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Attention Deficit Hyperactivity Disorder (ADHD) in Phenotypically Similar Neurogenetic Conditions: Turner Syndrome and the Rasopathies Tamar Green1, Paige E

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Attention Deficit Hyperactivity Disorder (ADHD) in Phenotypically Similar Neurogenetic Conditions: Turner Syndrome and the Rasopathies Tamar Green1, Paige E Green et al. Journal of Neurodevelopmental Disorders (2017) 9:25 DOI 10.1186/s11689-017-9205-x REVIEW Open Access Attention deficit hyperactivity disorder (ADHD) in phenotypically similar neurogenetic conditions: Turner syndrome and the RASopathies Tamar Green1, Paige E. Naylor2 and William Davies3,4,5* Abstract Background: ADHD (attention deficit hyperactivity disorder) is a common neurodevelopmental disorder. There has been extensive clinical and basic research in the field of ADHD over the past 20 years, but the mechanisms underlying ADHD risk are multifactorial, complex and heterogeneous and, as yet, are poorly defined. In this review, we argue that one approach to address this challenge is to study well-defined disorders to provide insights into potential biological pathways that may be involved in idiopathic ADHD. Main body: To address this premise, we selected two neurogenetic conditions that are associated with significantly increased ADHD risk: Turner syndrome and the RASopathies (of which Noonan syndrome and neurofibromatosis type 1 are the best-defined with regard to ADHD-related phenotypes). These syndromes were chosen for two main reasons: first, because intellectual functioning is relatively preserved, and second, because they are strikingly phenotypically similar but are etiologically distinct. We review the cognitive, behavioural, neural and cellular phenotypes associated with these conditions and examine their relevance as a model for idiopathic ADHD. Conclusion: We conclude by discussing current and future opportunities in the clinical and basic research of these conditions, which, in turn, may shed light upon the biological pathways underlying idiopathic ADHD. Keywords: Attention deficit hyperactivity disorder, Neurofibromatosis type 1, Noonan syndrome, RASopathies, Turner syndrome, X chromosome Background and environmental mechanisms underlying ADHD risk ADHD (attention deficit hyperactivity disorder, also are multifactorial, complex and heterogeneous [4, 5] known as hyperkinetic disorder) is currently defined in and, as yet, are poorly defined. There is accumulating diagnostic manuals such as DSM-5 [1] and ICD-10 [2] evidence that ADHD is associated with structural and by a collection of persistent and impairing cognitive and functional abnormalities across multiple brain circuits, behavioural symptoms, notably inattention, hyperactivity notably reduced volume of the basal ganglia, thinning of and pathological impulsivity. ADHD is the most com- the frontal and parietal cortex, and functional connecti- mon neurodevelopmental disorder in the USA, affecting vity between these regions [6]. In the absence of an up to 10% of children and exhibiting a pronounced established pathophysiology, we are limited to using male-biased diagnostic prevalence [3]. The biological treatments that target symptoms rather than core cellu- lar and molecular abnormalities; as a result, the efficacy and side-effect profile of these therapies is sub-optimal * Correspondence: [email protected] 3Medical Research Council Centre for Neuropsychiatric Genetics and and treatments cannot directly influence the course of Genomics and Division of Psychological Medicine and Clinical Neurosciences, the disorder. School of Medicine, Cardiff University, Cardiff, UK Identifying and characterising the many dysfunctional 4School of Psychology, Cardiff University, Tower Building, 70, Park Place, Cardiff CF10 3AT, UK biological pathways that culminate in the development Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Green et al. Journal of Neurodevelopmental Disorders (2017) 9:25 Page 2 of 12 of ADHD is a difficult, perhaps intractable, problem. On rates of ADHD have also been reported in several of the the one hand, studying children and adults with idio- RASopathies, including NF1 and NS, relative to the ge- pathic ADHD is hindered by limited sample sizes and neral population [9, 10]. For example, it has been re- other issues that stem from within-group heterogeneity. ported that in children with NF1, 38–49% meet On the other hand, it is difficult to model the complex diagnostic criteria for ADHD, whilst an even larger pro- cognitive and behavioural abnormalities seen in indivi- portion experience considerable difficulties with sus- duals with ADHD in animal models where experimental tained attention [9, 11]. Children with NF1 also exhibit control is more feasible. The study of well-defined neu- high rates of explicit autism spectrum disorder (~25% of rogenetic conditions in man circumvents, to some ex- cases) and autistic symptoms (~50% of cases), but these tent, challenges associated with etiological heterogeneity, diagnoses appear dissociable from ADHD-related beha- whilst allowing the measurement of complex human viours [12]. ~31% of children with NS have been re- behaviours in children and adult with these conditions. ported to meet diagnostic criteria for ADHD [10]. It In this review, we examine the premise that human neu- should be acknowledged that there may be an over- rogenetic conditions that are associated with increased estimation of psychological issues in TS, NF1 and NS ADHD rates may help to provide converging evidence for populations arising from an ascertainment bias whereby biological pathways involved in the development of idio- individuals with neurogenetic conditions are monitored pathic ADHD. Specifically, we compare two phenotypi- and assessed disproportionately deeply compared to cally similar classes of human genetic conditions that may members of the general population. serve as such ‘experimental models’: Turner syndrome The presentation of ADHD-related symptoms can vary (TS) and the RASopathies. Of the known RASopathies, between TS, NF1 and NS. Girls with TS and ADHD we focus on Noonan syndrome (NS) and neurofibroma- present with pronounced hyperactivity (comparable to tosis type 1 (NF-1), conditions about which most data has levels seen in idiopathic ADHD in boys) [13] and are been collated in the literature. Moreover, whilst ADHD more likely to be diagnosed with the hyperactive- symptomatology is reported across all of the RASopathies, impulsive presentation of the disorder [8]. Attention and including Costello syndrome, LEOPARD syndrome, and executive function deficits are, however, also apparent in cardiofaciocutaneous syndrome (CFC), these disorders are this population, and appear to be independent of other associated with pervasive effects on global cognitive func- cognitive deficits characteristic of this population such tion that might confound more specific genetic effects on as visuospatial impairment and general cognitive ability; ADHD-related symptoms [7]. TS, NF1 and Noonan syn- interestingly, there appears to be a bimodal distribution drome are mechanistically distinct conditions which result within the TS group with regard to one measure of at- in phenotypically aberrant behaviours and cognitive pro- tentional function [10]. In NF1 and NS, the primary cesses, but individuals affected by these conditions have ADHD-related symptoms appear to be difficulties with similar overall cognitive profiles which lie within the nor- attention. In both groups, parental reports indicate that mal range (Table 1). Importantly, the two classes of condi- children have clinically significant difficulties with self- tion show striking overlap with regard to their associated monitoring (36.5% children with NF1 and 38% of anatomical/physiological phenotypes (Table 1) and, as children with NS) and planning-organisation (42.9% such, there may feasibly be some degree of convergence children with NF1 and 38% with NS) [10, 14]. Direct across both with respect to the biological mechanisms neuropsychological measures of ADHD-related beha- underlying ADHD risk; clarifying the level at which the viours also indicate that both children with NF1 and NS genetically distinct aetiologies in TS and the RASopathies experience significant difficulties with sustained atten- might ultimately impact upon common brain substrates tion and inhibition. However, obtaining accurate mea- underlying ADHD-related phenotypes (e.g. molecular, cel- sures of ADHD-related behaviours in the RASopathies is lular or brain circuit) will comprise an important avenue difficult; in some studies, assessments of children with for future research. We start by critically reviewing the severe ADHD were excluded due to concerns regarding existing clinical and animal model literature relating to their validity [10], and there is some degree of hetero- cognitive, behavioural, neural and cellular phenotypes in geneity within the clinical population and in terms of these conditions (Fig. 1) and examine their relevance as a the assessment measures used (and the reporting of as- model for idiopathic ADHD. sociated results). An important question regarding ADHD-related phe- ADHD-related behavioural and cognitive notypes in these syndromes is whether
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