TIME · Time of damage in classic galactosemia: is prenatal toxicity a determinant factor?

Time of damage in classic galactosemia: is prenatal toxicity a determinant factor?

One of the long-standing questions in the galactosemia field is whether there is prenatal damage. With the TIME project, we provided evidence of early postnatal damage in classic galactosemia. Classic galactosemia (CG) is an inherited metabolic disorder in galactose metabolism. Galactose is a sugar extremely important as energy source for infants and for the glycosylation of complex molecules. The main pathway of galactose metabolism is the Leloir pathway. The Leloir pathway metabolizes galactose through the sequential action of three enzymes: galactokinase (GALK1), which converts galactose into galactose-1-phosphate (Gal-1-P); galactose-1-phosphate uridylyltransferase (GALT), which transfers a uridine monophosphate group from uridine diphosphate-glucose (UDP-Glc) to Gal-1-P, thereby releasing Glc-1-P and forming UDP-galactose (UDP-Gal); and UDP-Gal 4-epimerase (GALE), which interconverts UDP-Gal and UDP-Glc. In CG, there is an accumulation of galactose metabolites, namely of Gal-1-P. CG is caused by deficient activity of GALT. It affects between 1:16,000 and 1:60,000 live births and presents in the neonatal period as a life-threatening disease. Exclusion of galactose from the diet results in complete resolution of the acute complications. This treatment shows, however, limited efficacy in the prevention of long-term complications, with patients suffering from cognitive, fertility and social impairments. There is an urgent need to address the clinical and social impairments observed in CG patients. CG is an autosomal recessive disorder caused by mutations in the GALT gene. As with many other inherited metabolic diseases, CG mutational spectrum is dominated by missense mutations (>60%). Previous studies described that GALT impairment results from misfolding and aggregation, thus establishing CG as a conformational disorder. Conformational disorders are highly amenable to a pharmacological chaperones- and/or proteostasis modulators-based therapy. The recent description of the crystal structure of human GALT will greatly facilitate the design of GALT-targeted therapeutic compounds. These findings are extremely important towards the development of a truly effective therapy for CG. Accordingly, there is an urgent need to clarify the time of damage onset, as it will define the time at which therapy should be initiated in order to prevent the development of the chronic complications. The overall objective of this study is to provide new insights on time of damage onset in CG, particularly if it begins prenatally.

Data: CORDIS, © European Union