Autism Researchers Discover ‘Epigenetic’ Changes | Autism Speaks

Autism Researchers Discover ‘Epigenetic’ Changes | Autism Speaks

Disclaimer

All notes were taken in a very hurried manner, so information given below may not be in its entirety.  Please refer to websites listed in the blog for further information. 
Also, many times in the following notes, ASD is mentioned.  ASD is the abbreviation for autism spectrum disorders.  Thank you!

New Directions for Diagnosis and Screening in Autism Spectrum Disorders

Catherine Lord, Ph.D (http://www.umich.edu/~chgd/faculty/lord.html)

Dr. Lord is on the committee for the DSM-V.  They are working on changing the diagnostic criteria in the DSM-V for autism.

Implications of Diagnosis:

1.        Prognosis – Most people do not grow out of autism.

2.       Etiology – There is a strong genetic component.

3.       Course- Behaviors get worse in the early toddler years and then get better (although there is some withdrawal in adolescence).

4.       Appropriate treatments

5.       Risks for other difficulties, i.e., seizure disorder

Where are We Now in Diagnosis?

-          Diagnoses are generally stable.  Need the combined efforts of both the clinicians and the parents.

Definite Factors in Autism – Social Impairment, speech/communication impairment, repetitive behaviors and restricted interests.   However, a child showing only one of the above factors could have something different like a language disorder or intellectual disability.

In addition to the above factors, autism can also contribute to GI dysfunction, sleep disturbance, epilepsy (EEG abnormalities), immune dysfunction, motor problems/apraxia.

The Landscape of Autism has Changed

-          More toddlers

-          More older children without the intellectual disabilities

-          More adolescents and adults with other psych comorbidities

Then What?

There is a big trade off in time versus accuracy. 

-The faster the diagnoses, the narrower the comparison group.

-for more specific diagnoses need to compare age-related examples.

- Neurobiology = Dimensions (don’t know what was meant here, but I wrote it down J )

DSM V Developments

They are actually changing the DSM V to say DSM 5 so they can have new editions with the five and decimal.

Changes they are considering for the autism

 Diagnosis Criteria:

1.        They want to make it just one spectrum of autism disorder.  No longer separation between autism, PDD-NOS , Aspergers, etc.  It will just be a behavioral diagnosis because of concerns with scientific validity and concern about access to services.

2.       The focus will be on the behavioral aspect of the diagnosis rather than the speech aspect because there are many diagnoses out there involving speech impairment, but the behavior criteria always fits with autism.  Speech impairments will still be considered a trigger to evaluate a patient for an ASD.

3.       Want to be clear that they are not trying to get rid of Aspergers or PDD-NOS as a label for someone to use if they are more comfortable with that.  However, it will not be used as a medical diagnosis or for services.

Domains:

-ASD defined by 3 domains: Social, language and repetitive behaviors.  They are considering combining the social and language domains as one and having the repetitive behaviors as a separate domain.  Language level needs to be combined with social skills because conversation involves both language and social skills.  For those with no repetitive behaviors, they would now be diagnosed with social communication disorder.

-Have added specific criterion to repetitive behaviors to include unusual responses and sensory seeking behaviors.

Modifiers

With new DSM V they are hoping to use modifiers with autism diagnoses, ie., autism and ADHD can now be put together or autism and Rett syndrome or Autism and Fragile X.

ASD can be defined with or without intellectual disabilities.

Severity Checklist

-The board for the DSM V wants to have a way to diagnose autism levels of severity.  As part of that, they have to separate social deficits from repetitive behaviors.  The level of severity would be an assessment of overall impairment and would allow ASD with other disorders (modifiers), i.e., ADD, depression, sleep disorders.

- Define/divide severity by how much supports a person needs. 

- Limit diagnosis to people who have impairments.   (There would be a hard middle ground for those with autism.  Can have a disorder but not need help.)

Goal

-          Focus not only on what goes awry but what goes well with autism.  Build their trust, confidence.  Build their communication skills.  Help them learn to be more comfortable with who they are.

The Science of Teaching Social Skills to Teens and Young Adults with Autism Spectrum Disorders: The UCLA Peers Program.

Elizabeth Laugeson, Psy.D.

Social Deficits with ASD

1.   Poor social communication

-things to talk about

-focus on repetitive themes, disregard of other person (1-sided conversation)

-difficulty providing relevant information

-unexpected leaps in topics

-pedantic style of speaking (robotic)

- highly verbose (i.e., conversation hogging)

-difficulty interpreting verbal and social cues (sarcasm, tone, gesture, social touch).

2.  Social Awareness

- Poor eye contact (but may have over learned and may now stare)

-Difficulty with social cues.

-Poor social motivation (extracurricular activities)

- Lack of peer entry

- Poor social cognition (i.e., putting self in other’s shoes)

-friendships focused on restricted interests  (presenter said this wasn’t a bad thing because most friendships are based on similar interests).

Results of Above:

-Peer rejection

-Bad reputation, teasing, bullying.

-Social neglect and isolation

-Peer conflicts (arguments are more black and white and lead to end of friendship)

- Poor friendship quality – less companionship, less help from friends, less security in friendships and greater loneliness.

They want to be be social but don’t know how.

Importance of Improving Friendships:

-One or two close friends predict later adjustments.

-Buffer impact of stress.

-Correlates positively with a self esteem.

-Increases independence.

-Correlates negatively with depression and anxiety.

Peer Rejection

-One of the strongest predictors of later mental health problems

-Juvenile delinquency

-Early withdrawal from school

PEERS

-Manualized intervention

-Parent assisted/Caregiver assisted

-Address core deficits.

-Focus on friendship skills

-Teaches ecologically valid social skills

-Small group format

-Concurrent parent/caregiver sessions (work on expanding social opportunities and social coaching)

-Didactic Instruction (Structured lessons, concrete rules, steps of social etiquette)

-Socratic method of instruction

-Role playing/Modeling of both inappropriate and appropriate behaviors.

- Behavioral Rehearsal

-In-session coaching

-Real-life practice (homework assignment/parent assistance)

Treatment sessions

1.  Conversation skills

-Trade info

-Find common interests

-Reciprocal/2-way conversations

-Non-verbal communication

2. Electronic Communication – i.e., email, text, phone conversations

3.  Choose appropriate friends

- Identifying peer group and explain function of groups to find friends.

-Identifying extracurricular activities

4.  Appropriate use of humor

-Pay attention to humor feedback

5.  Peer entrance and exit strategies (conversation)

6. Get togethers

- Be a good host or guest during get togethers.  Don’t call them play dates.  J

7.  Dating Etiquette

8.  Good sportsmanship

9.  Peer rejection (save until the end of intervention when they are feeling better about themselves)

10.  Handling peer pressure

Ecologically Valid Skills

-Peer Entry in Conversation

1. Watch/Listen (using a prop is useful, i.e., looking at your phone)

-Listen for the topic

-Identify common interests

-Make periodic Eye Contact.

2.  Wait

-Wait for a pause (there is NEVER a perfect pause)

-look for a sign of receptiveness

3.  Join

-Move closer

-Make a comment or ask a question that is ON TOPIC

-Use gaze aversion at first

4.  Assess interest – Did they open the circle to include you?

-Handling Teasing (Verbal)

1.  Act like what the person said/did didn’t bother you.

2.  Do not walk away, ignore the person or tell an adult.

3.  Provide a brief comeback to make the other person feel lame:

-Whatever!

-Anyway…

-So what?

-Big deal!

-Who cares?

-Yeah…And??

-Handling Bullying (Physical)

1.  Avoid the bully

-lay low, stay out of reach of the bully

2.  Do not provoke the bully

3.  Do not use teasing strategies

4.  Do not act silly or tease the bully

5.  Don’t police the bully (i.e., tell on, etc.)

6.  Don’t try to make friends with the bully

7.  Hang out with other teens

-Bullies like to pick on teens who are by themselves.

8.  Hang out near adults when bully is nearby.

9.  (Only if you are in danger)get help from an adult

For more information on PEERS manuals and trainings, please see http://www.semel.ucla.edu/peers

Breakout Session C: Raising an Individual with Autism: Family Impact: Who? What ? Where? When and How? across the lifespan

Mary Baker-Ericzen, PhD

-There should be a coordination of care between educational, medical, developmental and mental health, etc.  However, what we are seeing is that it is a funnel system where all of these different services funnel to one place to coordinate the care, and that is by the family.

This leads to an extra burden on the family and the need to have extra skill sets (i.e., advacate, case manager, providing services)

-In recent study, 60-80% of parents of children with ASD have clinically elevated levels of stress. ( Most say that navigating the system is more stressful than the child’s behaviors.)

-In same study, 30-60% of parents experience clinical levels of depression.

Adaptation

-Adaptation is more than just adjustment.  It is acceptance, integration, feeling of knowledge, empowerment and support.

- The key to coping and adaptation is developing a system of support.

Conditioning Variables to Stress

1.  Empowerment/advocacy

2.  Social Support

3.  Coping/Problem Solving abilities

4.  Competence

5.  Information and knowledge

Transition Periods for ASD families

Bonnie Kraemer, PhD, BCBA-D
-Presentation based on research of period of transition for ASD families.

After exiting school (either graduating or aging out)
-living at home
-group home
-apartment or dorm

-post secondary ed
-work with support
-sheltered work (i.e., adult daycare)
-home with no work

In parents of ASD individuals making the transition, there is high stress about vocational, living and and social.  It impacts well being and affects the rest of the family.  60% of families where kids have exited school are reporting extreme impact.

They are hoping to develop a program that will have direct intervention for parents at 90 min a week. 

Family Life with Autism
Stephen Shore, Ed.D (an adult living with ASD)
-It is important to develop solid relationship before start teaching a child with ASD.  Be interactive with the child.  Get into their world.
-Notice and support special interests and focus.  Use these interests of such intensity as motivation.

For the Family:
Siblings: -Spend time with each child.  Be careful of "parentifying" siblings.  Be fair to each family member.  Fairness is NOT treating everyone the same.  Fairness is providing for each person's need (i.e., not everyone in the room needs CPR to be fair).

Child with autism as a catalyst
-Strong relationships bond tighter.
-Weak relationships torn asunder.

The Grieving Process...for the child you dreamed of
1.  Denial.  Not me...
2.  Anger.  Why me?  Why my child.  It is so unfair.
3.  Bargaining.  (i.e., Researching way too much on google trying to find that cure)
4.  Depression.
5.  Acceptance - Does not mean giving up, but rather finding balance in the family.  Appreciating, supporting and welcoming the child with ASD's contributions to the world.

- If you are productive and fulfilled with your life, you are probably successful.

- Don't focus on where they should be rather than on how to help them be successful.

Books by Stephen Shore:
http://www.amazon.com/Beyond-Wall-Personal-Experiences-Asperger/dp/1931282196/ref=sr_1_1?ie=UTF8&s=books&qid=1305553304&sr=1-1
http://www.amazon.com/Understanding-Autism-Dummies-Stephen-Shore/dp/0764525476/ref=sr_1_2?ie=UTF8&s=books&qid=1305553304&sr=1-2
http://www.amazon.com/Ask-Tell-Self-Advocacy-Disclosure-Spectrum/dp/1931282587/ref=sr_1_3?ie=UTF8&s=books&qid=1305553304&sr=1-3
http://www.amazon.com/Choosing-Home-Deciding-Homeschool-Aspergers/dp/1843107635/ref=sr_1_4?ie=UTF8&s=books&qid=1305553304&sr=1-4
http://www.amazon.com/Living-Well-Spectrum-Challenges-High-Functioning/dp/1606236342/ref=sr_1_5?ie=UTF8&s=books&qid=1305553304&sr=1-5
http://www.amazon.com/Integrated-Self-Advocacy-ISA-Curriculum-Self-Advocates/dp/1934575402/ref=sr_1_6?ie=UTF8&s=books&qid=1305553304&sr=1-6

John Elder Robinson (another adult with ASD)
-Encourage to offer self  to various autism research programs.
-One person can make a huge difference.

Books by John Elder Robinson
http://www.amazon.com/Look-Me-Eye-Life-Aspergers/dp/0307396185/ref=sr_1_1?ie=UTF8&qid=1305553548&sr=8-1
http://www.amazon.com/Different-Adventures-Free-Range-Aspergian-Aspergians/dp/0307884813/ref=sr_1_2?ie=UTF8&qid=1305553548&sr=8-2

Lunchtime Panel with ASD Individuals

Autism Defined:
"An odd state of focus."
"Hard to relate socially.  Poker face."
"After much consideration, research and many experiences...it is a mental upgrade with not so upgraded side effects."

Friendship Defined:
"Trust of other people.  Pushes you outside your comfort zone."
"A need based on trust."

Feelings and Emotions
"Don't outwardly express.  Can have outbursts."
"Heightened emotions."
"If you are abnormal, you might as well accept it."

What Makes You Happy?
"Reading."
"Long walks"
"Politics"
"Memorizing comedic routines."

What Are Your Pet Peeves?
"Speaking in public"
"The economy."
"Boys."

Well-Known Individuals on the Spectrum (per panel)
Bill Gates, Thomas Jefferson, Albert Einstein, Mozart, Temple Grandin

Progress and Challenges in the Genetics of Autism Spectrum

Disclaimer: Much of this Session went over my head, and I hope my notes make sense. 

Brett Abrahams, PhD  (http://neuroscience.aecom.yu.edu/faculty/secondary_faculty_pages/abrahams.html )

Genome - A big collection of 4 letters (AGCT) organized in chromosomes. 
-Sequencing genomes is a little bit like reading and recording 1500 times over. 
Genes- The portion of DNA that encodes proteins to make the cell work.
Allele-Different types of genes (ie., one letter difference).
-A single base pair change can have an effect on brain outcome.

What is being discovered about the genetics of autism, is there is a "Snowflake Hypothesis" - Every individual with autism is entirely unique.

-Common Alleles (polymorphism)
-Rare alleles (mutations)

-There are many kinds of autism genes, but most/many of these genes very subtly increase risk.  50% of us carry a particular gene.
-It takes many things to combine in a particular way that comprise the individuals with autism.
-Some variants within a specific gene can cause autism, but others do not cause disease but subtly affect aspects of language.
-Increased local connectivity.  Decreased long-term connectivity.

There are research banks to study blood of families affected by autism: http://agre.autismspeaks.org/site/c.lwLZKnN1LtH/b.5002149/k.E3CE/Overview.htm
https://sfari.org/simons-simplex-collection

Genetics-How They Research
-FISH
-aCGH

The variant that was studied by this researcher with mice was CNTNAP2 which is a neurexin homolog.  There were two groups of mice studied, the affected mice,"knockout mice" and "typical mice." 
-The knockout mice had restricted interest, (ie., increased grooming), suggestion of reduced flexibility, increased hyperactivity.  Some of these mice showed epilepsy as well.  Human disease was closely replicated by the mice.  Interestingly, risperidone was used to normalize the mice behavior, much in the same way it is used in many people with autism to normalize behavior.

Conclusion:  ASDs are common, but show variability.  There is not one single genetic variant that causes autism, but innumerable combinations of different genetic variants.

"Uh Huh, I Remember Those Days" - How Experienced Parents Help Newer Parents

George Singer, PhD (http://education.ucsb.edu/Faculty-Research/Faculty-Listing/bio.php?first=George%20H.%20S.&last=Singer)

In the network of resources for parents with autism, Dr. Singer's presentation was on the importance of other parents as a very important network of support.

Parent-to-Parent Organizations (http://www.p2pusa.org/p2pusa/sitepages/p2p-home.aspx)
-Run by parents
-Screens and trains volunteers
-One-to-one matches
-In study, 80% of parents found this helpful and made progress on their current issues. 
-Parents had more positive perceptions about family and felt more effective as parents.
-Gives information and emotional support. 
-Match leads to connectedness. The parent no longer feels isolated.  There is someone who understands.  There are shared insider meanings. 

When receiving support from other parents experiencing the same thing, it is different because anyone can be trained to listen, but not everyone can appreciate what you go through.  "You just don't know.  What it says in the book isn't necessarily what everyone goes through."  Parents can find the humor in their situations which is a great way to cope.  http://www.youtube.com/watch?v=m1BVs4pPNiA

There is a theory of "Life World" vs "Technical Rational."  The example was given of a sonogram.  The doctor sees the sonogram as a picture to help determine the health of the baby.  The family views the sonogram as a memento, as the first picture of their child.  In the case of autism, the technical rational would be the various people who work with your family and see that part of your life with autism.  The other parents who have shared experiences can relate to the "life world."

As parents of children with autism, we have both the "insider and outsider" framework.  We know both the autistic and the typical worlds and can go back and forth between the two and laugh.

Breakout Session H: Prenatal Causes and Early Brain Development in Autism

Presented by Eric Courchesne, PhD, Alysson Muotri, PhD, and Karen Pierce, PhD 

This breakout session was based on studies that were/are conducted at University of California, San Diego.  The first speaker, Karen Pierce, PhD, (http://www.autism-center.ucsd.edu/about-us/Pages/team.aspx)
discussed how there were rare-to-no studies on autism in infants and children under three at the time that they started their study.  She implemented the one-year well-baby approach with a network of pediatricians in the area.  The doctors would use the CSBS test (http://firstwords.fsu.edu/pdf/checklist.pdf) at the well-baby checkup.  If the baby failed the test, they would then be referred to the autism study at UCSD. 
A big part of the study was to take a sleep FMRI of the baby's brain.  This allowed researchers to compare the brains of the children at risk for autism with typically developing children.  During the FMRI, they would play different vocalizations to determine the brain activity.  (For example, they would read a bedtime story).  There was less response to language sounds for kids with autism.  The left side of the brain was not activated.  When looked at laterally to speech, ASD babies had right-sided dominance with the left side not having a normal response to language sounds.
-Social Orienting Defects
Another part of the FMRI was to use stimuli that would normally catch a child's attention, i.e., calling out their name, saying cautionary words or using directional phrases, i.e., "Look over here!"  With the social orienting FMRIs, there was normal stimuli with the typical kids, while the children with an ASD had no stimuli with social orienting.  The same thing was done with environmental stimuli, i.e., the sound of a bell, a horn honking, etc.  Social vs nonsocial - Not much differentiation. 
By 2 years, there is a lack of functional responding to social orienting stimuli, particularly in the temporal cortex of the brain.
Why?  Overabundance of neurons and faulty long-distance connections may lead to ineffective functional architecture which can lead the ASD child to difficulty switching between rest and evoked state.

Modeling Rett Syndrome Using Human Neurons
Alysson Muotri, PhD (http://cancer.ucsd.edu/research-training/people/Pages/summary-database.aspx)

Dr. Muotri is a researcher at UCSD.  His presentation was about an exciting new development in stem cell research.  Where as before, stem cells were either taken from post-mortem brain tissue, a mouse model or embryonic stem cells, this was not effective in treating patients because the newly developed undifferentiated cell systems could be rejected by the body because they were not the patient's own cells. 
In 2007 there was a huge breakthrough in stem cell research.  It was found that they could isolate cells by skin biopsy and differentiate cells into pluripotent state (embryonic-like state) which would also reduce the chance for rejection. 
They are hoping to begin a study where they can use stem cells to study neurons derived from an autistic patient.   They have already done this using a Rett Syndrome patient biopsy (because unlike autism, Rett Syndrome is a well-characterized genetic defect).  They were able to reprogram the biopsy to become neurons.  They can compare the neurons from a typical person's biopsy to that of Rett Syndrome.    Rett Syndrome neurons are smaller (10% reduction in size).  They replicated the typical to the Rett Syndrome neurons by removing the gene that is not there in Rett Syndrome, and they got the same result as Rett's.    Reduction of density of neuronal spines (less branches).  Neurons don't have spines when very immature.  The spines are where the neurons talk to each other and how information affects the brain.  Can affect networks which can affect brain circuit which then affects behavior.
Next, they wanted to see if they could revert the process (of Rett's) by injecting cells with IGF-1 (which had previously worked in a mouse model).  Can rescue the number of synapses which means you can manipulate.  Now, with clinical trial of IGF-1, need to work on dosing because it actually over corrected the Rett's Syndrome.  IGF-1 can affect more than one cell type.  It is a big molecule that cannot filtrate the brain.  Looking for a smaller version to get into the brain.

Major Goals of UCSD Autism Center of Excellence
Eric Courchesne, PhD (http://www.autism-center.ucsd.edu/about-us/Pages/team.aspx)

Major Goals of UCSD Autism Center of Excellence
-Identify the neural and genetic defects that cause early brain overgrowth and dysfunction in ASD.
-We theorize defects in prenatal regulation of neural genesis and apoptosis (cell death).

-In the first years of life, the autistic brain grows too large too fast.  This information has been found in numerous studies on autism by MRI or head circumference.  It was assumed that the growth was found in the frontal and temporal lobes because of the social/language association.  Discovered deviantly large, but posterior region of the brain was not. 

Differences in Age-Related FA changes in ASD and typically developing.
-Significant tracts.  What pathways of the brain are abnormally growing?
-What tracts are responsible?  Every signal tract that shows abnormality is frontal lobe or frontal lobe that connects with the temporal lobe (with emotions and tracts functional for language development) higher order frontal integration tracts.
-Growth of tracts start too fast, too large and too early.  Abnormal tracts flatten out and don't mature.
-We want to know about early frontal lobal overgrowth and  abnormal fiber tracts.  What starts this?

-Studied postmortem young ASD brains.  Counted the number of brain cells.  There are 65% more neurons in frontal (compared to typical child's) and 25% more in the medial.  The brain cells are generated before born, other than the dentate gyrus.  The increase of 65% is evidence that this is definitively prenatal.

-In 2 year olds with autism, there are twice as many brain cells than typical adults. 
-Autism is a continuous disorder of removal of excess brain cells and recircuiting of neurons.

Gene Regulations
-There are 102 genes that can abnormally express themselves in ASD toddlers. 

Disregulation in Genetic Pathways that Determine Cell Numbers and Functional Integrity:
-Neurogenesis
-Cell cycle regulation
-DNA damage responses (failure to get rid of damaged DNA in autism).
-Apoptosis and survival
-Migration and axon pathfinding (genes not properly functioning).
-Down regulation of neural-patterning genes (multiple genes turned down, showing not opearating correctly (ie., language), cause for right and left asymetry found in Dr. Pierce's study mentioned above.

-Genes are messed up from the very beginning because failure of the patterning gene. 
-Humans generate bulk of neurons in the middle of the second trimester.
-Patches of cortex that fail to develop normal layers of neurons-(failure of neurons)-do 3D reconstructions.
-Dysregulation of normal migration of cells.

Could be EITHER increased number of neurons OR failure of removal of bad cells.  If you had twice as many neurons, that means 4 times as many bad connections which is why autism is found many times in conjunction with other factors, ie., GI issues or seizure disorder.