Conference proceedings: Inaugural meeting of the consortium for autism, genetic neurodevelopmental disorders, and digestive diseases

Objectives: Individuals with neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), often experience a higher prevalence of gastrointestinal (GI) symptoms but have complex medical and behavioral comorbidities that make diagnosis and treatment difficult. A multi-stakeholder conference was convened to (a) determine patient and family experiences related to GI symptoms in NDDs, (b) review the clinicians’ and researchers’ perspectives, and (c) determine actionable steps for future research.

Methods: The Consortium for Autism, Neurodevelopmental Disorders and Digestive Diseases (CANDID; www.candidgi.com) virtually over 2 days in 2022 and consisted of four key activities: (1) an electronic family survey to assess underlying NDDs and GI symptoms, (2) a session focused on family perspectives, (3) review current clinical care and research, and (4) discussion to identify key next steps. Survey results were obtained electronically via the REDCap platform, and descriptive statistics were generated. The sessions were recorded, and themes were identified.

Results: The pre-conference survey ran for ~2 months and 739 families provided responses, with 634 completing all items. 83% had a child with an NDD under age 18, and most patients were White (85%) and non-Hispanic (87%). Constipation (80%), GI reflux disease (51%), and bloating (49%) were the most frequently reported symptoms. Families gave unstructured feedback that the measures used in the surveys were often difficult to answer for patients with NDDs or who were nonspeaking. Family and clinical/scientific sessions identified several common themes, including (1) the need for less invasive diagnostic modalities, (2) the need to validate or adapt existing diagnostic measures (e.g., the Rome IV criteria) and outcome assessments, and (3) the need for enhanced attention to parent and caregiver input in treatment plans.

Conclusions: Those providing care to children with NDDs, especially those with communication and cognitive challenges, should be aware of the differing needs in this community and consider family perspectives in managing, treating, and measuring GI issues. Future research should focus on adapting or creating diagnostic and research measures for those with NDDs, developing new diagnostic methods to account for diversity in neurodevelopment and communication, and improving methods for family and caregiver engagement in the care of GI disorders.

Are you the grandparent, cousin, aunt, uncle, sibling, or half-sibling of someone with autism and wondered “what is the likelihood of autism in families, and the likelihood of comorbid conditions if I have a family member with autism?” Listen to this week’s podcast. Researchers at the AJ Drexel Autism Research Institute and Aarhus University in Denmark collaborated to calculate probabilities between autism in a person and dozens of other comorbid conditions in family members. They not only made the paper open to the public for everyone to read it, but they also created a publicly available data visualization tool so anyone can go on and look at specific situations of particular family relationships relating to anything from autoimmune conditions to mental health and psychiatric diagnosis. Links below for reference:

https://pubmed.ncbi.nlm.nih.gov/39283002

Interactive graphs: https://public.tableau.com/app/profile/diana.schendel/viz/ASDPlots_16918786403110/e-Figure5

Individuals with profound autism may sometimes exhibit neuropsychiatric regression, which can include catatonia, hyper aggression, and cognitive decline. This regression has been linked to infection in girls with Phelan McDermid Syndrome, a genetic condition associated with profound autism. There is some preliminary evidence linking the administration of anti-inflammatory drugs to the reversal of this regression. This animal model study will look at whether mice with the genetic mutation associated with Phelan McDermid Syndrome are more susceptible to the effects of inflammation-inducing drugs, and whether these effects can be mediated by inflammation-reducing drugs.

There has been a strong push to test new gene therapies in autism, including use of new antisense oligonnucleotide therapy, which targets working copies of genes to increase production of its associated protein. This highly innovative approach could remove a major bottleneck in the development of gene therapies for autism by developing a new way to test genetic therapy targets genome-wide.

Many lines of evidence have shown that brain regions do not communicate well in people with autism, leading to symptoms of ASD.  This can include too much or too little connectivity between brain regions, causing decreased or misdirected connections. Applying a technology new to autism, individual neurons will be labeled with bar codes and then tracked to determine where and how brain cells connect. This novel approach will allow scientists to better understand the nature of connectivity problems in autism, and potentially provide clues to new druggable targets.

The autism genome is comprised of genes that directly regulate protein expression and genes that indirectly regulate activity by turning on or off genes that affect protein expression. The latter genes are described as  “epigenetic” and are influenced by both genetic mutations and environmental factors. What is not known is whether epigenetic mutations affect downstream processes related to autism like altering connections or function of brain cells. This project will use human induced pluripotent stem cells, or iPSCs, with a mutation of a gene called SETD1A that controls epigenetic gene regulation to examine the effects of mutations on gene expression in different types of cells. In addition, this fellow will examine how these mutations affect brain cell shape and functionality. Finally, they will investigate whether these effects are reversible, leading the way to new therapies that can help those with ASD.

The UBE3A gene is thought to be responsible for Dup15q Syndrome, one of the genetically derived autism spectrum disorders (ASD). Despite its clinical importance, we know very little about UBE3A distribution in the human brain. Most researchers assume it closely mirrors that of the rodent brain. This lack of knowledge could be catastrophic if the distribution of UBE3A in the human brain is improperly inferred from rodent studies and leads to inappropriate delivery and treatment strategies for autism. To assure the safe targeting of therapeutic approaches to normalizing UBE3A levels in individuals with Dup15q Syndrome, this fellow will study UBE3A developmental expression in the closest proxy we can get to the human brain – the brain of the rhesus monkey.

More and more evidence is pointing to sex-related differences in gene expression as a potential explanation of the male sex bias in autism diagnosis. This study will examine the role of a gene called MYT1L that has been linked to autism. Mouse models will examine the expression of this gene in the cortex (where there is no evidence of a sex difference in expression of MYT1L) and compare it to expression in the hypothalamus (where there are sex-specific differences linked to social behaviors). The fellow will also examine social learning in males and females and count neurons to look for both behavioral and cellular changes. This will determine where in the brain sex-differential effects in social behavior originate, providing evidence for more targeted intervention strategies in males and females with autism.

Autism has a well-established and prominent 4:1 male: female bias in diagnosis, but the biological basis for this difference remains unknown. One possible theory is that the presence of estrogen may play a role in the activity of brain cells that turn neurons on or off, which is part of the “excitation/inhibition” theory in autism. To test this theory, this fellow will create different types of neurons using induced pluripotent stem cells from both males and females with autism, with and without a rare genetic variation in an autism gene called neurexin. Then, estrogen will be applied to these cells and gene expression and functioning of different cell types will be compared. This gene-by-environment study will help identify the role of estrogen during development as a component in the later biological and behavioral features of females compared to males with autism.

Recent research has implicated the gene PTCHD1 on the X chromosome as contributing to the causes of autism and intellectual disability, but there is still very little known about what it does and how it leads to changes in the brain. This project will be the first-ever attempt to determine the function of the PTCHD1 protein in its natural biological setting. Cells will be manipulated to create mutations in PTCHD1, then turned into neurons, and then the proteins that are expressed will be measured. Finally, the fellow will measure how these proteins interact in the brain. This will enhance our understanding of how this gene interacts with the rest of the brain and expand the range of therapeutic approaches intended to target specific types of dysfunction in people with autism.

Oversensitivity to touch is common in autism and can lead to discomfort and harm. In some cases, people with autism avoid other people’s touch but seek out tactile stimulation through self- stimulatory behaviors. Self-stimulation can be anything from finger tapping to headbanging, which is harmful and dangerous. While the differences in the brain’s response to different types of touch have been studied in neurotypical people, there is little information on the different responses in people with autism. This fellow will examine how the autistic brain responds to different types of touch, ultimately providing a biological basis for determining why some touch is avoided while some is sought out, which could improve therapy for dangerous self-stimulatory behaviors.

Rett Syndrome is caused by a mutation on the X chromosome at MeCP2. Girls with Rett Syndrome share many features of autism, including delayed or lack of language development, impaired fine motor skills, repetitive behaviors and cognitive disability. MeCP2 activity is also regulated by environmental factors and has been implicated in autism when a genetic cause has not been identified. This fellow will look closely at changes in MeCP2 binding and how it regulates gene expression by isolating different types of neurons at different ages to determine which are critical in the progression of symptoms. The fellow will also employ a sophisticated analysis of machine learning techniques to integrate the data to predict how MeCP2 activity regulates different neuron types at different points in development. This will allow scientists to move closer to providing patients with targeted approaches to interventions.