IQSEC2 is an X-linked guanine nucleotide exchange factor (GEF) that regulates ARF6-GTP signaling at excitatory synapses 1. The protein is anchored to the postsynaptic density through interaction with PSD-95 and becomes activated when NMDA receptor stimulation triggers calcium/calmodulin binding to its IQ domain, enabling its SEC7 catalytic domain to promote GDP-to-GTP exchange on ARF6 1. This activation drives internalization of AMPA receptors via JNK-mediated pathways, regulating synaptic strength and neuronal development 1. IQSEC2 mutations cause severe neurodevelopmental disorders characterized by intellectual disability, autism spectrum features, and early-onset refractory epilepsy 2. De novo mutations in IQSEC2 were identified in exome screens for infantile spasms and Lennox-Gastaut syndrome 3, with diagnostic exome sequencing revealing IQSEC2 among the most frequently affected genes in epilepsy cohorts 4. Patient studies show seizure onset typically after one year of age, with global developmental delay preceding seizures in most cases 5. IQSEC2 knockout mice demonstrate impaired regulation of Arf6-GTP cycling and aberrant neuronal network maturation resulting in increased inhibition and reduced transmission 2. Emerging evidence suggests heat shock treatment may reduce seizure burden in specific IQSEC2 mutations 2, highlighting potential therapeutic avenues.