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Current State of Autism Research

Jan 28, 2016

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Current State of Autism Research. James B. Adams, Ph.D. Professor, Arizona State University Science Director, Autism Research Institute/Defeat Autism Now! Parent of a 17-year-old girl with autism. What is Autism?. Autism is a label for people who have major impairments in three areas: - PowerPoint PPT Presentation

  • Current State of Autism ResearchJames B. Adams, Ph.D.Professor, Arizona State UniversityScience Director, Autism Research Institute/Defeat Autism Now!Parent of a 17-year-old girl with autism

  • What is Autism?Autism is a label for people who have major impairments in three areas:speech/communicationsocial interaction/friendshipsrestricted, repetitive, stereotypic behaviors

    Autism is a spectrum disorder:Autism / PDD-NOS/ Aspergers Impairment in social skills is common to all

    Likely due to multiple causes.

  • Research Tools for Diagnosing AutismAutism Diagnostic Interview Revised (ADI-Revised): 2-4 hour interview with parents of childs history Autism Diagnostic Observation Schedule (ADOS) 1 hour structured interaction with child

    Primarily used for research, not by clinicians

  • Co-occurring symptomsMental Retardation but must be tested with non-verbal IQ testSeizures: 25% (and 60% without seizures have subclinical seizures)Diarrhea/Constipation: 50%Sleep problems: 50%Low muscle tone: 30%Pica: eating non-food items: 30%Sensory Sensitivies: touch, vision, sound, taste, smell, pain; under- and/or over-sensitive

  • Early Onset vs. RegressionData from Autism Research Institute (over 30,000 parental reports)

  • IncidenceIn US, latest report by CDC cites 1 in 150 for autism spectrum disorders (autism, PDD-NOS, Aspergers).In UK, a new unpublished study by Simon Baron-Cohen at Cambridge University found 1 in 100, and estimates the actual rate at 1 in 60.

  • Genetic or Environmental Cause?Studies of identical twins reveal:Co-occurrence is roughly 60% for autism, and roughly 90% for speech delays; if 100%, then only due to genes; so genes are important, but so are unknown environmental factors. If a couple has one child with autism, then 5-10% chance other children will have autism, and 25% chance of major speech delay (so carefully monitor siblings)

    Genetic vulnerability + environmental exposure

  • Which Genes?Many genetics studies of autism, but they generally disagree, since too few subjects and too many genesProbably 10-20 genes involved in complex mannerIn 2 similar conditions, Fragile X and Retts Syndrome, a single gene has been identified for each

  • Known Genetic FactorsThere are several rare genetic disorders that greatly increase the risk of developing autism. These disorders include PKU, creatine formation/transport deficiency (uncommon), adenylosuccinate lyase deficiency, Angelmans syndrome, Fragile X, Retts syndrome, neurofibromatosis, tuberous sclerosis, and others. However, these disorders account for only roughly 5-10% of the cases of autism.

  • Which Environmental Causes?No general agreementPossible causes with limited scientific data include:Impaired methylationOxidative stressMercury/toxic metals poisoning (due to limited excretion because of low glutathione)Pesticide exposure (esp. organophosphates and organochlorides)Excessive oral antibiotic usageVaccine damage (especially MMR)Lack of essential minerals (sulfate, iodine, lithium)Other unknown factors

  • Rapid increase in incidence1970s: 2-3 per 10,0002008: 1 per 150 (autism spectrum); Now affects about 1 in 94 boys, since 4:1 boy:girl ratioIn California (which has best statistics), autism now accounts for 45% of all new developmental disabilities

    Arizona: 1996: 633 people with moderate/severe autism served by DDD1999: 10572003: 19172005: 25002009: 3500

  • Why rising rate of autism?Partly due to better awareness/diagnosis, but that is only modest effect (per study by MIND Institute)Not due to genetics alone gene pool normally changes very slowly, although environmental toxicants can cause permanent genetic changes/damageSo, primary reason is increased exposure to environmental factor (toxid metals, pesticides, antibiotics, MMR, iodine deficiency, other?).

  • New Research on Risk of AutismPreliminary research by Jill James et al on abnormalities in methylation cycle and glutathione in MOTHERS of children with autism

  • SAM SAH

    HomocysteineB6Oxidative Stress and transmethylation/transsulfurationCystathionine Cysteine GSH GSSG Methionine AdenosineB6B6 5-CH3THF THF5,10-CH2THFCell Methylation1123Folate Cycle

    Transmethylation

    Transsulfuration 23 Antioxidant Redox Potential (GSH/GSSG)CBSMTaseMethylation Potential (SAM/SAH)MSMTHFRB12oxidized

  • Intervention Trial with MethylB12 and Folinic Acid

    Plasma Metabolite Concentration Autism Pre-treatment(n = 40)Autism Post-treatment(n = 40) p valueaMethionine 21 4b22 3nsSAM (nmol/L) 66 13b69 12nsSAH (nmol/L)15.2 514.8 4nsSAM/SAH (mol/L) 4.7 1.5b 5.0 2.0nsHomocysteine (mol/L) 4.8 1.8 5.3 1.10.04Cysteine (mol/L)191 24b215 190.001Total Glutathione (mol/L) 5.4 1.3b 6.2 1.20.001Free Glutathione (mol/L) 1.5 0.4b 1.8 0.4 0.008 GSSG (mol/L) 0.28 0.08b0.22 0.06 0.001tGSH/GSSG21 6b30 9 0.001fGSH/GSSG 6 2b 9 3 0.001b Signficantly different from age- matched control childrena Treatment effect

  • Research by Jill James et al. Autism Moms Control Moms (n = 46) (n= 200)

    Methionine (M/L) 24 5 26 6

    SAM (nM/L) 80 19 83 13

    SAH (nM/L) 33 14* 23 8.4 SAM/SAH Ratio 3.1 1.7*4.0 1.4

    Homocysteine (M/L) 11 3.9* 7.6 1.6

    *statistically significantMaternal Methionine Cycle Metabolites:It would be a very good idea to ask your physician to check your total homocysteine

  • Maternal Transsulfuration Metabolites

    Autism Moms ControlMoms Cysteine (M/L) 232 40 231 20 Total GSH (M/L) 5.1 1.7* 7.3 1.5

    Free GSH (M/L) 1.5 0.5* 2.6 0.6

    GSSG (M/L) 0.30 0.08* 0.240.04

    Total GSH/GSSG 17 8 31 10* *statistically significant

  • Metabolite imbalance and the risk of being a mother of a child with autism In other words, 41% of ASD mothers had a 46x higher chance of having a child with autism, associated with abnormal methylation and oxidative stress

    Stratified GroupControlMothers(N=200)CaseMothers (N=46)Odds Ratio (Risk) SAH >30Mol/L)14% 54% 6.9SAM/SAH

  • It is not possible to determine from this data whether the abnormal metabolic profile in parents is genetically determined or whether it simply reflects the stress of living with an autistic child

    Question: Would testing for abnormal methylation/glutathione in mothers and/or newborns, and treating it, reduce the risk of autism? Is this one possible method for preventing autism?IMPORTANT CAVEAT

  • Vulnerable to ToxinsDecreased glutathione would make fetus more vulnerable to toxins, including toxic metals and pesticidesConsistent with studies linking toxic metals (Windham et al 2006) and pesticide exposure (Roberts et al 2007) to risk of developing autism

  • New research on possible cause of 12% of cases of autism by Judy van de Water and colleagues at Mind InstituteA study of the mothers of children with autism (n=61) found that 12% of them had antibodies to fetal brain tissue. These antibodies were not found in any typical children (n=62). Larger study of 300 children ongoing, and results are similar.

  • Heavy ChainLight Chain

    Table 2. Summary of maternal autoantibody reactivity patterns for human fetal brain proteins and their significant associations.

    Prevalence (%)

    37kD & 73kD

    37kD

    73kd

    AU (n=61)

    7 (12%)*

    15 (25%)*

    10 (17%)

    AU Reg (n=36)

    6 (17%)*

    10 (28%)*

    9 (25%)*

    AU EO (n=25)

    1 (4%)

    5 (21%)

    1 (4%)

    TD (n=62)

    0 (0%)

    5 (8%)

    6 (9%)

    DD (n=40)

    0 (0%)

    2 (5%)

    7 (17%)

    Significance (p-value)

    AU vs TD

    0.0061*

    0.0086*

    0.2

    AU vs DD

    0.0401*

    0.002*

    0.79

    AU Reg vs. AU EO

    0.223

    0.777

    0.106

    AU Reg vs TD

    0.0019*

    0.0174*

    0.078

    AU Reg vs DD

    0.0089*

    0.0023*

    0.388

    AU EO vs. TD

    0.287

    0.0703

    1

    AU EO vs. DD

    0.385

    0.0109*

    0.4711

    AU= autism; TD= typically developing; DD= developmental delay

  • Summary of maternal antibodies to fetal brain proteins :

    Researchers found a specific subset of antibodies to fetal brain proteins in the blood of a subset of mothers whose children have autism.These antibodies occur most frequently in those mothers who have children with regressive autism.Similar findings have been demonstrated in work by Zimmerman and Singer against both rodent and human fetal brain.

  • The Autoimmune PhenomenonQuestion: Are the antibodies pathogenic?

    Researchers currently have both primate and murine (mouse) models underway to determine the potential effect of exposure to IgG from the autistic maternal population during gestation on behavioral outcome.

  • Primate model--Pilot studyThe gestating dams were exposed to 3 IV injections of IgG beginning late 1st trimester with 2 additional injections during the second trimester. Group A exposed animals had 4 live births.Group B exposed animals had 2 live births and will be repeated.The offspring were monitored for several developmental criteria including motor coordination, mother preference test, and social interaction.

  • Mother preference task Increased midline crossings Demonstrated no preference for own mother

  • Social Dyad: Measure of stereotypic episodes with familiar pairingsThe weaned animals were placed in the observation cage with either a familiar monkey from their social group or an unfamiliar monkey. The AU treated offspring demonstrated sever