfunction. Filipek, P.A., et
  al., Relative carnitine deficiency in autism. J
  Autism Dev Disord, 2004. 34(6) p. 615-23.
• 65 of autism pts referred for mitochondrial
  evaluation to specialty clinic positive for
  OxPhos disorder on muscle biopsy. Shoffner, J.,
  L.C. Hyams, and G.N. Langley, Oxidative
  Phosphorylation (OXPHOS) Defects in Children with
  Autistic Spectrum Disorders, in AAN. 2008
  Chicago.

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Can Autism Be A Manifestation of Mitochondrial
Encephalopathy? Clinical Evidence

• 3 systems involved, fluctuating symptoms,
  intolerance to fasting/dietary changes
• Nervous system, muscle, gut, immune system
  involvementmost energy dependent tissues
• Response to carbohydrate exclusive diets (GCFC,
  MAD, ketogenic, specific carbohydrate)
• High heritability by family history with near
  failure of classic Mendelian genetics to explain
• Spectrum of severity

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Proposed Criteria for Mitochondrial Disorder
Score 8 before biopsy, Score 12/12 after biopsy
Morava, E. et al. Neurology 2006671823-1826
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Biomarkers
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Differences in allele frequency and/or
significant genegene interactions were found for
relevant genes encoding the reduced folate
carrier (RFC 80GA), transcobalaminII (TCN2776GC)
,catechol-O-methyltransferase (COMT 472GA),
methylenetetrahydrofolate reductase (MTHFR 677CT
and 1298AC), and glutathione-S-transferase (GST
M1). We propose that an increased vulnerability
to oxidative stress (endogenous or environmental)
may contribute to the development and clinical
manifestations of autism.
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AAN 2009

• S50.003 Fever and Regression in Autistic
  Spectrum Disorder Patients with Mitochondrial
  DiseaseJohn Shoffner, Atlanta, GA OBJECTIVE
  To assess the characteristics of regression in
  patients with autistic spectrum disorders (ASD)
  and mitochondrial defects. BACKGROUND Worsening
  of clinical symptoms with fever is a recognized
  feature of neurometabolic/neurogenetic diseases
  (eg. mitochondrial disease, urea cycle disorders,
  fatty acid oxidation disorders, glycolysis
  defects, channelopathies, etc). In mitochondrial
  disorders, fever can be associated with increased
  dysfunction of oxidative phosphorylation
  (OXPHOS), particularly in the central nervous
  system. DESIGN/METHODS Retrospective analysis
  Clinical records of 26 patients with ASD were
  assessed. RESULTS Regression with fever was
  observed in 42 of mitochondrial disease patients
  (11/26). Regression was seen in conjunction with
  emergence of ASD features or after emergence of
  ASD features. In 11.5 (3/26), febrile regression
  occurred within the week following vaccination.
  No cases of afebrile regression with vaccination
  were observed. Evidence for poor mitochondrial
  coupling of the respiratory chain was observed in
  one family with two affected males who
  experienced multiple episodes of clinical
  worsening with fevers. Biochemical, protein
  chemistry and genetic features will be presented.
  
• CONCLUSIONS/RELEVANCE ASD and regression occurs
  in mitochondrial disease patients in conjunction
  with fever. We hypothesize that fever is an
  important risk factor for regression in ASD
  patients with mitochondrial defects. Although all
  26 patients received vaccinations, only those who
  developed febrile responses showed regression.
  Our data suggests that fever and not vaccination
  is the significant variable in ASD regression in
  patients with mitochondrial defects. Supported
  by Medical Neurogenetics, LLC Foundation of
  Molecular MedicineCategory - Child
  Neurology/Developmental Neurobiology -
  GeneticsThursday, April 30, 2009 200
  PMScientific Sessions Child Neurology
  Diagnosis and Treatment

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Conclusion These results suggest that the
autism LCLs exhibit a reduced glutathione reserve
capacity in both cytosol and mitochondria that
may compromise antioxidant defense and
detoxification capacity under prooxidant
conditions.
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Benzecrya JM, Deth R, Holtzman D. Are autistic
spectrum disorders an expression of mitochondrial
encephalopathies? Mitochondrion 2009962.
Lymphoblasts were obtained from the Autism
Genetic Resource Exchange (AGRE). Maximal
respiratory rates were measured polarographically
after adding an uncoupler, dinitrophenol. In 9/9
cell pairs, this rate was 4050 higher in cells
from Autistic donors compared to controls (p
.0096) These results suggest that cultured blood
cells from about 70 of ASD patients show
increased respiratory capacity as an adaptation
to inhibited electron transport in Complex I of
the ETC.
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Conclusions The significant improvements
observed in transmethylation metabolites and
glutathione redox status after treatment suggest
that targeted nutritional intervention with
methylcobalamin and folinic acid may be of
clinical benefit in some children who have
autism. This trial was registered at
clinicaltrials.gov as NCT00692315.
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MitochondriaCorner Piece of the Puzzle
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Summary

• Autism(s) likely results from multiple complex
  gene-environment interactions.
• Immune and Mitochondrial Dysfunction observed in
  autism deserve urgent focused research
  prioritization.
• Mitochondrial disorders may have a primary role
  in autistic regression.
• Biomarker defined mitochondrial Autism
  subpopulations should be intensively studied.
• In some cases, Autism may be a manifestation of a
  mitochondrial encephalopathy. Post-vaccine fever
  and not the vaccine per se may be a trigger for
  regression.