A quinidine non responsive novel KCNT1 mutation in an Indian infant with epilepsy of infancy with migrating focal seizures

Madaan, Priyanka; Jauhari, Prashant; Gupta, Ashutosh; Chakrabarty, Biswaroop; Gulati, Sheffali

doi:10.1016/j.braindev.2017.09.008

Cited by 40 publications

(47 citation statements)

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“…The discovery that the class I antiarrhythmic drug quinidine can reverse channel overactivity in vitro led to its rapid clinical application in a patient with EIMFS and an R428Q (c1283G>A, pArg428Gln) variant with reported in vivo efficacy . Subsequently, reductions in seizure frequency have been observed in few patients, some with functionally milder gain‐of‐function mutations in KCNT1 , but treatment failures in other patients were also reported . A dissociation with regard to in vitro efficacy of quinidine on potassium current and in vivo responsiveness has been noted, with a distinct patient with an R428Q variant demonstrating the least effective seizure reduction with quinidine .…”

Section: Introductionmentioning

confidence: 99%

“…11,15 Subsequently, reductions in seizure frequency have been observed in few patients, some with functionally milder gain-of-function mutations in KCNT1, but treatment failures in other patients were also reported. [16][17][18][19][20] A dissociation with regard to in vitro efficacy of quinidine on potassium current and in vivo responsiveness has been noted, with a distinct patient with an R428Q variant demonstrating the least effective seizure reduction with quinidine. 17 These findings raise the question about determinants of responsiveness to quinidine, including phenotype, time from symptom onset to the initiation of treatment, or dose.…”

Section: Introductionmentioning

confidence: 99%

“…Prior case series have described patients with seizure onset in the neonatal period in KCNT1-associated EIMFS, although only one case has been diagnosed so early on in the disease course. 18 All patients in this series initiated quinidine therapy at an early age, with 2 patients initiating therapy within the first 2 months of life. [15][16][17][18]33 Despite early targeting of the pathologic channel, no disease-modifying effects were noted in the clinical phenotype.…”

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confidence: 99%

“…18 All patients in this series initiated quinidine therapy at an early age, with 2 patients initiating therapy within the first 2 months of life. [15][16][17][18]33 Despite early targeting of the pathologic channel, no disease-modifying effects were noted in the clinical phenotype. In contrast to previous hypotheses, our data do not support "age at quinidine initiation" as a variable that can modify overall outcome.…”

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Lack of response to quinidine in KCNT1‐related neonatal epilepsy

et al. 2018

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Patients had no reported benefit to quinidine therapy despite age at treatment initiation. Pharmacogenetic results in oocytes were consistent with clinical treatment failure in 2 patients, suggesting that single-dose pharmacologic assessment may be helpful in predicting which patients are exceedingly unlikely to achieve benefit with quinidine. In the 2 patients who had a lack of therapeutic benefit despite sensitivity to high concentrations of quinidine with in vitro oocyte assay, it is likely that the achievable exposure levels in the brain were too low to cause significant in vivo channel blockade.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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Lack of response to quinidine in KCNT1‐related neonatal epilepsy

et al. 2018

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“…It is therefore notable that the antihelminthic drug niclosamide, which activates K Na channels (60), has long been known to uncouple mitochondria (61) and was recently shown to confer benefits in a mouse high-fat diet model of diabetes (62). Furthermore, a recent case report highlighted a patient with a K Na 1.2 mutation (Q 270 E) who had migrating focal seizures that were nonresponsive to the ketogenic diet typically used to treat such symptoms (63). Cardiac metabolomics also revealed a potential upregulation of PLC signaling in the Kcnt2 2/2 heart (Fig.…”

Section: Discussionmentioning

confidence: 99%

Cardiac metabolic effects of K_Na1.2 channel deletion and evidence for its mitochondrial localization

et al. 2018

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Controversy surrounds the molecular identity of mitochondrial K channels that are important for protection against cardiac ischemia-reperfusion injury. Although K1.2 (sodium-activated potassium channel encoded by Kcn2) is necessary for cardioprotection by volatile anesthetics, electrophysiological evidence for a channel of this type in mitochondria is lacking. The endogenous physiological role of a potential mito-K1.2 channel is also unclear. In this study, single channel patch-clamp of 27 independent cardiac mitochondrial inner membrane (mitoplast) preparations from wild-type (WT) mice yielded 6 channels matching the known ion sensitivity, ion selectivity, pharmacology, and conductance properties of K1.2 (slope conductance, 138 ± 1 pS). However, similar experiments on 40 preparations from Kcnt2 mice yielded no such channels. The K opener bithionol uncoupled respiration in WT but not Kcnt2 cardiomyocytes. Furthermore, when oxidizing only fat as substrate, Kcnt2 cardiomyocytes and hearts were less responsive to increases in energetic demand. Kcnt2 mice also had elevated body fat, but no baseline differences in the cardiac metabolome. These data support the existence of a cardiac mitochondrial K1.2 channel, and a role for cardiac K1.2 in regulating metabolism under conditions of high energetic demand.-Smith, C. O., Wang, Y. T., Nadtochiy, S. M., Miller, J. H., Jonas, E. A., Dirksen, R. T., Nehrke, K., Brookes, P. S. Cardiac metabolic effects of K1.2 channel deletion and evidence for its mitochondrial localization.

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Efficacy and Safety of Dietary Therapies for Childhood Drug-Resistant Epilepsy

et al. 2023

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ImportanceDespite advances in the understanding of dietary therapies in children with drug-resistant epilepsy, no quantitative comparison exists between different dietary interventions.ObjectiveTo evaluate the comparative efficacy and safety of various dietary therapies in childhood drug-resistant epilepsy.Data SourcesSystematic review and network meta-analysis (frequentist) of studies in PubMed, Embase, Cochrane, and Ovid published from inception to April 2022 using the search terms ketogenic diet, medium chain triglyceride diet, modified Atkins diet, low glycemic index therapy, and refractory epilepsy.Study SelectionRandomized clinical trials comparing different dietary therapies (ketogenic diet, modified Atkins diet, and low glycemic index therapy) with each other or care as usual in childhood drug-resistant epilepsy were included. Abstract, title, and full text were screened independently by 2 reviewers.Data Extraction and SynthesisData extraction was conducted following Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline. Cochrane risk-of-bias tool was used to assess the study quality. Effect sizes were calculated as odds ratio with 95% CI using random-effects model. The hierarchy of competing interventions was defined using the surface under the cumulative ranking curve.Main Outcomes and MeasuresShort-term (≤3 months) 50% or higher and 90% or higher reduction in seizure frequency and treatment withdrawal due to adverse events were the primary efficacy and safety outcomes.ResultsOf 2158 citations, 12 randomized clinical trials (907 patients) qualified for inclusion. In the short term, all dietary interventions were more efficacious than care as usual for 50% or higher seizure reduction (low glycemic index therapy: odds ratio [OR], 24.7 [95% CI, 5.3-115.4]; modified Atkins diet: OR, 11.3 [95% CI, 5.1-25.1]; ketogenic diet: OR, 8.6 [95% CI, 3.7-20.0]), while ketogenic diet (OR, 6.5 [95% CI, 2.3-18.0]) and modified Atkins diet (OR, 5.1 [95% CI, 2.2-12.0]) were better than care as usual for seizure reduction of 90% or higher. However, adverse event–related discontinuation rates were significantly higher for ketogenic diet (OR, 8.6 [95% CI, 1.8-40.6]) and modified Atkins diet (OR, 6.5 [95% CI, 1.4-31.2]) compared with care as usual. Indirectly, there was no significant difference between dietary therapies in efficacy and safety outcomes.Conclusions and RelevanceThis study found that all dietary therapies are effective in the short term. However, modified Atkins diet had better tolerability, higher probability for 50% or higher seizure reduction, and comparable probability for 90% or higher seizure reduction and may be a sounder option than ketogenic diet. Direct head-to-head comparison studies are needed to confirm these findings.

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A quinidine non responsive novel KCNT1 mutation in an Indian infant with epilepsy of infancy with migrating focal seizures

Cited by 40 publications

References 8 publications

Lack of response to quinidine in KCNT1‐related neonatal epilepsy

Lack of response to quinidine in KCNT1‐related neonatal epilepsy

Cardiac metabolic effects of K_Na1.2 channel deletion and evidence for its mitochondrial localization

Efficacy and Safety of Dietary Therapies for Childhood Drug-Resistant Epilepsy

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A quinidine non responsive novel KCNT1 mutation in an Indian infant with epilepsy of infancy with migrating focal seizures

Cited by 40 publications

References 8 publications

Lack of response to quinidine in KCNT1‐related neonatal epilepsy

Lack of response to quinidine in KCNT1‐related neonatal epilepsy

Cardiac metabolic effects of KNa1.2 channel deletion and evidence for its mitochondrial localization

Efficacy and Safety of Dietary Therapies for Childhood Drug-Resistant Epilepsy

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Cardiac metabolic effects of K_Na1.2 channel deletion and evidence for its mitochondrial localization