ORAL D-GALACTOSE SUPPLEMENTATION IN PGM1-CDG

BACKGROUND/PURPOSE: Phosphoglucomutase-1 deficiency is a subtype of congenital disorders of glycosylation (PGM1-CDG). Previous case-reports in PGM1-CDG patients receiving oral D-galactose (D-gal) showed clinical improvement. So far no systematic in vitro and clinical studies assessed safety and benefits of D-gal supplementation. In a prospective pilot study, we evaluated the effects of oral D-gal in nine patients. METHODS/RESULTS: D-gal supplementation was increased to 1.5 g/kg/day (maximum 50 g/day) in three increments over 18 weeks. Laboratory studies were performed before and during treatment to monitor safety and effect on serum transferrin-glycosylation, coagulation, liver and endocrine function. Additionally, the effect of D-gal on cellular glycosylation was characterized in vitro. Eight patients were compliant with D-gal supplementation. No adverse effects were reported. Abnormal baseline results (ALT/AST/aPTT) improved or normalized already using 1g/kg/day D-gal. Antithrombin-III levels and Transferrin-glycosylation showed significant improvement, and increase in galactosylation and whole glycan content. In vitro studies before treatment showed N-glycan hyposialylation, altered O-linked glycans, abnormal LLO-profile, and abnormal nucleotide-sugars in patient fibroblasts. Most cellular abnormalities improved or normalized following D-gal treatment. CONCLUSION: D-gal increased both UDP-Glc and UDP-gal levels and improved LLO fractions in concert with improved glycosylation in PGM1-CDG. Oral D-gal supplementation is a safe and effective treatment for PGM1-CDG in this pilot study. Transferrin glycosylation and ATIII levels were useful trial end points. Larger, longer duration trials are ongoing.