Jane E. Roberts

The fragile X premutation (FXpm) is a relatively common condition caused by an expansion of 55–200 cytosine–guanine–guanine (CGG) repeats in the fragile X messenger ribonucleoprotein 1 (FMR1) gene. Previous studies have identified sensory processing challenges in children with the FXpm and reduced autonomic regulation in FXpm infants; no research has examined the relationship between autonomic nervous system (ANS) functioning or molecular variables and sensory responsiveness during infancy. This study examined parent-reported sensory responsiveness and its association with baseline respiratory sinus arrhythmia (RSA), interbeat interval (IBI), and CGG repeat length in 12-month-old infants with the FXpm (n = 35) and neurotypical (NT) controls (n = 55). Results indicated no significant differences in hyporesponsive or hyperresponsive sensory behaviors and no significant associations between baseline RSA or IBI and sensory responsiveness in either group. Within the FXpm group, however, greater CGG repeat length was associated with lower hyperresponsive sensory scores. These findings suggest that sensory processing differences may not be behaviorally evident at 12 months of age despite the presence of biological variability associated with the premutation. The study contributes to the emerging literature on early FXpm development and highlights the importance of examining genetic and physiological factors that may precede later-emerging behavioral phenotypes.

The fragile X premutation (FXpm) is caused by a CGG repeat expansion on the FMR1 gene. In adults, FXpm is linked with autonomic nervous system (ANS) dysfunction and impairment is associated with CGG repeat length. Given scant infancy research, we examined ANS functioning, via respiratory sinus arrhythmia (RSA) and interbeat interval (IBI), in 82 FXpm and neurotypical infants and their associations with CGG repeats. FXpm infants exhibited lower RSA but no IBI differences. There were no associations between ANS functioning and CGG repeat length. These findings identify an ANS biomarker consistent with the emerging pediatric phenotype in FXpm.

Inhibitory control (IC), the ability to suppress inappropriate responses, emerges late in the first year of life and improves across typical development, concurrent with brain maturation. The development of IC is critical to various social-emotional and behavioral functions, with IC difficulties being linked to numerous neurodevelopmental disorders, including attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Fragile X syndrome (FXS) is a single-gene disorder characterized by IC difficulties, and elevated rates of ADHD and ASD, making it a useful model for understanding the early development and consequences of IC. In this longitudinal study, we characterized IC trajectories across multiple time points between 16 and 71 months of age in young males with FXS (n = 79) relative to neurotypical (NT) controls (n=49). To explore the association between behavioral outcomes and IC, we identified a subsample of 50 children with longitudinal IC data and an outcome assessment for ADHD and ASD symptoms at age 5 (FXS: n = 26, NT: n = 24). Results indicated that, compared to their NT peers, young males with FXS exhibit differences in IC as early as 24 months, with group differences increasing through age 5. Additionally, we determined that lower IC levels at 24 months were associated with later ADHD symptoms and a decreasing slope in IC over time was associated with later ASD symptoms in male children with FXS. These findings help refine early developmental phenotypes of FXS and highlight IC as a potential target for early detection and intervention of ASD and ADHD symptoms in male children with FXS.

Background: Social anxiety is highly prevalent in neurotypical children and children with fragile X syndrome (FXS). FXS is a genetic syndrome that is characterized by intellectual disability and an increased risk for autism spectrum disorder. If social anxiety is left untreated, negative outcomes are highly prevalent later in life. However, early detection of social anxiety is challenging as symptoms are often subtle or absent very early in life. Given the prevalence and impairment associated with childhood social anxiety, efforts have accelerated to identify risk markers of anxiety. A cluster of early features of anxiety have been identified including elevated behavioral inhibition, attentional biases, and physiological dysregulation that index early emerging markers of social anxiety. Infants with FXS provide a unique opportunity to study the earlier predictors of social anxiety. The current study utilized a multi-method approach to investigate early markers of social anxiety in 12-month-old infants with FXS.Method: Participants included 32 infants with FXS and 41 low-risk controls, all approximately 12 months old. Parent-reported social behavioral inhibition was recorded from the Infant Behavior Questionnaire (IBQ-R). Direct observations of behavioral inhibition and attention were measured during a stranger approach task with respiratory sinus arrhythmia collected simultaneously.Results: Parent-reported social behavioral inhibition was not significantly different between groups. In contrast, direct observations suggested that infants with FXS displayed elevated behavioral inhibition, increased attention towards the stranger, and a blunted respiratory sinus arrhythmia response.Conclusions: Findings suggest that infants with FXS show both behavioral and physiological markers of social anxiety at 12 months old using a biobehavioral approach with multiple sources of input. Results highlight the importance of a multi-method approach to understanding the complex early emergent characteristics of anxiety in infants with FXS.

Background Fragile X syndrome (FXS) is a single‐gene disorder highly associated with anxiety; however, measuring anxiety symptoms in FXS and other neurogenetic syndromes is challenged by common limitations in language, self‐awareness and cognitive skills required for many traditional assessment tasks. Prior studies have documented group‐level differences in threat‐related attentional biases, assessed via eye tracking, in FXS and non‐FXS groups. The present study built on this work to test whether attentional biases correspond to clinical features of anxiety among adolescents and young adults with FXS. Methods Participants included 21 male adolescents with FXS ages 15–20 years who completed an adapted eye‐tracking task that measured attentional bias towards fearful faces of varied emotional intensity. Results Among participants without anxiety disorders, attentional bias towards fear increased across age, similar to non‐FXS paediatric anxiety samples. In contrast, participants with anxiety disorders exhibited greater stability in fear‐related attentional biases across age. Across analyses, subtle fear stimuli were more sensitive to within‐group anxiety variability than full‐intensity stimuli. Conclusions Our results provide novel evidence that although threat‐related attentional biases may correspond with anxiety outcomes in FXS, these associations are complex and vary across developmental and task factors. Future studies are needed to characterise these associations in more robust longitudinal samples, informing whether and how eye‐tracking tasks might be optimised to reliably predict and track anxiety in FXS.

Fragile X syndrome (FXS) is characterized by both social approach and social avoidance. However, the age of emergence and developmental trajectory of social avoidance has not been examined. This study investigates the longitudinal developmental trajectory and dynamic nature of social avoidance in males with FXS from infancy through young adulthood (n = 191). Multiple facets of social avoidance were collected using the Social Avoidance Scale (Roberts et al. 2007, 2009). Overall, 81% of males with FXS displayed social avoidance, which emerged during infancy, increased in severity across childhood, and stabilized through adolescence and early adulthood. An exaggerated “warm up” effect was also observed in FXS. This study delineates the complex profile of social avoidance, a common and impairing behavioral feature of FXS.

Effortful control, or the ability to suppress a dominant response to perform a subdominant response, is an early-emerging temperament trait that is linked with positive social-emotional development. Fragile X syndrome (FXS) is a single-gene disorder characterized by hallmark regulatory impairments, suggesting diminished effortful control. This study compared the development of effortful control in preschool boys with FXS (n = 97) and typical development (n = 32). Unlike their typical peers, the boys with FXS did not exhibit growth in effortful control over time, which could not be accounted for by adaptive impairments, FMR1 molecular measures, or autism symptoms. These results contribute to our understanding of the childhood phenotype of FXS that may be linked to the poor social-emotional outcomes seen in this group.

Background: Fragile X syndrome (FXS) and non‐syndromic autism spectrum disorder (ASD) are distinct disorders with overlapping behavioral features. Both disorders are also highly associated with anxiety with abnormal physiological regulation implied mechanistically. Some reports suggest atypical hypothalamus‐pituitary‐adrenal (HPA) axis function, indexed via aberrant cortisol reactivity, in both FXS and non‐syndromic ASD. However, no study has compared cortisol reactivity across these two disorders, or its relationship to ASD symptom severity.Methods: Cortisol reactivity (prior to and following a day of assessments) was measured in 54 adolescent/young adult males with FXS contrasted to 15 males with non‐syndromic ASD who had low cognitive abilities.Results: Greater ASD symptom severity was related to increased cortisol reactivity and higher levels at the end of the day, but only in the non‐syndromic ASD group. Elevated anxiety was associated with increased HPA activation in the group with FXS alone.Conclusions: Taken together, findings suggest a unique neuroendocrine profile that distinguishes adolescent/young adult males with FXS from those with non‐syndromic ASD. Severity of ASD symptoms appears to be related to cortisol reactivity in the non‐syndromic ASD sample, but not in FXS; while anxiety symptoms are associated with HPA activation in the FXS sample, but not in ASD despite a high prevalence of ASD, anxiety and physiological dysregulation characteristic in both populations.

Background: The FMR1 premutation, caused by a CGG trinucleotide repeat expansion on the FMR1 gene, has been identified as a genetic risk factor for mood and anxiety disorders. Building on recent studies identifying increased risk for mood and affective disorders in this population, we examined effects of potential protective factors (optimism, religion, hope) on depression and anxiety diagnoses in a prospective, longitudinal cohort.Methods: Eighty‐three women with the FMR1 premutation participated in the Structured Clinical Interview for DSM‐IV‐TR Disorders at two‐time points, 3 years apart. Participants also completed measures of optimism, religion, personal faith, hope, and child and family characteristics. We used logistic regression to examine correlates of major depressive disorder (MDD) and anxiety disorders at the initial assessment, as well as predictors of the diagnostic course over time.Results: Lower optimism and higher religious participation relevant to fragile X syndrome at the initial assessment were associated with a lifetime history of MDD. Lower optimism also predicted the occurrence and reoccurrence of an anxiety disorder 3 years later.Conclusions: In women with the FMR1 premutation, elevated optimism may reduce the occurrence or severity of MDD and anxiety disorders. These findings underscore the importance of supporting mental health across the FMR1 spectrum of involvement.

Studying anxiety in neurogenetic syndromes may inform the intersection of biological and developmental risks, facilitating effective and targeted interventions. We longitudinally examined stranger fear in infants and toddlers with fragile X syndrome (FXS; n = 46) and typical controls (n = 33), as well as associations between observed stranger fear and rating scales of anxiety, withdrawal and autism features within FXS. Results indicated atypical facial fear in FXS, although facial fear did not index anxiety, autistic symptoms or social withdrawal. Instead, lower withdrawal was associated with decreased distress vocalizations across age, and higher autistic symptoms were associated with lower intensity escape behaviors. Early stranger fear in FXS reflects both typical and atypical dimensions and may help index emergence of social anxiety in this population.