Neural and Metabolic Dysregulation in PMM2 deficient human in vitro neural models

PMM2-CDG is a rare inborn error of metabolism caused by deficiency of the phosphomannomutase-2 (PMM2) enzyme, which leads to impaired protein glycosylation. While the disorder presents with primarily neurological symptoms, there is limited knowledge about the specific brain-related changes that result from PMM2 deficiency. We found aberrant neural activity in 2D neuronal networks from individuals with PMM2-CDG. Utilizing multi-omics datasets from 3D brain organoids derived from individuals with PMM2-CDG, we found widespread decreases in protein glycosylation, highlighting impaired glycosylation as a key pathological feature of PMM2-CDG. Furthermore, we identified impaired mitochondrial structure and abnormal glucose metabolism in PMM2-CDG brain organoids, indicating disturbances in energy metabolism. Correlation between PMM2 enzymatic activity in brain organoids and symptom severity suggests that the level of PMM2 enzyme function directly influences neurological manifestations. These findings enhance our understanding of specific brain-related perturbations associated with PMM2-CDG, offering insights into the underlying mechanisms and potential directions for therapeutic interventions.