Aberrant Frontal Lobe Maturation in Adolescents with Fragile X Syndrome is Related to Delayed Cognitive Maturation

Background: Fragile X syndrome (FXS) is the most common known heritable cause of intellectual disability. Prior studies in FXS have observed a plateau in cognitive and adaptive behavioral development in early adolescence, suggesting that brain development in FXS may diverge from typical development during this period. Methods: In this study, we examined adolescent brain development using structural magnetic resonance imaging data acquired from 59 individuals with FXS and 83 typically developing control subjects aged 9 to 22, a subset of whom were followed up longitudinally (1-5 years; typically developing: 17, FXS: 19). Regional volumes were modeled to obtain estimates of age-related change. Results: We found that while structures such as the caudate showed consistent volume differences from control subjects across adolescence, prefrontal cortex (PFC) gyri showed significantly aberrant maturation. Furthermore, we found that PFC-related measures of cognitive functioning followed a similarly aberrant developmental trajectory in FXS. Conclusions: Our findings suggest that aberrant maturation of the PFC during adolescence may contribute to persistent or increasing intellectual deficits in FXS.