Autism Twin Studies Point to Key Next Steps

Angelica Ronald and Rosa Hoekstra have written a nice review of recent twin studies in autism spectrum and autism traits.  The review is online prior to print in the American Journal of Medical Genetics Neuropsychiatric Genetics.

They note in the review that twin studies have evolved from a perspective of looking at narrowly defined autism, to the broader category of autism spectrum to an even broader phenotype, the dimensional character of autistic traits in the general population.

I don't know much about autism traits in the general population but this twin studies review highlighted some current understanding.

• Relatives of individuals with autism spectrum disorder show elevated autistic traits
• Autistic traits in the general population show a smooth distribution through the normal range to the clinical extreme--this suggests a biological continuum rather than a normal or disease clinical status
• Understanding the cause of variation of autistic traits in the general population is likely to aid in the understanding of autism
• The heritability of autistic traits in the population is very heritable (genetic) ranging from 40 to 60% in young twins but increasing to 60 to 90% in adolescence.

Another insightful section of the manuscript dealt with the degree of genetic and environmental overlap between different autistic symptoms.  Autism spectrum is made up of a triad of symptoms: social impairment, communication impairment and restrictive behaviors and interests.  Twin studies suggest these different symptom clusters may be "fractionable", meaning they may have some independence from each of the other clusters.  The authors note more genetic and twin studies should focus on one symptom cluster of the triad, rather than only studying those who have all three components.

The authors note that twin studies have helped explain the relationship between autism and intellectual disability and low IQ.  There appears to be some common genetic contribution to autism and intellectual disability.  However, since some individuals with autism and ASD have relatively normal intelligence, the picture is complex.  Studying ASD in those with normal intelligence may provide further insight into specific autism genetic influences. 

What needs to be done in the future?

Need for twin studies to tease out genetic and environmental factors that explain the common co-occurence of autism, ASD and autism traits with conduct disorder, sleep disorders, antisocial behavior and depression.

More attention needs to focus on genetic and environmental effects on developmental change in ASD and autistic traits in children (only two current studies published) and in adults (zero studies published).

More research on age-appropriate measures of autism traits--measures appropriate for one developmental age may not be appropriate for other ages.

More studies are necessary to look at cognitive phenotypes in autism and autism traits .

Photo of St. Louis Cardinal Daniel Descalso Courtesy of Yates Photography

Ronald, A., & Hoekstra, R. (2011). Autism spectrum disorders and autistic traits: A decade of new twin studies American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 156 (3), 255-274 DOI: 10.1002/ajmg.b.31159

Autism: Social Lives of Young Adults

One of the problems with understanding the natural history of autism is the lack of well-designed outcome studies in the disorder.  Outcome studies tend to be expensive and grant agencies commonly do not fund studies longer than a few years. However, given the increased interest and funding in autism, I suspect there will be more research in this area.

An example of how outcome studies help in understanding the natural history of autism is a study published ahead of print by the Journal of Developmental and Behavioral Pediatrics.  Dr. Gregory Liptak and colleagues from SUNY Upstate present a four year follow up of 725 adolescents with autism.  The average age at intake was 15.4 years with average age at follow up 19.2 years.

The study examined some key global items in function and social interaction.  I summarize some of the factors related to three key areas of function (% with this variable):

Being employed (48%) or in postsecondary education: This two-option level of achievement was positively correlated with higher family socioeconomic status (above the poverty level), not needing prescription drugs to control symptoms, good general physical health and having a parent who was involved in the school.  Negative correlations for this level of achievement was associated with conversational difficulty, a history of being teased and lower IQ.

Obtaining a driver's license (4.5%):  Few adolescents or young adults in this sample had a drivers's license.  Again this achievement was associated with higher socioeconomic status, caucasian race, a two-parent household and parental involvement in school activities.  A negative correlation with obtaining a driver's license was higher number of required school services.

Getting together with friends at least once in last 12 months (44.6%):   A positive correlation was noted with communication ability and good general health status.  A weak negative association was noted with non-white race status and male gender.

The authors note that this group of young adults with autism showed persistent differences in academic achievement and  social behavior compared to age-matched adults without autism.  In the young adults with autism 83% were living with their parents and 75% never used instant messaging, a chat room or e-mail.

The authors noted that their study did not examine whether young adults with autism (or their families) wanted more social interaction.  We often assume the more social participation the better, but this may not be the same for all. 

Even prospective studies have some limitations on interpreting causal contributions to outcome.  However, this study supports several components to planning services for children with autism.  These include reducing effects of poverty, reducing teasing/bullying in the environment, encouraging parents to be active in the school setting, early social and speech therapy and management of physical and mental co-occurring conditions.  

Photo of Female Cardinal Courtesy of Yates Photography

Liptak GS, Kennedy JA, & Dosa NP (2011). Social Participation in a Nationally Representative Sample of Older Youth and Young Adults With Autism. Journal of developmental and behavioral pediatrics : JDBP PMID: 21285894

How a Physician with Asperger Syndrome Made $100 Million

Life histories form one method of understanding some of the diversity of outcomes for clinical neuroscience disorders.  I had the opportunity over the holidays to read Michael Lewis’ The Big Short, a summary of some of the key players in the subprime mortgage debacle.  Expecting a financial education, it was a surprise to find an interesting story about a physician with high functioning Asperger syndrome.

Asperger syndrome is an autism spectrum disorder that includes difficulties in social interaction often paired with a restricted but intense focus on specific interests.  Cognitive development can be quite preserved in some individuals with Asperger syndrome, although most suffer from some cognitive impairment. 

The Big Short follows the history of the subprime mortgage problem as it developed in the mid 2000 time period.   A central question in the book is:  Why were so many experts surprised by the subprime crisis and unable to protect their financial assets from the manifestations of the subprime collapse?  A corollary to this question is:  Who were the people who saw the problem early and were able to financially benefit from their unique perspective and wisdom?

Enter Dr. Michael Burry.  Dr. Burry is a physician with an outstanding academic record.  Graduating from Vanderbilt University School of Medicine, Dr. Burry entered a prestigious residency in neurology at Stanford University.  Along with his busy medical career, Dr. Burry was fascinated by analysis of securities and other stocks.  He spent long hours at night during medical training pouring over financial statements and posting on financial message boards. 

During his residency training, he came to decide that he was more interested in financial analysis and money management.   To the dismay of family and colleagues he decided in 2000 to quit medicine and start his own hedge fund.  With $145,000 in student loan debt, such a decision seemed foolish to many.  But Dr. Burry knew he had good skills in finance and he also knew that some of the interpersonal aspects of medicine were not his strengths.

Dr. Burry was able to recruit investors to his hedge fund and received money by selling a portion of the fund.    Continuing his financial research, he identified the extreme risk associated with subprime mortgages, accurately assessing the risk for high default risks in these bonds.  Knowing the higher risk, he placed big bets the mortgage bonds would collapse.  Placing short investments in these bonds, he and his investors benefited with the collapse of the bonds.  Dr. Burry profited by taking $1 million to $100 million in only a few years. 

The neuroscience part of the story is unraveled late in the book.  After getting married, Dr. Burry has a son who displays problems with social interaction and restricted focus.   His son receives a comprehensive assessment and is given a diagnosis of Asperger syndrome.  As he receives this information, he and his wife begin to understand that Dr. Burry also has Asperger syndrome.  Despite his academic brilliance and medical training, it wasn’t until his son received an assessment that his own diagnosis became clear.

Since his diagnosis, Dr. Burry has received counseling specifically to help him understand his social limitations and how he can better relate to his family.  He understands that the intense interest in obscure subject matter is part of Asperger syndrome.  His intense interest in financial analysis led to his ability to be one of the first people to predict (and personally benefit) from the subprime mortgage collapse.

So here are the take away neuroscience messages for me on this story.  First, many adults with Asperger syndrome are undiagnosed with some only receiving a proper diagnosis later in life.  Second, although this disorder causes significant impairment in most, some individuals may turn their intense focus (a symptom of Asperger) into important discoveries in finance and well as other arenas, i.e. science or computer technology.   It’s a complex disorder with heterogeneous outcomes.  We need to better understand the neuroscience of this condition.

Vanity Fair article summarizing the Dr. Burry part of The Big Short

Amazon link to Michael Lewis’ The Big Short

Bloomberg video with Dr. Burry (September 2010) showing his current financial investments

Photo of Lions in Kenya Courtesy of Sarah Yates

Should Every Child with Autism Have an EEG?

TED presentation by Dr. Aditi Shankardass brings up an important question--should all children with autism (or those undergoing an assessment for autism) have an EEG.  The presenter notes that in her experience in India, up to 50% of children referred with a diagnosis of autism have a seizure disorder or some other neurodevelopmental disorder.  The TED talk is posted above (7 minutes) and here are my notes from the presentation.

• 1 in 6 children suffer from developmental disorder
• Most diagnosed solely on symptoms
• Accuracy of diagnosis improved with laboratory measures
• Technology holds hope for diagnosing brain disorder
• She worked in a Harvard lab studying mathematical models to measure brain activity
• Statistical probability mapping combines EEG and statistical science
• She is setting up this technology in India

• Case study--seven year old referred with a diagnosis of autism
• EEG study was quite helpful
• Child did not have autism but had a seizure disorder
• Antieplileptic medication resulted in dramatic improvement
• She has found a significant number of children diagnosed with autism that had seizure disorders in the Indian referral population, this may be up to 50% of cases

So what about assessment guidelines for autism in the United States and Europe?  One of the best autism guidelines I could track down came from the Scottish Intercollegiate Guidelines Network.  This free guideline pdf document can be located here.  The guideline is titled:  "Assessment, diagnosis and clinical interventions for people with autism spectrum disorders. A national clinical guideline".

The guidelines provide a comprehensive review of the evidence supporting a variety of measures in the assessment process. The recommendation from the guideline related to standard EEG assessment is summarized: "Whilst epilepsy is common in children with ASD, there is no indication for an electroencephalogram (EEG) in the absence of other clinical criteria."  This recommendation comes with a citation from a 2005 review article by Kagan-Kushnir.

This review notes that seizures occur in 20-30% of children with autism and EEG abnormalities have been found in 10 to 72% of study samples.  Subclinical EEG abnormalities have been found in 6-30% of samples.  The authors note "There is insufficient evidence to recommend for or against the use of screening EEGs in autistic patients.  Given the frequency of seizure disorders in this patient population, a high index of clinical suspicion should be maintained for subtle symptoms of seizures".

The EEG technique referenced by Dr. Shankardassappears to be quantitative EEG or qEEG, a more complex EEG analysis than that done in a clinical setting.  qEEG research is ongoing at the TRANSCEND Research laboratory at Harvard directed by Dr. Martha Herbert. Dr. Herbert and colleagues have investigated a variety of EEG research measures in autism.  Recent findings indicate that autism subjects show decreased synchrony between the right and left brain hemispheres.  The clinical implications of these findings are unclear at this point.

It is unlikely that the percentage of undiagnosed clinically significant seizure disorders in autism in developed countries is high.  Nevertheless, clinicians and parents should be alert to potential subtle and non-subtle signs of seizure disorder in those with autism.  Additionally, it is not common for a child diagnosed with epilepsy to be misdiagnosed as autistic and to be "cured" by anti-epileptic therapy in the U.S. or Europe.  Although not unheard of, this misdiagnosis is reduced with comprehensive multidisciplinary assessments.  Concurrent autism and epilepsy (and EEG abnormalities) is a more likely clinical scenario than one disorder being misdiagnosed an the other.

The clinical diagnosis of autism and differential diagnosis of epilepsy continues to be one made primarily by careful history, observation and application of diagnostic criteria. Although this approach is not perfect, it does approach the reliability and validity found for other common medical conditions. When applied in a multidisciplinary setting, this approach is unlikely to misdiagnose a child with epilepsy as having autism alone.

So I think the question of need for an EEG in the context of autism should be left to the discretion of the managing physician.  Many will need an EEG as part of the assessment and differential diagnosis.  Some may not need them and the the managing physician is best able to make this distinction.

Kagan-Kushnir T, Roberts SW, & Snead OC 3rd (2005). Screening electroencephalograms in autism spectrum disorders: evidence-based guideline. Journal of child neurology, 20 (3), 197-206 PMID: 15832609

Isler JR, Martien KM, Grieve PG, Stark RI, & Herbert MR (2010). Reduced functional connectivity in visual evoked potentials in children with autism spectrum disorder. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology PMID: 20605520