Applying lessons learned from fever for the precision medicine treatment of IQSEC2 mutations

Purposeful induction of fever as a tool for healing, including the treatment of epilepsy, was used 2000 years ago by Hippocrates. More recently, fever was demonstrated to rescue behavioral defects in children with autism. However, the mechanism for benefit from fever has remained elusive due to the lack of human disease models recapitulating the disease-fever association. IQSEC2 gene mutations account for 2-5% of children presenting with intellectual disability, autism and epilepsy. We have worked closely with parents of these children to understand features of the disorder that may provide insights into treatment. One observation, occurring with diverse IQSEC2 mutations, is that fever is associated with a marked clinical improvement manifested as an abatement in seizures and an improvement in social interactions. Moreover, purposefully raising the temperature of these children in a Jacuzzi reduces seizures and improves social interactions. We have recently described a murine IQSEC2 disease model which recapitulates important aspects of the human IQSEC2 disease phenotype and the favorable response to a rise in core temperature with heat therapy. The pathophysiological abnormalities underlying diverse IQSEC2 mutations appear to converge with increased levels of Arf6-GTP and we have proposed that this increase in Arf6-GTP is responsible for the synaptic dysfunction resulting in seizures, behavioral abnormalities and cognitive dysfunction observed with IQSEC2 mutations. We have found that heat therapy rapidly downregulates Arf6-GTP and normalizes synaptic function in IQSEC2 mutant neurons. Moreover, preliminary data demonstrates that drugs which can normalize levels of Arf6-GTP can partially rescue the IQSEC2 phenotype.