Epigenetic, ribosomal, and immune dysregulation in paediatric acute-onset neuropsychiatric syndrome.

Paediatric Acute-Onset Neuropsychiatric Syndrome (PANS) is characterised by abrupt onset obsessive compulsive disorder and regression in neurodevelopmental skills, triggered by infection or stress. Whether PANS is a distinct entity or part of a neurodevelopmental spectrum is uncertain, and its pathophysiology remains unclear. We show that children with PANS (n = 32) and other non-PANS (n = 68) neurodevelopmental disorders (total n = 100) have higher reported early childhood infections and a loss of previously acquired developmental skills compared to neurotypical controls (n = 58). Children with PANS have normal routine immune testing, however bulk RNA-sequencing (PANS n = 20 vs controls n = 15) revealed upregulated pathways in ribosomal biogenesis and RNA methyltransferases, and downregulated pathways in diverse cellular functions such as mitochondrial activity, cell signalling, endocytosis, and immune responses. Single-cell RNA-sequencing (PANS n = 2 vs controls n = 2) confirmed these findings but showed heterogeneity across immune cell types. Toll-like receptor stimulation assay using peripheral blood mononuclear cells revealed reduced TNF and interleukin-6 responses in PANS patients (n = 7) compared to controls (n = 7). RNA sequencing before and after intravenous immunoglobulin treatment in PANS patients (n = 9 vs controls n = 10) revealed reversal of the dysregulated ribosomal, epigenetic, and cell signaling pathways. Given the central role of the immune system in synaptic pruning and neurodevelopment, these insights provide rationale for novel epigenetic and immune modulating therapies to optimize neurodevelopmental trajectories and minimize neuropsychiatric impairment in PANS.