Triosephosphate isomerase deficiency: historical perspectives and molecular aspects

In this chapter, the original descriptions and pre-molecular studies of triosephosphate isomerase (TPI) deficiency are summarized, and the molecular aspects of the disease presented. The gene is well characterized, and several mutations have been described. Structure-function studies have led to an increased understanding of impaired catalysis. All kindreds that have been studied with the predominant Glu104Asp mutation are linked by a common haplotype, indicating descent from a common ancestor. Variant upstream substitutions occur in high frequency in persons of African and East Asian lineage and in lower frequency in other groups, but the possible role, if any, of these variants in clinical TPI deficiency requires further investigation. The possible contribution of deviant lipid metabolism to the pathogenesis of the disorder has been extensively investigated, and an intriguing new area of inquiry is the apparent cell-to-cell transfer of enzyme in cell culture systems, raising the question of the feasibility of enzyme or gene replacement therapy.