*6.1. Inherited Retinal Degeneration*

Inherited retinal degeneration (IRD) can arise from mutations in various genes linked to photoreceptor development and structure or genes involved in phototransduction. To add to the complexity of IRDs, patients with similar mutations may present with very di fferent phenotypes [80]. This is indicative of other underlying factors that can contribute to disease manifestation. It has been shown that metabolic dysregulation is a common element of various IRD models [81]. One example that has recently emerged is the dysregulation of sphingolipid metabolism [3]. Many investigators have shown that ceramide toxicity is elevated in various models of IRD [22]. In contrast, levels of the protective sphingolipid, sphingosine-1-phosphate, are significantly reduced [22]. What is ye<sup>t</sup> to be determined is why and how the toxic ceramides are increased while sphingosine-1-phosphate levels diminish. One mechanism that has been postulated suggests that serine deficiency forces the sphingolipid metabolism to switch to the incorporation of alanine for sphingolipid synthesis [22]. However, in doing so, the reaction is skewed towards the formation of ceramides. Further investigation is required to determine why there is reduced serine availability. Since the glycolytic precursor, phosphoglycerate, is the primary source for serine biosynthesis, it is possible that dysregulation in glucose metabolism is the cause for the reduced serine availability.
