KCNQ2 encephalopathy: Emerging phenotype of a neonatal epileptic encephalopathy

Authors

  • Sarah Weckhuysen MD,

    1. Neurogenetics Group, VIB-Department of Molecular Genetics, University Hospital of Antwerp, Antwerp, Belgium
    2. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
    3. Epilepsy Centre Kempenhaeghe, Oosterhout, the Netherlands
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  • Simone Mandelstam MB ChB,

    1. Florey Neurosciences Institutes, Austin Health, Melbourne, Australia
    2. Department of Radiology, Royal Children's Hospital, Melbourne, Australia
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  • Arvid Suls PhD,

    1. Neurogenetics Group, VIB-Department of Molecular Genetics, University Hospital of Antwerp, Antwerp, Belgium
    2. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
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  • Dominique Audenaert PhD,

    1. Neurogenetics Group, VIB-Department of Molecular Genetics, University Hospital of Antwerp, Antwerp, Belgium
    2. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
    3. Department of Plant Systems Biology, VIB, Ghent University, Ghent, Belgium
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  • Tine Deconinck MSc,

    1. Neurogenetics Group, VIB-Department of Molecular Genetics, University Hospital of Antwerp, Antwerp, Belgium
    2. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
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  • Lieve R.F. Claes PhD,

    1. Neurogenetics Group, VIB-Department of Molecular Genetics, University Hospital of Antwerp, Antwerp, Belgium
    2. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
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  • Liesbet Deprez PhD,

    1. Neurogenetics Group, VIB-Department of Molecular Genetics, University Hospital of Antwerp, Antwerp, Belgium
    2. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
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  • Katrien Smets MD,

    1. Neurogenetics Group, VIB-Department of Molecular Genetics, University Hospital of Antwerp, Antwerp, Belgium
    2. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
    3. Department of Neurology, University Hospital of Antwerp, University Hospital of Antwerp, Antwerp, Belgium
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  • Dimitrina Hristova MD,

    1. Children Neurology Unit, Pediatrics Clinic, Tokuda Hospital-Sofia, Sofia, Bulgaria, Medical University-Sofia, Sofia, Bulgaria
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  • Iglika Yordanova MSc,

    1. National Genetics Laboratory, Medical University-Sofia, Sofia, Bulgaria
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  • Albena Jordanova PhD,

    1. Neurogenetics Group, VIB-Department of Molecular Genetics, University Hospital of Antwerp, Antwerp, Belgium
    2. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
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  • Berten Ceulemans MD, PhD,

    1. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
    2. Pediatric Neurology, Department of Neurology, University Hospital of Antwerp, Antwerp, Belgium
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  • An Jansen MD, PhD,

    1. Pediatric Neurology Unit, Department of Pediatrics, UZ Brussel
    2. Department of Public Health, Vrije Universiteit Brussel, Brussels, Belgium
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  • Danièle Hasaerts MD,

    1. Pediatric Neurology Unit, Department of Pediatrics, UZ Brussel
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  • Filip Roelens MD,

    1. Department of Pediatrics, Heilig Hart Ziekenhuis, Roeselare, Belgium
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  • Lieven Lagae MD, PhD,

    1. Department of Pediatric Neurology, University Hospital Gasthuisberg, Leuven, Belgium
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  • Simone Yendle BSc (Hons),

    1. Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health
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  • Thorsten Stanley MD,

    1. Department of Paediatrics, University of Otago, Wellington, New Zealand
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  • Sarah E. Heron PhD,

    1. Epilepsy Research Program, School of Pharmacy and Medical Sciences, The University of South Australia
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  • John C. Mulley PhD,

    1. Epilepsy Research Program, SA Pathology at Women's and Children's Hospital, University of Adelaide, Adelaide, Australia
    2. School of Molecular and Biomedical Sciences and School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, Australia
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  • Samuel F. Berkovic MD, FRS,

    1. Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health
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  • Ingrid E. Scheffer MBBS, PhD,

    1. Florey Neurosciences Institutes, Austin Health, Melbourne, Australia
    2. Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health
    3. Department of Paediatrics, Royal Children's Hospital, University of Melbourne, Melbourne, Australia
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  • Peter de Jonghe MD, PhD

    Corresponding author
    1. Neurogenetics Group, VIB-Department of Molecular Genetics, University Hospital of Antwerp, Antwerp, Belgium
    2. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
    3. Department of Neurology, University Hospital of Antwerp, University Hospital of Antwerp, Antwerp, Belgium
    • VIB-Department of Molecular Genetics, Neurogenetics Group, University of Antwerp, Campus CDE, Parking P4, Building V, Universiteitsplein 1, 2610 Antwerp, Belgium
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Abstract

Objective:

KCNQ2 and KCNQ3 mutations are known to be responsible for benign familial neonatal seizures (BFNS). A few reports on patients with a KCNQ2 mutation with a more severe outcome exist, but a definite relationship has not been established. In this study we investigated whether KCNQ2/3 mutations are a frequent cause of epileptic encephalopathies with an early onset and whether a recognizable phenotype exists.

Methods:

We analyzed 80 patients with unexplained neonatal or early-infantile seizures and associated psychomotor retardation for KCNQ2 and KCNQ3 mutations. Clinical and imaging data were reviewed in detail.

Results:

We found 7 different heterozygous KCNQ2 mutations in 8 patients (8/80; 10%); 6 mutations arose de novo. One parent with a milder phenotype was mosaic for the mutation. No KCNQ3 mutations were found. The 8 patients had onset of intractable seizures in the first week of life with a prominent tonic component. Seizures generally resolved by age 3 years but the children had profound, or less frequently severe, intellectual disability with motor impairment. Electroencephalography (EEG) at onset showed a burst-suppression pattern or multifocal epileptiform activity. Early magnetic resonance imaging (MRI) of the brain showed characteristic hyperintensities in the basal ganglia and thalamus that later resolved.

Interpretation:

KCNQ2 mutations are found in a substantial proportion of patients with a neonatal epileptic encephalopathy with a potentially recognizable electroclinical and radiological phenotype. This suggests that KCNQ2 screening should be included in the diagnostic workup of refractory neonatal seizures of unknown origin. ANN NEUROL 2012;71:15–25

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