The inefficacy of dietary treatment of galactose-1-phosphate uridyltransferase (GALT) deficiency galactosemia in preventing mental impairment, ovarian failure and late neurological complications requires new therapeutic strategies. This proposal focuses on metabolic investigations involving two approaches. If chronic self-intoxication via endogenous galactose-1-phosphate (Gal-1-P) underlies the problems, one strategy is augmentation of the capability of Gal-1-P utilization of patients by enhancing residual GALT activity and/or flux through the pathway. Our preliminary data indicate folic acid may be an effector with the potential for doing this. The first objective of this proposal is the delineation of folic acid effects on the enzymes of galactose metabolism and metabolic flux through the pathway in intact rats from fetal to adult ages, the assessment of possible prevention of galactose-induced toxicity and the examination of the response of GALT deficient cells and patients. If a cellular lack of UDPgalactose is responsible for failure of dietary therapy a second possibility is administration of uridine to boost levels of cell nucleotide sugars. Our preliminary data indicate that uridine and its nucleotides can inhibit normal GALT making administration of the compound a potential hazard if disposition of endogenous Gal-1-P is the root of the difficulty and any residual GALT activity is inhibited. The second objective of this proposal is delineation of the ramifications of uridine on galactose metabolism both in normal rats and affected human cells with the goal of formulating a rational approach to uridine as a therapeutic modality.
