Sensory Symptoms and Signs of Hyperarousal in Individuals with Fragile X Syndrome: Findings from the FORWARD Registry and Database Multisite Study.

This study was designed to increase our understanding about characteristics and the impact of sensory symptoms (SS) and signs of hyperarousal (HA) in individuals with fragile X syndrome (FXS) from childhood through early adulthood and by gender. Data derived from the Fragile X Online Registry With Accessible Research Database (FORWARD), a natural history study of FXS, were analyzed using descriptive statistics and multivariate linear and logistic regression models to examine SS and signs of HA, their impact on behavioral regulation and limitations on the subject/family. The sample (N = 933) consisted of 720 males and 213 females. More males were affected with SS (87% vs. 68%) and signs of HA (92% vs. 79%). Subjects who were endorsed as having a strong sensory response had more comorbidities, including behavioral problems. The predominant SS was difficulty with eye gaze that increased with age in both genders. As individuals age, there was less use of non-medication therapies, such as occupational therapy (OT)/physical therapy (PT), but there was more use of psychopharmacological medications and investigational drugs for behaviors. Multiple regression models suggested that endorsing SS and signs of HA was associated with statistically significantly increased ABC-C-I subscale scores and limited participation in everyday activities. This study improves our understanding of SS and signs of HA as well as their impact in FXS. It supports the need for more research regarding these clinical symptoms, especially to understand how they contribute to well-known behavioral concerns.

High performing male with fragile X syndrome with an unmethylated FMR1 full mutation: The relevance of clinical and genetic correlations.

A high performing male with an unmethylated full mutation in the fragile X messenger ribonucleoprotein 1 (FMR1) gene surpassed our expectations into young adulthood. Although initial genetic findings helped make a correct fragile X syndrome (FXS) determination, the report was insufficient. Ten years later, we repeated and conducted additional genetic and clinical studies to determine whether more information could assist with treatment and counseling. The genetic findings were very consistent with his high functioning and would have enabled us to be more confident about a good developmental outcome had they been available previously. As FXS enters the mainstream of well-understood genetic disorders and technological advancements improve genetic tests, it should be clearer to clinical providers what a full FXS assessment could include to provide high quality information for care. For individuals with FXS who are high functioning, their families and clinical professionals would benefit from knowing more genetic findings, including, most importantly, methylation status, but also the FMR1 protein (FMRP) level and mRNA level. While we now know that obtaining only the CGG repeat number is not always adequate to inform accurate clinical care, future studies are likely to show the benefit of studying other biomarkers, such as mRNA levels.

Toilet Training in Fragile X Syndrome.

OBJECTIVE: To characterize bladder and bowel toileting skill acquisition in children with fragile X syndrome and to identify associated demographic, behavioral, and clinical factors. METHODS: Using baseline data from the Fragile X Online Registry With Accessible Research Database (FORWARD), bivariate analyses and logistic regression models were used to identify differences between subjects who were and were not bowel and/or bladder trained by the age of 10 years. Cox proportional hazard models were used to assess the rate of completion of toilet training (TT) as a function of sex and autism spectrum disorder (ASD) diagnosis. RESULTS: In bivariate analyses, male sex, lower language level, inability to write one's name, more impaired intellectual level, ASD, and more severe behavioral deficits all predicted lack of bladder training (n = 313, p < 0.001) and bowel training (n = 300, p = 0.0004-0.0001) by the age of 10 years. In logistic regression models, lower level of language acquisition (p < 0.001) and higher Aberrant Behavior Checklist Irritability scores (p < 0.04) were associated with lower odds of bladder training by the age of 10 years. Lower level of language acquisition (p < 0.001) and ASD (p < 0.025) were associated with lower odds of bowel training by the age of 10 years. For both bladder and bowel training, Cox proportional hazard models indicated that delayed training was associated with male sex, lower levels of language acquisition, and ASD for both bladder training (n = 486; p < 0.001) and bowel training (n = 472; p < 0.001). CONCLUSION: These findings emphasize the importance of both slower language development and ASD diagnosis in predicting bowel and bladder training delays and can be used to develop and evaluate targeted approaches to TT based on sex, ASD diagnosis, and other clinical features identified in this study.

Best Practices in Fragile X Syndrome Treatment Development.

Preclinical studies using animal models of fragile X syndrome have yielded several agents that rescue a wide variety of phenotypes. However, translation of these treatments to humans with the disorder has not yet been successful, shedding light on a variety of limitations with both animal models and human trial design. As members of the Clinical Trials Committee of the National Fragile X Foundation, we have discussed a variety of recommendations at the level of preclinical development, transition from preclinical to human projects, family involvement, and multi-site trial planning. Our recommendations are made with the vision that effective new treatment will lie at the intersection of innovation, rigorous and reproducible research, and stakeholder involvement.

Fragile X syndrome: a review of associated medical problems.

Fragile X syndrome (FXS) is the most common known genetic cause of inherited intellectual disability and the most common known single-gene cause of autism spectrum disorder. It has been reported that a spectrum of medical problems are commonly experienced by people with FXS, such as otitis media, seizures, and gastrointestinal problems. Previous studies examining the prevalence of medical problems related to FXS have been challenging to interpret because of their marked differences in population, setting, and sampling. Through this comprehensive review, we update the literature by reviewing studies that have reported on prominent medical problems associated with FXS. We then compare prevalence results from those studies with results from a large cross-sectional database consisting of data collected by fragile X clinics that specialize in the care of children with FXS and are part of the Fragile X Clinical and Research Consortium. It is vital for pediatricians and other clinicians to be familiar with the medical problems related to FXS so that affected patients may receive proper diagnosis and treatment; improved care may lead to better quality of life for these patients and their families.

Psychometric study of the Aberrant Behavior Checklist in Fragile X Syndrome and implications for targeted treatment.

Animal studies elucidating the neurobiology of fragile X syndrome (FXS) have led to multiple controlled trials in humans, with the Aberrant Behavior Checklist-Community (ABC-C) commonly adopted as a primary outcome measure. A multi-site collaboration examined the psychometric properties of the ABC-C in 630 individuals (ages 3-25) with FXS using exploratory and confirmatory factor analysis. Results support a six-factor structure, with one factor unchanged (Inappropriate Speech), four modified (Irritability, Hyperactivity, Lethargy/Withdrawal, and Stereotypy), and a new Social Avoidance factor. A comparison with ABC-C data from individuals with general intellectual disability and a list of commonly endorsed items are also reported. Reformulated ABC-C scores based on this FXS-specific factor structure may provide added outcome measure specificity and sensitivity in FXS clinical trials.

Indicators of anxiety and depression in women with the fragile X premutation: assessment of a clinical sample.

BACKGROUND: Current research suggests that depression and anxiety may be common problems in women with the fragile X (FMR1) premutation. METHODS: To learn more about this in a clinical setting, we asked 33 women with the FMR1 premutation and 20 women without the FMR1 premutation to complete the Brief Carroll Depression Scale (Brief CDS) and the Multidimensional Anxiety Questionnaire (MAQ) and to provide information about mental health medication use. Questionnaire findings were compared between groups and with normative samples. Trinucleotide (CGG) repeat counts were also correlated to checklist findings. RESULTS: Both women with the FMR1 premutation and the comparison group had high current mental health medication use (33% vs. 35%). Approximately 1/3 of the women from both groups had high Brief CDS Total T-scores (33% vs. 30%). More women with the FMR1 premutation had at least one elevated MAQ Total or sub-scale T-score than the comparison group (39% vs. 10%, P = 0.03). Twenty-one per cent of women with the FMR1 premutation had all three of the indicators of distress targeted in this study vs. none of the women in the comparison samples (P < 0.05). There was no statistically significant correlation between CGG repeat size and abnormal checklist findings using the Spearman rank correlation, although a higher percentage of women with >100 CGG repeats (57%) had an elevated Brief CDS Total T-score than women with 100 CGG repeats also had all three indicators of anxiety and depression (P = 0.03). CONCLUSIONS: Women with the FMR1 premutation appear to have a high incidence of depression and increased symptoms of anxiety. Screening tools like the Brief CDS and the MAQ may be useful to identify these women in the clinic setting. Positive identification could lead to increased mental health care and treatment.

Genetic variants in SLC9A9 are associated with measures of attention-deficit/hyperactivity disorder symptoms in families.

OBJECTIVE: A family was previously identified that cosegregates a pericentric inversion, inv(3)(p14 : q21), with an early-onset developmental condition, characterized by impulsive behavior and intellectual deficit. The inversion breakpoints lie within DOCK3 and SLC9A9 at the p-arm and q-arm, respectively. Based on this report, these genes were selected to be evaluated in a family-based attention-deficit/hyperactivity disorder (AD/HD) association study. METHODS: Conners' Parent (CPRS) and Teacher (CTRS) Rating Scales of AD/HD symptoms and Conners' Continuous Performance Test (CPT) measures were collected and a minimal number of tagging single-nucleotide polymorphisms (SNPs) in each gene were selected for analysis. Analyses were performed on families who met research criteria for AD/HD. Using the program, QTDT, each tagging SNP was tested for association with T-scores from the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) subscales according to the CTRS and CPRS, and five CPT measures. RESULTS: After adjusting for multiple testing, a SNP in the 3' UTR of SLC9A9, rs1046706, remained significantly associated (false discovery rate, q value <0.05) with scores on the DSM-IV hyperactive-impulsive and total symptom subscales according to the CTRS and errors of commission on the CPT. In addition, an intronic SLC9A9 SNP, rs2360867, remained significantly associated with errors of commission. CONCLUSION: Our results suggest that SLC9A9 may be related to hyperactive-impulsive symptoms in AD/HD and the disruption of SLC9A9 may be responsible for the behavioral phenotype observed in the inversion family. The association with SLC9A9 is particularly interesting as it was recently implicated in a genome-wide association study for AD/HD. Further investigation of the role of SLC9A9 in AD/HD and other behavioral disorders is warranted.

Effects of postnatal parental smoking on parent and teacher ratings of ADHD and oppositional symptoms.

To assess the effects of postnatal parental smoking on subsequent parent and teacher ratings of DSM-IV attention deficit hyperactivity disorder (ADHD) symptoms and oppositional behaviors in children diagnosed with ADHD and their siblings. Children between 5 and 12 years of age with ADHD and their siblings were included. DSM-IV ADHD symptom subscales (Inattentive and hyperactive-impulsive), and oppositionality subscale scores from Conners' Rating Scales were predicted on the basis of parental smoking status in the first 7 years after birth using Generalized Estimating Equations controlling for a range of relevant covariates. Postnatal parental smoking was associated with both parent and teacher ratings of ADHD symptoms and oppositional behavior. After controlling for a number of covariates, several of these relationships were still significant. The risk of maternal smoking for the development of ADHD symptoms does not end during pregnancy. Research on the mechanisms underlying the observed associations is needed.

Advances in the treatment of fragile X syndrome.

The FMR1 mutations can cause a variety of disabilities, including cognitive deficits, attention-deficit/hyperactivity disorder, autism, and other socioemotional problems, in individuals with the full mutation form (fragile X syndrome) and distinct difficulties, including primary ovarian insufficiency, neuropathy and the fragile X-associated tremor/ataxia syndrome, in some older premutation carriers. Therefore, multigenerational family involvement is commonly encountered when a proband is identified with a FMR1 mutation. Studies of metabotropic glutamate receptor 5 pathway antagonists in animal models of fragile X syndrome have demonstrated benefits in reducing seizures, improving behavior, and enhancing cognition. Trials of metabotropic glutamate receptor 5 antagonists are beginning with individuals with fragile X syndrome. Targeted treatments, medical and behavioral interventions, genetic counseling, and family supports are reviewed here.

Living with genetic risk: effect on adolescent self-concept.

The purpose of this study is to describe the interplay of adolescent girls' and young womens' self-concept, coping behaviors, and adjustment associated with knowledge of genetic risk for fragile X syndrome. We will report here findings on self-concept. Using a multi-group cross-sectional design this study focused on girls ages 14-25 years from families previously diagnosed with fragile X syndrome, who knew they were (1) carriers (n = 20; mean age 18.35 years s.d. 2.5), or (2) noncarriers (n = 18; mean age 17.78 years s.d. 2.69), or (3) at-risk to be carriers (n = 15; mean age 17.87 s.d. 3.18). The girls completed the Tennessee Self-Concept Scale (TSCS:2), a visual analog scale, and a guided interview. Total and all subscale scores on the TSCS:2 were in the normal range for all three groups. However, threats to self-concept were found in personal self (physical self, genetic identity, and parental role), social self, and family self (family genetic identity) as they specifically related to the meaning of genetic information and varied based on risk status. Our findings suggest that risk information itself is threatening and for some girls, may be as threatening as learning one is a carrier. Certainty related to genetic risk status appears to make a positive difference for some girls by allowing them the opportunity to face the challenge of their genetic risk status and to begin to consider the meaning of this information.

Arithmetic difficulties in females with the fragile X premutation.

Females with the fragile X full mutation have been reported to have difficulty learning mathematics. Women with the fragile X premutation often give a history of mathematics difficulties in themselves especially with higher level math. In order to evaluate whether women with the premutation have difficulty with math, we asked women with both the fragile X premutation and full mutation to complete the Wide Range Achievement Test-3. For the group of 39 women with the fragile X premutation, the median standard score on the Arithmetic portion was 93, which was significantly lower (P = 0.001) than the median of the standardized norm of 100. Only nine of the women had Arithmetic scores at or above the 50th centile, while over half of the women had standard scores at or above the 50th centile in Reading and Spelling. The eight women with the full mutation also had lower Arithmetic scores than Reading and Spelling scores. These data suggest that mathematics may be an area of relative weakness for the women with the premutation as well as the full mutation. This possibility should be evaluated further by using other measures. This information is important both for counseling purposes and to understand whether a mathematics deficit is evidence of low expression of the FMR1 gene in the premutation state.

Carrier testing in fragile X syndrome: when to tell and test.

This study explored age preferences about when to learn at-risk status and have carrier testing in women who were undergoing testing for fragile X. Forty-two women (20 carriers and 22 noncarriers) completed a structured interview prior to carrier testing and after learning their result. The majority favored learning at-risk status and carrier status at < 18 years for themselves and their children. Preferred ages fell into four developmental categories: early childhood (0-9), preteen (10-13), teen (14-17), and adult (>or= 18). Although no significant mean changes in age responses were found between interviews or between carrier and noncarrier responses, a difference in the pattern of responses related to age categories was suggested. There appeared to be an increase in the number of responses in the 0-9 category at time 2. Also, the mean ages for testing were older than they were for telling at time 1, but not at time 2. For women indicating ages 0-9, the most frequent reason was to provide children with time to adjust. Those reporting ages 10-13 felt that the onset of puberty as well as a child's ability to understand, adjust, and cope were key determinants. Those preferring the teen years felt the possibility of sexual activity and planning for the future were important considerations. The developmental focus for adults was serious relationships. This study, through its unique longitudinal perspective of transition from uncertainty to certainty, builds on prior knowledge, has implications for genetic counseling, and suggests that the developmental stage of the child is important in determining when to tell and test.