Characterization of rare neurodevelopmental disorders: enhancing diagnosis, providing prognostic insight, and improving treatment

This doctoral thesis explores the genetic and clinical characteristics of selected rare neurodevelopmental disorders (NDDs), with a particular focus on the role of genetic diagnostics and the potential for precision medicine. NDDs comprise a heterogeneous group of conditions characterized by impairments in cognition, communication, behavior, and motor skills. Despite significant advances in genetic testing for NDDs, its application remains limited in clinical settings. The first section presents a longitudinal study of 49 patients with CACNA1A-related epilepsy, detailing age of onset, seizure types, treatment responses, and the functional impact of identified variants. The study reveals marked phenotypic variability and a high prevalence of drug-resistant epilepsy, with gain-of-function variants associated with status epilepticus, drug-resistant epilepsy and abnormal MRI. The second section examines CNTNAP2-related disorders, presenting 22 novel cases alongside a comprehensive literature review. The findings support a recessive inheritance model for CNTNAP2-related disorders, and link biallelic variants to a phenotype characterized by global developmental delay, epilepsy, autism spectrum disorder, and severe cognitive impairment. The third section expands the phenotypic spectrum of the NAA20-related disorder through the description of two sisters with compound heterozygous variants. Their clinical presentation, including adolescent-onset epilepsy, highlights a dynamic evolution of the syndrome and underscores the need for further functional studies. Finally, the thesis describes the use of trametinib, a MEK inhibitor, as a precision treatment for refractory epilepsy in two patients with RASopathies. This section provides a proof of concept for targeted therapy, while also addressing its limitations and potential safety issues. In conclusion, this thesis emphasizes the clinical relevance of genetic diagnostics in NDDs, refines genotype-phenotype correlations in several rare NDDs, and supports the development of personalized therapeutic strategies in pediatric neurology.