PMM2-CDG, the most frequent form of congenital disorders of glycosylation, is characterized by alterations in the processes by which cells incorporate sugars into proteins and lipids. A deficiency in the enzyme phosphomannomutase 2 is the underlying cause, affecting numerous organs with a significant prevalence of neurological manifestations. Current treatment is primarily symptomatic, with no therapies capable of broadly modifying the disease's course.
To address the challenge of understanding how a primary defect in glycosylation leads to such diverse alterations in cellular function and various organs, researchers employed a multi-omic strategy. This methodology combines transcriptomics (analyzing gene activity), proteomics (studying proteins), and metabolomics (measuring small molecules) to gain a comprehensive view of the disease.
The integration of new proteomic and metabolomic data with previously generated transcriptomic data has allowed researchers to link changes in gene expression with alterations in proteins and metabolites. Proteomic analysis identified 43 proteins with significantly altered levels in patient cells, highlighting pathways related to the synthesis of retinoic acid, a molecule crucial for development and cell differentiation. A decrease in the enzyme ALDH1A1, involved in retinoic acid production, was observed.
Metabolomic findings revealed modifications in various amino acids and metabolites related to sugar metabolism. A key finding was the increase in UDP-GlcNAc, a molecule used as a sugar donor in glycosylation processes, and of the enzyme GFPT2, suggesting an activation of the hexosamine biosynthetic pathway. This observation directly connects the primary defect of the disease with a broader reorganization of sugar metabolism within the cell.
Furthermore, an increase in myo-inositol was observed, with intracellular levels associated with the clinical severity of the disease in an integrated analysis. While not yet a clinical biomarker, further studies on larger cohorts will be necessary to confirm these results.
Overall, the study demonstrates that PMM2-CDG results not only in an isolated glycosylation defect but is accompanied by coordinated changes at different levels of cell biology. The integration of omics has identified key pathways such as retinoic acid synthesis and the hexosamine pathway, and has also linked certain metabolic alterations, like myo-inositol, to clinical variability among patients. The work provides new hypotheses on the disease's pathophysiology and points to cellular processes for future in-depth study.
