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

Abstract

Fragile X syndrome (FXS) is a genetic condition known to increase the risk of cognitive impairment and socio-emotional challenges in affected males and females. To date, the vast majority of research on FXS has predominantly targeted males, who usually exhibit greater cognitive impairment compared to females. Due to their typically milder phenotype, females may have more potential to attain a higher level of independence and quality of life than their male counterparts. However, the constellation of cognitive, behavioral, and, particularly, socio-emotional challenges present in many females with FXS often preclude them from achieving their full potential. It is, therefore, critical that more research specifically focuses on females with FXS to elucidate the role of genetic, environmental, and socio-emotional factors on outcome in this often-overlooked population.

Keywords: FMR1; X chromosome; anxiety; avoidance; behavior; brain; cognition; females; fragile X syndrome.

Figure 1

X-chromosome inactivation in females with fragile X syndrome and corresponding production of fragile X mental retardation 1 (FMR1) protein in each cell. (A) Group of progenitor cells. (B) Each cell contains two X chromosomes. The unaffected chromosomes are shown in solid green, and affected chromosomes are depicted with a red band. (C) One of the two chromosomes in each cell will be silenced at random indicated with red shading. In cells where the affected chromosome is silenced, there is normal production of the FMR1 protein. In cells where the unaffected chromosome is silenced, there is reduced production of the FMR1 protein. FMR1: fragile X mental retardation 1; FMRP: fragile X mental retardation protein.

Figure 2

Cognitive and achievement score profiles. Each dot indicates a participant, solid horizontal line represents median, dashed horizontal line represents mean, box represents interquartile range, and vertical lines upper and lower extremes (excluding outliers). (A) Distribution of participant cognitive scores on verbal, nonverbal, and overall composite of the Differential Ability Scales, 2nd Edition (DAS-II). (B) Distribution of participant achievement scores on reading, math, and composite achievement on the Kaufman Test of Educational Achievement Third Edition Brief Form (KTEA-3 Brief).

Figure 3

Correlations between cognition and adaptive behavior. (A) Correlations of the DAS-II verbal reasoning subscale with communication, daily living, and socialization subscales and overall adaptive behavior composite of the Vineland Adaptive Behavior Scales, Third Edition—Interview Form (VABS-III). (B) Correlations of the DAS-II nonverbal reasoning subscale with all domains of the VABS-III.

Figure 4

Correlations between social skills and adaptive behavior. Correlations between difficulties with social skills as measured by total score reported by caregivers on the Social Responsiveness Scale-2 (SRS) and the communication, daily living, and socialization subscales and overall adaptive behavior composite scores of the Vineland Adaptive Behavior Scales, Third Edition—Interview Form (VABS-III).

Figure 5

Genes, environment, cognitive, and socio-emotional factors all intersect to determine outcome. Anxiety may be inversely related to social skills, adaptive behavior, and cognitive abilities.