Cholesterol is essential for many life processes, including correct development, fluidity of cell membranes, production of steroid hormones and bile acids, and is a major component of myelin. Smith-Lemli-Opitz Syndrome (SLOS) and Niemann-Pick disease type C (NPC) are devastating diseases and both involve dysregulation of cholesterol homeostasis. SLOS is caused by a defect in 7-dehydrocholesterol reductase (DHCR7), resulting in increased levels of 7-dehydrocholesterol (7DHC) and decreased levels of cholesterol. On the other hand, NPC is caused by defects in NPC1 or NPC2. These genes encode two lysosomal proteins that are responsible for the transport of cholesterol and other lipids out of lysosomes. Consequently, defects in these proteins results in accumulation of unesterified cholesterol within late endosomes/lysosomes. The severity ranges of both disorders are broad, and no or limited therapeutic options are available. This thesis aimed to establish the incidence and mechanisms behind SLOS and NPC in order to aid development of novel therapeutic interventions. Using a bioinformatics approach, <b>Chapter 2</b> showed that the estimated incidences of classical SLOS and NPC were similar to clinical reports. However, the analysis suggested that a late onset form of NPC1 could be more prevalent. <b>Chapter 3</b> investigated the behavioural phenotype of the SLOS Dhcr7^{T93M/&Delta;3-5} mouse model and it was found that some parallels could be drawn to the behaviour observed in SLOS patients. It also highlighted some defects in neuro-anatomy that could potentially explain certain cognitive defects. <b>Chapter 4</b> explored the suggestion of oxidative stress in the Dhcr7^{T93M/&Delta;3-5} mouse model. However, this study did not support a role for oxidative stress in this model. Genetic insights were generated via an RNAseq study on SLOS and NPC patient fibroblasts, which suggested that the WNT signalling pathway could play a role in the pathogenesis of SLOS. This pathway was also highlighted when the cells were treated with miglustat, the only approved therapy for NPC. However, the main pathway apparently affected by this drug in both SLOS and NPC was cell proliferation.

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