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

Mathieu Milh 1, 2, * Nadia Boutry-Kryza 3 Julie Sutera-Sardo 2 Cyril Mignot 4, 5 Stéphane Auvin 6 Caroline Lacoste 7, 2 Nathalie Villeneuve 2 Agathe Roubertie 8, 9 Bénédicte Heron 2 Maryline Carneiro 2 Anna Kaminska 10 Cécilia Altuzarra 11 Gaëlle Blanchard 12 Dorothée Ville 2 Marie Barthez 13 Delphine Heron 2 Domitille Gras 6 Alexandra Afenjar 2 Nathalie Dorison 2 Diane Doummar 2 Thierry Billette de Villemeur 2 Isabelle An 14 Aurélia Jacquette 2 Perrine Charles 2 Julie Perrier 15 Bertrand Isidor 16 Laurent Vercueil 17 Brigitte Chabrol 2, 18 Catherine Badens 2, 19, 7 Gaetan Lesca 2 Laurent Villard 2
* Corresponding author
1 Neurologie pédiatrique, Pneumologie pédiatrique et médecine infantile
2 GMGF - Génétique Médicale et Génomique Fonctionnelle
3 Laboratoire de Génétique
4 Unité Fonctionnelle de Génétique Médicale
5 Service de Neuropédiatrie [CHU Trousseau]
6 Service de neuropédiatrie [Debré]
7 Département de génétique médicale [Hôpital de la Timone - APHM]
8 Service de Neuropédiatrie
9 INM - Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs
10 Service de Neurophysiologie Clinique
11 Service de Neuropédiatrie
12 Service de Neuropédiatrie
13 Service de Neuropédiatrie [Clocheville]
14 Service de Neurologie [Salpétrière]
15 Service de Pédiatrie
16 Service de Génétique Médicale
17 Service d'Electrophysiologie Clinique
18 Service de pédiatrie et neurologie pédiatrique
19 Centre de référence maladie rare Thalassémie
Abstract : BACKGROUND: 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 mutated 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. METHODS: 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. RESULTS: 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. CONCLUSION: This study confirms that KCNQ2 is frequently mutated in neonatal onset epileptic encephalopathy. We show here that despite a relatively stereotyped beginning of the condition, the evolution is highly variable in terms of epilepsy and of cognitive evolution.
Keywords : Epilepsy Genetics KCNQ2 Encephalopathy
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Mathieu Milh, Nadia Boutry-Kryza, Julie Sutera-Sardo, Cyril Mignot, Stéphane Auvin, et al.. Similar early characteristics but variable neurological outcome of patients with a de novo mutation of KCNQ2.. Orphanet Journal of Rare Diseases, BioMed Central, 2013, 8 (1), pp.80. ⟨10.1186/1750-1172-8-80⟩. ⟨inserm-00829466⟩

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