Lead researcher: Dr. Karlien Coene, Radboud umc, Nijmegen, The Netherlands

Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is a devastating metabolic disease, for which diagnostic delay hampers optimal clinical and cognitive outcome of patients. Based on population genetics data, the estimated incidence of this disease is 1:60.000, which is higher than the observed incidence. This indicates that this condition is likely underdiagnosed. Unfortunately, PDE has not been included in newborn screening (NBS) so far due to the lack of a suitable blood-based biomarker. The aim of our research is to further validate the novel PDE-biomarker 2-OPP, which we have recently identified in our lab through an untargeted metabolomics approach (link naar Engelkerke 2021), for application in NBS. A pilot study into validation of this new biomarker for NBS was funded by United for Metabolic Diseases NL. We aim to further scale up this validation with the goal to achieve implementation of PDE-ALDH7A1 in NBS in the Netherlands and beyond.

This research is funded by United for Metabolic Diseases NL.

Lead researcher: Dr. Eduard Struijs, Amsterdam UMC, Amsterdam, The Netherlands

Metabolomics in combination with transcriptomics analyses will be performed to identify new aspects of the pathophysiology of PDE.

This research is funded by Amsterdam Gastroenterology and Metabolism (AGEM).

Consortium coordinator: Clara van Karnebeek, Radboudumc, Nijmegen, The Netherlands

Rare inborn errors of lysine metabolism such as pyridoxine-dependent epilepsy (PDE) and glutaric aciduria type 1 (GA1) cause debilitating, often progressive neurologic symptoms with chronic care dependency. The international CHARLIE project synergizes the expertise of patient representatives, basic and clinical scientists, to collaboratively develop and validate new therapies and biomarkers. We pursue different strategies to avoid brain damage: inhibition of the enzyme upstream to GA1 and PDE with the potential to prevent build-up of highly reactive metabolites as well as gene therapy to replace the missing GA1 enzyme. We will first apply these in PDE and GA1 model systems, such as neuronal stem cells, mouse and zebrafish models. To evaluate and compare the efficacy of these different treatment approaches, we will perform biochemical, morphological, neurobehavioural analyses. We will develop tools for monitoring therapeutic effect, enabling personalized medicine. With our patient advocacy organizations, we will prioritize the most promising treatment strategy/-ies and enhance trial readiness. To inform families, professionals, and stakeholders, we will organize regular meetings and create digital platforms. For successful exploitation, we engage industry and policymakers. Together our CHARLIE consortium will translate knowledge from bench to bedside, with drug access for improved outcomes for PDE and GA1 patients and families.