Clinical issue
Classic galactosemia is a potentially lethal metabolic disorder affecting one in every 60,000 live births. It results from profound impairment of galactose-1-phosphate uridylyltransferase (GALT), the second of three enzymes in the Leloir pathway, which catalyses the interconversion of biological galactose and glucose-1-phosphate. Although apparently healthy at birth, affected infants develop a rapidly escalating progression of acute symptoms following exposure to milk and, in the absence of intervention, such babies often die in the neonatal period. Early detection, generally by newborn screening, coupled with strict lifelong dietary restriction of galactose prevents or reverses the potentially lethal acute symptoms. Unfortunately, a large percentage of patients go on to experience serious long-term complications, including significant cognitive and/or speech disabilities, primary or premature ovarian insufficiency in females, and a variety of other complications ranging from neuromuscular problems to diminished bone density. The underlying basis of the pathophysiology of classic galactosemia remains poorly understood, in part owing to the absence of an animal model that recapitulates aspects of the patient phenotype.
Results
In this paper, the authors describe the development and preliminary characterization of a GALT-deficient Drosophila melanogaster model of classic galactosemia. Reminiscent of the human neonatal syndrome, GALT-deficient Drosophila die as larvae in a dose-dependent and sugar-specific manner if exposed to food that contains galactose. Viability can be rescued by feeding affected flies a galactose-restricted diet, or by artificial expression of a human GALT transgene. GALT-deficient animals exposed to galactose show an accumulation of gal-1P, a metabolic abnormality that is also a characteristic of patients exposed to dietary galactose. Finally, GALT-deficient flies demonstrate a galactose-independent neurological or neuromuscular deficit that is also rescued by the expression of human GALT.
Implications and future directions
These results confirm that GALT-deficient D. melanogaster mimic aspects of both the acute and long-term outcomes of classic galactosemia, paving the way for future studies to explore the genetic and environmental factors that underlie and modify these phenotypes.