Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort

被引：304

作者：

Symonds, Joseph D. ^{[1
,2
]}

Zuberi, Sameer M. ^{[1
,2
]}

Stewart, Kirsty ^{[3
]}

McLellan, Ailsa ^{[4
]}

O'Regan, Mary ^{[1
]}

MacLeod, Stewart ^{[1
]}

Jollands, Alice ^{[5
]}

Joss, Shelagh ^{[3
]}

Kirkpatrick, Martin ^{[5
]}

Brunklaus, Andreas ^{[1
,2
]}

Pilz, Daniela T. ^{[3
]}

Shetty, Jay ^{[4
]}

Dorris, Liam ^{[1
,2
]}

Abu-Arafeh, Ishaq ^{[6
]}

Andrew, Jamie ^{[7
]}

Brink, Philip ^{[5
]}

Callaghan, Mary ^{[7
]}

Cruden, Jamie ^{[8
]}

Diver, Louise A. ^{[3
]}

Findlay, Christine ^{[9
]}

Gardiner, Sarah ^{[3
]}

Grattan, Rosemary ^{[6
]}

Lang, Bethan ^{[10
]}

MacDonnell, Jane ^{[11
]}

McKnight, Jean ^{[12
]}

Morrison, Calum A. ^{[9
]}

Nairn, Lesley ^{[13
]}

Slean, Meghan M. ^{[2
]}

Stephen, Elma ^{[14
]}

Webb, Alan ^{[15
]}

Vincent, Angela ^{[10
]}

Wilson, Margaret ^{[1
]}

机构：

[1] Royal Hosp Children, Paediat Neurosci Res Grp, Glasgow G51 4TF, Lanark, Scotland

[2] Univ Glasgow, Coll Med Vet & Life Sci, Glasgow, Lanark, Scotland

[3] Queen Elizabeth Univ Hosp, West Scotland Reg Genet Serv, Glasgow, Lanark, Scotland

[4] Royal Hosp Sick Children, Dept Paediat Neurosci, Sciennes Rd, Edinburgh, Midlothian, Scotland

[5] Tayside Childrens Hosp, Paediat Neurol, Dundee, Scotland

[6] Forth Valley Royal Hosp, Dept Paediat, Larbert, Scotland

[7] Univ Hosp Wishaw, Dept Paediat, Netherton St, Wishaw, Scotland

[8] Victoria Hosp, Dept Paediat, Kirkcaldy, Scotland

[9] Univ Hosp Crosshouse, Dept Paediat, Kilmarnock, Scotland

[10] John Radcliffe Hosp, Nuffield Dept Clin Neurosci, Level 6, Oxford, England

[11] Borders Gen Hosp, Dept Paediat, Melrose, Scotland

[12] Dumfries & Galloway Royal Infirm, Dept Paediat, Dumfries, Scotland

[13] Royal Alexandra Hosp, Dept Paediat, Paisley, Renfrew, Scotland

[14] Royal Aberdeen Childrens Hosp, Dept Paediat, Aberdeen, Scotland

[15] Raigmore Hosp, Dept Paediat, Inverness, Scotland

来源：

BRAIN | 2019年 / 142卷

关键词：

epilepsy; genetics; epidemiology; incidence; precision; SEVERE MYOCLONIC EPILEPSY; DRAVET SYNDROME; GLUCOSE-TRANSPORTER-1; DEFICIENCY; DEVELOPMENTAL DELAY; ABSENCE EPILEPSY; CLINICAL UTILITY; KETOGENIC DIET; 1ST YEAR; SEIZURES; MUTATION;

D O I：

10.1093/brain/awz195

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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 (410 min) febrile seizures; febrile or afebrile status epilepticus (430 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.

引用

页码：2303 / 2318

页数：16

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