Genetic and clinical characterization of rare pediatric movement disorders in the next-generation sequencing era

In the era of next-generation sequencing, significant advances have been made in the genetic and clinical characterization of rare pediatric movement disorders (MDs), enabling more accurate diagnoses and tailored therapeutic approaches. This thesis investigates the genetic basis and phenotypic variability of selected monogenic MDs addressing diagnostic challenges and clinical complexities in pediatric cases. A primary focus of this work is on GNAO1-related disorder, which is typically associated with severe, early-onset MD, life-threatening paroxysmal exacerbations, neurodevelopmental disorders, and epilepsy. GNAO1 haploinsufficiency is discussed separately, as it presents with milder clinical features and a later onset compared to classical phenotype. Additionally, the phenotypic expression, genetic background, and biochemical correlates of recessive guanosine triphosphate cyclohydrolase I deficiency have been examined to broaden the understanding of its clinical spectrum and outcomes. Finally, preliminary findings from exome-wide sequencing in a cohort of dystonic patients are presented to assess the diagnostic yield of WES and to identify causative and novel potential candidate genes in dystonia. These findings may help enhance our understanding of how genetic advancements are gradually improving diagnostic accuracy and informing therapeutic approaches for rare and complex movement disorders.