Mediators of outcome in a Drosophila model and patients with classic galactosemia Open Access

Ryan, Emily (2012)

Permanent URL: https://etd.library.emory.edu/concern/etds/wm117p71p?locale=en
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Abstract

Classic galactosemia is a rare autosomal recessive disorder caused by the loss of
function of galactose-1-phosphate uridylyltransferase (GALT), the second enzyme in the
Leloir pathway of galactose metabolism. Most cases in the US are diagnosed through
newborn screening and dietary galactose is restricted before the disease can progress to
life threatening symptoms like severe E. coli sepsis. Unfortunately, even with dietary
restriction most individuals with classic galactosemia will go on to experience quality of
life complications, including cognitive disability and movement disorders, among others.
Patient studies suggest these long-term complications are independent of dietary
galactose exposure and may be more common in individuals with certain GALT
mutations.
A GALT knockout mouse was generated almost 20 years ago but these animals
did not recapitulate any of the symptoms seen in the human disease, including dietary
galactose toxicity. The work detailed here establishes the first two phenotypes found in a
Drosophila melanogaster model of classic galactosemia. GALT null Drosophila exhibits
both a dietary galactose dependent larval lethality and an adult climbing defect.
We investigated the effects of dietary galactose exposure and low levels of GALT
activity on these phenotypes. The timing, duration, and level of dietary galactose
exposure modified the larval lethality; however dietary galactose exposure at low levels
had no effect on the adult movement defect even though the animals accumulated high
levels of galactose-1phosphate, the metabolite upstream of GALT. Both phenotypes were
rescued by transgenic expression of human GALT.
We also explored the scholastic and behavioral consequences of GALT deficiency
in school age children. In our study of such children with classic galactosemia we saw a
higher than expected incidence of behavior problems. Cryptic GALT activity explained
some of the variation in our population. Combined, these results help further our
understanding of the complications that result from loss of GALT in fruit flies and in
humans.

Table of Contents



Table of Contents

Page
Chapter 1
Introduction
1
1.1
Classic galactosemia
2
1.2
Galactose metabolism
5
1.3
Genetic models of classic galactosemia
12
1.4
Incidence and patho-physiology of the long-term

consequences of classic galactosemia
17
1.5
Summary
26
1.6
References
30
Chapter 2
A Drosophila melanogaster model of classic galactosemia
44
2.1
Abstract
45
2.2
Introduction
46
2.3
Materials and Methods
50
2.4
Results
58
2.5
Discussion
74
2.6
References
79
Chapter 3
Mediators of a long-term movement abnormality in a

Drosophila melanogaster model of classic galactosemia.
83
3.1
Abstract
84
3.2
Introduction
86
3.3
Materials and Methods
89
3.4
Results
93
3.5
Discussion
109


3.6
References
112
Chapter 4
Cryptic residual GALT activity is a modifier of outcome

in school age children with classic galactosemia
114
4.1
Abstract
115
4.2
Introduction
116
4.3
Materials and Methods
121
4.4
Results
125
4.5
Discussion
145
4.6
References
150
Chapter 5
Conclusion
157
5.1
Summary
158
5.2
Modeling classic galactosemia in Drosophila

melanogaster
160
5.3
Scholastic and behavioral consequences in classic

galactosemia
168
5.4
References
172







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