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Pontocerebellar Hypoplasia (PCH) is a rare heterogeneous group of neurodegenerative disorders, often with a prenatal onset. Patients have severe hypoplasia or atrophy of cerebellum and pons, with variable involvement of supratentorial structures. Although clinical and neuroradiological features are variable, most patients suffer from severe motor and cognitive impairments. PCH often leads to death during infancy. Based on distinct clinical features and genetic causes, current classification comprises eleven types of PCH. This thesis focuses on the identification of novel disease genes and the description of new phenotype-genotype correlations in PCH. In addition, the neuroradiological features of the most frequent subtypes of PCH (PCH1B/PCH2A) are studied in detail. The expression patterns of the PCH related genes in the developing and adult brain will be shortly discussed in an effort to explain the specific cerebellar involvement in PCH. Finally, the clinical applicability of the ever expanding PCH classification, which now includes a large variety of phenotypes, will be considered.

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.