Quinidine-associated skin discoloration in
            <i>KCNT1</i>
            -associated pediatric epilepsy

Bäumer, F; Sheehan, Maureen G.

doi:10.1212/wnl.0000000000004674

Cited by 13 publications

(8 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Epilepsy (ADNFLE) and Ohtahara syndrome (Heron et al, 2012;Martin et al, 2014). To date, around 60 patients associating KCNT1 mutations and EIMFS are reported with variable and often incomplete information on seizures, EEGs, therapies, MRI and neurodevelopmental status (McTague et al, 2018;Ishii et al, 2013;McTague et al, 2013;Bearden et al, 2014, Mikati et al, 2015bMøller et al, 2015;Ohba et al, 2015;Mori et al, 2016;Rizzo et al, 2016;de Kovel et al, 2016;Baumer and Sheehan, 2017;Zhang et al, 2017;Jee N et al, 2017;Kawasaki et al, 2017;Madaan et al, 2017;Abdelnour et al, 2018;Numis et al, 2018;Dilena et al, 2018). Many questions remain unanswered, mainly on the prognosis and the long-term outcome.…”

Section: Mutations Of This Gene Have Been Also Reported In Autosomal mentioning

confidence: 99%

KCNT1 epilepsy with migrating focal seizures shows a temporal sequence with poor outcome, high mortality and SUDEP

Kuchenbuch

Barcia

Chémaly

et al. 2019

Brain

View full text Add to dashboard Cite

Data on KCNT1 epilepsy of infancy with migrating focal seizures are heterogeneous and incomplete. Kuchenbuch et al. refine the syndrome phenotype, showing a three-step temporal sequence, poor prognosis with acquired microcephaly, high prevalence of extra-neurological manifestations and early mortality, particularly due to SUDEP. Refining the electro-clinical spectrum should facilitate early diagnosis.

show abstract

Section: Mutations Of This Gene Have Been Also Reported In Autosomal mentioning

confidence: 99%

KCNT1 epilepsy with migrating focal seizures shows a temporal sequence with poor outcome, high mortality and SUDEP

Kuchenbuch

Barcia

Chémaly

et al. 2019

Brain

View full text Add to dashboard Cite

show abstract

“…Gain of function variants in KCNT1 have also been found in patients with other epileptic syndromes including Autosomal Dominant Nocturnal Frontal Lobe Epilepsy, Ohtahara syndrome, and Lennox-Gastaut syndrome (3,5,7,8,20,21). The antiarrhythmic drug quinidine has been shown to reduce the pathogenic currents produced by some of the mutant KCNT1 channels in vitro (11,17,(22)(23)(24)(25) but has had a limited clinical translation due to unwanted side effects (QTc prolongation and increased risk for arrhythmia) thereby resulting in a limited therapeutic window (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37). To date, there is no effective therapy to treat KCNT1 associated epilepsies.…”

Section: Introductionmentioning

confidence: 99%

Antisense oligonucleotide therapy for KCNT1 encephalopathy

Burbano

Jancovski

et al. 2022

JCI Insight

View full text Add to dashboard Cite

Developmental and epileptic encephalopathies (DEE) are characterized by pharmacoresistant seizures with concomitant intellectual disability. Epilepsy of infancy with migrating focal seizures (EIMFS) is one of the most severe of these syndromes. De novo variants in ion channels, including gain-of-function variants in KCNT1, have been found to play a major role in the etiology of EIMFS. Here, we test a potential precision therapeutic approach in KCNT1-associated DEE using a gene silencing antisense oligonucleotide (ASO) approach. We generated a mouse model carrying the KCNT1 p.P924L pathogenic variant; only the homozygous animals presented with the frequent, debilitating seizures and developmental compromise that are seen in patients. After a single intracerebroventricular bolus injection of a Kcnt1 gapmer ASO in symptomatic mice at postnatal day 40, seizure frequency was significantly reduced, behavioral abnormalities improved, and overall survival was extended compared to mice treated with a control ASO (non-hybridizing sequence). ASO administration at neonatal age was also well-tolerated and effective in controlling seizures and extending the lifespan of treated animals. The data presented here provide proof of concept for ASO-based gene silencing as a promising therapeutic approach in KCNT1-associated epilepsies.

show abstract

“…The search yielded 319 records of which 138, 151 and 30 were from PubMed, Embase and Cochrane Online Library databases, respectively. Of these, only 27 studies met the inclusion and exclusion criteria, and were thus analysed in this study; 25 studies reported on the effect of quinidine in patients with KCNT1 ‐related epileptic disorders and six studies tested the effect of quinidine in Kcnt1 mutations in vitro 5,7–10,15–36 . The study identification procedure is illustrated in Figure 1.…”

Section: Resultsmentioning

confidence: 99%

Precision therapy with quinidine of KCNT1‐related epileptic disorders: A systematic review

Chen

Yang

et al. 2022

Brit J Clinical Pharma

View full text Add to dashboard Cite

Aims Despite numerous studies on quinidine therapies for epilepsies associated with KCNT1 gene mutations, there is no consensus on its clinical utility. Thus, we reviewed studies evaluating the efficacy and safety of quinidine in KCNT1‐related epileptic disorders. Methods Electronic databases were queried for in vivo and in vitro studies on quinidine therapy in KCNT1‐related epilepsies published on or before 1 May 2022. The evaluation of evidence was done as per the American Academy of Neurology's classification scheme. Identification of significant factors that possibly influenced therapeutic effects of quinidine were performed using χ2 tests. Results Twenty‐seven studies containing 82 patient records were reviewed. Records of 80 patients with 33 KCNT1 mutations were analysed, of which 20 patients had gained ≥50% seizure reduction due to quinidine therapy. However, quinidine therapy often had different effects on patients with the same KCNT1 mutation. Age, genotypes of KCNT1 mutations, seizure types and brain MRI did not significantly influence the therapeutic effect of quinidine. Prolonged QTc was the most common among all adverse events with quinidine. Notably, results of in vitro quinidine tests did not correspond with in vivo tests. Conclusions Therapeutic effects of quinidine on KCNT1‐related epilepsies remained indefinite as contradictory results were detected in similar patients. Age, seizure types, genotypes of KCNT1 mutations and brain MRI did not influence the therapeutic effects of quinidine. Insensitivity to quinidine by a certain Kcnt1 genotype in molecular tests is predictive of its inefficacy in human populations of the respective mutation.

show abstract

Quinidine-associated skin discoloration in KCNT1 -associated pediatric epilepsy

Cited by 13 publications

References 1 publication

KCNT1 epilepsy with migrating focal seizures shows a temporal sequence with poor outcome, high mortality and SUDEP

KCNT1 epilepsy with migrating focal seizures shows a temporal sequence with poor outcome, high mortality and SUDEP

Antisense oligonucleotide therapy for KCNT1 encephalopathy

Precision therapy with quinidine of KCNT1‐related epileptic disorders: A systematic review

Contact Info

Product

Resources

About