Pyridoxine-dependent epilepsy Towards newborn screening

The aim of this thesis is to provide and discuss evidence that enables informed decision making on inclusion of pyridoxine-dependent epilepsy due to α-aminoadipic semialdehyde dehydrogenase deficiency (PDE-ALDH7A1) in newborn screening programs.
PDE-ALDH7A1 is a neurometabolic disorder of lysine catabolism, characterized by (neonatal) seizures. While pyridoxine (vitamin B₆) treatment leads to adequate seizure control, the majority of patients suffer developmental delay and intellectual disability. Novel lysine reduction therapies (LRT) showed promising results on improving neurodevelopmental outcomes by lowering potential neurotoxic intermediates, but these results needed validation.
This thesis comprises a number of studies aiming to improve knowledge about phenotype and disease course, pathophysiology, and treatment outcomes, with a focus on the effect of LRT and timing of therapy on neurodevelopmental outcomes. Additionally, an international guideline and national care pathway are provided to optimize standardized management of PDE-ALDH7A1. Subsequently, these studies provide evidence for several newborn screening inclusion criteria.