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Similar early characteristics but variable neurological outcome of patients with a de novo mutation of KCNQ2

Mathieu Milh12*, Nadia Boutry-Kryza3, Julie Sutera-Sardo12, Cyril Mignot456, Stéphane Auvin7, Caroline Lacoste8, Nathalie Villeneuve2, Agathe Roubertie109, Bénédicte Heron6, Maryline Carneiro9, Anna Kaminska11, Cécilia Altuzarra12, Gaëlle Blanchard13, Dorothée Ville13, Marie Anne Barthez14, Delphine Heron45, Domitille Gras7, Alexandra Afenjar56, Nathalie Dorison6, Dianne Doummar6, Thierry Billette de Villemeur56, Isabelle An15, Aurélia Jacquette4, Perrine Charles4, Julie Perrier16, Bertrand Isidor17, Laurent Vercueil18, Brigitte Chabrol12, Catherine Badens1198, Gaétan Lesca3 and Laurent Villard119

Author Affiliations

1 INSERM, UMR_S 910 Faculté de médecine, Boulevard jean MOULIN F13005, Marseille, France

2 APHM, Service de neurologie pédiatrique, CHU Timone, Marseille, France

3 Hospices civils de Lyon. Laboratoire de génétique, Hôpital Edouard Herriot. Bron, Lyon, France

4 APHP, Unité Fonctionnelle de Génétique Médicale, Département de Génétique, Groupe Hospitalier Pitié-Salpêtrière, Paris, France

5 Centre de Référence des Déficiences Intellectuelles de Causes Rares, Paris, France

6 APHP. Service de Neuropédiatrie, Hôpital Armand Trousseau, Paris, France

7 APHP. Service de neuropédiatrie, Hopital Robert Debré, Paris, France

8 APHM. Département de Génétique Médicale et Biologie Cellulaire CHU Timone, Marseille, France

9 CHU Montpellier. Service de neuropédiatrie, Montpellier, France

10 INSERM U1051, INM Montpellier, Montpellier, France

11 APHP. Service de neurophysiologie clinique Hôpital Necker, Paris, France

12 CHU Besancon. Service de neuropédiatrie, Besancon, France

13 Hospices civils de Lyon, Service de neuropédiatrie. HFME. Bron, Lyon, France

14 CHU de Tours. Service de neuropédiatrie, Beranger, France

15 APHP. Groupe hospitalier Pitié Salpétrière. Service de neurologie, Paris, France

16 CHU de Nantes. Service de pédiatrie, Nantes, France

17 CHU de Nantes. Service de génétique médicale, Nantes, France

18 CHU de Grenoble. Service d’électrophysiologie clinique, Grenoble, France

19 Aix Marseille Université, Faculté de Médecine, Marseille, France

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Orphanet Journal of Rare Diseases 2013, 8:80  doi:10.1186/1750-1172-8-80

Published: 22 May 2013



Early onset epileptic encephalopathies (EOEEs) are dramatic heterogeneous conditions in which aetiology, seizures and/or interictal EEG have a negative impact on neurological development. Several genes have been associated with EOEE and a molecular diagnosis workup is challenging since similar phenotypes are associated with mutations in different genes and since mutations in one given gene can be associated with very different phenotypes. Recently, de novo mutations in KCNQ2, have been found in about 10% of EOEE patients. Our objective was to confirm that KCNQ2 was an important gene to include in the diagnosis workup of EOEEs and to fully describe the clinical and EEG features of mutated patients.


We have screened KCNQ2 in a cohort of 71 patients with an EOEE, without any brain structural abnormality. To be included in the cohort, patient’s epilepsy should begin before three months of age and be associated with abnormal interictal EEG and neurological impairment. Brain MRI should not show any structural abnormality that could account for the epilepsy.


Out of those 71 patients, 16 had a de novo mutation in KCNQ2 (23%). Interestingly, in the majority of the cases, the initial epileptic features of these patients were comparable to those previously described in the case of benign familial neonatal epilepsy (BFNE) also caused by KCNQ2 mutations. However, in contrast to BFNE, the interictal background EEG was altered and displayed multifocal spikes or a suppression-burst pattern. The ongoing epilepsy and development were highly variable but overall severe: 15/16 had obvious cognitive impairment, half of the patients became seizure-free, 5/16 could walk before the age of 3 and only 2/16 patient acquired the ability to speak.


This study confirms that KCNQ2 is frequently mutated de novo in neonatal onset epileptic encephalopathy. We show here that despite a relatively stereotyped beginning of the condition, the neurological and epileptic evolution is variable.

Epilepsy; Genetics; KCNQ2; Encephalopathy