Neural correlates of face processing among preschoolers with fragile X syndrome, autism spectrum disorder, autism siblings, and typical development.

The current study examined patterns of event-related potential (ERP) responses during a face processing task in groups of preschoolers uniquely impacted by autism spectrum disorder (ASD), including (1) children with ASD; (2) children with fragile X syndrome (FXS); (3) children with familial risk for ASD, but without a diagnosis (i.e., ASIBs); and (4) a low-risk control (LRC) group. Children with FXS have a high incidence of ASD diagnoses, but there have been no studies of the ERP response to faces in children with FXS and little work focused on children with ASD who have cognitive impairment. The current study examined children's ERP responses to faces and houses in four groups: LRC (N = 28, age = 5.2 years), ASIB (N = 23, age = 5.5 years), FXS (N = 19, age = 5.82 years), and ASD (N = 23, age = 5.5 years). The FXS and ASD groups were characterized by the presence of cognitive impairment. Pictures of upright and inverted faces and houses were presented while recording EEG with a 128-channel system. The N170 occurred at about 200 ms post stimulus onset, was largest on the posterior-lateral electrodes, and was larger for faces than houses. The P1 and N170 ERP components were larger for the FXS group than for the other three groups. The N170 ERP amplitude for the ASD and ASIB groups was smaller than both the LRC and FXS groups, and the LRC and FXS groups had the largest N170 responses on the right side. No difference was found in N170 latency between groups. The similarity of the ASD and ASIB responses suggest a common genetic or environmental origin of the reduced response. Although children with FXS have a high incidence of ASD outcomes, they differed from ASD and ASIB children in this study. Specifically, the children with FXS were hyperresponsive to all stimulus types while the ASD and ASIB groups showed attenuated responses for specific stimuli.

Insight and Recommendations for Fragile X-Premutation-Associated Conditions from the Fifth International Conference on FMR1 Premutation.

The premutation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene is characterized by an expansion of the CGG trinucleotide repeats (55 to 200 CGGs) in the 5' untranslated region and increased levels of FMR1 mRNA. Molecular mechanisms leading to fragile X-premutation-associated conditions (FXPAC) include cotranscriptional R-loop formations, FMR1 mRNA toxicity through both RNA gelation into nuclear foci and sequestration of various CGG-repeat-binding proteins, and the repeat-associated non-AUG (RAN)-initiated translation of potentially toxic proteins. Such molecular mechanisms contribute to subsequent consequences, including mitochondrial dysfunction and neuronal death. Clinically, premutation carriers may exhibit a wide range of symptoms and phenotypes. Any of the problems associated with the premutation can appropriately be called FXPAC. Fragile X-associated tremor/ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI), and fragile X-associated neuropsychiatric disorders (FXAND) can fall under FXPAC. Understanding the molecular and clinical aspects of the premutation of the FMR1 gene is crucial for the accurate diagnosis, genetic counseling, and appropriate management of affected individuals and families. This paper summarizes all the known problems associated with the premutation and documents the presentations and discussions that occurred at the International Premutation Conference, which took place in New Zealand in 2023.

Behavioural and physiological indicators of anxiety reflect shared and distinct profiles across individuals with neurogenetic syndromes.

Anxiety is heightened in individuals with intellectual disability, particularly in those with specific neurogenetic syndromes. Assessment of anxiety for these individuals is hampered by a lack of appropriate measures that cater for communication impairment, differences in presentation, and overlapping features with co-occurring conditions. Here, we adopt a multi-method approach to identify fine-grained behavioural and physiological (via salivary cortisol) responses to anxiety presses in people with fragile X (FXS; n = 27; Mage = 20.11 years; range 6.32 - 47.04 years) and Cornelia de Lange syndromes (CdLS; n = 27; Mage = 18.42 years; range 4.28 - 41.08 years), two neurogenetic groups at high risk for anxiety, compared to neurotypical children (NT; n = 21; Mage = 5.97 years; range 4.34 - 7.30 years). Results indicate that physical avoidance of feared stimuli and proximity seeking to a familiar adult are prominent behavioural indicators of anxiety/stress in FXS and CdLS. Heightened pervasive physiological arousal was identified in these groups via salivary cortisol. An association between autistic characteristics and anxiety was evident in the FXS group but not in the CdLS group pointing to syndrome-specific nuances in the association between anxiety and autism. This study furthers understanding of the behavioural and physiological presentation of anxiety in individuals with intellectual disability and progresses theoretical developments regarding the development and maintenance of anxiety at the intersection of autism.

Brief Report: Prevalence and Predictors of DSM-Specific and Distinct Anxiety in Cognitively Impaired Autistic Preschool Children.

Autistic individuals are twice as likely to meet criteria for anxiety than neurotypical children; yet we lack understanding of early presentations of anxiety in young autistic children, especially those with cognitive impairment. This study is the first to utilize an autism-specific anxiety diagnostic interview with 28 preschool cognitively impaired, autistic children and 18 neurotypical, age-matched controls. Results indicate that 64% of autistic children met criteria for DSM-specified or "other specified," herein referred to as "distinct," anxiety disorders; 32% met criteria for multiple anxiety disorders, with phobias occurring most often. Results indicate that anxiety is highly prevalent in cognitively-impaired, autistic preschool children, highlighting the need for developmentally-tailored assessment and treatment in early childhood.

ADHD and ASD symptoms in young males with fragile X syndrome: associations with early trajectories of inhibitory control.

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.

Slower Peak Pupillary Response to Emotional Faces in Parents of Autistic Individuals.

Background: Atypical autonomic arousal has been consistently documented in autism spectrum disorder (ASD) and is thought to contribute to the social-communication phenotype of ASD. Some evidence suggests that clinically unaffected first-degree relatives of autistic individuals may also show subtle differences in indices of autonomic arousal, potentially implicating heritable pathophysiological mechanisms in ASD. This study examined pupillary responses in parents of autistic individuals to investigate evidence that atypical autonomic arousal might constitute a subclinical physiological marker of ASD heritability within families of autistic individuals. Methods: Pupillary responses to emotional faces were measured in 47 ASD parents and 20 age-matched parent controls. Macro-level pupillary responses (e.g., mean, peak, latency to peak) and dynamic pupillary responses over the course of the stimulus presentation were compared between groups, and in relationship to subclinical ASD-related features in ASD parents. A small ASD group (n = 20) and controls (n = 17) were also included for exploratory analyses of parent-child correlations in pupillary response. Results: Parents of autistic individuals differed in the time course of pupillary response, exhibiting a later primary peak response than controls. In ASD parents, slower peak response was associated with poorer pragmatic language and larger peak response was associated with poorer social cognition. Exploratory analyses revealed correlations between peak pupillary responses in ASD parents and mean and peak pupillary responses in their autistic children. Conclusion: Differences in pupillary responses in clinically unaffected parents, together with significant correlations with ASD-related features and significant parent-child associations, suggest that pupillary responses to emotional faces may constitute an objective physiological marker of ASD genetic liability, with potential to inform the mechanistic underpinnings of ASD symptomatology.

Neural Correlates of Infant Face Processing and Later Emerging Autism Symptoms in Fragile X Syndrome.

Fragile X syndrome (FXS) is the leading known genetic cause of autism spectrum disorder (ASD) with 60-74% of males with FXS meeting diagnostic criteria for ASD. Infants with FXS have demonstrated atypical neural responses during face processing that are unique from both typically developing, low-risk infants and infants at high familial risk for ASD (i.e., infants siblings of children with ASD). In the current study, event-related potential (ERP) responses during face processing measured at 12 months of age were examined in relation to ASD symptoms measured at ~48 months of age in participants with FXS, as well as siblings of children with ASD and low-risk control participants. Results revealed that greater amplitude N290 responses in infancy were associated with more severe ASD symptoms in childhood in FXS and in siblings of children with ASD. This pattern of results was not observed for low-risk control participants. Reduced Nc amplitude was associated with more severe ASD symptoms in participants with FXS but was not observed in the other groups. This is the first study to examine ASD symptoms in childhood in relation to infant ERP responses in FXS. Results indicate that infant ERP responses may be predictive of later symptoms of ASD in FXS and the presence of both common and unique pathways to ASD in etiologically-distinct high-risk groups is supported (i.e., syndromic risk vs. familial risk).

Trajectories of Heart Activity Across Infancy to Early Childhood Differentially Predict Autism and Anxiety Symptoms in Fragile X Syndrome.

Background: Fragile X syndrome (FXS) is a monogenic disorder characterized by high rates of autism spectrum disorder (ASD) and anxiety. A longstanding "hyperarousal hypothesis" in FXS has argued that ANS dysfunction underpins many symptoms of FXS. However, the developmental onset and trajectory of ANS dysfunction, as well as the consequences of ANS dysfunction on later psychiatric symptoms, remain poorly understood in FXS. Insight into the emergence, trajectory, and consequences of ANS dysfunction across early development in FXS has critical implications for prevention, intervention, and optimal outcomes in both typical and atypical development. This longitudinal study investigated whether and when males with FXS evidence atypical ANS function from infancy through early childhood, and how trajectories of ANS function across infancy and early childhood predict ASD and anxiety symptom severity later in development. Methods: Participants included 73 males with FXS and 79 age-matched typically developing (TD) males. Baseline heart activity was recorded at multiple assessments between 3 and 83 months of age, resulting in 372 observations. General arousal and parasympathetic activity were indexed via interbeat interval (IBI) and respiratory sinus arrhythmia (RSA), respectively. ASD and anxiety symptoms were assessed at 36 months of age or later in a subgroup of participants (FXS n = 28; TD n = 25). Results: Males with FXS exhibited atypical patterns of developmental change in ANS function across infancy and early childhood. As a result, ANS dysfunction became progressively more discrepant across time, with the FXS group exhibiting significantly shorter IBI and lower RSA by 29 and 24 months of age, respectively. Shorter IBI at 24 months and a flatter IBI slope across development predicted elevated anxiety symptoms, but not ASD symptoms, later in childhood in both FXS and TD males. Reduced RSA at 24 months predicted elevated ASD symptoms, but not anxiety symptoms, in both groups. Developmental change in RSA across early development did not predict later anxiety or ASD symptoms. Conclusion: This is the first longitudinal study to examine the "hyperarousal hypothesis" in infants and young children with FXS. Findings suggest that hyperarousal (i.e., shorter IBI, lower RSA) is evident in males with FXS by 24-29 months of age. Interestingly, unique aspects of early ANS function differentially relate to later ASD and anxiety symptoms. General arousal, indexed by shorter IBI that becomes progressively more discrepant from TD controls, predicts later anxiety symptoms. In contrast, parasympathetic-related factors, indexed by lower levels of RSA, predict ASD symptoms. These findings support the "hyperarousal hypothesis" in FXS, in that ANS dysfunction evident early in development predicts later-emerging symptoms of ASD and anxiety. This study also have important implications for the development of targeted treatments and interventions that could potentially mitigate the long-term effects of hyperarousal in FXS.

A single-session behavioral protocol for successful event-related potential recording in children with neurodevelopmental disorders.

Event-related potentials (ERPs) are an ideal tool for measuring neural responses in a wide range of participants, including children diagnosed with neurodevelopmental disorders (NDDs). However, due to perceived barriers regarding participant compliance, much of this work has excluded children with low IQ and/or reduced adaptive functioning, significant anxiety symptoms, and/or sensory processing difficulties, including heterogeneous samples of children with autism spectrum disorder (ASD) and children with fragile X syndrome (FXS). We have developed a behavioral support protocol designed to obtain high-quality ERP data from children in a single session. Using this approach, ERP data were successfully collected from participants with ASD, FXS, and typical development (TD). Higher success rates were observed for children with ASD and TD than children with FXS. Unique clinical-behavioral characteristics were associated with successful data collection across these groups. Higher chronological age, nonverbal mental age, and receptive language skills were associated with a greater number of valid trials completed in children with ASD. In contrast, higher language ability, lower autism severity, increased anxiety, and increased sensory hyperresponsivity were associated with a greater number of valid trials completed in children with FXS. This work indicates that a "one-size-fits-all" approach cannot be taken to ERP research on children with NDDs, but that a single-session paradigm is feasible and is intended to promote increased representation of children with NDDs in neuroscience research through development of ERP methods that support inclusion of diverse and representative samples.

Attention Bias and Prodromal Anxiety Symptoms in Toddlers With Fragile X Syndrome and Down Syndrome.

Early identification of behavioral risk markers for anxiety is essential to optimize long-term outcomes in children with neurodevelopmental disorders. This study analyzed attentional avoidance and its relation to anxiety and autism spectrum disorder (ASD) symptomatology during social and nonsocial fear conditions in toddlers with fragile X syndrome (FXS) and Down syndrome (DS). Toddlers with FXS and DS exhibited increased nonsocial attentional avoidance relative to typically developing (TD) toddlers. Attentional avoidance was not related to anxiety symptom severity in any group; however, higher ASD symptom severity was related to more social attentional avoidance in the FXS and TD groups. Findings suggest that there may be different underlying mechanisms driving attentional avoidance across neurodevelopmental disorders.

Early behavioral and physiological markers of social anxiety in infants with fragile X syndrome.

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.

Cardiac Startle Response and Clinical Outcomes in Preschool Children With Fragile X Syndrome and Autism Spectrum Disorder.

Objective: Poor physiological regulation in response to threat is linked to multiple negative developmental outcomes including anxiety, which is highly prevalent and impairing in young children with neurodevelopmental disabilities like fragile X syndrome (FXS) and autism spectrum disorder (ASD). The present study contrasted cardiac startle response in pre-school-aged children with FXS, with and without ASD, to children with non-syndromic ASD (nsASD) and neurotypical controls (NT). The relationship of cardiac startle to non-verbal mental age (NVMA), ASD severity, and parent-reported anxiety was also examined. Method: Four age-matched groups of pre-school children participated including those with FXS without ASD (FXS-Only, n = 21), FXS with ASD (FXS+ASD, n = 17), nsASD (n = 42), and NT children (n = 27). Participants viewed a silent movie during which a single 200 ms 98-decibel white noise burst occurred. Cardiac activity was analyzed for pre-stimulus respiratory sinus arrhythmia (RSA) and the inter-beat intervals (IBI) at the auditory stimulus and 10 s post-stimulus. The Spence Pre-school Anxiety Scale, Autism Diagnostic Observation Schedule-2nd Edition, and Mullen Scales of Early Learning were examined in relation to startle response. Results: The nsASD group demonstrated heightened cardiac activity at the auditory stimulus and 10 s post-stimulus compared to the NT controls. Neither of the FXS groups showed differences from any other group. Higher pre-stimulus RSA was associated with reduced cardiac response across groups, while the relationship between cognitive ability and ASD severity to cardiac response varied between groups. Parent-reported anxiety was not associated with cardiac response for any group. Conclusion: These findings demonstrate group distinctions in cardiac responses to auditory startle. Although FXS and ASD share behavioral characteristics, the nsASD group showed a heightened cardiac startle response compared to the NT group that was not present in the FXS groups with or without ASD. Non-verbal mental age was associated with greater stimulus or post-stimulus reactivity for all groups except the FXS+ASD group, which showed no association between startle response and any clinical outcomes. Increased understanding of the relationship between physiological regulation and clinical outcomes will assist in identifying the timing and targets for effective interventions for individuals with neurodevelopmental disabilities.

Emergence and rate of autism in fragile X syndrome across the first years of life.

Prospective longitudinal studies of idiopathic autism spectrum disorder (ASD) have provided insights into early symptoms and predictors of ASD during infancy, well before ASD can be diagnosed at age 2-3 years. However, research on the emergence of ASD in disorders with a known genetic etiology, contextualized in a developmental framework, is currently lacking. Using a biobehavioral multimethod approach, we (a) determined the rate of ASD in N = 51 preschoolers with fragile X syndrome (FXS) using a clinical best estimate (CBE) procedure with differential diagnoses of comorbid psychiatric disorders and (b) investigated trajectories of ASD symptoms and physiological arousal across infancy as predictors of ASD in preschoolers with FXS. ASD was not diagnosed if intellectual ability or psychiatric disorders better accounted for the symptoms. Our results determined that 60.7% of preschoolers with FXS met the Diagnostic and Statistical Manual of Mental Disorders (fifth edition) (DSM-5) criteria for ASD using the CBE procedure. In addition, 92% of these preschoolers presented with developmental delay and 45.4% also met criteria for psychiatric disorders, either anxiety, ADHD, or both. ASD diagnoses in preschoolers with FXS were predicted by elevated scores on traditional ASD screeners in addition to elevated autonomic arousal and avoidant eye contact from infancy.

Physiological regulation and social-emotional processing in female carriers of the FMR1 premutation.

The FMR1 gene is associated with a wide range of clinical and cognitive phenotypes, ranging from intellectual disability and autism symptoms in fragile X syndrome (caused by the FMR1 full mutation), to a more varied, and still poorly understood range of clinical and cognitive phenotypes among carriers of the gene in its premutation state. Because the FMR1 premutation is relatively common among women (as high as 1 in 150), investigations of its phenotypic impact could have broad implications for understanding gene-behavior relationships underlying complex human traits, with potential clinical implications. This study investigated physiological regulation measured by pupillary responses, along with fixation patterns while viewing facial expressions among women who carry the FMR1 premutation (PM group; n = 47), to examine whether the FMR1 gene may relate to physiological regulation, social-emotional functioning, and social language skills (where subclinical differences have been previously reported among PM carriers that resemble those documented in autism-related conditions). Relative to controls (n = 25), the PM group demonstrated atypical pupillary responses and fixation patterns, controlling for IQ. In the PM group, pupillary response and fixation patterns were related to social cognition, social language abilities, and FMR1-related variation. Results indicate a pattern of atypical attention allocation among women who carry the FMR1 PM that could reflect different emotion-processing strategies mediated by autonomic dysregulation and the FMR1 gene. These findings lend insight into the FMR1 gene's potential contributions to complex human traits such as social emotional processing and social language.

Early negative affect in males and females with fragile X syndrome: implications for anxiety and autism.

BACKGROUND: Fragile X syndrome (FXS) is a genetic disorder that is highly comorbid with anxiety and autism spectrum disorder (ASD). Elevated negative affect in young children has been associated with increased risk for both anxiety and ASD; however, these relations remain poorly understood in FXS. METHODS: The present prospective longitudinal study examined the trajectory of negative affect from infancy through preschool in males and females with FXS and typical development and its relation to anxiety and ASD. RESULTS: Results indicate a complex association reflecting group, developmental, and sex effects. Specifically, the group with FXS displayed a trajectory of increasing negative affect across age that was distinct from the typical controls. This atypical trajectory of negative affect in FXS was driven by sex effects in that males showed lower negative affect during infancy followed by steep increases across the toddler and preschool years whereas the females displayed a flatter trajectory. Finally, elevated negative affect predicted anxiety symptoms in males, but not females, with no relationship to ASD in males or females with FXS. CONCLUSIONS: The current work addresses the importance of studying the development of psychopathology in a specific neurogenetic population. Temperamental negative affect was shown to be an important early marker for anxiety in young children with FXS, with subtle differences observed between males and females.

Language processing skills linked to FMR1 variation: A study of gaze-language coordination during rapid automatized naming among women with the FMR1 premutation.

The FMR1 premutation (PM) is relatively common in the general population. Evidence suggests that PM carriers may exhibit subtle differences in specific cognitive and language abilities. This study examined potential mechanisms underlying such differences through the study of gaze and language coordination during a language processing task (rapid automatized naming; RAN) among female carriers of the FMR1 PM. RAN taps a complex set of underlying neuropsychological mechanisms, with breakdowns implicating processing disruptions in fundamental skills that support higher order language and executive functions, making RAN (and analysis of gaze/language coordination during RAN) a potentially powerful paradigm for revealing the phenotypic expression of the FMR1 PM. Forty-eight PM carriers and 56 controls completed RAN on an eye tracker, where they serially named arrays of numbers, letters, colors, and objects. Findings revealed a pattern of inefficient language processing in the PM group, including a greater number of eye fixations (namely, visual regressions) and reduced eye-voice span (i.e., the eyes' lead over the voice) relative to controls. Differences were driven by performance in the latter half of the RAN arrays, when working memory and processing load are the greatest, implicating executive skills. RAN deficits were associated with broader social-communicative difficulties among PM carriers, and with FMR1-related molecular genetic variation (higher CGG repeat length, lower activation ratio, and increased levels of the fragile X mental retardation protein; FMRP). Findings contribute to an understanding of the neurocognitive profile of PM carriers and indicate specific gene-behavior associations that implicate the role of the FMR1 gene in language-related processes.

Social Avoidance Emerges in Infancy and Persists into Adulthood in Fragile X Syndrome.

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.

Gesture Frequency and Function in Infants With Fragile X Syndrome and Infant Siblings of Children With Autism Spectrum Disorder.

Purpose Infant siblings of children with autism spectrum disorder (ASIBs) and infants with fragile X syndrome (FXS) are both at risk for developing autism spectrum disorder (ASD) and communication disorders; however, very few studies have examined 1 of the earliest forms of intentional communication in infants from these groups: gestures. This study examined the frequency and function of gesture use across 12-month-old infant ASIBs, infants with FXS, and low-risk controls. Method Participants included 23 ASIBs who did not later meet diagnostic criteria for ASD, 18 infants with FXS, and 21 low-risk controls. Gestures were coded from a semistructured play-based interaction. Results Overall, infants with FXS displayed fewer gestures than low-risk infants, whereas ASIBs did not differ from the FXS or low-risk groups in overall gesture frequency. In terms of the communicative function of the gestures used, the FXS and ASIB groups displayed significantly fewer social interaction gestures than the low-risk controls, with large effect sizes. Conclusion This study contributes to scant knowledge of early communication phenotypes of infant ASIBs who do not meet criteria for ASD and infants with FXS. Results indicated that gesture function, not frequency, best discriminated at-risk infants from low-risk infants at 12 months of age. Findings have implications for the clinical evaluation and treatment of infants at high risk for ASD and communication disorders.

Infant Social Avoidance Predicts Autism but Not Anxiety in Fragile X Syndrome.

Objective: Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and anxiety are three of the most common childhood psychiatric disorders. Early trajectories of social avoidance have been linked with these psychiatric disorders in previous studies, but it remains unclear how social avoidance differentially predicts comorbid disorders in a high-risk genetic subgroup. Here, we delineate the association between trajectories of social avoidance from infancy and subsequent ASD, ADHD, and anxiety outcomes at preschool in children with fragile X syndrome (FXS), a well-characterized single-gene disorder highly associated with social avoidance as well as elevated rates of ASD, ADHD, and anxiety. Method: Males with FXS (n = 78) aged 4-62 months participated in a longitudinal study resulting in 201 assessments. The Social Avoidance Scale (SAS) documented socially avoidant behaviors from infancy in three domains-physical movement, facial expression, and eye contact during both the first minute and the last hour of an interaction. ASD, ADHD, and anxiety symptom outcomes at preschool were measured via parent-report questionnaires. Results: Increased social avoidance across infancy and preschool predicted elevated ASD symptom severity but reduced ADHD and anxiety symptom severity in males with FXS. Conclusion: ASD, ADHD, and anxiety symptoms relate inconsistently to social avoidance behaviors, providing new insight toward the debate of independence or overlap among these disorders in FXS and other disorders (i.e., ASD). The results suggest that the nuanced profile of the developmental and temporal aspects of social avoidance may inform more the accuracy of differential diagnoses of comorbid psychiatric disorders in FXS.

Prevalence and Predictors of Anxiety Disorders in Adolescent and Adult Males with Autism Spectrum Disorder and Fragile X Syndrome.

Anxiety disorders affect ~ 15-20% of youths without neurodevelopmental disorders, with persons having autism spectrum disorder (ASD) and fragile X syndrome (FXS) at elevated risk for anxiety disorders. Few studies have compared rates and predictors of anxiety disorders in adolescents with FXS or ASD. This study directly compares rates, predictors, and medication of anxiety disorders between age-matched, male adolescents with FXS (n = 31) or ASD (n = 20). Results indicate that 51.6% of FXS and 50.0% of ASD adolescents met criteria for an anxiety disorder. Cognitive scores and ASD severity did not predict anxiety. Of those with anxiety, ~ 40% of the FXS and 20% of the ASD participants were prescribed medications for anxiety.