Markers and Models of Outcome in Galactosemia Open Access

Sanders, Rebecca (2009)

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Galactose metabolism occurs via the Leloir pathway, a highly conserved series of reactions catalyzed by three enzymes: galactokinase (GALK), galactose-1-phosphate uridylyltransferase (GALT), and UDP-galactose-4'-epimerase (GALE). When dietary galactose is insufficient, the Leloir pathway permits galactose synthesis through GALE, which interconverts UDP-galactose and UDP-glucose. In some species GALE also interconverts UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine. These four UDP-sugars are essential for the biosynthesis of glycoproteins and glycolipids.
Impairment of any Leloir pathway enzyme causes galactosemia. Despite treatment with dietary galactose restriction, many galactosemics with profound GALT or GALE deficiency develop neurological complications. Additionally, 80-90% of women with severe GALT impairment develop premature ovarian insufficiency (POI). Understanding the pathophysiology of these complications has been hindered by lack of a suitable animal model. This dissertation presents a focused examination of the nature of galactosemia-associated POI, and a more general exploration of GALE deficiency using a novel D. melanogaster model.
Galactosemia-associated POI has been attributed to effects of galactose and its metabolites in the ovary, or to dysfunction of follicle-stimulating hormone (FSH) secondary to glycosylation defects. To evaluate these explanations, we tested FSH and anti-Mullerian hormone (AMH) in serum from galactosemic girls and women. FSH bioactivity, a measure of the hormone's ability to activate its receptor, was normal in our study population. However, AMH abundance, a reflection of number and quality of ovarian follicles, was strikingly low, even in girls younger than two years old. These results indicate that POI in galactosemia is not caused by ineffective FSH signaling, but by damage to the ovary in early childhood or even prenatally.
To elucidate the pathophysiology of severe GALE deficiency, we have generated the first whole animal model of GALE impairment. Our studies in D. melanogaster confirm that total loss of GALE is incompatible with life, and reveal that GALE is required throughout development. Furthermore, we demonstrate that GALE expression is only essential in certain tissues, and that intermediate enzyme impairment permits survival but also confers sensitivity to environmental galactose. This model of both profound and intermediate GALE-deficiency recapitulates aspects of the human disease and provides insight into the essential role of GALE in tissues.

Table of Contents

Table of Contents
Chapter 1 Introduction 1.1 Galactose Metabolism 1.2 Galactosemia 1.3 Experimental Models Of Galactosemia 1.4 The Pathophysiology of Galactosemia 1.5 Summary 1.6 References Chapter 2 Biomarkers Of Ovarian Function In Girls And Women With Classic Galactosemia 2.1 Abstract 2.2 Introduction 2.3 Materials and Methods 2.4 Results 2.5 Discussion 2.6 References Chapter 3 Role of GALE in Drosophila Development and Homeostasis 3.1 Abstract 3.2 Introduction 3.3 Materials and Methods 3.4 Results 3.5 Discussion 3.6 References Chapter 4 Conclusion 4.1 Summary 4.2 POI in Classical Galactosemia 4.3 GALE in Drosophila Development and Homeostasis 4.4 References Appendix Origins, Distribution, and Expression of the Duarte-2 (D2) Allele of Galactose-1-P Uridylyltransferase A1.1 Abstract A1.2 Introduction A1.3 Materials and Methods A1.4 Results A1.5 Discussion A1.6 References

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