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Epilepsy severity mediates association between mutation type and ADHD symptoms in tuberous sclerosis complex

Research output: Contribution to journalArticlepeer-review

Charlotte Tye, Fiona McEwen, Holan Liang, Emma Woodhouse, Lisa Underwood, Elizabeth Shephard, Edward Barker, Fintan Sheerin, Nicholas Higgins, Juul Steenbruggen, Patrick Bolton

Original languageEnglish
Pages (from-to)e30-e35
Issue number3
Early online date12 Jan 2023
Accepted/In press9 Jan 2023
E-pub ahead of print12 Jan 2023
Published2 Feb 2023

Bibliographical note

Funding Information: We wish to thank all of the families for their time and help with this study. The members of the Tuberous Sclerosis 2000 Study Group are: V Attard, A Clarke, FV Elmslie, AK Saggar, St George's Hospital, London; D Baines, BA Kerr, Royal Manchester Children's Hospital, Manchester; C Brayne, Institute of Public Health, University of Cambridge; I Carcani-Rathwell, C Connolly, M Clifford, A Lydon, F Oluwo, H Rogers, C Srivastava, Institute of Psychiatry, Psychology & Neuroscience, King's College London; JA Cook, Sheffield Children's Hospital, Sheffield; C Falconer, St James's University Hospital, Leeds; DM Davies, JR Sampson, Institute of Medical Genetics, Cardiff; AE Fryer, Alder Hey Children's Hospital, Liverpool; M Haslop, Y Granader*, University of Cambridge (*currently Yeshiva University, New York); PD Griffiths, University of Sheffield; A Hunt, Tuberous Sclerosis Association; WWK Lam, Western General Hospital, Edinburgh; JC Kingswood, Royal Sussex County Hospital, Brighton; ZH Miedzybrodzka, College of Life Sciences and Medicine, Aberdeen; H Crawford, PJ Morrison, Belfast City Hospital; FJK O'Callaghan, Great Ormond Street Hospital/Institute of Child Health, University College London; SG Philip, Birmingham Children's Hospital, Birmingham; S Seri, Aston Brain Centre, School of Life and Health Sciences, Aston University, Birmingham; R Sheehan-Dare, The General Infirmary, Leeds; CH Shepherd, Craigavon Area Hospital, Craigavon. Funding Information: This study was supported by grants awarded to Patrick Bolton from the Baily Thomas Charitable Fund, Tuberous Sclerosis Association (TSA), and Autism Speaks. Charlotte Tye was funded by a Medical Research Council studentship and supported by the Tuberous Sclerosis Association and the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the NHS, NIHR, or the Department of Health and Social Care. Elizabeth Shephard is supported by the Sao Paulo Research Foundation (FAPESP; grant number 2020/05964–1). Publisher Copyright: © 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.


King's Authors


The association between attention-deficit/hyperactivity disorder (ADHD) and tuberous sclerosis complex (TSC) is widely reported, with support for the role of epilepsy, yet the mechanisms underlying the association across development are unclear. The Tuberous Sclerosis 2000 Study is a prospective longitudinal study of TSC. In Phase 1 of the study, baseline measures of epilepsy, cortical tuber load, and mutation were obtained with 125 children ages 0–16 years. In Phase 2, at an average of 8 years later, ADHD symptoms were measured for 81 of the participants. Structural equation modeling revealed an indirect pathway from genetic mutation, to cortical tuber load, to epileptic spasm severity in infancy, to ADHD symptoms in middle childhood and adolescence, in addition to a pathway linking current seizure severity to ADHD symptoms. Findings were retained when intelligence quotient (IQ) was entered as a correlated factor. The findings support a cascading developmental pathway to ADHD symptoms mediated by early-onset and severe epilepsy in the first 2 years of life. This warrants detailed investigation of seizure characteristics and cognitive and behavioral sequelae associated with ADHD from early in life, to further the understanding of the association between ADHD and early-onset epilepsy across syndromic and non-syndromic populations.

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