Protective effect of the ketogenic diet in Scn1a mutant mice

Abstract

Summary Purpose We evaluated the ability of the ketogenic diet (KD) to improve thresholds to flurothyl-induced seizures in two mouse lines with Scn1a mutations: one that models Dravet syndrome (DS) and another that models genetic (generalized) epilepsy with febrile seizures plus (GEFS+). Methods At postnatal day 21, mouse models of DS and GEFS+ were fasted for 12–14 hours and then placed on either a 6:1 KD or a standard diet (SD) for two weeks. At the end of the two-week period, we measured thresholds to seizures induced by the chemiconvulsant flurothyl. Body weight, β-hydroxybutyrate (BHB) levels, and glucose levels were also recorded every two days over a two-week period in separate cohorts of mutant and wild-type mice that were either on the KD or the SD. Key Findings Mice on the KD gained less weight and exhibited significantly higher BHB levels compared to mice on the SD. Importantly, thresholds to flurothyl-induced seizures were restored to more normal levels in both mouse lines after two weeks on the KD. Significance These results indicate that the KD may be an effective treatment for refractory patients with SCN1A mutations. The availability of mouse models of DS and GEFS+ also provides an opportunity to better understand the mechanism of action of the KD, which may facilitate the development of improved treatments.

Efficacy and tolerability of the ketogenic diet in Dravet syndrome – Comparison with various standard antiepileptic drug regimen

“…There is strong evidence that the KD effectively controls seizures in patients with DS (Caraballo, 2011;Caraballo et al, 2005;Kang et al, 2005;Korff et al, 2007;Laux and Blackford, 2013), especially when added to the gold standard triple combination (Nabbout et al, 2011). Further, the diet has been reported to exhibit neuroprotective effects (Dutton et al, 2011;Luan et al, 2012) and to control long lasting SE refractory to conventional AED treatment (Nabbout et al, 2010).…”

Pathogenesis and new candidate treatments for infantile spasms and early life epileptic encephalopathies: A view from preclinical studies

“…In the N1417H SCN1A rat, methylphenidate inhibited thermally induced seizures and improved hyperactivity and spatial learning (Ohmori et al 2014). Ketogenic diet improved flurothyl seizure thresholds in the heterozygous SCN1A KO and R1648H mice (Dutton et al 2011). Genetic ablation of tau protein in the R1407X KI mouse reduced mortality and epilepsy severity, suggesting that targeting this pathway might be of benefit (Gheyara et al 2014).…”

SCN2A mutation in a Chinese boy with infantile spasm - response to Modified Atkins Diet

“…MAD is a modified form of ketogenic diet. The ketogenic diet was showed to improve the seizure thresholds in mice with SCN1A mutation which is the major cause of Dravet syndrome [14]. Previous studies demonstrated a significant reduction of seizure frequency in patients with Dravet syndrome who were maintained on this diet [15,16].…”