Q&A Report - LIVE SEssion with researchers
To provide information and support to the families of patients with TRIO gene mutation, a live meeting was held on November 14, 2023.
The question were answered by researchers from the Department of Molecular Biotechnology at the University of Turin, Prof. Giorgio Merlo and Dr. Carla Liaci, and Prof. Giorgia Quadrato (University of Southern California, Los Angeles, USA).
These researchers are working on human neurons carrying the TRIO mutation.
The meeting was organized by Team TRIO.
This page presents a summary of the Q&A session of the live meeting, where the researchers addressed some of the most common and important questions from the families
Q1: Can you discuss the link, if any, between trio and autism?
A: Mutations in the TRIO gene, which provides instructions for making a protein involved in brain development, have been linked to autism spectrum disorder (ASD). Studies show individuals with ASD have TRIO gene mutations, which can disrupt the protein's function and lead to changes in brain development and function. The link between TRIO ablation and ASD pathoetiology has been investigated in the context of GABAergic interneurons (i.e., inhibitory neurons) functionality (DOI: 10.1038/s41380-021-01109-x).
Q2: Can your microcephaly study findings aid TRIO macrocephaly research? Considering macrocephaly stem cell studies in the future?
A: Yes, it does. The findings of the study on TRIO-linked microcephaly can potentially aid macrocephaly research in several ways, including identifying common molecular pathways, understanding cellular processes, developing a proper research model, and screening for potential therapies.
Q3: Does any investigation exist about neurocognitive processes in the TRIO gene?
A: Neurocognitive processes are mental activities that are supported by the brain and include perception, attention, memory, language, learning, and executive functioning. For example, TRIO gene mutations can disrupt the formation of synapses, the communication between neurons, and the formation of dendritic spines, which receive and integrate signals from other neurons. This can lead to neurodevelopmental abnormalities, neurotransmitter imbalances, and impaired learning, memory, and attention.
Q4: How can brain organoids be used to study the long-term effects of neurodevelopmental disorders?
A: Brain organoids are three-dimensional structures that self-organize into mini-brains when grown from human pluripotent stem cells. They have emerged as powerful tools for studying neurodevelopmental disorders, allowing researchers to investigate the long-term effects of these conditions on brain development and function. Their ability to be grown for extended periods of time grants researchers the ability to trace the development of neurodevelopmental disorders over the embryonic period, providing insights into the underlying defects responsible for pathological neurocognitive phenotypes.
Q5: How can brain organoids be used to test the efficacy of drugs for neurodevelopmental disorders?
A: By understanding the molecular mechanisms underlying neurodevelopmental disorders, brain organoids can be used to identify potential therapeutic targets. Moreover, they can be grown in large numbers and manipulated to exhibit various disease traits, enabling researchers to perform high-throughput drug screenings to identify compounds that effectively target specific neurological disorders. This scalability facilitates the identification of promising drug candidates from a vast pool of potential therapies.
Q6: If you find interesting results, how will they be made available to the scientific community?
A: We will make the results of our research available in the form of open-access scientific publications. The publication of scientific results provides the scientific community with new knowledge as well as an important communication tool aimed at collaboration and progress in the field.
Q7: Is there any database containing updated and truthful information about TRIO, so that we as family or doctors can learn about TRIO gene mutation?
A: Databases have been shared with Paolo and he will add them in a page in the TeamTRIO.org website as a resource for families. Please find the page at this link.
Q8: Prof. Merlo, what are the limits of your research?
A: Some of limitations of Brain Organoids models are the following:
- Simplified Brain Architecture: they lack the complex and organized structure of the human brain, including the intricate connections between different brain regions. This simplified architecture can limit the ability of organoids to accurately recapitulate the complex cellular interactions and signaling pathways involved in neurodevelopmental disorders.
- Limited Cell Types: they typically contain a restricted range of neural cell types compared to the diverse cell populations found in the human brain. This limitation can hinder the study of disorders that affect specific cell types or their interactions.
- Absence of Vasculature: they lack a functional vascular system, which is essential for providing nutrients and oxygen to the developing brain and removing waste products. The absence of vasculature can affect the growth, maturation, and function of neural cells in organoids.
As the technology continues to develop, researchers are working to address these limitations and enhance the accuracy and utility of brain organoids as a valuable tool for neurodevelopmental disorder research.
Q9: Will the current research gather information on the actual mutation all our children have? There is a huge spectrum of mutations and symptoms.
A: It is difficult to define the correlation between genetic changes and the wide range of symptoms that individuals with TRIOpathies exhibit. A type of research such as that proposed through the use of human brain organoids can certainly help us to better define the alterations derived from different mutations in a model of human neurological development.
Q10: Children with TRIO syndrome are experiencing short stature. Seeking insights on "delayed" vs. "stunted" growth and effectiveness of human GH for TRIO
A: A specific growth chart for patientTRIO gene mutations does not yet exist. As the latest study published by Baralle shows, there are no TRIO patients who have received GH therapy. However, in the truncation group in the cohort they have collected so far, there are some patients with short stature and especially the older patients seem to be shorter, there is a 16 year old whose height is -4 standard deviations, another patient at 7 years old has -2.29SD and a 5 year old has a SD of -3.39SD.
One patient had hypothyroidism (which could manifest as short stature) and required thyroxine, so it is also suggest a review of thyroid function tests in this case.
We still need evidence of the effectiveness of GH treatment in TRIO children and, if the trial are possible and successful, it should be reported so that it can be used in discussions with the own doctors.
Q11: Could we found a worldwide TRIO fundation or does it have to be separated for each country?
A (Team TRIO): Funding an international or national TRIO foundations poses challenges due to the limited number of members, geographic dispersion, and funding. For the time being, this activity is in hold by Team TRIO.
Anyhow, we invite families in creating a foundation for TRIO gene mutation patients to further raise awareness, fund research, and support affected families. Team TRIO community will be there to support you and you´ll not be alone.
Q12: Do many children have another rare Gene Mutation with their Trio gene mutation?
A (Team TRIO): In our Community about 7-10%.
Q13: Does any investigation exist about neurocognitive processes in trio gene?
A (Team TRIO): Yes, for example you can contact the BINGO Team.
Q14: I have the trio gene mutation and have not been significantly affected comparing with my son. Does Trio become more severe down the generations?
A: The severity of the TRIO gene mutation can vary significantly amongst individuals, even within the same family. It's intriguing how some people may exhibit no symptoms whatsoever, while others experience a wide array of health issues, ranging from mild to severe. This diversity in outcomes could be attributed to a phenomenon called mosaicism, which refers to the presence of the mutation in certain cells but not others.
However, it's important to note that additional factors such as the intricate interplay between other genes and external elements like the environment could also contribute to the manifestation of the mutation's differing effects.
Q15: I’ve noticed that the de novo carrier of the Trio mutation appears to be less affected than subsequent carriers. Is this something that’s been researched?
A: see Q14 above
Q16: My son and I have TRIO gene mutation. I also have 2 other children with some difficulties (ASD/ADHD) but tested negative for TRIO. Could it be an error?
We cannot exclude technical errors of the test or limitation of the performed test (not all tests have the same accuracy), but also mosaicism could be an explanation (see above). If you are concerned about the possibility of a false negative, you can talk to your doctor about getting your children retested.
Q17: Would you consider allowing professionals involved in the care of a TRIO patient join the fb group?
A (Team TRIO): We created a new FB group called TRIO gene society that is open for therapists, doctors and researchers. We will keep TeamTRIO facebook group exclusive for parents and very close relatives. We want TeamTRIO group to be a safe and secure place for families.
Q18: Seeking advice for managing 8-year-old granddaughter with mutations leading to behavior problems, attention deficit, and developmental delays
A: We do recommend that you consult therapists or doctors to get professional help for your granddaughter. It is essential to take a individual and holistic approach and follow a treatment plan that addresses the cognitive, motor, emotional and social dimensions of the child's development.
Therefore, it is very important to create a team of specialists and develop a customised treatment plan.