Deciphering the Neurological Puzzle in ALG13-CDG Through Cutting-Edge Brain Organoid Modeling

Asparagine-linked glycosylation 13 (ALG13) is an X-linked congenital disorder of glycosylation (CDG) with limited treatment options and mechanistic understanding. Investigating ALG13-CDG has been challenging due to elusive glycosylation defects in patient samples, particularly in blood and fibroblasts. However, profound neurological symptoms strongly suggest a primary impact on the brain. To explore this, we developed an in vitro ALG13-CDG 3D human cortical brain organoid (hCOs) model using induced pluripotent stem cells (iPSCs) derived from fibroblasts. Both iPSCs and hCOs revealed X-inactivation skewing. Our multi-omics analysis unveiled reductions in glycosylation of key proteins crucial for brain function, along with alterations in proteins and transcripts linked to neuronal migration, nucleotide synthesis, epilepsy risk, and lipid metabolism. Metabolomic analyses in ALG13-CDG hCOs showed elevated GlcNAc levels and decreased nucleotide synthesis metabolites. Our study sheds light on the unrecognized protein glycosylation defect in ALG13-CDG, offering insights into its brain-related disturbances and potential for guiding clinical management, especially in addressing seizures, a critical unmet medical need.