Background: SLOS is caused by inactivating mutations of the DHCR7 gene leading to cholesterol deficiency. It is characterized by a broad phenotypic spectrum typically including congenital malformations and mental retardation. SLOS pathophysiology remains poorly understood and there is no effective treatment. Objectives: to characterize the molecular changes caused by DHCR7 deficiency. Specifically, to obtain baseline gene expression profiles in affected and non-affected cells. Methods: Genome wide expression profiling (RNA-Seq) was performed using skin fibroblasts isolated from a patient with severe SLOS and neural stem cells (NSC) isolated from Dhcr7−/− mice (E18). Results: The SLOS fibroblast gene expression profile showed down regulation of genes involved in mitochondrial function, calcium homeostasis, cytoskeleton, lysosomal function, signaling (caveolin1, Na+/K+ ATPase), folate metabolism and defense against oxidative stress. Genes related to apoptosis, ubiquitination and extracellular matrix synthesis were upregulated. Such expression profile was not observed in Dhcr7−/− NSCs. In these cells, stem-cell marker nestin and cell-replication genes were downregulated whereas genes implicated in synaptic transmission, signaling, and cell differentiation were upregulated, suggesting abnormal NSCto-neuron differentiation in vivo. Conclusion: Cell biology is profoundly altered in SLOS. Future studies with cell lines from other patients and from NSC-derived neurons are needed to confirm and expand these findings. Background: An increase of plasma 25-and 27-hydroxycholesterols (25-OHC and 27-OHC) have been reported in hereditary spastic paraplegia type 5 (SPG5). In addition, 24-S-hydroxycholesterol (24-OHC) may be a biomarker of disease progression in patients with Huntington disease (HD) and Niemann Pick C1 (NPC1). Therefore, we have developed a highly sensitive and specific method to measure simultaneously these 3 plasma oxysterols. Method: Plasma oxysterols 24, 25 and 27-OHC were analysed by a LC-MSMS method with isotopic dilution after sterols derivatization into picolinyl esters (Honda et al; 2008) . Derivatized sterols were analysed by an UPLC-TQD system, consisting of a triple quadrupole mass spectrometer equipped with an ESI probe and UPLC-system. Oxysterols were separated on a C-18 RP-BEH column and detected by using multiple reaction monitoring. Results: This method provides high precision and accuracy (intra-assay reproducibility 7% CV, inter-assay reproducibility 10%, accuracy 93-106%). We identified a 15 fold increase of 25-OHC and a 7 fold increase of 27-OHC ratios to cholesterol in 8 SPG5 patients compared to 10 controls. Conclusion: The present UPLC-MS method provides a reliable and reproducible tool to quantify oxysterols in order to identify new SPG5 patients and to monitor disease progression in HD and NPC1 patients.