Neurogenetics in Movement Disorders: focus on Primary Familial Brain Calcifications

Primary Familial Brain Calcification (PFBC) is a rare neurogenetic disorder characterized by calcium deposits in basal ganglia and other brain areas. Despite identification of several causative genes, PFBC often remains underdiagnosed, with substantial heterogeneity in clinical expression among different studies. So far, mutations in recessive genes have been associated with severe phenotypes and extensive calcifications, though significant variability exists among patients, with some subjects remaining asymptomatic despite extensive calcifications. The absence of standardized assessment protocols and of follow-up studies contributes to data gaps in the literature and hampers understanding of disease progression and prognosis. This PhD project aimed at providing a multimodal characterization of PFBC integrating genetic, imaging, neuropsychological and clinical data, exploring new potential biomarkers. For this purpose, we present a collection of peer-reviewed articles and unpublished data on the PFBC-Padua cohort, combining a cross-sectional and longitudinal approach. We report the diagnostic yield of a custom gene panel and identify novel variants in known PFBC genes, analyzing genotype-phenotype correlations. We assess disease course using quantitative motor and cognitive scales defining different progression trajectories. We explore the potential role of skin biopsy as a complementary diagnostic tool, demonstrating converging biological processes at a peripheral level, and of MRI, detecting white matter changes with possible prognostic significance. Our results highlight the value of a comprehensive approach in complex neurogenetic disorders and expands current understanding of PFBC as a multisystem progressive disorder, supporting the integration of a common extensive evaluation protocol, of quantitative measures over time and of diverse diagnostic tools into clinical practice.