Real-World Experience Treating Pediatric Epilepsy Patients With Cenobamate

IntroductionIn one third of all patients with epilepsy, seizure freedom is not achieved through anti-seizure medication (ASM). These patients have an increased risk of earlier death, poorer cognitive development, and reduced quality of life. Cenobamate (CNB) has recently been approved as a promising novel ASM drug for the treatment of adults with focal-onset epilepsy. However, there is little experience for its application in pediatric patients.MethodsIn a multicenter study we evaluated retrospectively the outcome of 16 pediatric patients treated “off label” with CNB.ResultsIn 16 patients with a mean age of 15.38 years, CNB was started at an age of 15.05 years due to DRE. Prior to initiation of therapy, an average of 10.56 (range 3–20) ASM were prescribed. At initiation, patients were taking 2.63 (range 1–4) ASM. CNB was increased by 0.47 ± 0.27mg/kg/d every 2 weeks with a mean maximum dosage of 3.1 mg/kg/d (range 0.89–7) and total daily dose of 182.81 mg (range 50–400 mg). Seizure freedom was achieved in 31.3% and a significant seizure reduction of >50% in 37.5%. Adverse events occurred in 10 patients with fatigue/somnolence as the most common. CNB is taken with high adherence in all but three patients with a median follow-up of 168.5 daysConclusionCenobamate is an effective ASM for pediatric patients suffering from drug-resistant epilepsy. In addition to excellent seizure reduction or freedom, it is well-tolerated. Cenobamate should be considered as a novel treatment for DRE in pediatric patients

The ataxia-linked E1081Q mutation affects the sub-plasma membrane Ca2+-microdomains by tuning PMCA3 activity

Calcium concentration must be finely tuned in all eukaryotic cells to ensure the correct performance of its signalling function. Neuronal activity is exquisitely dependent on the control of Ca(2+) homeostasis: its alterations ultimately play a pivotal role in the origin and progression of many neurodegenerative processes. A complex toolkit of Ca(2+) pumps and exchangers maintains the fluctuation of cytosolic Ca(2+) concentration within the appropriate threshold. Two ubiquitous (isoforms 1 and 4) and two neuronally enriched (isoforms 2 and 3) of the plasma membrane Ca(2+)ATPase (PMCA pump) selectively regulate cytosolic Ca(2+) transients by shaping the sub-plasma membrane (PM) microdomains. In humans, genetic mutations in ATP2B1, ATP2B2 and ATP2B3 gene have been linked with hearing loss, cerebellar ataxia and global neurodevelopmental delay: all of them were found to impair pump activity. Here we report three additional mutations in ATP2B3 gene corresponding to E1081Q, R1133Q and R696H amino acids substitution, respectively. Among them, the novel missense mutation (E1081Q) immediately upstream the C-terminal calmodulin-binding domain (CaM-BD) of the PMCA3 protein was present in two patients originating from two distinct families. Our biochemical and molecular studies on PMCA3 E1081Q mutant have revealed a splicing variant-dependent effect of the mutation in shaping the sub-PM [Ca(2+)]. The E1081Q substitution in the full-length b variant abolished the capacity of the pump to reduce [Ca(2+)] in the sub-PM microdomain (in line with the previously described ataxia-related PMCA mutations negatively affecting Ca(2+) pumping activity), while, surprisingly, its introduction in the truncated a variant selectively increased Ca(2+) extrusion activity in the sub-PM Ca(2+) microdomains. These results highlight the importance to set a precise threshold of [Ca(2+)] by fine-tuning the sub-PM microdomains and the different contribution of the PMCA splice variants in this regulation