Classic galactosemia (CG) is a potentially lethal genetic disease that results from profound loss of galactose-1P uridylyltransferase (GALT); CG is the second most common metabolic disorder identified by newborn screening in the US. Despite neonatal diagnosis and lifelong dietary restriction of galactose, which is the current standard of care, a majority of affected children grow to experience a constellation of debilitating cognitive, behavioral, movement, female reproductive, and other disabilities. The mechanisms that underlie these long-term complications remain unknown, hindering prognosis and the development of more effective treatments. The goals of this project are to define the mechanism(s) of acute and long-term outcomes associated with GALT deficiency and leverage that knowledge in a preclinical setting to identify and test candidate pharmacological interventions for CG. To achieve these goals we will apply a combined model system plus human subjects approach. Specifically, we will conduct systems-level biochemical and genetic studies in a Drosophila melanogaster model of GALT deficiency that demonstrates both acute galactose sensitivity in development and also galactose-independent adult movement, female fertility, and learning- related behavioral phenotypes, with targeted follow-up studies using patient samples to ensure relevance. This strategy circumvents the otherwise crippling effect of limited patient numbers to enable the open-minded studies of mechanism needed to understand the bases of acute and long-term outcomes in CG.
Our Specific Aims i nclude: (1) define the metabolomic consequences of GALT deficiency in both Drosophila and humans, (2) identify genetic modifiers of acute and long-term outcomes in GALT deficient Drosophila and patients, and (3) test candidate pharmacological modifiers of outcome using a GALT-null Drosophila model of CG. The results of these studies will reveal what causes the acute and long-term sequelae of CG and will provide a first evidence-based step toward improved intervention.
Classic galactosemia (CG) is the second most common metabolic disorder identified by newborn screening in the US. Despite neonatal diagnosis and lifelong dietary restriction of galactose, a majority of affected children grow to experience debilitating long-term cognitive, behavioral, movement, and other disabilities. The proposed research will apply a fruit fly model of classic galactosemia with follow-up studies using patient samples to (1) define the mechanisms and modifiers of outcomes in GALT deficiency and (2) identify and test candidate pharmacological interventions to prevent or reverse these negative outcomes.
