Cortisol and behavior in fragile X syndrome

OBJECTIVE: The purpose of this study was to determine if children with fragile X syndrome, who typically demonstrate a neurobehavioral phenotype that includes social anxiety, withdrawal, and hyper-arousal, have increased levels of cortisol, a hormone associated with stress. The relevance of adrenocortical activity to the fragile X phenotype also was examined. METHOD: One hundred and nine children with the fragile X full mutation (70 males and 39 females) and their unaffected siblings (51 males and 58 females) completed an in-home evaluation including a cognitive assessment and a structured social challenge task. Multiple samples of salivary cortisol were collected throughout the evaluation day and on two typical non-school days. Measures of the fragile X mental retardation (FMR1) gene, child intelligence, the quality of the home environment, parental psychopathology, and the effectiveness of educational and therapeutic services also were collected. Linear mixed-effects analyses were used to examine differences in cortisol associated with the fragile X diagnosis and gender (fixed effects) and to estimate individual subject and familial variation (random effects) in cortisol hormone levels. Hierarchical multiple regression analyses were conducted to determine whether adrenocortical activity is associated with behavior problems after controlling for significant genetic and environmental factors. RESULTS: Results showed that children with fragile X, especially males, had higher levels of salivary cortisol on typical days and during the evaluation. Highly significant family effects on salivary cortisol were detected, consistent with previous work documenting genetic and environmental influences on adrenocortical activity. Increased cortisol was significantly associated with behavior problems in boys and girls with fragile X but not in their unaffected siblings. CONCLUSIONS: These results provide evidence that the function of the hypothalamic-pituitary-adrenal axis may have an independent association with behavioral problems in children with fragile X syndrome.     

Self-injurious behavior and fragile X syndrome: findings from the national fragile X survey

We used National Fragile X Survey data in order to examine reported self-injurious behavior (SIB) to (a) generate lifetime and point prevalence estimates, (b) document detailed features of SIB (frequency, types, location, severity) in relation to gender, and (c) compare comorbid conditions between matched pairs (SIB vs. no SIB). Results indicate significant gender differences in frequency, topography, and location of SIB as well as sleep difficulties, comorbid conditions, pain sensitivity, and seizures. Matched pair comparisons (SIB vs. no SIB) revealed differences for males in sensory and attention problems, hyperactivity, aggression, autism, and anxiety and for females, in autism, attention, and anxiety. These results further clarify gender differences as well as comorbidity patterns between children with fragile X syndrome with and without SIB.     

Adaptive behavior in children with fragile X syndrome

Adaptive behavior over time in 70 children with fragile X syndrome, ages 1 to 12 years, was examined using the Vineland Adaptive Behavior Scales. With a mean of 4.4 assessments per child, adaptive behavior skills increased steadily and gradually over time. Children with less autistic behavior and higher percentages of FMPR expression showed better performance on all areas of adaptive behavior. Children without autistic behavior displayed higher scores and rates of growth on the Daily Living Skills domain, with the lowest scores in Socialization. Comparison to Brief IQs indicate that children with fragile X syndrome display nonverbal IQs superior to their adaptive behavior when they are below age 10 but that these skills seem to converge as they get older.     

Longitudinal trajectories of aberrant behavior in fragile X syndrome

The Aberrant Behavior Checklist-Community (ABC-C; Aman et al., 1995) has been increasingly adopted as a primary tool for measuring behavioral change in clinical trials for individuals with fragile X syndrome (FXS). To our knowledge, however, no study has documented the longitudinal trajectory of aberrant behaviors in individuals with FXS using the ABC-C. As part of a larger longitudinal study, we examined scores obtained on the ABC-C subscales for 124 children and adolescents (64 males, 60 females) with FXS who had two or more assessments (average interval between assessments was approximately 4 years). Concomitant changes in age-equivalent scores on the Vineland Adaptive Behavior Scales (VABS) were also examined. As expected for an X-linked genetic disorder, males with FXS obtained significantly higher scores on all subscales of the ABC-C and significantly lower age-equivalent scores on the VABS than females with FXS. In both males and females with FXS, scores on the Irritability/Agitation and Hyperactivity/Noncompliance subscales of the ABC-C decreased significantly with age, with little to no change occurring over time on the Lethargy/Social Withdrawal, Stereotypic Behavior, and Inappropriate Speech subscales. The decrease in scores on the Hyperactivity/Noncompliance domain was significantly greater for males than for females. In both males and females, age-equivalent scores on the VABS increased significantly over this developmental period. These results establish a basis upon which to evaluate long-term outcomes from intervention-based research. However, longitudinal direct observational studies are needed to establish whether the severity of problem behavior actually decreases over time in this population.     

Trajectory of adaptive behavior in males with fragile X syndrome

Adaptive behavior in males with fragile X syndrome was longitudinally examined in 17 subjects, ages 1 to 17. Subjects received adaptive behavior evaluations on two occasions within one of three age periods. All domains of the Vineland Adaptive Behavior Scales increased from youngest to oldest age groups, yet older subjects (ages 10 to 17) shoed significant declines in their adaptive behavior scores from first to second testing. A relative strength in Daily Living Skills and weakness in Socialization emerged only among older subjects. There was a significant relationship between adaptive behavior and mental age scores in all subjects. Discussion emphasized the parallels between declines in IQ and adaptive behavior as well as the need for further research on adaptive skills in young adults with fragile X syndrome.This research was supported, in part, by the John Merck Fund, the Joseph P. Kennedy Jr. Foundation, NIH Grants RR00125 and HD03008, and NIMH grants MH18268 and MH30929.     

Early behavior signs of psychiatric phenotypes in fragile X syndrome

Whether preschool males with fragile X syndrome can be distinguished from those with idiopathic developmental delay in the four problem behavior areas associated with the fragile X phenotypes was examined. Males with fragile X (n = 41) and age- and IQ-matched controls (n = 16) were rated by their mothers on the Dimensions of Temperament Scale-Revised, the Child Behavior Checklist, and the Aberrant Behavior Checklist--Community. The fragile X group showed deficits in motor skills, increased initial avoidance, decreased social withdrawal, deficits in attention, increased hyperactivity, and positive mood. They were distinguished from controls on all of these variables except hyperactivity and attention. When maternal characteristics were controlled for, the fragile X group showed a significantly higher level of generalized activity level than did controls.     

Compulsive, self-injurious, and autistic behavior in children and adolescents with fragile X syndrome

Compulsive, self-injurious, and autistic behaviors were examined in 31 boys and 29 girls with fragile X syndrome aged 5 to 20 years. Self-injurious behavior occurred in 58% of boys and 17% of girls, whereas compulsive behavior occurred in 72% of boys and 55% of girls and did not appear to be associated with self-injurious behavior. Fifty percent of boys and 20% of girls met diagnostic criteria for autism on the ADOS-G. Girls who showed compulsive behavior had lower levels of FMRP than girls who did not show compulsive behavior, and boys with autistic symptoms had lowered levels of cortisol. Taken together, these data suggest that autistic and compulsive behaviors are highly prevalent in fragile X syndrome and that lowered levels of FMRP and cortisol may be biological markers for these behaviors.     

Maternal well-being and child behavior in families with fragile X syndrome

The purpose of this study was to examine the bidirectional relationships relationship between maternal mental health status, maternal stress, family environment and behavioral functioning of children with fragile X syndrome (FXS), the leading cause of inherited intellectual disability. Children with FXS commonly demonstrate challenging behavior related to anxiety, attention, and aggression, whereas mothers of children with FXS have been identified as susceptible to mental health challenges due to their status as genetic carriers of the FXS premutation, as well as the environmental stressors of raising children with special needs. The longitudinal design of this study builds upon prior work that established a concurrent relationship among these factors in families of children with other intellectual disorders. Findings indicated that maternal mental health status was not significantly related to changes in levels of child challenging behavior, heightened child challenging behavior was related to improvements in maternal depression over time, and heightened levels of child challenging behavior was related to increased feelings of maternal closeness toward the child over time. The unexpected nature of the results regarding maternal depression and closeness provides new and more complex hypotheses about how mothers of special needs children demonstrate adaptation and resilience. The findings have implications for maternal and familial mental health treatment as well as future research.     

Family environment and behavior problems in children, adolescents, and adults with fragile X syndrome

We examine how the family environment is associated with aspects of the Fragile X syndrome phenotype during childhood, adolescence, and adulthood. Mothers of children (n = 48), adolescents (n = 85), and adults (n = 34) with Fragile X syndrome participated in a multisite study. For children and adults with Fragile X syndrome, the presence of warmth and positivity and the absence of criticism were associated with fewer behavior problems. Although a higher level of criticism was significantly associated with greater behavior problems, there were only trend-level associations between levels of warmth and positivity and behavior problems during the adolescent years. The provision of family psychoeducation programs, which can reduce parental criticism, would likely benefit both the individual with Fragile X syndrome and the family.     

Autistic behavior in boys with fragile X syndrome: social approach and HPA-axis dysfunction

The primary goal of this study was to examine environmental and neuroendocrine factors that convey increased risk for elevated autistic behavior in boys with Fragile X syndrome (FXS). This study involves three related analyses: (1) examination of multiple dimensions of social approach behaviors and how they vary over time, (2) investigation of mean levels and modulation of salivary cortisol levels in response to social interaction, and (3) examination of the relationship of social approach and autistic behaviors to salivary cortisol. Poor social approach and elevated baseline and regulation cortisol are discernible traits that distinguish boys with FXS and ASD from boys with FXS only and from typically developing boys. In addition, blunted cortisol change is associated with increased severity of autistic behaviors only within the FXS and ASD group. Boys with FXS and ASD have distinct behavioral and neuroendocrine profiles that differentiate them from those with FXS alone and typically developing boys.     

Examining the function of problem behavior in fragile X syndrome: preliminary experimental analysis

Fragile X syndrome is the most common inherited cause of intellectual and developmental disability. The influence of environmental variables on behaviors associated with the syndrome has received only scant attention. The current study explored the function served by problem behavior in fragile X syndrome by using experimental functional analysis methodology with 8 children with fragile X. No child met criteria for attention-maintained problem behavior, 5 children met criteria for escape-maintained problem behavior, and 4 children met criteria for tangible-maintained problem behavior. Results are discussed and compared with previous findings on the function of problem behavior in fragile X syndrome, and implications for intervention are discussed. It is noted that the external validity of these findings is limited by the small sample size.     

A randomized double-blind,placebo-controlled trial of ganaxolone in children and adolescents with fragile X syndrome

Background

Gamma-aminobutyric acid (GABA) system deficits are integral to the pathophysiologic development of fragile X syndrome (FXS). Ganaxolone, a GABA_A receptor positive allosteric modulator, is hypothesized to improve symptoms such as anxiety, hyperactivity, and attention deficits in children with FXS.

Methods

This study was a randomized, double-blind, placebo-controlled, crossover trial of ganaxolone in children with FXS, aged 6–17 years.

Results

Sixty-one participants were assessed for eligibility, and 59 were randomized to the study. Fifty-five participants completed at least the first arm and were included in the intention-to-treat analysis; 51 participants completed both treatment arms. There were no statistically significant improvements observed on the primary outcome measure (Clinical Global Impression-Improvement), the key secondary outcome measure (Pediatric Anxiety Rating Scale-R), or any other secondary outcome measures in the overall study population. However, post-hoc analyses revealed positive trends in areas of anxiety, attention, and hyperactivity in participants with higher baseline anxiety and low full-scale IQ scores. No serious adverse events (AEs) occurred, although there was a significant increase in the frequency and severity of AEs related to ganaxolone compared to placebo.

Conclusions

While ganaxolone was found to be safe, there were no significant improvements in the outcome measures in the overall study population. However, ganaxolone in subgroups of children with FXS, including those with higher anxiety or lower cognitive abilities, might have beneficial effects.

Trial registration

ClinicalTrials.gov, NCT01725152

     

Trajectories and profiles of adaptive behavior in males with fragile X syndrome: Multicenter studies

We conducted two multicenter studies on adaptive trajectories and profiles in males with fragile X syndrome. Study 1 longitudinally assessed 29 males ages 1–20 years using ageequivalent scores from the Vineland Adaptive Behavior Scales. Fragile X boys ages 1–10 years showed significant gains in adaptive skills from first to second testing; males ages 11–20 years were stable in their adaptive development. Study 2 cross-sectionally examined 132 males ages 1–20 years. Significant age-related gains were found in boys ages 1–10, particularly in preschool children. Subjects ages 11–20 showed increased variability and nonsignificant relations between age and adaptive skills. Preliminary findings from 26 young adults with fragile X syndrome ages 21–40 years showed stable age-equivalent adaptive scores during these years. Relative strengths in daily living skills and weaknesses in communication were only evident among older subjects. Significant relations were found between adaptive behavior standard scores and IQ; these two scores also showed age-related declines that likely parallel one another. Findings are related to adaptive features in other genetic syndromes, and to directions for future adaptive behavior research.     

Heart activity and autistic behavior in infants and toddlers with fragile X syndrome

The present study contrasted physiological arousal in infants and toddlers with fragile X syndrome to typically developing control participants and examined physiological predictors early in development to autism severity later in development in fragile X syndrome. Thirty-one males with fragile X syndrome (ages 8-40 months) and 25 age-matched control participants were included. The group with fragile X syndrome showed shorter interbeat intervals (IBIs), lower vagal tone (VT), and less modulation of IBI. Data suggested a nonlinear effect with IBI and autistic behavior; however, a linear effect with VT and autistic behavior emerged. These findings suggest that atypical physiological arousal emerges within the first year and predicts severity of autistic behavior in fragile X syndrome. These relationships are complex and dynamic, likely reflecting endogenous factors assumed to reflect atypical brain function secondary to reduced fragile X mental retardation protein. This research has important implications for the early identification and treatment of autistic behaviors in young children with fragile X syndrome.     

Early identification of autism in fragile X syndrome: a review

Fragile X syndrome (FXS) is the leading genetic cause of autism, accounting for approximately 5% of autism cases with as many as 50% of individuals with FXS meeting DSM‐IV‐TR criteria for autistic disorder. Both FXS and idiopathic autism (IA) are attributed to genetic causes; however, FXS is an identified single gene disorder whereas autism is a complex disorder with multiple potential causes, some of which have been identified. Studies in IA have focused on the prospective longitudinal examination of infant siblings of children with autism as a target group due to their high risk of developing the disorder. We propose that this same model be applied to the study of infants with FXS. There is a lack of research focusing on the early development of autism within FXS and debate in the literature regarding how to best conceptualise this co‐morbidity or whether it should be considered a co‐morbid condition at all. Studying the emergence and stability of autism in infants with FXS has multiple benefits such as clarifying the underlying mechanisms of the development of autism in FXS and solidifying similarities and differences between co‐morbid FXS with autism and IA. Infant research in both IA and FXS are discussed as well as conclusions and implications for practice and future research.     

Signaling noncomprehension of language: a comparison of fragile X syndrome and Down syndrome

Signaling noncomprehension of the spoken messages of others was examined for youth with fragile X or Down syndrome in comparison with each other and nonverbal MA-matched typically developing children. A direction-following task was used in which some of the directions were inadequate. Both syndrome groups signaled noncomprehension less often than did the typically developing children. The ability to signal noncomprehension appropriately was related to a measure of receptive vocabulary and syntax. Preliminary analyses indicated that males with fragile X syndrome signaled noncomprehension less often than did their female peers, even after controlling for differences in nonverbal MA.     

Impact of antioxidants, zinc, and copper on cognition in the elderly: a randomized, controlled trial

Participants in the Age-Related Eye Disease Study were randomly assigned to receive daily antioxidants (vitamin C, 500 mg; vitamin E, 400 IU; beta carotene, 15 mg), zinc and copper (zinc, 80 mg; cupric oxide, 2 mg), antioxidants plus zinc and copper, or placebo. A cognitive battery was administered to 2,166 elderly persons after a median of 6.9 years of treatment. Treatment groups did not differ on any of the six cognitive tests (p > 0.05 for all). These results do not support a beneficial or harmful effect of antioxidants or zinc and copper on cognition in older adults.