• Roald A Lambrechts, Sjoukje S Polet, Alejandra Hernandez-Pichardo, Lisa van Ninhuys, Jenke A Gorter, Nicola A Grzeschik, Marina A J de Koning-Tijssen, Tom J de Koning, and Ody C M Sibon.
• Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Neurology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
• Neuroscience. 2019 Dec 15; 423: 1-11.

AbstractProgressive 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.Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.

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