Dottorato in NEUROSCIENZE CLINICO-SPERIMENTALI E PSICHIATRIA

Titolo della tesi: GENETIC EPILEPSIES AND EPILEPTIC/DEVELOPMENTAL ENCEPHALOPATHIES WITH MOVEMENT DISORDERS

The association between epilepsy or developmental epileptic encephalopathies (DEE) and both paroxysmal and chronic movement disorders (MD) has been increasingly recognized in medical literature and in clinical practice. We explored this association by reviewing three main phenotypes in medical literature: genetic, neonatal-onset epilepsies and DEE, in order to define the associated MD; Rett syndrome spectrum secondary to DEE- and epilepsy-causing genes; monogenic and copy number variation (CNV) causes of epilepsy or DEE and early-onset parkinsonism. We also reported on our experience with diagnosing these rare and ultra-rare disorders by providing a detailed clinical, EEG, neuroimaging and genetic description of 23 patients with a CNV or monogenic cause for their complex phenotype associating DEE or epilepsy and a MD. Nineteen patients had a monogenic condition and four a CNV. Epilepsy onset occurred in the neonatal period in 13% of cases, between 1-6 months in 26%, at 7-12 months in 17%, at 13-36 months in 9%, and > 12 years in 4%. DEE was diagnoses in 52% of cases versus epilepsy in 48% (82% of focal onset). The MD was chronic in 78% of cases, and complex in 52%, evolving over time in 22% of patients. It was hyperkinetic in 95% of cases. The most represented type was stereotypies (61%), followed by dystonia (22%), myoclonus (17%), and unstable broad-based gait (13%). Choreo-athethosis, action and postural tremor and ataxia were present in 9% of patients. Global developmental delay and/or intellectual disability were diagnosed in 74% of cases. Some MECP2-negative patients had features reminiscent of the Rett syndrome spectrum. The detected pathogenic or likely pathogenic variant was novel in 48% of patients with a monogenic disorder. We also described in more detail some novel or unusual phenotypes. Some conditions proved difficult to control with medications. Reaching a specific etiological diagnosis carried management implications in 52% of cases. We found high genetic and phenotypic variability and highly complex epilepsy and MD phenotypes. Genetic diagnosis has important therapeutic and management implications, which are likely to further increase in the future owing to the advances of precision medicine.