Science with Sara

In this month’s Science with Sara blog entry, I’ve asked two researchers from the University of Washington & Seattle Children’s Research Institute — whose work falls under the broad area of the Biology Underlying ASD – to highlight an important or informative review or summary paper from their field.

Dr. Stephen Smith PhD is an Assistant Professor at the UW and Seattle Children’s Research Institute. His work focuses on how proteins located at the junctions between brain cells (called synapses) work or, in the case of neurodevelopmental disorders, why they might malfunction. Dr. Smith uses multiple animal models of ASD in order to understand how different genetic variants impact synapse function, and in turn, how this changes how a person learns and remembers.

Dr. Smith’s Pick:
• Sestan, N., & State, M. W. (2018). Lost in Translation: Traversing the Complex Path from Genomics to Therapeutics in Autism Spectrum Disorder. Neuron, 100(2), 406-423. https://www.sciencedirect.com/science/article/pii/S0896627318309036

“This beast of a review paper is co-authored by Dr. Matthew State, who has been at the forefront of gene discovery in Autism for many years. I hesitate to recommend this paper for a non-specialist audience because it is so dense, but its depth and quality make it worth the effort. While it’s a bit heavy on the details of the genetics (Dr. State is a geneticist, after all), the main takeaway is that, after many years of gene discovery, we are beginning to understand the central pathways that are disrupted in autism- neuronal signaling, dynamic control of DNA translation, and how those processes play central roles in development. State and his co-author Dr. Nenad Sestan then discuss future efforts to understand how mutated genes lead to atypical behavior. Although this is clearly a difficult path, they outline a plausible route that many research groups, including mine, will be taking in the years ahead.“

You can find a full list of Dr. State’s work on pubmed.gov.

Dr. Smith’s website provides updates on the work in his lab.

Dr. Smita Yadav PhD is an Assistant Professor in Pharmacology at the UW. Her work focuses on neuronal networks (networks of brain cells) and specifically on how molecules regulate communication between brain cells. One focus of Dr. Yadav’s research is in the 16p11.2 genetic location – there are 29 genes that are in this region of our DNA, and structural changes to this area of our DNA are associated with both ASD and schizophrenia.

Dr. Yadav’s pick:
• Quesnel-Vallières, M., Weatheritt, R. J., Cordes, S. P., & Blencowe, B. J. (2018). Autism spectrum disorder: insights into convergent mechanisms from transcriptomics. Nature Reviews Genetics, 1. https://www.nature.com/articles/s41576-018-0066-2

“The first one is a review about understanding the ~75% non-syndromic, idiopathic cases of autism. The authors argue that a common pathway is emerging from transcriptome analyses that implicates RNA processing in ASD. The evidence includes: (1) cortical patterning of gene expression is lost in autism; (2) mRNA, lncRNA, miRNA and other non-coding RNA programmes are disrupted in ASD; (3) subsets of mRNAs regulating neuronal processes are consistently downregulated in individuals with ASD; and (4) RNA splicing regulatory programmes disrupted in ASD are responsive to neuronal activity and, conversely, affect neuronal activity.”

• Amin, N. D., & Paşca, S. P. (2018). Building models of brain disorders with three-dimensional organoids. Neuron, 100(2), 389-405. https://www.sciencedirect.com/science/article/pii/S089662731830895X?via%3Dihub

“The second paper is a review on using 3D brain organoids to model neuropsychiatric diseases. While this review is not specific to autism, in my view, this space is where a lot of the research on the biological basis of autism will be in the future. The different kinds of organoids and the questions that we can now ask are quite amazing. Some caveats of this technology remain.”

Additional References

IACC Office of Autism Research Coordination Summary of Advances in Autism Spectrum Disorder Research: Calendar Year 2017. Question 2: What is the Biology Underlying ASD?
https://iacc.hhs.gov/publications/summary-of-advances/2017/question2.shtml

IACC Office of Autism Research Coordination Strategic Plan For Autism Spectrum Disorder Research 2016-2017 Update. Question 2: What is the Biology Underlying ASD?
https://iacc.hhs.gov/publications/strategic-plan/2017/question2.shtml

For this blog, I invite Dr. Emily Neuhaus (who also blogs under “Ask Dr. Emily”) to join me in talking about her recent paper — Gastrointestinal and Psychiatric Symptoms Among Children and Adolescents with Autism Spectrum Disorder.

With Dr. Raphe Bernier (Executive Director of the Seattle Children’s Autism Center) and Dr. See Wan Tham (Anesthesiologist and specialist in GI pain management), we examined the relation between GI problems and other problem behaviors in children with ASD. To do this, we used the large Simon’s Simplex Sample (SSC) data set– which is a data set of 2,800 4 to 18 year old children and adolescents  with ASD, and includes detailed information about the child’s symptoms, adaptive functioning (ability to handle everyday tasks like getting dressed, eating, grooming, etc.), medical concerns, and genetic events. The paper is available free through Frontiers in Psychiatry.

Why examine the relation between GI symptoms and psychiatric problems? The actual prevalence of GI problems in children with autism varies wildly across different reports – some estimates are relatively low, suggesting that 15-20% of children with autism experience GI difficulties, while other researchers have found rates of GI problems as high as 90% (see Neuhaus et al., 2018). While the links between GI problems and ASD is unclear, it is clear that children with ASD have elevated rates of GI problems.

Individuals with ASD are also at elevated risk for developing additional psychiatric problems across the lifespan with over 92% of children aged 4-14 with ASD reported as meeting criteria for attention-deficit/hyperactivity disorder, oppositional defiant disorder, anxiety, or mood disorder (Brookman-Frazee et al., 2018).

Given that GI problems can cause significant pain and disruption of daily activities, might they also be playing a role in whether or not children develop other psychiatric problems?

What are GI problems?

In the SSC sample data set, 7 GI problems were included in our analyses– constipation, diarrhea, severe abdominal pain, gastro-esophageal reflux, vomiting, excessive gas, and bloating. We limited our analysis to symptoms that occurred after 36 months of age, were recurrent, not attributed to illness, and caused “significant bother”. We examined psychiatric problems via parent report of internalizing (anxiety and depression), externalizing (aggression and rule breaking) and self-injurious behavior (e.g., biting or hitting self). (We will focus on externalizing and self-injury in this blog.) In addition, we considered child characteristics such as race/ethnicity, sex, age, extent of ASD symptoms, IQ (verbal and non-verbal), and adaptive behavior; as well as family factors such as household income.

Results

 Overall, 37.7% of the children with ASD were reported as having at least 1 GI problem, including constipation (24.1%), diarrhea (10.6%), and gas, reflux, and abdominal pain (~5-6% each). Moreover, 22.8% of the children had clinical levels of externalizing problems (aggression and rule breaking), suggesting that these were meaningful issues for those children and their families.

 What childhood characteristics were related to externalizing problems (aggression and rule breaking) and self-injury? In children aged 4-18 years, children with more ASD symptoms, better language, lower adaptive skills, lower household income, and more GI problems had more externalizing problems (aggression and rule breaking). Similarly, more self-injurious behavior was also related to more ASD symptoms, lower adaptive skills, and lower household income. In the younger group (4 to 9 years) (but not in the older group aged 10 to 18 years), more GI problems were also related to self-injury.

 Of note, a similar study by Rattaz et al. in 106 young adults with ASD found that more autism symptoms and more GI problems predicted the development of more stereotypy behaviors in adulthood.

 Thus, in children with ASD, GI problems may be contributing to the presence of externalizing behaviors in children with ASD, and self-injury in younger children with ASD. This is important to consider in providing mental health care to children and families with ASD, since addressing GI problems could be a helpful part of reducing behavior problems.

While we can’t determine if GI problems play a role in whether or not a child will develop other psychiatric problems – we would need a longitudinal study to do this– GI problems likely negatively impact daily living and quality of life.

Resources

Another resource for an update on GI issues in ASD is the recent ASF podcast by Alycia Halladay.

 References

Brookman-Frazee L, Stadnick N, Chlebowski C, Baker-Ericzén M, Ganger W. Characterizing psychiatric comorbidity in children with autism spectrum disorder receiving publicly funded mental health services. Autism. SAGE PublicationsSage UK: London, England; 2018 Nov;22(8):938–952. PMID: 28914082. https://doi.org/10.1177/1362361317712650

Halladay, A. (2018, Nov). Scientist know in their gut how the GI symptoms are linked to autism.

https://asfpodcast.org/archives/660

Neuhaus E, Bernier RA, Tham SW, Webb SJ. (2018). Gastrointestinal and Psychiatric Symptoms Among Children and Adolescents With Autism Spectrum Disorder. Frontiers in Psychiatry. 9:515. PMCID: PMC6204460. https://www.frontiersin.org/article/10.3389/fpsyt.2018.00515/full

Rattaz C, Michelon C, Munir K, Baghdadli A. Challenging behaviours at early adulthood in autism spectrum disorders: topography, risk factors and evolution. Journal of Intellectual Disability Research. Wiley/Blackwell (10.1111); 2018 Jul;62(7):637–649. PMID: 29797498. https://onlinelibrary.wiley.com/doi/abs/10.1111/jir.12503

Welcome to Dr. Dimitri Christakis who joins me in writing today’s blog. Dr. Christakis is a noted expert in the effects of media use on child development and author of The Elephant in The Living Room: Make Television Work for Your Kids.

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