What Causes Autism?What Causes Autism?

What We KnowWhat 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

The PhysicalityThe 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.

1. Genetic susceptibility1. Genetic susceptibility2. Environmental exposure2. Environmental exposure3. Stage of development3. Stage of development

The Three FactorsThe Three Factors

1.1. Genetic SusceptibilityGenetic Susceptibility(Family Studies)(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

• 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

Twin StudiesTwin 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

2. Environmental Exposure2. 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?

ToxinsToxins

• 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

• 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

3. Stages of Development3. 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)

Regressive vs. Non-Regressive AutismRegressive 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 child’s 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

• 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

Genome-wide StudiesGenome-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

Genome-wide StudiesGenome-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.– 4:1 ratio male: female with higher IQ autism– 1:1 ratio male: female with lower IQ autism– But why…?

Genome-wide StudiesGenome-wide Studies

A Few More Theories, Anyone?A Few More Theories, Anyone?

Specific Language Impairment (SLI)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

Immune System InfiltrationImmune 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.

What makes studying the genetics of autism What makes studying the genetics of autism so damned difficult?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

Some Future Study Methods…Some Future Study Methods…A Little HopeA Little Hope

• Maternal hair sample studies– If hair is long enough, could provide a “record” of toxic

exposure during child’s 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

• 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

Some Future Study Methods…Some Future Study Methods…A Little HopeA Little Hope

ConclusionsConclusions

• None that I can think of…

ConclusionsConclusions

• Most theories at this point are still simply poignant questions

• Much research has resulted in contradictory findings. What can we trust?

• We don’t know if genetic variants that cause autism will ever be defined.

• But, we have hope in future studies