A characterization of prenatal metabolites in GALT-null rat fetuses Open Access
Dallas, Sabrina (Spring 2022)
Published
Abstract
Classic galactosemia (CG) is a rare genetic disorder characterized by a profound deficiency of galactose-1-phosphate uridylyltransferase (GALT). Accumulation of metabolites involved in the Leloir Pathway, of which GALT is an integral enzyme, starting during gestation and continuing through life is thought to be responsible for the complications observed, which include developmental delays, motor control issues, speech and cognitive disorders, and premature ovarian insufficiency. In the GALT-null rat model used in the Fridovich-Keil Lab to model CG, excess pre-weaning neonatal demise was observed in GALT-null pups from GALT-null by GALT-null crosses only. This study aimed to gain a better understanding of changes in Leloir Pathway metabolites through gestation and determine if there is a prenatal cause for early neonatal demise of GALT-null pups with two GALT-null parents. Galactitol, galactose, and galactose-1-phosphate (Gal-1P) levels were measured in livers, brains, and amniotic fluid at gestational days (GDs) 15, 17, 19, and 21 in order to address these goals. Results indicated that increased metabolite accumulation was present in GALT-null rat fetuses compared to heterozygous fetuses by GD 15, and that this metabolite accumulation increased through gestation. This ultimately suggests that treatments designed for CG must either be administered prior to this point in gestation or correct previous damage as well as preventing future damage. Results also indicated that increased proportions of co-gestating heterozygous siblings had a negative correlation with overall metabolite levels, suggesting some sort of cross-correction happening between fetuses. This suggests that prenatal accumulation of metabolites in GALT-null fetuses from crosses involving no heterozygotes may be one cause of excess neonatal demise observed in these rats.
Table of Contents
CHAPTER 1: Classic Galactosemia and the GALT-null Rat Model ... 1
CHAPTER 2: Changes in Metabolite Levels through Gestation in GALT-null Rat Fetuses with Heterozygous Mothers ... 10
CHAPTER 3: Partial Prenatal Metabolic Correction of GALT-null Rat Fetuses from Co-Gestating Heterozygous Siblings ... 47
CHAPTER 4: Partial Prenatal Metabolic Correction of GALT-null Rat Fetuses from Gestation within a Heterozygous Mother ... 57
CHAPTER 5: General Discussion ... 67
APPENDIX ... 71
REFERENCES ... 74
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