Sleep health and sufficient sleep are particularly important during adolescence when important physical, cognitive, emotional, and social changes occur. Given the potential role of PAX6 in pineal development and circadian regulation, adolescents with PAX6 haploinsufficiency may be more likely to experience sleep-related problems compared to adolescents without these deletions or mutations. Haploinsufficiency of PAX6 can result from WAGR syndrome, a contiguous gene deletion syndrome in which multiple genes are involved, or point mutations and microdeletions affecting only PAX6, which result in isolated aniridia. The purpose of this dissertation is to examine pineal volume, melatonin concentrations, and sleep disturbance in individuals with PAX6 haploinsufficiency, as well describe validity of self-report measures of sleep problems in adolescents. Results are presented in three papers.
Although PAX6 haploinsufficiency is rare and minimal research has focused on the role of PAX6 in circadian regulation, irregular patterns of sleep-wake rhythm have been studied in children and adolescents with neurodevelopmental disorders (e.g. autism spectrum disorders), another population with possible abnormalities in melatonin physiology. The first paper presents an integrative review to synthesize the literature regarding the sleep-related measures currently being used to assess sleep disturbance in adolescents with a neurodevelopmental disorder. The second paper reports significantly reduced pineal volume, reduced melatonin secretion, and greater parent-report of sleep disturbance in individuals with PAX6 haploinsufficiency versus controls. Paper 3 further characterizes the sleep-related-phenotype associated with an abnormality in the PAX6 gene using self-report questionnaires and actigraphy in adolescents with PAX6 haploinsufficiency, as well as performs preliminary validation studies on age-appropriate self-report tools to measure sleep in adolescents. Results demonstrate similar self-reported daytime sleepiness, sleep disturbance, and sleep-related impairment in adolescents with PAX6 haploinsufficiency compared to the healthy comparison group; however, actigraphy data documented increased time from lights off to sleep in the PAX6 haploinsufficiency group. Self-reported sleep questionnaire scores and objective actigraphy variables (e.g. total sleep time) were significantly correlated in the healthy comparison group only; however, a lack of correlation among sleep-related measures in adolescents with PAX6 haploinsufficiency suggests potential limitations in using self-reported sleep measures in this population. This study used a combination of physiological and patient-reported health measures, and although WAGR syndrome and isolated aniridia due to PAX6 insufficiency are rare disorders, describing the sleep-related phenotypes in this population contributes to knowledge of assessment and treatment of sleep disorders in general, facilitating research in additional adolescent populations.