Does age affect response to quinidine in patients with KCNT1 mutations? Report of three new cases and review of the literature

Abdelnour, Elie; Gallentine, William B.; McDonald, Marie; Sachdev, Monisha; Jiang, Yong‐Hui; Mikati, Mohamad A.

doi:10.1016/j.seizure.2017.11.017

Cited by 58 publications

(63 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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 . Perhaps then, single gene mutations cause more widespread problems that targeted therapy even when initiated at an early age in development cannot overcome.…”

Section: Discussioncontrasting

confidence: 99%

“…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%

See 2 more Smart Citations

Lack of response to quinidine in KCNT1‐related neonatal epilepsy

et al. 2018

View full text Add to dashboard Cite

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.

show abstract

Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Lack of response to quinidine in KCNT1‐related neonatal epilepsy

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Sodium channel inhibitors such as phenytoin or carbamazepine, including lidocain and mexiletine, are efficient in NMDA‐pathies in the neonate and infant with SCN2A and SCN8A gene mutations causing gain‐of‐function . Quinidine, a potassium channel blocker, was effective in some patients with KCNT1 encephalopathy, provided it was given before the age of 4 years . However, sodium channel inhibitors worsen phasic GABA‐pathies, namely Dravet syndrome.…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

“…61,62 Quinidine, a potassium channel blocker, was effective in some patients with KCNT1 encephalopathy, provided it was given before the age of 4 years. 63 However, sodium channel inhibitors worsen phasic GABA-pathies, namely Dravet syndrome. Furthermore, NMDA-pathies seem to be worsened in neonates by depolarizing GABA transmission because inhibition of the cotransporter NKCC1 by bumetanide controls epilepsy.…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Gene mutations in paediatric epilepsies cause NMDA‐pathy, and phasic and tonic GABA‐pathy

Gataullina

Bienvenu

Nabbout

et al. 2019

Develop Med Child Neuro

View full text Add to dashboard Cite

The aim of this study was to disentangle mechanisms of epileptogenesis in monogenic epilepsies in children. We reviewed paediatric monogenic epilepsies excluding brain malformation or an inborn error of metabolism, but including the gene function whether there is loss‐of‐function or gain‐of‐function, age at gene expression when available, and associated epilepsy syndrome. Genes for which at least five patients with similar epilepsy phenotype had been reported were selected. Three mechanisms are shared by most monogenic epilepsies: (1) excess of N‐methyl‐d‐aspartate (NMDA) transmission activation (NMDA‐pathies); (2) abnormal gamma‐aminobutyric acid (GABA) transmission with reduced inhibition (phasic GABA‐pathies); and (3) tonic activation of extrasynaptic GABAA receptors by extracellular GABA (tonic GABA‐pathies). NMDA‐pathies comprise early epileptic encephalopathy with suppression‐burst, neonatal/infantile benign seizures, West and Lennox–Gastaut syndromes, and encephalopathy with continuous spike waves in slow sleep, thus brief seizures with major interictal spiking. Phasic GABA‐pathies comprise mostly generalized epilepsy with febrile seizures plus and Dravet syndrome, thus long‐lasting seizures with mild interictal spiking. Tonic GABA‐pathies cause epilepsy with myoclonic–atonic seizures and Angelman syndrome, thus major high‐amplitude slow‐wave activity. This pathophysiological approach to monogenic epilepsies provides diagnostic clues and helps to guide treatment strategy. What this paper adds In paediatric monogenic epilepsies, electroclinical patterns point to three main mechanisms: NMDA‐pathies, and phasic and tonic GABA‐pathies. Antiepileptic treatment choice could be guided by each of these mechanisms.

show abstract

Efficacy of anti‐seizure medications and alternative therapies (ketogenic diet, CBD, and quinidine) in KCNT1‐related epilepsy: A systematic review

Gras,

Bearden,

West

et al. 2024

Epilepsia Open

View full text Add to dashboard Cite

ObjectiveKCNT1‐related epilepsies encompass three main phenotypes: (i) epilepsy of infancy with migrating focal seizures (EIMFS), (ii) autosomal dominant or sporadic sleep‐related hypermotor epilepsy [(AD)SHE], and (iii) different types of developmental and epileptic encephalopathies (DEE). Many patients present with drug‐resistant seizures and global developmental delays. In addition to conventional anti‐seizure medications (ASM), multiple alternative therapies have been tested including the ketogenic diet (KD), cannabidiol (CBD—including Epidyolex © and other CBD derivatives) and quinidine (QUIN). We aimed to clarify the current state of the art concerning the benefits of those therapies administered to the three groups of patients.MethodsWe performed a literature review on PubMed and EMBase with the keyword “KCNT1” and selected articles reporting qualitative and/or quantitative information on responses to these treatments. A treatment was considered beneficial if it improved seizure frequency and/or intensity and/or quality of life. Patients were grouped by phenotype.ResultsA total of 43 studies including 197 patients were reviewed. For EIMFS patients (32 studies, 135 patients), KD resulted in benefit in 62.5% (25/40), all types of CBD resulted in benefit in 50% (6/12), and QUIN resulted in benefit in 44.6% (25/56). For (AD)SHE patients (10 studies, 32 patients), we found only one report of treatment with KD, with no benefit noted. QUIN was trialed in 8 patients with no reported benefit. For DEE patients (10 studies, 30 patients), KD resulted in benefit for 4/7, CBD for 1/2, and QUIN for 6/9. In all groups, conventional ASM are rarely reported as beneficial (in 5%–25% of patients).SignificanceKetogenic diet, CBD, and QUIN treatments appear to be beneficial in a subset of patient with drug‐resistant epilepsy. The KD and CBD are reasonable to trial in patients with KCNT1‐related epilepsy. Further studies are needed to identify optimal treatment strategies and to establish predictive response factors.Plain Language SummaryWe performed an extensive review of scientific articles providing information about the therapeutic management of epilepsy in patients with epilepsy linked to a mutation in the KCNT1 gene. Conventional anti‐seizure treatments were rarely reported to be beneficial. The ketogenic diet (a medical diet with very high fat, adequate protein and very low carbohydrate intake) and cannabidiol appeared to be useful, but larger studies are needed to reach a conclusion.

show abstract

Does age affect response to quinidine in patients with KCNT1 mutations? Report of three new cases and review of the literature

Abstract: The above-mentioned findings support performance of prospective controlled studies of quinidine efficacy in children with KCNT1 gain-of-function mutations that control for age as a possible variable affecting response.

Cited by 58 publications

References 4 publications

Lack of response to quinidine in KCNT1‐related neonatal epilepsy

Lack of response to quinidine in KCNT1‐related neonatal epilepsy

Gene mutations in paediatric epilepsies cause NMDA‐pathy, and phasic and tonic GABA‐pathy

Efficacy of anti‐seizure medications and alternative therapies (ketogenic diet, CBD, and quinidine) in KCNT1‐related epilepsy: A systematic review

Contact Info

Product

Resources

About