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. 2019 Oct 25;5(6):e363.
doi: 10.1212/NXG.0000000000000363. eCollection 2019 Dec.

Epilepsy with migrating focal seizures: KCNT1 mutation hotspots and phenotype variability

Giulia Barcia  1 , Nicole Chemaly  1 , Mathieu Kuchenbuch  1 , Monika Eisermann  1 , Stéphanie Gobin-Limballe  1 , Viorica Ciorna  1 , Alfons Macaya  1 , Laetitia Lambert  1 , Fanny Dubois  1 , Diane Doummar  1 , Thierry Billette de Villemeur  1 , Nathalie Villeneuve  1 , Marie-Anne Barthez  1 , Caroline Nava  1 , Nathalie Boddaert  1 , Anna Kaminska  1 , Nadia Bahi-Buisson  1 , Mathieu Milh  1 , Stéphane Auvin  1 , Jean-Paul Bonnefont  1 , Rima Nabbout  1
Affiliations

Epilepsy with migrating focal seizures: KCNT1 mutation hotspots and phenotype variability

Giulia Barcia et al. Neurol Genet. .

Abstract

Objective: To report new sporadic cases and 1 family with epilepsy of infancy with migrating focal seizures (EIMFSs) due to KCNT1 gain-of-function and to assess therapies' efficacy including quinidine.

Methods: We reviewed the clinical, EEG, and molecular data of 17 new patients with EIMFS and KCNT1 mutations, in collaboration with the network of the French reference center for rare epilepsies.

Results: The mean seizure onset age was 1 month (range: 1 hour to 4 months), and all children had focal motor seizures with autonomic signs and migrating ictal pattern on EEG. Three children also had infantile spasms and hypsarrhythmia. The identified KCNT1 variants clustered as "hot spots" on the C-terminal domain, and all mutations occurred de novo except the p.R398Q mutation inherited from the father with nocturnal frontal lobe epilepsy, present in 2 paternal uncles, one being asymptomatic and the other with single tonic-clonic seizure. In 1 patient with EIMFS, we identified the p.R1106Q mutation associated with Brugada syndrome and saw no abnormality in cardiac rhythm. Quinidine was well tolerated when administered to 2 and 4-year-old patients but did not reduce seizure frequency.

Conclusions: The majority of the KCNT1 mutations appear to cluster in hot spots essential for the channel activity. A same mutation can be linked to a spectrum of conditions ranging from EMFSI to asymptomatic carrier, even in the same family. None of the antiepileptic therapies displayed clinical efficacy, including quinidine in 2 patients.

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Figures

Figure 1
Figure 1. Pedigree of patient 2
The sign ± points to family members carrying the heterozygous c.1193G>A KCNT1 pathogenic variant; −/− indicates the patients with wild-type variants. Individual I2 presented nocturnal paroxysmal events, behavioral and psychiatric disorders; II2, 30 years, had ADNFLE and was seizure-free with AEDs; II3, 36 years, had a single episode of TC seizure at age 25 years, average intellect, and fair social and professional integration. II4, 34 years, healthy, average intellect, and fair social and professional integration; III1 (proband) had EIMFS (patient 2, table). ADNFLE = autosomal dominant nocturnal frontal lobe epilepsy; AED = antiepileptic drug; EIMFS = epilepsy of infancy with migrating focal seizures; NA = blood sample not available.
Figure 2
Figure 2. EEG recording of patient 9 at age 6 months
(A) Display of the migrating pattern. (B) Intermittent suppression burst pattern. (C) EEG recording of right hemispheric discontinuous background concomitant to left posterior rhythmic alpha discharge.
Figure 3
Figure 3. Schematic localization of KCNT1 mutations reported in this series and in previous studies
KCNT1 encodes the sodium-activated potassium channel KCa4.1 (also called SLACK and Slo2.2), composed by a short cytoplasmic N-terminal region, 6 transmembrane domains with a pore-forming region, and a large C-terminal region with 2 regulators of potassium conductance domains (RCK1 and RCK2). Mutations associated with EIMFS shaded in yellow, and ADNFLE mutations shaded in light blue. Mutations involved in several phenotypes, including EIMFS and ADNFLE, are indicated in blue. Mutations involved in phenotypes other than EIMFS and ADNFLE shaded in green. The size of each circle is proportional to the number of reported patients (present series and previous report). ADNFLE = autosomal dominant nocturnal frontal lobe epilepsy; EIMFS = epilepsy of infancy with migrating focal seizure.
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