Elucidating X chromosome influences on Attention Deficit Hyperactivity Disorder and executive function

Abstract

Objective To identify distinct behavioral and cognitive profiles associated with ADHD in Turner syndrome (TS), relative to idiopathic ADHD and neurotypical controls, in order to elucidate X-linked influences contributing to ADHD. Methods We used a multilevel-model approach to compare 49 girls with TS to 37 neurotypical females, aged 5–12, on established measures of behavior (BASC-2) and neurocognitive function (NEPSY). We further compared girls with TS to BASC-2 and NEPSY age-matched reference data obtained from children with idiopathic ADHD. Results Within the TS group, 51% scored at or above the “at-risk” range for ADHD-associated behaviors on the BASC-2 (TS/+ADHD). The BASC-2 behavioral profile in this TS/+ADHD-subgroup was comparable to a reference group of boys with ADHD with respect to attentional problems and hyperactivity. However, the TS/+ADHD-subgroup had significantly higher hyperactivity scores relative to a reference sample of girls with ADHD (p=0.016). The behavioral profile in TS was associated with significantly lower attention and executive function scores on the NEPSY relative to neurotypical controls (p=0.015); but was comparable to scores from a reference sample of children with idiopathic ADHD. Deficits in attention and executive function were not observed in girls with TS having low levels of ADHD-associated behavior (TS/−ADHD). Conclusions ADHD-associated behavioral and cognitive problems in TS are prevalent and comparable in severity to those found in children with idiopathic ADHD. The ADHD phenotype in TS also appears relatively independent of cognitive features typically associated with TS, like visuospatial weaknesses. These findings suggest that X-linked haploinsufficiency and downstream biological effects contribute to increased risk for ADHD.

Recognition and management of adults with Turner syndrome: From the transition of adolescence through the senior years

“…Beginning in adolescence, women with Turner syndrome are more likely to be diagnosed with attention deficit hyperactivity disorder (ADHD) with approximately 25% meeting diagnostic criteria (McCauley, Feuillan, Kushner, & Ross, ; Russell et al, ). In our clinical experience with adult women, this is most likely to be the inattentive subtype of ADHD, although higher rates of hyperactivity have been reported in children and adolescents with Turner syndrome (Green et al, ). There are usually difficulties initiating tasks that are perceived to be challenging and disengagement on tasks that are uninteresting or overstimulating.…”

Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting

“…It is unclear if these symptoms continue in adulthood. Executive impairments are less common in girls with TS without ADHD behaviors and appear to be independent of visuospatial deficits (473). Problems stemming from executive function issues -in children or adults -can be ameliorated via cognitivebehavior therapy (482,483,484).…”

“…Studies on the incidence of anxiety or depression in girls (473,475,523) and women (516, 524, 525) with TS show conflicting data, possibly due to selection bias, disparate outcome measures and small sample sizes. In general, girls (526, 527) and women (205, 524, 528) with TS experience lower self-concept compared to girls/women without TS.…”

“…Interventions specifically targeting biological mechanisms related to the core cognitive phenotype of TS have yet to be developed. However, the cognitive and psychosocial challenges associated with TS align with recognized diagnoses, including attentiondeficit/hyperactivity disorder (ADHD) (72,473), specific learning disorders (474), social communication disorder, autism spectrum disorders (475) and developmental coordination disorder (476), and evidence suggests that generic interventions developed for non-TS populations may be adapted with similar positive effects (477) ( Table 10). As in other genetic syndromes, it is critical to note the high degree of individual variability in the somatic, cognitive and psychosocial phenotypes of girls and women with TS; one should never assume the presence (or absence) of a deficit based on karyotype.…”

Sex differences in psychiatric disorders: what we can learn from sex chromosome aneuploidies

“…Other prominent features can include congenital renal and cardiovascular defects, webbed neck, sensorineural hearing loss, and short stature [28]. TS is associated with neurodevelopmental and psychiatric disorders including a significantly elevated risk of ADHD [62][63][64], ASD [65], anxiety, and depression [66].…”