Background: Genetic leukoencephalopathies are a group of neurodegenerative diseases imposing a great burden on patients and families. There is no previous systematic study looking at the impacts of these diseases. Methods: HRQOL was assessed using the Pediatric Quality of Life Inventory (PedsQL) model. A total of 24 patients with genetically determined leukoencephalopathies and their family members completed the PedsQL questionnaires. Detailed clinical assessments were performed at the time the questionnaires were filled. HRQOL results were correlated with the severity of the clinical features and the presence vs. absence of a definitive molecular diagnosis. Results: Preliminary results show lower PedsQL total scores for patients without compared to with a molecular diagnosis. Emotional and physical functioning scores were significantly impaired in patients without a molecular diagnosis. Lower total scores were obtained for patients who presented more severe clinical features such as lost ambulatory functions and dysphagia. Conclusions: Overall, our preliminary results indicate that patients without a molecular diagnosis have an impaired HRQOL and that more severely affected patients have a poorer HRQOL. Further analyses and studies on a larger population of patients in a prospective fashion are required to assess the burden of these diseases and identify potential modifiable factors.