Elucidating X chromosome influences on Attention Deficit Hyperactivity Disorder and executive function☆
Introduction
Sex differences in the manifestation of psychiatric disorders, including Attention Deficit Hyperactivity Disorder (ADHD), are among the most prominent findings in psychiatry (Holden, 2005). For ADHD, sexual dimorphism is observed in prevalence, clinical manifestation, course, and in the comorbidities of the disorder. For example, ADHD manifestations differ between males and females with higher levels of inattentive type and lower hyperactive/impulsive behavior disorders in females (Biederman et al., 1999, Biederman et al., 2002). This might result in sex-based referral biases and lead to underdiagnosis and undertreatment of females. This, in turn, could result in an increased risk for psychological morbidity and academic problems in females with ADHD, thereby increasing the public health burden due to the effects of undertreated ADHD on academic and occupational performance. In males, ADHD is prevalent and associated with distinct comorbid psychiatric disorders such as conduct and oppositional defiant disorders. In females, ADHD is associated with depressive and anxiety disorders (McGough et al., 2005). Thus, ADHD is associated with significant lifetime comorbidity in males and females, yet the topography of the disorder is different in each of the sexes.
The sexual dimorphism in ADHD suggests involvement of biological mechanisms related to the sex chromosomes including number of X chromosomes and X-linked gene haploinsufficiency (Davies, 2014). As idiopathic ADHD is a highly heterogeneous disorder, elucidating these putative contributory mechanisms can be a challenging task. Traditional methods comparing males and females with idiopathic ADHD to controls have yielded limited information. This is likely due to the fact that ADHD subtypes, comorbidities and developmental effects significantly increase symptom heterogeneity, thereby affecting our ability to detect differences between the sexes. Moreover, research focused on underlying neural substrates using neuroimaging of individuals with idiopathic ADHD (iADHD) is usually underpowered to detect sex effects (Davies, 2014).
A promising strategy for advancing our understanding of ADHD is to identify tractable models for this behaviorally defined disorder. A model that potentially incorporates several of the factors noted above is Turner syndrome (TS), a common genetic condition caused by absence of most or all of one of two X chromosomes (Stochholm et al., 2006). TS is associated with significantly increased risk for ADHD in the context of normal overall intellectual function. Approximately 25% of girls and adolescents with TS meet the DSM-IV diagnostic criteria for ADHD (Russell et al., 2006). Individuals diagnosed with ADHD tend to have associated deficits in executive function (EF) (Willcutt et al., 2005), visuospatial working memory (Martinussen et al., 2005) and social cognition (Cadesky et al., 2000). Individuals with TS also suffer from specific deficits in EF and social cognition, and a global impairment in visuospatial abilities (Lepage et al., 2011, Romans et al., 1998, Ross et al., 2002) including associated visuospatial working memory (Ross et al., 2002).
As the genetic cause for TS is X-monosomy, this model allows us to make inferences about the potential contribution of X-linked biological mechanisms to attention problems and hyperactivity. In typically developing females, inactivation of one of the X chromosomes occurs such that females will have a similar level of X chromosome expression for most genes relative to males. However, some of the genes on the inactivated X chromosome escape the inactivation process. For these genes, two copies are expressed in typically developing females, whereas only one of these genes is expressed in males and in females with X-monosomy (Arnold, 2004). Thus, TS is a unique human condition with X-linked genetic haploinsufficiency but without Y-linked genes affecting the phenotype. Accordingly, the study of attention problems and hyperactivity in this syndrome can potentially advance our understanding of sexual dimorphism in ADHD.
The primary goal of this study was to delineate the behavioral and cognitive profiles associated with ADHD in TS relative to age-matched children with iADHD and age and IQ-matched neurotypical female controls. This novel approach allows for the identification of distinct behavioral and cognitive profiles associated with ADHD in TS relative to iADHD, which will help elucidate putative X chromosome linked biological mechanisms that contribute to this common behavioral disorder. To accomplish this goal we: (1) examined behavioral characteristics associated with ADHD, and (2) assessed neurocognitive features that may be specifically tied to the ADHD phenotype in TS, relative to iADHD and neurotypical controls. Given that X-monosomy occurs naturally in males, and as a genetic anomaly associated with TS, we hypothesized that our TS group with high levels of ADHD behaviors would demonstrate a behavioral profile comparable to boys with iADHD. We also predicted that girls with TS would demonstrate specific neurocognitive deficits in attention and EF compared to neurotypical controls, and that these deficits would be comparable to an iADHD group. Furthermore, given the association between ADHD and EF deficits in clinical populations of children with iADHD (Martinussen et al., 2005), we expected that neuropsychological impairment in attention and EF abilities would be specific to girls with TS who had high levels of ADHD behaviors, while weaknesses in visuospatial and sensorimotor abilities would be present in all girls with TS.
Section snippets
Study design
This study included four groups: girls with TS; neurotypical controls; BASC-2 reference data collected from children diagnosed with iADHD (BASC-2/iADHD) and NEPSY reference data collected from children diagnosed with iADHD (NEPSY/iADHD) (Fig. 1). To accomplish the study goals, the following comparisons were made:
- 1)
Behavioral features of the entire TS group to age-, sex- and verbal IQ-matched healthy (i.e., neurotypical) controls, and to children with iADHD (BASC-2/iADHD);
- 2)
Cognitive features of the
Demographic and cognitive measures
There were no significant differences in age and parent's education between the TS, neurotypical, and NEPSY/iADHD groups. In TS, FSIQ is not considered a reliable representation of overall intellectual ability due to visual-spatial weaknesses often causing a significant discrepancy between VIQ and PIQ (Hong et al., 2009). As expected, we found a discrepancy of 11 points between VIQ (106.1 ± 11.97) and PIQ (95.1 ± 10.73) in the TS group. Thus, girls with TS and neurotypical girls were
Discussion
In the current study, we sought to elucidate behavioral and cognitive profiles associated with Turner syndrome due to X-monosomy in order to investigate possible X-linked factors contributing to, and sexual dimorphism associated with, ADHD. Our findings of a distinctive profile of ADHD symptoms that include a high rate of hyperactivity symptoms in girls with TS are in line with earlier findings (Rovet, 1993, Russell et al., 2006). However, our results significantly extend these previous
Role of funding source
This work was supported by grants from the NICHD (HD049653), NIMH (MH099630), and the Chain of Love and Sharon Levine Foundations to A.L.R. T.G. was supported by a grant from the Gazit-Globe Post-Doctoral Fellowship Award, D.S.H. was supported by funding from the NIMH (MH092170). Dr. Reiss is an unpaid medical advisor for the Turner Syndrome Society and Turner Syndrome Foundation. The funding sources mentioned above had no role in the study design; in the collection, analysis and interpretation
Author contribution
Study concept and design: Green, Bade Shrestha, Pennington, Hong and Reiss.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Green, Bade Shrestha, Chromik and Rutledge.
Critical revision of the manuscript for important intellectual content: Green, Pennington, Hong and Reiss.
Statistical analysis: Green, Rutledge and Pennington.
Administrative, technical, or material support: Green, Bade Shrestha, Rutledge and Chromik.
Study supervision: Green, Hong and Reiss.
Conflicts of interest
T.G., S.B.S, L.C.C., K.R., B.F.P. D.S.H. and A.L.R. have nothing to declare.
Acknowledgements
The authors would like to thank Pearson Inc for providing us with standardization data from the NEPSY. The Turner Syndrome Society and the Turner Syndrome Foundation made this work possible. The authors would like to sincerely thank all of the families who kindly volunteered to participate.
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2021, European Journal of Medical GeneticsCitation Excerpt :Affected individuals typically demonstrate a verbal IQ (VIQ) similar or marginally lower than that of individuals without TS; subjects with TS have a performance IQ (PIQ) around 20 points lower than this (Green et al., 2017) with the VIQ-PIQ discrepancy being largely due to visuospatial perceptual and processing deficits (Murphy et al., 1994; Pennington et al., 1985; Temple and Carney, 1995). The visuospatial deficits, and the elevated risk of developmental conditions such as ADHD in TS, appear related to underlying impaired executive function (Lepage et al., 2011); executive function deficits in TS appear to be largest with respect to attentional control and working memory, and also encompass problems with cognitive flexibility and behavioural inhibition (Green et al., 2015; Mauger et al., 2018; Romans et al., 1998; Ross et al., 1995; Ross et al., 2002; Rovet and Ireland, 1994). Neuropsychological analyses have revealed impaired perception of emotional state in others in subjects with TS, particularly with respect to fear recognition (Hong et al., 2014; Lawrence et al., 2003).
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Previous presentation: AACAP 61st Annual Meeting, San Diego, CA, US, October 2014.