eprintid: 10048791 rev_number: 33 eprint_status: archive userid: 608 dir: disk0/10/04/87/91 datestamp: 2018-05-21 10:09:50 lastmod: 2021-09-26 22:37:56 status_changed: 2018-12-12 14:36:01 type: article metadata_visibility: show creators_name: Barkhuizen, M creators_name: Brogueira Rodrigues, FA creators_name: Anderson, DG creators_name: Winkens, B creators_name: REGISTRY Investigators of the European Huntington's Disease Netw, creators_name: Wild, EJ creators_name: Kramer, BW creators_name: Gavilanes, AWD title: Perinatal insults and neurodevelopmental disorders may impact Huntington's disease age of diagnosis ispublished: pub divisions: UCL divisions: B02 divisions: C07 divisions: D07 divisions: F86 keywords: Huntington's disease; Neonatal; Developmental disorders; Epidemiological; Modifier note: © 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/) 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. date: 2018-05-18 date_type: published publisher: Elsevier official_url: https://doi.org/10.1016/j.parkreldis.2018.05.016 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green article_type_text: Article verified: verified_manual elements_id: 1556748 doi: 10.1016/j.parkreldis.2018.05.016 lyricists_name: Brogueira Rodrigues, Filipe lyricists_name: Wild, Edward lyricists_id: FBROG17 lyricists_id: EJWIL36 actors_name: Brogueira Rodrigues, Filipe actors_id: FBROG17 actors_role: owner full_text_status: public publication: Parkinsonism and Related Disorders volume: 55 pagerange: 55-60 issn: 1353-8020 citation: Barkhuizen, M; Brogueira Rodrigues, FA; Anderson, DG; Winkens, B; REGISTRY Investigators of the European Huntington's Disease Netw; Wild, EJ; Kramer, BW; Barkhuizen, M; Brogueira Rodrigues, FA; Anderson, DG; Winkens, B; REGISTRY Investigators of the European Huntington's Disease Netw; Wild, EJ; Kramer, BW; Gavilanes, AWD; - view fewer <#> (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 <https://doi.org/10.1016/j.parkreldis.2018.05.016>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10048791/7/Brogueira%20Rodrigues%20_Perinatal%20insults%20and%20neurodevelopmental%20disorders%20may%20impact%20Huntington%27s%20disease%20age%20of%20diagnosis_VoR.pdf