Sjogren-Larsson syndrome (SLS) is an inherited disorder characterized by congential ichthyosis, mental retardation and spasticity. Preliminary studies show that cultured skin fibroblasts from SLS patients have altered fatty alcohol metabolism due to deficiency of the enzyme, fatty alcohol: NAD- oxidoreductase (FAO). Normal fatty alcohol metabolism is poorly understood and no information is known about the clinical effects of altered fatty alcohol metabolism. Furthermore, human FAO has not been characterized. A long-term objective of this proposal is to understand normal fatty alcohol metabolism and how FAO deficiency may lead to the clinical phenotype of SLS. We propose to investigate fatty alcohol metabolism in cultured skin fibroblasts from normal and SLS subjects to understand the deranged fatty alcohol metabolism in SLS. Using techniques of gas-liquid chromatography in combination with radiochemical tracer studies, we will investigate the regulation of fatty alcohol levels in normal and SLS fibroblasts. FAO acitivity will be characterized in normal human fibroblasts and compared to the residual FAO activity in SLS cells to determine whether the FAO enzyme is kinetically or structurally altered. We will search for genetic heterogeneity in SLS by gene complementation analysis using the techniques of somatic cll fusion. To uderstand fatty alcohol metabolism in tissues with quite different FAO activities, metabolic studies will be performed in rat hepatocytes and brain tissue slices using radiochemnical and enzymatic techniques. The subcellualr location of enzymes involved in fatty alcohol metabolic pathways will be determined using methods of differential and density-gradient centrifugation. The pathogenesis of SLS will be investigate in rat feeding studies to establish whether tissue fatty alcohol accumulation leads to biochemical and clinical changes characteristic of SLS. These studies will provide fundamental information about normal fatty alcohol metabolism and the deranged fatty alcohol metabolism in SLS.
