The Nodding Syndrome Cerebrospinal Fluid Proteome: A Lens into Neurodevelopmental Failure

Nodding Syndrome (NS), a pediatric epileptic encephalopathy of East Africa, has long defied etiological classification. Here, we report high-resolution untargeted proteomics of cerebrospinal fluid from Ugandan NS patients and controls that reveals widespread disruption across immune, proteostatic, synaptic, metabolic, transcriptional, and neurovascular domains, with tauopathy as a secondary amplifier. This molecular signature closely resembles MECP2 duplication syndrome (MDS), an X-linked disorder of methyl-CpG binding protein 2 (MECP2) overexpression characterized by systemic immune-metabolic dysfunction and tau instability. Importantly, NS also shares features with Rett syndrome, the genetic converse of MDS, which results from MECP2 loss-of-function mutations or underexpression. Together, these parallels position NS along a MECP2 dysregulation axis, wherein dosage imbalance destabilizes convergent neurodevelopmental and systemic pathways. We propose that NS represents an environmentally imprinted phenocopy of MECP2-axis collapse, primed by prenatal maternal immune activation (MIA) and exacerbated by postnatal malnutrition, biotoxin exposures, and nematode and other infections. This framework repositions NS as a multisystem disorder of environmentally-driven MECP2 dysregulation, bridging genetic and environmental paradigms of tauopathy, and opening new avenues for multipronged intervention.