Category: Rare Genetic and Metabolic Diseases
Objective: To determine the effect of conventional anti-epileptic drugs in a North Sea Progressive Myoclonus Epilepsy (NS-PME) Drosophila model.
Background: In 2011, Corbett et al. reported for the first time homozygous partial loss-of-function GOSR2 mutations (c.430G>T; p. Gly144Trp) as a novel cause of childhood-onset progressive myoclonus epilepsy (PME) with ataxia. Despite combinations of on average 3-5 anti-epileptic drugs (mainly levetiracetam, clonazepam, valproic acid), debilitating myoclonus and seizures persist. Here we evaluated the individual effect of anti-epileptic drugs in an animal model for NS-PME.
Method: In our lab a Drosophila model for NS-PME was generated, which displays progressive heat-sensitive seizures. This is consistent with heat-sensitivity reported in patients. Here, we tested the effect of either sodium barbital, clonazepam, valproic acid or levetiracetam in this model. Sodium barbital was previously shown to effectively suppress seizures in this Drosophila model . The other three compounds represent the most common prescribed drugs for myoclonus and seizures in NS-PME . Compounds were administered by adding them to the food medium in a range of concentrations. After 7 days of treatment, the amount of seizures during a heat-induced seizure assay was determined and compared to a non-treated control (the vehicle; DMSO, ethanol or water).
Results: As previously reported in our Drosophila model, sodium barbital results in significant seizure suppression, with increasing effect at higher dosages. Clonazepam also resulted in seizure suppression when administered at the highest concentration possible. Valproic acid was lethal at higher dosages, however the highest non-lethal concentration showed no improvements in amount of seizures. Levetiracetam did not show any improvement in seizures up to a concentration of 200mM, however no toxicity was observed either.
Conclusion: Interestingly, although three out of the four drugs are commonly prescribed to manage symptoms in NS-PME, only out of the three resulted in seizure suppression in our NS-PME Drosophila model. Of the four drugs tested, the two showing effective seizure suppression (sodium barbital and clonazepam) are primarily known for their direct effect on GABA-A receptors. This suggests that GABA-A could be a potentially important target in the treatment of North Sea Progressive Myoclonus Epilepsy.
References:  Lambrechts RA, Polet SS, Hernandez-Pichardo A, van Ninhuys L, Gorter JA, Grzeschik NA, de Koning-Tijssen MAJ, de Koning TJ, Sibon OCM. North Sea Progressive Myoclonus Epilepsy is Exacerbated by Heat, A Phenotype Primarily Associated with Affected Glia. Neuroscience. 2019 Dec 15;423:1-11.
 Polet SS, Anderson DG, Koens LH, van Egmond ME, Drost G, Brusse E, Willemsen MA, Sival DA, Brouwer OF, Kremer HP, de Vries JJ, Tijssen MA, de Koning TJ. A detailed description of the phenotypic spectrum of North Sea Progressive Myoclonus Epilepsy in a large cohort of seventeen patients. Parkinsonism Relat Disord. 2020 Mar;72:44-48.
To cite this abstract in AMA style:S. Polet, R. Lambrechts, M. de Koning-Tijssen, O. Sibon, T. de Koning, J. Gorter. Conventional anti-epileptic drugs used in North Sea Progressive Myoclonus Epilepsy revisited in a Drosophila model [abstract]. Mov Disord. 2023; 38 (suppl 1). https://www.mdsabstracts.org/abstract/conventional-anti-epileptic-drugs-used-in-north-sea-progressive-myoclonus-epilepsy-revisited-in-a-drosophila-model/. Accessed September 23, 2023.
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MDS Abstracts - https://www.mdsabstracts.org/abstract/conventional-anti-epileptic-drugs-used-in-north-sea-progressive-myoclonus-epilepsy-revisited-in-a-drosophila-model/