Brain development involves a sequence of steps tightly regulated in time and space. When a single aspect of this process is disrupted, structural and functional problems can arise, leading to neurodevelopmental disorders (NDDs). The cause of these NDDs is often genetic, leading to rare syndromes comprising symptoms like intellectual disability, autism spectrum disorders, attention-deficit/hyperactivity, schizophrenia and motor and language disorders. Focusing on the monogenic NDDs Witteveen-Kolk syndrome and Lesch-Nyhan disease, this research employs multiple disease models to investigate how distinct biological alterations disrupt brain development. The results show that, despite their distinct genetic causes, these disorders affect overlapping developmental processes. At the same time, the work shows that no single experimental model can fully mirror the complexity of these disorders. Instead, combining human stem cell–derived neural organoids together with mouse and zebrafish models provides a more complete and informative picture. Each model offers specific advantages, allowing different aspects of the disease to be studied in a targeted way. These findings illustrate a practical strategy for studying rare NDDs and lay the foundations for the development of therapeutic approaches.
Sara Sebastiani (1995) obtained a Bachelor's and Master’s degree in Medical Biotechnology at the University of Milan. During her studies and internships, her interest in neurobiology developed even further with a focus on neurodevelopment. After graduating cum laude, motivated to continue studying rare neurodevelopmental disorders, Sara moved to Nijmegen to start her PhD research at the Donders Center for Neuroscience of Radboud University. In her research, she combined human and animal disease models to study the pathogenic mechanisms of two rare neurodevelopmental disorders.