Epilepsy with migrating focal seizures KCNT1 mutation hotspots and phenotype variability

Giulia Barcia (1, 2) , Nicole Chemaly (2) , Mathieu Kuchenbuch (3) , Monika Eisermann (2) , Stephanie Gobin-Limballe (2) , Viorica Ciorna , Alfons Macaya (4) , Laetitia Lambert , Fanny Dubois (5) , Diane Doummar (6) , Thierry Billette (6) , Nathalie Villeneuve (7) , Marie-Anne Barthez (6) , Caroline Nava (8) , Nathalie Boddaert (2) , Anna Kaminska (9, 2) , Nadia Bahi-Buisson (1, 2) , Mathieu Milh (7, 10, 8, 2) , Stephane Auvin , Jean-Paul Bonnefont (2) , Rima Nabbout (1, 9, 2)

1 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
2 CHU Necker - Enfants Malades [AP-HP]
3 LTSI - Laboratoire Traitement du Signal et de l'Image
4 UAB - Universitat Autònoma de Barcelona
5 CHU Grenoble
6 Hôpital Trousseau
7 Service de pédiatrie multidisciplinaire [Hôpital de la Timone Enfants - APHM]
8 CHU Pitié-Salpêtrière [AP-HP]
9 U1129 - Epilepsies de l'Enfant et Plasticité Cérébrale
10 MMG - Marseille medical genetics - Centre de génétique médicale de Marseille

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 icta1 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.

Domains: Life Sciences [q-bio]; Neurons and Cognition [q-bio.NC]; Life Sciences [q-bio]; Genetics; Human genetics

Giulia Barcia, Nicole Chemaly, Mathieu Kuchenbuch, Monika Eisermann, Stephanie Gobin-Limballe, et al.. Epilepsy with migrating focal seizures KCNT1 mutation hotspots and phenotype variability. Neurology Genetics, 2019, 5 (6), pp.e363. ⟨10.1212/NXG.0000000000000363⟩. ⟨hal-02498046⟩