Characterization of two de novo KCNT1 mutations in children with malignant migrating partial seizures in infancy

Rizzo, Francesca; Ambrosino, Paolo; Guacci, Anna; Chetta, Massimiliano; Marchese, Giovanna; Rocco, Teresa; Soldovieri, Maria Virginia; Manocchio, Laura; Mosca, Ilaria; Casara, Gianluca; Vecchi, Marilena; Taglialatela, Maurizio; Coppola, Giangennaro; Weisz, Alessandro

doi:10.1016/j.mcn.2016.01.004

Cited by 87 publications

(153 citation statements)

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“…In Patient 2, a de novo A259D variant was found, and functional assessment showed a characteristic gain‐of‐function in current magnitude and activation kinetics (Figure A‐C) as seen in various other EIMFS patients. Previous reports have demonstrated KCNT1 mutants expressing M516V (Patient 3) or R428Q (Patient 4) and result in gain‐of‐effect with increased K+ conductance compared to WT channels …”

Section: Resultsmentioning

confidence: 95%

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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: Resultsmentioning

confidence: 95%

“…Genetic testing showed predicted disease‐causing variants in KCNT1 in all patients. Mutations were reported previously and characterized in 2 patients (R428Q [c1283G>A] and M516V [c1546 A>G]). One patient had a novel variant in KCNT1 at A259D.…”

Section: Resultsmentioning

confidence: 99%

Lack of response to quinidine in KCNT1‐related neonatal epilepsy

et al. 2018

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“…We classified this variant as “likely pathogenic” since it was previously reported to be disease causing by Rizzo et al. ().…”

Section: Resultsmentioning

confidence: 99%

Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes

et al. 2016

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Targeted resequencing gene panels are used in the diagnostic setting to identify gene defects in epilepsy. We performed targeted resequencing using a 30-genes panel and a 95-genes panel in 349 patients with drugresistant epilepsies beginning in the first years of life. We identified 71 pathogenic variants, 42 of which novel, in 30 genes, corresponding to 20.3% of the probands. In 66% of mutation positive patients, epilepsy onset occurred before the age of 6 months. The 95-genes panel allowed a genetic diagnosis in 22 (6.3%) patients that would have otherwise been missed using the 30-gene panel. About 50% of mutations were identified in genes coding for sodium and potassium channel components. SCN2A was the most frequently mutated gene followed by SCN1A, KCNQ2, STXBP1, SCN8A, CDKL5, and MECP2. Twenty-nine mutations were identified in 23 additional genes, most of them recently associated with epilepsy. Our data show that panels targeting about 100 genes represent the best cost-effective diagnostic option in pediatric drug-resistant epilepsies. They enable molecular diagnosis of atypical phenotypes, allowing to broaden phenotype-genotype correlations. Molecular diagnosis might influence patients' management and translate into better and specific treatment recommendations in some conditions. Hum Mutat 38:216-225, 2017. C 2016 Wiley Periodicals, Inc.

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“…These include malignant migrating partial seizures in infancy (Barcia et al, 2012;Ishii et al, 2013;McTague et al, 2013;Rizzo et al, 2016), autosomal dominant frontal lobe epilepsy (Heron et al, 2012;, Ohtahara syndrome , and other epilepsies (Juang et al, 2014;Vanderver et al, 2014). Mutations in the gene for K Na 1.1 have also been documented in autism (Iossifov et al, 2014).…”

Section: The K Ca 2 Family-small Conductance Channels Regulated mentioning

confidence: 99%

“…Quinidine is a very effective blocker of these channels in both expression systems and neurons (Bhattacharjee et al, 2003;Yang et al, 2006Yang et al, , 2007Milligan et al, 2014;Rizzo et al, 2016). It has been reported that quinidine ameliorated the symptoms of a patient with malignant migrating partial seizures in infancy, but because this agent blocks a wide variety of other channels, the mechanism is not known (Bearden et al, 2014).…”

Section: The K Ca 2 Family-small Conductance Channels Regulated mentioning

confidence: 99%