Zellweger spectrum disorders: From bench to bedside

This thesis describes translational studies in patients with a Zellweger spectrum disorder (ZSD), aimed at providing a framework for the in vitro development of therapies for ZSDs and for testing potential therapies in future clinical trials. ZSDs are a heterogeneous group of disorders characterized by a defect in peroxisome formation and are caused by mutations in one of the PEX genes. Because of the defect in peroxisome formation, multiple metabolic pathways are impaired resulting in metabolic abnormalities. Currently, no curative therapy is available. We studied whether autophagy inhibitors are capable of restoring peroxisomal function in ZSD cells and found no improvement of peroxisomal function by inhibition of autophagy. Moreover, we studied the clinical and biochemical effects of cholic acid treatment in a cohort of ZSD patients. Cholic acid therapy led to a decrease in toxic bile acid intermediates in plasma of the majority of patients, but gave rise to a worsening of liver tests in patients with advanced liver disease. No improvement of clinically relevant parameters could be observed. Furthermore, we describe the validation of two potential new biomarkers for ZSDs: C26:0-lysophosphatidylcholine and C26:0-carnitine in dried blood spots from a large cohort of ZSD patients and healthy individuals. ZSDs comprise a spectrum of disorders in which patients can present with a broad range of symptoms and widely varying clinical severity. The lack of a validated severity scoring system for patients with a ZSD hampers clinical research in this disease. In this thesis, we present the first severity scoring system for ZSD and its validation in a large, well-characterized cohort of ZSD patients.