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

Abstract

Objectives: To determine whether early-life factors, like perinatal insults or neurodevelopmental disorders, are associated with the age of diagnosis of Huntington’s disease (HD). Methods: We used data from 13,863 participants from REGISTRY and Enroll-HD, 2 large international multicenter observational studies. Disease-free survival analyses of mutation carriers with an HTT CAG repeat expansion size > 36 were computed through Kaplan–Meier estimates of median survival time until a diagnosis of HD. Between groups, comparisons were computed using a Cox proportional hazard survival model adjusted for the CAG-repeat expansion length. All tests were 2-sided with a significance level of 0.05. Results: Our results showed that insults in the perinatal period were associated with an earlier median age of diagnosis of 45.00 years [95% confidence interval (CI) 42.07–47.92) versus 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 of 47.00 years (95% CI 43.63–50.36) with a CAG-adjusted hazard ratio of 1.41 (95% CI 1.15–1.73). Discussion: These results, derived from large observational datasets and using robust survival analysis methods, 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. Even with a survival analysis, this association does prove causation. Further research is needed on the basis of this interaction