Genetic and maternal predictors of cognitive and behavioral trajectories in females with fragile X syndrome

Abstract

BackgroundFragile X syndrome (FXS) is caused by a mutation in the FMR1 gene on the X chromosome, leading to decreased levels of FMR1 protein (FMRP), which causes the array of neuropsychological impairments that define FXS. Because FXS is an X-linked condition, fewer females display FXS and females with FXS are more mildly affected than males, on average. However, there is a considerable variability in terms of severity of affectedness among females with FXS. The current study was designed to investigate potential genetic (FMRP level and ratio of affected to total chromosomes) and environmental factors (maternal psychological distress and closeness in the mother–child relationship) influencing the cognitive (fluid and crystallized intelligence) and behavioral (anxiety and withdrawal) phenotype of females with FXS.MethodsWe conducted a prospective 3-year longitudinal study of 16 females with FXS (with up to four assessments, each separated by a year) using an accelerated longitudinal design so that we had coverage of the age range of 10–15 years at study start and 13–18 at study end. We focused on both the level of functioning related to chronological age expectations (standard scores) and absolute change in skill (raw scores) over the 3-year period.ResultsAt a cross-sectional level, fluid intelligence and crystallized intelligence were both predicted by a closer mother–child relationship and lower maternal psychological distress. However, only fluid intelligence was predicted by a lower ratio of affected to total chromosomes. Anxiety and withdrawal were predicted by a higher ratio of affected to total chromosomes. Withdrawal was also predicted by lower closeness in the mother–child relationship and higher maternal distress. In terms of longitudinal change, gains were observed in fluid and crystallized intelligence, whereas anxious and withdrawn behaviors remained stable over visits. Gains in fluid intelligence were solely predicted by FXS biomarkers (higher FMRP level and lower ratio of affected to total chromosomes), while gains in crystallized intelligence were not predicted by any of the biological and environmental variables.ConclusionsOur results show that FXS biomarkers and maternal variables contribute differentially to the cognitive and behavioral features of the adolescent female with FXS. These findings can help in the design of treatment studies aimed at enhancing cognitive and behavioral abilities in the FXS population.

Closing the Gender Gap in Fragile X Syndrome: Review of Females with Fragile X Syndrome and Preliminary Research Findings

“…The variation in phenotype among females with full mutation FXS can, at least in part, be attributed to a phenomenon known as X inactivation [11,13]. X inactivation is thought to occur so that females have approximately equal X chromosome gene dosage despite having twice as many X chromosomes (known as “dosage compensation” [14]).…”

“…It is likely that these declines are not due to the loss of skills, but rather to a slowing rate of acquisition of new skills compared to typically developing peers, as well as the increasingly strenuous cognitive demands placed on children as they age. A recent longitudinal study on girls with FXS suggested that, while fluid intelligence was predicted only by biological or genetic factors, crystalized intelligence may be related to maternal mental health and perceived closeness of mother–child relationship [13]. Taken together, these studies suggest a vulnerable time frame in which girls with FXS are prone to decline in cognitive scores, and the importance of protective factors, such as an enriched environment, that may help mitigate this decline.…”

“…Specifically, reported increases in parent psychopathology were correlated with an increase of child anxiety and depression, while increased efficacy of services was correlated with a decrease in thought and attention problems for the individual with FXS [35]. Another study found that increased quality of home environment corresponded with an increase in verbal IQ as well as an increase in freedom from distractibility [36], and a recent study published exclusively on girls with FXS demonstrated that lower IQ and increased social aversion could be predicted by higher levels of maternal distress and reduced perceived closeness of parent–child relationships [13]. These studies emphasize the importance of providing resources and support for families of girls with FXS to create home, family, and educational environments that promote their development and optimize behavioral, cognitive, and quality of life outcomes.…”

Expressive language development in adolescents with Down syndrome and fragile X syndrome: change over time and the role of family-related factors

“…In this respect, the language environment in which an individual develops can have strong influences on language development [70,71]. In addition, higher levels of parental education are associated with better expressive language skills in TD children [72,73], as well as in individuals with ID [6,[74][75][76][77]. Studies focused on individuals with FXS or DS have also suggested a positive association of maternal education with expressive vocabulary outcomes after controlling for CA [78].…”

“…Maternal mental health has also been found to be associated with expressive language development in TD children [86] and in individuals with ID [75][76][77]. Depression, for example, can impede a person's ability to respond optimally in interactions with their children, which, in turn, can impede language development [87].…”