Translational studies in Zellweger spectrum disorders

Zellweger spectrum disorders (ZSDs) are inherited metabolic diseases characterized by a (partial) deficiency of peroxisomal function, leading to accumulation of several toxic metabolites in organs and blood. Currently, there is no curative therapy for the diseases and intervention is supportive and based on symptoms. In this thesis we have studied the effect of a possible novel therapy, arginine, in skin fibroblasts of mildly affected ZSD patients.
Supplementing arginine to the culture medium of these skin fibroblasts resulted in an increase in the amount of peroxisomes as well as peroxisomal functions. Moreover the effect of cholic acid was studied for the first time in a large cohort of patients. We have demonstrated that cholic acid lowers the concentration of specific toxic metabolites in plasma in the majority of the patients. We also generated a new mouse model for the disease, which resembles the relatively milder human phenotype. In the near future, this model can be used to study disease pathogenesis at the organ level and test future therapies. Research in this thesis emphasizes that ZSDs should no longer be considered solely as paediatric diseases, but rather as slowly progressive diseases with patients surviving into adulthood, presenting with age specific (neurological) symptoms as described in our cohort study.