Metabolomics changes in patients with PAPP-A2 deficiency in response to rhIGF1 treatment

Abstract Objective Mutations in the pregnancy-associated plasma protein A2 (PAPP-A2) gene have recently been shown to cause postnatal growth failure in two prepubertal patients from a non-consanguineous Spanish family due to the resulting decrease in IGF1 bioavailability. Although a specific pharmacological treatment of this entity is yet to be established, both children received progressive subcutaneous doses (40 to 120 μg/kg) of rhIGF1 twice daily for 2 years. The improvements in growth, hyperinsulinemia and bone mineral density have been previously reported. The objective of this study was to analyze the changes in metabolism associated with these responses to rhIGF1 treatment. Design Herein we present a detailed characterization of the acute and long-term changes in the metabolic profiles of these two siblings with PAPP-A2 deficiency after the initial injections of rhIGF1 and after two years of treatment. Results By using a GC-MS-based untargeted metabolomics approach, metabolic fingerprinting yielded the identification of 70 serum metabolites including amino acids (46%), organic acids (21%) carbohydrates (16%), fatty acids (14%), and purine bases (3%). Free fatty acids (FFAs) and amino acids showed the largest changes in the compared metabolic profiles, suggesting that rhIGF1 treatment has the greatest effects on lipid and protein metabolic pathways in the PAPP-A2 deficient subjects. Conclusions The administration of rhIGF1 resulted in changes related to crucial metabolic pathways, including lipid and protein metabolism, and this could be associated with the previously reported treatment-induced improvement in the mild basal hyperinsulinemia.