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Summary of Advances Cover 2013
Summary of Advance
In Autism Spectrum Disorder Research
2013
Question 2: How Can I Understand What Is Happening?

Gastrointestinal problems in children with autism, developmental delays or typical development - Chaidez V, Hansen RL, Hertz-Picciotto I. J Autism Dev Disord. 2013 Nov. [Epub ahead of print] [PMID: 24193577]

Gastrointestinal (GI) problems associated with ASD are a common concern among many families who have a child with ASD. Though recently a number of studies have been undertaken to better understand the prevalence and characteristics of GI disruption, limitations posed by factors such as methodology, study population characteristics, and definitions of GI symptoms have presented some challenges in determining the scope of the issue. Researchers involved in the ongoing Childhood Autism Risks from Genetics and Environment (CHARGE) study examined this issue using their ethnically-diverse cohort. The aim was to learn more about not only the prevalence of GI disturbances (including abdominal pain, diarrhea, constipation, and food sensitivity), but to also gain a better understanding of the relationship between GI issues and maladaptive behaviors such as irritability, lethargy/ social withdrawal, stereotypical behaviors, hyperactivity, and inappropriate speech. The researchers compared GI symptoms and maladaptive behaviors in 960 children who were age, gender, and ethnically-matched among three categories: children with ASD, children with developmental delay (DD), and typically developing (TD) children. Data was gathered using self-administered standardized questionnaires including the CHARGE gastrointestinal history (GIH) questionnaire and the Aberrant Behavior Checklist (ABC), as well as through clinician-administered standardized instruments such as the Mullen Scales of Early Learning and the Vineland Adaptive Behavior Scales. Results indicated that children with ASD are approximately six to eight times more likely to report frequent gaseousness/bloating, constipation, diarrhea, and sensitivity to foods than TD children, with constipation, diarrhea, and food sensitivities or dislikes being the most common GI symptoms. The researchers suggested that their data support the possibility that some GI issues in children with ASD could be related to or exacerbated by food selectivity and restricted diets that may result from sensory issues or insistence on sameness, but further research would be needed to determine if this is the case. The data also indicated that children with ASD who experienced GI problems exhibited greater severity in certain maladaptive behaviors (irritability, social withdrawal, repetition, and hyperactivity). The researchers suggested that chronic GI symptoms causing pain, discomfort and anxiety, could potentially contribute to increased irritability and social withdrawal, particularly in someone with deficits in social and communicative skills, and that stereotypy and hyperactivity may represent coping mechanisms for the discomfort associated with GI conditions. The study results suggest that it is important for providers to consider GI issues that may be present when planning ASD therapy approaches, as addressing these issues could potentially help children with ASD address not only the discomforts associated with GI dysfunction, but also could result in improvement in behavioral symptoms. In addition, further research on GI issues in ASD may be helpful in determining the roles of the microbiome, the immune system, and the functioning of neurons in both the brain and gut in ASD.

Comorbidity clusters in autism spectrum disorders: an electronic health record time-series analysis - Doshi-Velez F, Ge Y, Kohane I. Pediatrics. 2014 Jan;133(1):e54-63. [PMID: 24323995]

ASD is sometimes accompanied by one or more comorbid health condition, such as gastrointestinal (GI) issues, seizures, sleep disorders and psychiatric disorders. However, the relationship between ASD and comorbidity is poorly understood, and although previous research has quantified the prevalence of various comorbidities, they do not occur evenly across the ASD population. The current study investigated the patterns of co-occurrence of these comorbid health conditions in those with ASD, identifying ASD subgroups with different sets (clusters) of co-occurring conditions. Researchers analyzed electronic health records from 4,927 individuals at least 15 years of age with a diagnosis of ASD, aggregating the standard international diagnostic classification codes found in the records (representing diagnoses each patient had received between the ages of 0 and 15 years) into categories in order to characterize the key patterns of ASD comorbidities that appeared in the records. This clustering analysis revealed three ASD subgroups, representing approximately 11% of the total study population, that exhibited different specific comorbidity patterns: one group was characterized by seizure disorders (120 people), one was characterized by psychiatric disorders such as depression and anxiety disorders (197 people), and one was characterized by more complex multisystem disorders (212 people), including auditory and GI disorders and infections. The remainder (4,316 people, or 89%) could not be grouped into meaningful clusters. Interestingly, across the 15-year period studied, the developmental trajectories—including developmental delays and age of diagnosis—of the different subgroups varied from one another. For example, those in the psychiatric disorder subgroup were more likely to be diagnosed with ASD earlier than those in the other subgroups, and the seizure subgroup was characterized by a spike in ASD diagnosis at age 10. The prevalence of psychiatric disorders was not correlated with seizure activity, but a significant correlation was found between GI disorders and seizures. These correlational results were validated using a second, smaller sample of 496 individuals from a hospital located in another geographic region. Delineated by different patterns of comorbidities, these ASD subgroups might reflect distinct biological underpinnings due to different genetic and environmental contributions. However, prospective longitudinal studies and additional clinical and molecular characterizations will be needed to validate and refine these findings. Such efforts will be helpful to further differentiate the developmental trajectories associated with each subgroup, providing valuable information about potential windows for intervention to reduce the disabling effects of these comorbidities.

Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders - Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde ER, McCue T, Codelli JA, Chow J, Reisman SE, Petrosino JF, Patterson PH, Mazmanian SK. Cell. 2013 Dec 19;155(7):1451-63. [PMID: 24315484]

Gastrointestinal (GI) problems frequently co-occur with ASD, and research has suggested that the presence of GI symptoms is correlated with more severe ASD symptoms. The composition of the bacteria found in the gastrointestinal tract, collectively referred to as gut microbiota, is vital to proper GI functioning, and several studies have suggested that people with ASD may have differences in their gut microbiota, though the nature of those possible differences has not yet been characterized. Some data from animal and human studies suggest that the gut microbiota could potentially affect social behaviors, emotion, and brain development, all of which are also impacted in ASD. In this study, researchers investigated how changes in the gut microbiota might affect behaviors in the offspring of maternal immune activation (MIA) mice, a mouse model whose offspring exhibit ASD-like behavioral characteristics, including problems with sensory processing, communication, and social behaviors. Examination of the GI tract of MIA mice showed a nearly three-fold increase of the permeability of the intestinal barrier, or the tendency of molecules in the gut to cross the intestinal wall and exit into the general circulation. These mice also had a different composition of species within their gut microbiota compared to control mice and higher expression of cytokines (proteins associated with immune response and inflammation). Next, the MIA mice were given an oral probiotic supplement containing the bacterial species Bacteroides fragilis, which is found in the human gut and has previously been shown to effectively treat experimental colon inflammation in an animal model. Remarkably, the MIA mice treated with an oral probiotic containing B.fragilis restored intestinal barriers, repopulated gut microbial species that more closely resembled controls, and normalized cytokine levels.

Treatment with B.fragilis also corrected behavioral symptoms of MIA mice; their abnormalities in sensory processing, communication, repetitive behaviors, and anxiety were reversed. Only social interactions remained altered in MIA mice after B.fragilis treatment; both treated and untreated MIA mice chose to spend significantly less time in proximity to other mice. Finally, the researchers examined the levels of certain metabolites—or molecules that result from the process of metabolism in the gut—that have been shown to cross the weakened intestinal barrier into the bloodstream in MIA mice (a process that is reversed in these mice by probiotic treatment with B.fragilis). They found that not only can an induced increase in some of these metabolites cause anxiety-like behaviors in normal mice, but both normal metabolite levels and normal behaviors can be restored by B.fragilis treatment. In summary, this study establishes the presence of GI symptoms in a mouse strain that exhibits ASD-like symptoms, suggesting the possibility that in humans, the roles of the gut, the microbiome, and the brain may be similarly intertwined in causing ASD symptoms. The study demonstrates the ability of B.fragilis to correct both GI and behavioral symptoms in these mice, suggesting that if similar relationships are found in human ASD, it may be possible to develop innovative new treatments for ASD that target the composition of the gut microbiota.

Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism - Willsey AJ, Sanders SJ, Li M, Dong S, Tebbenkamp AT, Muhle RA, Reilly SK, Lin L, Fertuzinhos S, Miller JA, Murtha MT, Bichsel C, Niu W, Cotney J, Ercan-Sencicek AG, Gockley J, Gupta AR, Han W, He X, Hoffman EJ, Klei L, Lei J, Liu W, Liu L, Lu C, Xu X, Zhu Y, Mane SM, Lein ES, Wei L, Noonan JP, Roeder K, Devlin B, Sestan N, State MW. Cell. 2013 Nov 21;155(5):997-1007. [PMID: 24267886]

As techniques for studying the human genome have advanced, an increasing number of genes are being associated with ASD; it is important to find the connections between these ASD-linked genes in order to understand how they may contribute to ASD. A new resource called the BrainSpan1 atlas provides researchers with three dimensional maps showing when and where genes turn on and off in the human brain, from embryonic stages through older adulthood. This study used the BrainSpan atlas to identify commonalities in when and where ASD-associated genes are expressed. It focused on nine genes with de novo (or spontaneous) loss of function (LoF) mutations that have each been identified in multiple families with ASD, providing a high level of confidence that these genes are associated with ASD; these are notated as "high-confidence" ASD genes or "hcASD genes." Comparison of the expression patterns of these genes throughout the structures of the brain as it develops revealed that the greatest overlap of hcASD genes occurred in deep layers of the cortex during the period of fetal development ranging from 10-24 weeks post-conception (the midfetal period, during the first and second trimesters of pregnancy). Next, this time and location of overlap in hcASD gene expression were examined for expression of de novo LoF mutations that have been associated with ASD in one family, referred to as "probable ASD" (pASD) genes. This analysis showed enrichment of pASD genes in two specific brain regions, the prefrontal and primary motor-somatosensory cortex, during the midfetal period. The researchers also looked at hcASD gene products (RNA and protein) in brain tissue taken during this midfetal developmental time point, and found high expression in deep cortical layer neurons that send information over long distances, called cortical projection neurons. The finding that midfetal brain development is important in ASD corroborates previous studies that have shown pregnancy to be a key time window in the development of ASD. The findings also have important treatment implications by linking genetic information to the specific functional processes they control. By using the shared characteristics of different gene mutations implicated in ASD, this study creates a picture of the developmental processes that are changed in these cases. This image provides a sharper focus for the development of targeted treatments, and even holds potential for the development of personalized interventions based on genotype.

References

1 BrainSpan atlas

Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism - Parikshak NN, Luo R, Zhang A, Won H, Lowe JK, Chandran V, Horvath S, Geschwind DH. Cell. 2013 Nov 21;155(5):1008-21. [PMID: 24267887]

New research is grouping together ASD-linked genes based on similarities in the timing and location of their expression. As more information is collected and analyzed about the genetic differences found in people with ASD, an increasing number of genes have been identified that could potentially play a role in the development of the condition. The next step is to understand how these genes may be altering brain development in ways that result in ASD. Genes turn on and off in different brain areas at different times during development, and this information has now been collected in the BrainSpan atlas, a powerful new database that shows the expression of genes in three dimensions across the entire human brain as it develops from infancy into adulthood. Many genes can also be grouped broadly by their function, such as a role in building connections between neurons (synapses) or in nervous system development.

In this study, the researchers used the BrainSpan atlas to group all genes that are expressed in the brain based on their timing of expression during brain development, location of expression, and function; they called the 12 resulting groups of related genes "modules." Next, they examined these modules for genes that have previously been associated with ASD or intellectual disability (ID). The results showed that ID-associated genes were not overrepresented in any of the 12 modules, while ASD-associated genes were mostly found (enriched) in modules 13, 16, and 17, which are groups of genes that are responsible for establishing synapse function during prenatal and early postnatal development. The highest enrichment of ASD genes was found in module 16, whose expression increases during fetal development, starting in the 10th week after conception. A separate analysis of rare de novo gene mutations linked to ASD revealed enrichment in modules 2 and 3, modules whose expression peaks between the 10th and 22nd week after conception (the midfetal period, during the first and second trimesters of pregnancy) and whose genes are involved in neuronal differentiation and migration. The study also looked at factors related to the ways in which ASD-related genes are expressed. Gene expression turns on and off with the help of proteins known as transcription factors and translational regulators—and more than one gene can be controlled by the same factor or regulator. The researchers found 17 transcription factors whose targets link the different modules enriched for ASD-related genes. One translational regulator strongly associated with the ASD modules was FMRP, which is the protein mutated in Fragile-X syndrome, which can also cause ASD. Finally, the researchers looked for whether these ASD and ID gene sets were more likely to be found in particular cortical layers. Interestingly, the localization of expression of ASD and ID genes differed, with ASD genes being more highly expressed in a different cortical layer than the one that was enriched for ID genes, a finding that suggests that ASD and ID are biologically distinct. This study and the Willsey et al. study (also included in the Top 20 Summary of Advances) both used the BrainSpan atlas, although the criteria they used for including genes in the studies were different. However, both studies converged on the importance of prenatal brain development and the role of cortical neurons in ASD. Both also contribute to a better understanding of how genes are linked to ASD symptoms, which may lead to improved treatments.

Question 2

 
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