What Causes Autism

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What Causes Autism?
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What We Know

• About 5 of autism cases caused by gross
  disruptions of chromosomal material
• About 5 of cases caused by disorders of known
  genetic etiology
• Tuberous sclerosis
• Neurofibromatosis
• Other 90. being studied for links to
  heritability

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The Physicality

• Postmortem studies and autopsies have found
  common abnormalities of the cerebral cortex,
  brainstem, cerebellum, subnuclei of amygdale, and
  others
• Kemper and Bauman 2002 found small and closely
  packed neurons in the amygdale, hippocampus, and
  entorhinal cortex.
• A general decrease in Purkinje cells in young and
  old patients alike
• Purkinje cells transmit information put out by
  the cerebellum. Control over refinement of motor
  activities.

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1. Genetic susceptibility 2. Environmental
exposure 3. Stage of development
The Three Factors
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Genetic Susceptibility(Family Studies)

• Leo Kauner in 1943, while studying autism,
  noticed common traits among parents of autistic
  children
• Serious-minded
• Perfectionist
• Lack of interest in forming relationships

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• More recently attributed to the fact that a broad
  spectrum of autistic-like behaviors exist, from
  minor aloofness and language abnormalities, to
  full-fledged autism. Parents were probably
  displaying heritable traits that children
  happened to receive, in combination with other
  genetic and/or environmental factors.
• Broader Autism Phenotype
• Hence, ASD autism spectrum disorder

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Twin Studies

• 1977 study showed 82 of MZ twins (one with ASD)
  sharing behavioral
• Only 10 DZ, showing that there is a familial
  link, and also suggesting that it is not a solely
  environmentally-induced phenomenon
• Compare 10 concordance rate with population
  average, which is approximately .006
• The risk of autism and autism-like traits
  decreases as you go outward on a family tree,
  from an autistic person
• Supports the idea that multiple genes are at play
• Might explain the spectral tendency of the
  disorder
• Estimates range from 3 at-risk genes to over 100

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2. Environmental Exposure

• Speculated that neurotoxins interact with genes
  (at crucial time in development), but we are far
  from knowing exactly what neurotoxins come into
  play. All we have are scattered results and
  limited access to appropriate populations to
  study.
• Children on farms?
• Larger ASD population than 50 years ago could be
  indicative of an increase in the number of people
  affected. If this is the case, why?
• Simply more cases being documented?
• More exposure to neurotoxins?

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Toxins

• Up to 50 known agents produce developmental
  toxicity in humans
• E.g. alcohol, cocaine, organic mercury compounds,
  pharmaceuticals like thalidomide and valproic
  acid antiseizure medication
• Exposed pregnant mother could bad news
• Up to 1,000 agents produce developmental toxicity
  in animals
• Probably more, with undetectable results to a lab
  experimenter
• Lead, Mercury, pesticides, polychlorinated
  biphenyls (PCBs) shown to disturb the processes
  of neurogenesis and migration, as well as general
  immune functioning
• Many chemicals in use for industrial or
  agricultural purposes have not been tested for
  neuro-developmental toxicity

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• Dose-effect amount of exposure vs. how much of
  a neuro-developmental effect it will have.
• Possible link of ASD to vaccines, including MMR
  (however unlikely)
• Also concern about phthalates and polybrominated
  diphenyl ether compounds, but no direct evidence
  supports its contribution to ASD
• This example seems to epitomize ASD causal
  research. Many theories exist, with no solid
  disorder-wide evidence to support.
• Chemicals alone are not likely to cause autism

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3. Stages of Development

• Neurodevelopment begins in the early embryonic
  stage and continues on through postnatal and even
  adolescence to a degree. Autistic children seem
  to be most prone during embryonic stages to the
  affects of neurotoxicity.
• Processes of neuro-development
• Neurogenesis
• Proliferation
• Migration
• Differentiation
• Synapse formation
• Myelination
• Each process is susceptible to alteration via
  environmental agent interaction
• Day 20-25 of gestation, brain thought to be most
  susceptible to thalidomide (possible cause of ASD)

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Regressive vs. Non-Regressive Autism

• Regressive autism refers to a postnatal onset of
  autism, allegedly triggered by some
  environmental factor
• Does this even exist? It seems to
• Vaccination or illness sometimes marks a
  noticeable difference in a young childs behavior
• Could it be a latent onset of an already-present
  disorder?
• We need to determine whether the etiology of
  Regressive Autism differs from that of
  Non-Regressive Autism

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Genome-wide Studies

• Neuroligin has been targeted for study (NLGN3 and
  NLGN4) both X chromosome genes
• No conclusiveness needs to be studied more for
  link
• Neurotransmitter abnormalities
• Serotonin (increase is most common finding)
• Although, SSRIs have been shown to quell
  repetitive behavior
• Serotonin transporter (SLC6A4) modulates levels
  of extracellular and synaptic serotonin
  malfunction in this?
• Dopamine
• Norepinephrine
• Gamma-aminobutryic acid (GABA)
• Glutamate
• Neuropeptides

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Genome-wide Studies

• Neuropeptides like oxytocin and vasopressin can
  serve as immunomodulators. If affected by
  environmental toxins, they could lead to ASD.
• Autopsies have found the presence of anti-brain
  autoantibodies in 30-70 of ASD patients
• The problem is that these are found in healthy
  brains as well.
• 17 of 22 autosomal chromosomes seem to indicate a
  relation to autism
• Chromosome 7 has been scrutinized with definitive
  support in some studies, and none in others

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Genome-wide Studies

• Chromosome 2q may have some genetic link (as of
  2001 study)
• Chromosome 15q11-q13 a possible candidate
• GABA-A receptor subunits cluster together in
  deletion region associated with autism
• GABRB3
• GABRG3
• GABRA5
• X chromosome in question males 4 times more
  likely to be diagnosed with
• ASD.
• 41 ratio male female with higher IQ autism
• 11 ratio male female with lower IQ autism
• But why?

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A Few More Theories, Anyone?
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Specific Language Impairment (SLI)

• Language and grammatical deficits have been
  linked to the 7q chromosome
• SLI impairments seem related to language
  impairments of some autistic patients
• SLI is easier to study genetically, as some form
  or other occurs in 7 of the population

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Immune System Infiltration

• There is also the idea that ASD could result from
  nervous system dysfunction via immune system
  impairment during critical neurodevelopmental
  embryonic stages
• Heritability causes immune system weakness ?
  particular neurotoxins attack immune system ?
  nervous system weakens, possibly resulting in
  autism
• We know the immune system to be affected by heavy
  metals such as lead (Pb) and mercury (Hg). Rat
  testing has shown early pre-natal exposure to Hg
  to affect lifelong immune efficiency.

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What makes studying the genetics of autism so
damned difficult?

• Diagnosis of autism is based on observable
  behavioral criteria, and cannot be performed
  until the child is several years old
• Expense and logistical difficulties prevent
  long-term phenotype change studies over a wide
  population
• Autism difficult to document through the ages,
  because the diagnostical procedures and
  operational definitions have changed over time.
  Many people throughout history have been
  mis-diagnosed with retardation or other disorder
• Ethics limit the ability to do pharmacokinetic
  experiments on children
• Because studies are done based on parental
  consent, it is not always possible to get the
  type of willing sample population that a
  researcher desires.
• School-wide populations would be valuable
  resources, but there is little incentive for
  administrators to cooperate and provide
  sufficient data.
• Also the question of consent from parents

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Some Future Study MethodsA Little Hope

• Maternal hair sample studies
• If hair is long enough, could provide a record
  of toxic exposure during childs gestation
• Shed baby teeth
• Once they have fallen out, they can be studied
  for traces of toxins
• Parental recall of exposure
• This method seems shaky at best
• With the spread of information, but parents of
  ASD children know the theories, which tends to
  bias their recall of exposure to proposed
  neurotoxins

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Some Future Study MethodsA Little Hope

• Study future children of ASD mother
• Knowing she is capable of producing an ASD child
  can allow a study during a subsequent pregnancy
  to monitor
• Study communities with a known exposure to
  pesticides or other environmental toxins

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Conclusions

• None that I can think of

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Conclusions

• Most theories at this point are still simply
  poignant questions
• Much research has resulted in contradictory
  findings. What can we trust?
• We dont know if genetic variants that cause
  autism will ever be defined.
• But, we have hope in future studies