Dottorato in NEUROSCIENZE CLINICO-SPERIMENTALI E PSICHIATRIA

Titolo della tesi: Pediatric Movement Disorders: expansion of clinical and diagnostic spectra of neurometabolic and neurogenetic conditions, use of new diagnostic tools and new pharmacologic therapies

Pediatric movement disorders (MDs) include a large group of conditions divided into hyperkinetic and hypokinetic disorders, such as dystonia, chorea, parkinsonism, tremor, tics, myoclonus, and ataxia, often presenting with complex clinical picture and associated to neurological and non-neurological features. The characterization of the clinical phenotype and the identification of the underlying etiology is often difficult, given the wide differential diagnosis and the increasing number of possible genetic causes. The introduction of Next Generation Sequencing (NGS) technique greatly advanced our understanding of underling genetic mutations and etiological molecular pathways, and biochemical “omics” approaches expanded the spectrum of Inborn Error of Metabolism (IEM) conditions. Recent findings show that multiple genes involved in hyperkinetic and hypokinetic movement disorders often share the same biological pathways, and many functional relationships between apparently unrelated genes have been discovered. These findings can lead to the development of new classification systems of genetic disorders based on shared molecular pathways, and can contribute to the identification of novel targets for therapeutic intervention. In my project, which was conducted predominantly in the Neurometabolic and Movement Disorder Unite of Sant Joan de Déu Hospital of Barcelona, I decided to deeply investigate the clinical characterization of some categories of pediatric MD, such as hypokinetic patterns falling in the definition of pediatric parkinsonism, abnormal movement patterns of the neonatal population affected by inherited metabolic disorders (IMD) and a rare genetic form of early-onset ataxia. Moreover, in collaboration with other research institutes, we experimented new potential diagnostic tools by the use of volumetric analysis of brain magnetic resonance images in two different populations (neurotransmitter disorders and some subgroups of neonatal IMDs). Finally, in collaboration with the Synaptic metabolism laboratory, we proposed a new potential treatment for a subcategory of neurometabolic disorder with pediatric parkinsonism phenotype.