The Nodding syndrome cerebrospinal fluid proteome: a lens into neurodevelopmental failure consistent with environmentally triggered MECP2 dysregulation?

INTRODUCTION: Nodding Syndrome (NS) is a childhood-onset epileptic encephalopathy of unknown etiology, occurring in clustered outbreaks across East Africa. Despite extensive investigation, its molecular underpinnings remain unresolved. METHODS: We performed an 18-plex tandem mass tag (TMT)-based quantitative proteomic analysis of immunodepleted cerebrospinal fluid (CSF) from Ugandan NS patients (n = 9) and age-comparable Ugandan Controls (n = 9). Differential protein abundance and pathway-level enrichment analyses were conducted to identify dysregulated molecular networks. RESULTS: A total of 2,195 CSF proteins were quantified, of which 544 showed statistically significant differential abundance. Dysregulated pathways spanned immune signaling, proteostasis, synaptic function, metabolism, transcriptional regulation, neurovascular integrity, and tau-associated processes. Notably, the NS CSF proteomic profile showed substantial pathway-level convergence with that reported in MECP2 duplication syndrome (MDS), an X-linked neurodevelopmental disorder marked by MECP2 overexpression and systemic immune-metabolic dysfunction. Clinically, NS shares features with both MDS and its mechanistic converse, Rett syndrome, characterized by MECP2 loss-of-function. DISCUSSION: These convergent molecular and clinical signatures suggest that NS may involve aberrant regulation of MECP2-associated networks. We propose a provisional model in which NS represents an environmentally induced functional phenocopy of MECP2 network dysregulation, shaped by early-life immune and epigenetic perturbations and amplified by postnatal environmental stressors. Although direct epigenetic data and detailed exposure histories are currently limited, this integrative framework provides a testable model linking proteomic alterations and clinical observations to neurodevelopmental and immune-metabolic mechanisms, offering tractable directions for future mechanistic and therapeutic inquiry.