Abstract
ABSTRACTClassic galactosemia (CG) is a potentially lethal inborn error of metabolism that results from the profound loss of galactose-1-phosphate uridylyltransferase (GALT), the second enzyme in the Leloir pathway of galactose metabolism. Neonatal detection and dietary restriction of galactose minimizes or resolves the acute sequelae of CG, but fails to prevent the long-term complications experienced by a majority of patients. One of the substrates of GALT, galactose-1-phosphate (Gal-1P), accumulates to high levels in affected infants, especially following milk exposure, and has been proposed as the key mediator of acute and long-term pathophysiology in CG. However, studies of treated patients demonstrate no association between red blood cell Gal-1P level and long-term outcome severity. Here, we used genetic, epigenetic and environmental manipulations of a Drosophila melanogaster model of CG to test the role of Gal-1P as a candidate mediator of outcome in GALT deficiency. Specifically, we both deleted and knocked down the gene encoding galactokinase (GALK) in control and GALT-null Drosophila, and assessed the acute and long-term outcomes of the resulting animals in the presence and absence of dietary galactose. GALK is the first enzyme in the Leloir pathway of galactose metabolism and is responsible for generating Gal-1P in humans and Drosophila. Our data confirmed that, as expected, loss of GALK lowered or eliminated Gal-1P accumulation in GALT-null animals. However, we saw no concomitant rescue of larval survival or adult climbing or fecundity phenotypes. Instead, we saw that loss of GALK itself was not benign and in some cases phenocopied or exacerbated the outcome seen in GALT-null animals. These findings strongly contradict the long-standing hypothesis that Gal-1P alone underlies pathophysiology of acute and long-term outcomes in GALT-null Drosophila and suggests that other metabolite(s) of galactose, and/or other pathogenic factors, might be involved.
Highlights
Galactosemia is one of the most common metabolic diseases identified by newborn screening (NBS) in the United States (CDC, 2012)
Newborn screening for galactosemia coupled with rapid dietary restriction of galactose has saved the lives of thousands of infants born with classic galactosemia (CG) in the United States in the past 50 years (Pyhtila et al, 2015)
We applied our previously described Drosophila melanogaster model of Classic galactosemia (CG) (Kushner et al, 2010) in experiments testing whether Gal-1P accumulation is either necessary or sufficient for acute larval galactose sensitivity and two adult phenotypes associated with galactose-1-phosphate uridylyltransferase (GALT) deficiency
Summary
Galactosemia is one of the most common metabolic diseases identified by newborn screening (NBS) in the United States (CDC, 2012). The early detection and rapid restriction of dietary galactose enabled by NBS for galactosemia prevent or resolve the acute and potentially lethal symptoms of CG. Life-long dietary restriction of galactose remains the only accepted treatment for patients with CG (Berry, 2014). A literature trail extending back more than 30 years documents that this treatment fails to prevent the long-term complications experienced by most patients (Gitzelmann and Steinmann, 1984; Hughes et al, 2009; Jumbo-Lucioni et al, 2012; Schweitzer et al, 1993; Segal, 1995). The mechanisms underlying acute and long-term outcomes in CG remain unclear, limiting prognosis and hampering efforts at improved intervention
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