Sex differences in neurodevelopmental disorders

Male predominance in incidence of neurodevelopmental disorders is often highlighted. Many active strands research are exploring possible mechanisms, including genetic and hormonal factors, their interplay with environmental variables. However, for many conditions (e.g. attention-deficit/hyperactivity disorder [ADHD], autism spectrum [ASD], intellectual disability, cerebral palsy [CP]), the reason this implications prevention remain poorly understood. For monogenic X-linked inheritance, explanation appears to be more obvious. Males have only one X chromosome, so they necessarily homozygous causative mutation; whereas females, having two chromosomes, can heterozygous thus harbour copy unmutated gene. This provides females a protective advantage, as material on second chromosome act buffer. In fragile syndrome, example, who mutation asymptomatic carriers or show an attenuated phenotype due differences X-chromosome inactivation, some cells expressing allele other. A similar reasoning explains why Rett syndrome affects young almost exclusively, homozygotic lethal. The number chromosomes has also been suggested impact inflammatory processes independently context prepubescent (46,XX), males (46,XY), Klinefelter (47,XXY).1 These findings might explain better outcomes acute inflammation reported contrary observed chronic diseases. inflammation, higher levels pro-inflammatory cytokines IL-1β, IL-6, TNF-α documented males, associated less efficient response effective feedback when returning homeostasis. may relevant disorders, given increasing recognition pathophysiology. Interestingly, those neurological CP.2 gene expression modulate effects exposure antenatal stress programming, resulting vulnerability resilience females.3 Moreover, sex-linked disparities common across human genome. Fetal testosterone hypothesized ‘masculinize’ brain, leading social patterns that increase risk ASD.4 extreme male brain theory disputed – but it introduces notion varying genderization. Some propose different symptom hampers diagnosis ASD ADHD females. Females camouflage impaired interactions by staying close peers weaving out activities.5 Behaviours sex constructs expectations possibly interfere process diagnosis. It inequality access diagnostic services biases ratios. We need insights into mechanisms underlie improve develop targeted, interventions. But achieved if we questions, based understanding distinction between set biological variables construct. must very specific addressing factors contribute disorders. aware meaning variable: whether actually control variable, indeed main predictor explaining differences, even explanatory variable; confounder both outcome lying outside pathway; effect modifier modulates not exposure, testing new treatments. As conditions, from cardiovascular disease cancer rheumatic diseases, should designed analysed take account sex-based variance order health all individuals