biostudies-literatureShah Rthe National Institute of Neurological Diseases and Stroke (NINDS), the National Center for Advancing Translational Sciences (NCATS), the National Institute of Child Health and Human Development (NICHD), and the Rare Disorders Consortium Disease Network (NCI NIH HHSDBT/Wellcome Trust India Alliance147https://www.ebi.ac.uk/biostudies/studies/S-EPMC12839988biostudies-literatureUnknown15(2)<h4>Background</h4>ALG13-CDG is an X-linked N-linked glycosylation disorder caused by pathogenic variants in the glycosyltransferase ALG13, leading to severe neurological manifestations. Despite the clear CNS involvement, the impact of ALG13 dysfunction on human brain glycosylation and neurodevelopment remains unknown. We hypothesize that ALG13-CDG causes brain-specific hypoglycosylation that disrupts neurodevelopmental pathways and contributes directly to cortical network dysfunction.<h4>Methods</h4>We generated iPSC-derived human cortical organoids (hCOs) from individuals with ALG13-CDG to define the impact of hypoglycosylation on cortical development and function. Electrophysiological activity was assessed using MEA recordings and integrated with multiomic profiling, including scRNA-seqCellsNetwork Hypoactivity in ALG13-CDG: Disrupted Developmental Pathways and E/I Imbalance as Early Drivers of Neurological Features in CDG.PMC128399881U54NS115198-01IA/CRC/20/1/600002P30CA150831P01NS138003-01A1King ATBleukx CStaff NPMorava EDrake RShah RChandran JSabry SByeon SKKozicz TShammas IRadenkovic SPreston GSmith DYBudhhraja RYoung LPandey AHrstka RSloan SAfalseNetwork Hypoactivity in ALG13-CDG: Disrupted Developmental Pathways and E/I Imbalance as Early Drivers of Neurological Features in CDG.<h4>Background</h4>ALG13-CDG is an X-linked N-linked glycosylation disorder caused by pathogenic variants in the glycosyltransferase ALG13, leading to severe neurological manifestations. Despite the clear CNS involvement, the impact of ALG13 dysfunction on human brain glycosylation and neurodevelopment remains unknown. We hypothesize that ALG13-CDG causes brain-specific hypoglycosylation that disrupts neurodevelopmental pathways and contributes directly to cortical network dysfunction.<h4>Methods</h4>We generated iPSC-derived human cortical organoids (hCOs) from individuals with ALG13-CDG to define the impact of hypoglycosylation on cortical development and function. Electrophysiological activity was assessed using MEA recordings and integrated with multiomic profiling, including scRNA-seq2026-01-01T00:00:00Z2026 Jan2026-06-13T03:17:44.061Z2026-06-13T03:09:12.855ZS-EPMC128399884159722210.3390/cells15020147