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Perinatal insults and neurodevelopmental disorders may impact Huntington's disease age of diagnosis

Barkhuizen, M; Brogueira Rodrigues, FA; Anderson, DG; Winkens, B; REGISTRY Investigators of the European Huntington's Disease Netw; Wild, EJ; Kramer, BW; (2018) Perinatal insults and neurodevelopmental disorders may impact Huntington's disease age of diagnosis. Parkinsonism and Related Disorders , 55 pp. 55-60. 10.1016/j.parkreldis.2018.05.016. Green open access

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Abstract

INTRODUCTION: The age of diagnosis of Huntington's disease (HD) varies among individuals with the same HTT CAG repeat expansion size. We investigated whether early-life events, like perinatal insults or neurodevelopmental disorders, influence the diagnosis age. METHODS: We used data from 13,856 participants from REGISTRY and Enroll-HD, two large international multicenter observational studies. Disease-free survival analyses of mutation carriers with an HTT CAG repeat expansion size above and including 36 were computed through Kaplan-Meier estimates of median time until an HD diagnosis. Comparisons between groups were computed using a Cox proportional hazard survival model adjusted for CAG-repeat expansion length. We also assessed whether the group effect depended on gender and the affected parent. RESULTS: Insults in the perinatal period were associated with an earlier median age of diagnosis of 45.00 years (95%CI: 42.07–47.92) compared to 51.00 years (95%CI: 50.68–51.31) in the reference group, with a CAG-adjusted hazard ratio of 1.61 (95%CI: 1.26–2.06). Neurodevelopmental disorders were also associated with an earlier median age of diagnosis than the reference group of 47.00 years (95% CI: 43.38–50.62) with a CAG-adjusted hazard ratio of 1.42 (95%CI: 1.16–1.75). These associations did not change significantly with gender or affected parent. CONCLUSIONS: These results, derived from large observational datasets, show that perinatal insults and neurodevelopmental disorders are associated with earlier ages of diagnosis of magnitudes similar to the effects of known genetic modifiers of HD. Given their clear temporal separation, these early events may be causative of earlier HD onset, but further research is needed to prove causation.

Type: Article
Title: Perinatal insults and neurodevelopmental disorders may impact Huntington's disease age of diagnosis
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.parkreldis.2018.05.016
Publisher version: https://doi.org/10.1016/j.parkreldis.2018.05.016
Language: English
Additional information: © 2018 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Keywords: Huntington's disease; Neonatal; Developmental disorders; Epidemiological; Modifier
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10048791
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