North Sea Progressive Myoclonus Epilepsy is Exacerbated by Heat, A Phenotype Primarily Associated with Affected Glia

• Published in: Neuroscience Vol. 423; pp. 1 - 11
• Main Authors: Lambrechts, Roald A., Polet, Sjoukje S., Hernandez-Pichardo, Alejandra, van Ninhuys, Lisa, Gorter, Jenke A., Grzeschik, Nicola A., de Koning-Tijssen, Marina A.J., de Koning, Tom J., Sibon, Ody C.M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 15.12.2019
• Subjects: childhood onset; glia; GOSR2; myoclonic epilepsy; childhood onset; myoclonic epilepsy; glia; GOSR2
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2019.10.035

•North Sea progressive myoclonus epilepsy (NS-PME), a disease caused by mutations in the GOSR2 gene, is exacerbated by heat.•Consistently, a Drosophila fruitfly model for NS-PME shows heat-induced seizure-like behavior.•Membrin, the Drosophila orthologue of GOSR2, is required in glia, but not in neurons to prevent heat-induced seizures.•Sodium barbital treatment to NS-PME flies decreased heat-induced seizures.•The fly model can be used to understand the pathophysiology of NS-PME and to identify treatment strategies. Progressive myoclonic epilepsies (PMEs) comprise a group of rare disorders of different genetic aetiologies, leading to childhood-onset myoclonus, myoclonic seizures and subsequent neurological decline. One of the genetic causes for PME, a mutation in the gene coding for Golgi SNAP receptor 2 (GOSR2), gives rise to a PME-subtype prevalent in Northern Europe and hence referred to as North Sea Progressive Myoclonic Epilepsy (NS-PME). Treatment for NS-PME, as for all PME subtypes, is symptomatic; the pathophysiology of NS-PME is currently unknown, precluding targeted therapy. Here, we investigated the pathophysiology of NS-PME. By means of chart review in combination with interviews with patients (n = 14), we found heat to be an exacerbating factor for a majority of NS-PME patients (86%). To substantiate these findings, we designed a NS-PME Drosophila melanogaster model. Downregulation of the Drosophila GOSR2-orthologue Membrin leads to heat-induced seizure-like behaviour. Specific downregulation of GOSR2/Membrin in glia but not in neuronal cells resulted in a similar phenotype, which was progressive as the flies aged and was partially responsive to treatment with sodium barbital. Our data suggest a role for GOSR2 in glia in the pathophysiology of NS-PME.