Galactosemia is an inherited metabolic disorder that occurs in roughly 1 of 60,000 babies. It is caused by enzymatic defects in the pathway that processes galactose, a sugar common in dairy products. Affected babies seem healthy at birth but quickly develop acute symptoms when exposed to milk and often die unless the condition is diagnosed. With early detection and strict avoidance of galactose, however, affected babies can survive the neonatal period. Unfortunately, many of them experience severe long-term complications, including organ damage or failure and neurological disabilities. The mechanisms underlying galactosemia are poorly understood; there is no cure, and appropriate treatment is poorly defined. This lack of understanding is partly attributed to the lack of an animal model that accurately mirrors the symptoms and development of galactosemia in humans.

Credit: Tomasz Zachariasz

A decade ago, a group of researchers attempted to create a mouse model of galactosemia by deactivating the galactose-processing enzyme (galactose-1-phosphate uridylyltransferase, GALT) that is defective in affected humans, but the mice did not develop any symptoms of the disease.

Now, Judith Fridovich-Keil and colleagues (Emory University, Atlanta, GA) have created the first animal model of GALT-deficient galactosemia in the fruit fly (Drosophila melanogaster). They first verified that the genes encoding galactose-processing enzymes were similar in flies and humans and then deactivated the gene encoding GALT in flies (Dis. Models Mech. doi:10.1242/dmm.005041; published online 2 June 2010). The GALT-deficient larvae died if they were fed galactose but survived if they were fed only glucose, like humans with galactosemia and unlike GALT-deficient mice. Galactose-induced lethality was dose-dependent and sugar-specific. Restricting galactose in the flies' diet allowed them to survive, but they still experienced neurological or neuromuscular deficits, like humans with galactosemia. Notably, sensitivity to galactose in the larvae was also time-dependent; GALT-deficient larvae died within days if they were transitioned from a glucose-only diet to a glucose–galactose diet, whereas adult GALT-deficient flies did not.

Next, the scientists engineered the GALT-deficient flies to express a human GALT transgene. Expression of the transgene prevented galactose-induced lethality and neurological symptoms in GALT-deficient flies.

These results confirm that GALT-deficient fruit flies recapitulate both acute and long-term symptoms of galactosemia in humans. Establishment of this model opens the door for studies to explore the factors that contribute to development of this disease as well as its ongoing pathophysiology. Fridovich-Keil and her group have already started to investigate the timing, extent and causes of sensitivity to galactose in this fly model.