Cerebrospinal fluid N-glycans as potential biosignatures for developmental and epileptic encephalopathy in children.

Epilepsy is the most prevalent neurological disorder in children, significantly impacting the growth and development of future generations. Despite substantial progress in biomarker discovery, numerous challenges persist in the accurate diagnosis and prognosis of pediatric epilepsy. Glycosylation is known to play a critical role in neuronal function and neuroinflammation, but the differential glycome profile associated with the onset and progression of pediatric epilepsy has not been investigated. This study investigates the alterations in N-glycan signatures present in plasma and cerebrospinal fluid (CSF) from individuals experiencing focal and generalized epilepsy and developmental and epileptic encephalopathies (DEE). Discriminative models demonstrate distinct N-glycome profiles in both plasma and CSF that effectively differentiate between control subjects and those with epilepsy, identifying a specific set of 11 N-glycans common to both biological fluids. Notably, we observed a significant elevation in mannosylation and mono-sialylation of CSF in cases of DEE. High mannosylated and mono-sialylated N-glycans exhibited strong diagnostic potential for DEE. The biosynthetic network of CSF N-glycans indicated that sialylation, galactosylation, and bisection are the primary contributors to the transition from controls to DEE. Furthermore, the abundance of sialylation, fucosylation, and bisection correlated positively with the levels of proteins and sugars in CSF. These findings identify N-glycosylation changes in CSF as biosignatures associated with pediatric epilepsy, especially DEE, and support further evaluation of glycoprotein N-glycome profiling for disease classification and clinical stratification.