Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort
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- Joseph D Symonds
- Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, UK
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- Sameer M Zuberi
- Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, UK
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- Kirsty Stewart
- West of Scotland Regional Genetics Service, Queen Elizabeth University Hospitals, Glasgow, UK
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- Ailsa McLellan
- Department of Paediatric Neurosciences, Royal Hospital for Sick Children, Sciennes Road, Edinburgh, UK
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- Mary O‘Regan
- Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, UK
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- Stewart MacLeod
- Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, UK
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- Alice Jollands
- Paediatric Neurology, Tayside Children’s Hospital, Dundee, UK
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- Shelagh Joss
- West of Scotland Regional Genetics Service, Queen Elizabeth University Hospitals, Glasgow, UK
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- Martin Kirkpatrick
- Paediatric Neurology, Tayside Children’s Hospital, Dundee, UK
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- Andreas Brunklaus
- Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, UK
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- Daniela T Pilz
- West of Scotland Regional Genetics Service, Queen Elizabeth University Hospitals, Glasgow, UK
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- Jay Shetty
- Department of Paediatric Neurosciences, Royal Hospital for Sick Children, Sciennes Road, Edinburgh, UK
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- Liam Dorris
- Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, UK
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- Ishaq Abu-Arafeh
- Department of Paediatrics, Forth Valley Royal Hospital, Larbert, UK
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- Jamie Andrew
- Department of Paediatrics, University Hospital Wishaw, Netherton Street, Wishaw, UK
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- Philip Brink
- Paediatric Neurology, Tayside Children’s Hospital, Dundee, UK
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- Mary Callaghan
- Department of Paediatrics, University Hospital Wishaw, Netherton Street, Wishaw, UK
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- Jamie Cruden
- Department of Paediatrics, Victoria Hospital, Kirkcaldy, UK
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- Louise A Diver
- West of Scotland Regional Genetics Service, Queen Elizabeth University Hospitals, Glasgow, UK
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- Christine Findlay
- Department of Paediatrics, University Hospital Crosshouse, Kilmarnock, UK
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- Sarah Gardiner
- West of Scotland Regional Genetics Service, Queen Elizabeth University Hospitals, Glasgow, UK
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- Rosemary Grattan
- Department of Paediatrics, Forth Valley Royal Hospital, Larbert, UK
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- Bethan Lang
- Nuffield Department of Clinical Neurosciences, Level 6, West Wing, John Radcliffe Hospital, Oxford, UK
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- Jane MacDonnell
- Department of Paediatrics, Borders General Hospital, Melrose, UK
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- Jean McKnight
- Department of Paediatrics, Dumfries and Galloway Royal Infirmary, Dumfries, UK
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- Calum A Morrison
- Department of Paediatrics, University Hospital Crosshouse, Kilmarnock, UK
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- Lesley Nairn
- Department of Paediatrics, Royal Alexandra Hospital, Paisley, UK
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- Meghan M Slean
- College of Medical, Veterinary and Life Sciences, University of Glasgow, UK
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- Elma Stephen
- Department of Paediatrics, Royal Aberdeen Children’s Hospital, Aberdeen, UK
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- Alan Webb
- Department of Paediatrics, Raigmore Hospital, Inverness, UK
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- Angela Vincent
- Nuffield Department of Clinical Neurosciences, Level 6, West Wing, John Radcliffe Hospital, Oxford, UK
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- Margaret Wilson
- Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, UK
Description
<jats:title>Abstract</jats:title><jats:p>Epilepsy is common in early childhood. In this age group it is associated with high rates of therapy-resistance, and with cognitive, motor, and behavioural comorbidity. A large number of genes, with wide ranging functions, are implicated in its aetiology, especially in those with therapy-resistant seizures. Identifying the more common single-gene epilepsies will aid in targeting resources, the prioritization of diagnostic testing and development of precision therapy. Previous studies of genetic testing in epilepsy have not been prospective and population-based. Therefore, the population-incidence of common genetic epilepsies remains unknown. The objective of this study was to describe the incidence and phenotypic spectrum of the most common single-gene epilepsies in young children, and to calculate what proportion are amenable to precision therapy. This was a prospective national epidemiological cohort study. All children presenting with epilepsy before 36 months of age were eligible. Children presenting with recurrent prolonged (>10 min) febrile seizures; febrile or afebrile status epilepticus (>30 min); or with clusters of two or more febrile or afebrile seizures within a 24-h period were also eligible. Participants were recruited from all 20 regional paediatric departments and four tertiary children’s hospitals in Scotland over a 3-year period. DNA samples were tested on a custom-designed 104-gene epilepsy panel. Detailed clinical information was systematically gathered at initial presentation and during follow-up. Clinical and genetic data were reviewed by a multidisciplinary team of clinicians and genetic scientists. The pathogenic significance of the genetic variants was assessed in accordance with the guidelines of UK Association of Clinical Genetic Science (ACGS). Of the 343 patients who met inclusion criteria, 333 completed genetic testing, and 80/333 (24%) had a diagnostic genetic finding. The overall estimated annual incidence of single-gene epilepsies in this well-defined population was 1 per 2120 live births (47.2/100 000; 95% confidence interval 36.9–57.5). PRRT2 was the most common single-gene epilepsy with an incidence of 1 per 9970 live births (10.0/100 000; 95% confidence interval 5.26–14.8) followed by SCN1A: 1 per 12 200 (8.26/100 000; 95% confidence interval 3.93–12.6); KCNQ2: 1 per 17 000 (5.89/100 000; 95% confidence interval 2.24–9.56) and SLC2A1: 1 per 24 300 (4.13/100 000; 95% confidence interval 1.07–7.19). Presentation before the age of 6 months, and presentation with afebrile focal seizures were significantly associated with genetic diagnosis. Single-gene disorders accounted for a quarter of the seizure disorders in this cohort. Genetic testing is recommended to identify children who may benefit from precision treatment and should be mainstream practice in early childhood onset epilepsy.</jats:p>
Journal
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- Brain
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Brain 142 (8), 2303-2318, 2019-07-13
Oxford University Press (OUP)
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Details 詳細情報について
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- CRID
- 1362262943886582400
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- ISSN
- 14602156
- 00068950
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- Data Source
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- Crossref