A comparison of two studies and the prevalence and sex ratio of Neurodevelopmental conditions in Tuberous Sclerosis Complex

Abstract

© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Various forms of psychopathology have been associated with Tuberous sclerosis complex (TSC) including autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD) and intellectual disability (ID) [1, 2], but prevalence estimates have varied widely in studies. The TOSCA (TuberOus SClerosis registry to increase disease Awareness) international disease registry study first described rates of TSC Associated Neuropsychiatric Disorders (TAND) in a large sample size of 2216 participants in 2018 [3]. More recently the TOSCA team [3] have reported further results on TAND data from the TOSCA study [4]. They report prevalence rates, as well as sex (male preponderance of ASD and ADHD) and age differences (higher rates of ADHD in children) in the prevalence of ASD and ADHD. The authors acknowledge various methodological limitations (ascertainment bias, reliance on clinical diagnosis rather than systematic standardised evaluation and very high (60%) rates of missing data), but they suggest that these methodological limitations are partly offset by the large-scale “real world” nature of their study. In our view, the nature and extent of the methodological limitations in the study may not be fully appreciated by readers. We highlight the potential impact of these methodological shortcomings by contrasting the TOSCA TAND results with findings from a high quality, methodologically rigorous prospective longitudinal study of a general population representative sample of individuals with TSC—the Tuberous Sclerosis 2000 (TS 2000) study (1,3,4,6,8, 12–14). In the first phase of the TS 2000 study, 125 children with TSC (63 females, 62 males; median age = 39mo) were recruited. In the second phase of the study, at an average of 8 years later, neurodevelopmental outcomes were assessed with 88 participants (median age = 148 mo) (1,3,4,6,8, 12–14). First, we discuss significant methodological considerations for studies determining prevalence of psychopathology in TSC: