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.

Face-sensitive brain responses in the first year of life.

Cortical areas in the ventral visual pathway become selectively tuned towards the processing of faces compared to non-face stimuli beginning around 3 months of age and continuing over the first year. Studies using event-related potentials in the EEG (ERPs) have found an ERP component, the N290, that displays specificity for human faces. Other components, such as the P1, P400, and Nc have been studied to a lesser degree in their responsiveness to human faces. However, little is known about the systematic changes in the neural responses to faces during the first year of life, and the localization of these responses in infants' brain. We examined ERP responses to pictures of faces and objects in infants from 4.5 months through 12 months in a cross-sectional study. We investigated the activity of all the components reported to be involved in infant face processing, with particular interest to their amplitude variation and cortical localization. We identified neural regions responsible for the component through the application of cortical source localization methods. We found larger P1 and N290 responses to faces than objects, and these components were localized in the lingual and middle/posterior fusiform gyri, respectively. The amplitude of the P400 was not differentially sensitive to faces over objects. The Nc component was different for faces and objects, was influenced by the infant's attentional state, and localized in medial-anterior brain areas. The implications of these results are discussed in the identification of developmental ERP precursors to face processing.

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.

A novel eye-tracking paradigm for indexing social avoidance-related behavior in fragile X syndrome.

Fragile X syndrome (FXS) is characterized by hallmark features of gaze avoidance, reduced social approach, and social anxiety. The development of therapeutics to manage these symptoms has been hindered, in part, by the lack of sensitive outcome measures. This study investigated the utility of a novel eye-tracking paradigm for indexing social avoidance-related phenotypes. Adolescent/young adult-aged males with FXS (n = 24) and typical development (n = 23) participated in the study. Participants viewed faces displaying direct or averted gaze and the first fixation duration on the eyes was recorded as an index of initial stimulus registration. Fixation durations did not differ across the direction of gaze conditions in either group, although the control group showed longer initial fixations on the eyes relative to the FXS group. Shorter initial fixation on averted gaze in males with FXS was a robust predictor of the severity of their social avoidance behavior exhibited during a social greeting context, whereas parent-reported social avoidance symptoms were not related to performance in the semi-naturalistic context. This eye-tracking paradigm may represent a promising outcome measure for FXS clinical trials because it provides a quantitative index that closely maps onto core social avoidance phenotypes of FXS, can be completed in less than 20 min, and is suitable for use with individuals with low IQ.

Infant Temperament in the FMR1 Premutation and Fragile X Syndrome.

Although temperament has been studied for decades as a predictor of psychopathology in the general population, examining temperament in neurogenetic groups has unique potential to inform the genetic and biological factors that may confer risk for psychopathology in later development. The present study examined early temperament in two heritable neurogenetic conditions associated with atypical CGG repeat expansions on the FMR1 gene: the FMR1 premutation (FXpm; 55-200 repeats) and fragile X syndrome (FXS; > 200 repeats). We focus specifically on the FXpm, as the condition is highly prevalent (1:209-291 female individuals, 1:430-855 male individuals) and has been preliminarily associated with increased risk for pediatric psychopathology, including attention problems, autism, and anxiety. In contrast, FXS is a low-incidence disorder (1:7,143 males, 1:11,111 females) often associated with intellectual disability and severe co-occurring psychosocial conditions, particularly in male individuals. Given information on infant clinical phenotypes in the FXpm and FXS is sparse, we aimed to characterize parent-reported infant temperament in infants with the FXpm (n = 22) relative to FXS (n = 24) and controls (n = 24) assessed on 1 to 3 occasions each. Temperament in infants with the FXpm largely fell between TD and FXS groups, with trends toward suppressed negative affect in younger participants, similar to lower negative affect previously reported in FXS. The FXS group consistently demonstrated lower negative affect and surgency than TD controls. These data suggest that FMR1 gene mutations are associated with atypical temperament that emerges as early as infancy, particularly among infants with FXS, warranting further study of whether temperament may index emergent clinical risks in these populations.

Cortisol profiles differentiated in adolescents and young adult males with fragile X syndrome versus autism spectrum disorder.

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.

Biobehavioral composite of social aspects of anxiety in young adults with fragile X syndrome contrasted to autism spectrum disorder.

Social anxiety is a common disorder that has negative impacts across multiple domains of function. Several clinical groups are at elevated risk for social anxiety, including those with fragile X syndrome and those with autism spectrum disorder. Measuring social anxiety in these clinical subgroups is fraught with challenge, however, given the complexity of social anxiety and measurement limitations that are particularly acute in persons with neurodevelopmental disorders. The over-arching aim of this study was to contribute to our understanding of the nature of social anxiety in fragile X syndrome and its association with autism spectrum disorder. To address this aim, we created a multi-faceted composite representing behavioral and biological aspects of social anxiety and examined differences in two adolescent and young adult-aged groups: 59 males with fragile X syndrome and 18 males with autism spectrum disorder. Results indicated a lower score on the multivariate composite for the males with fragile X syndrome relative to autism spectrum disorder but with evidence that traits of autism and social anxiety overlap. We conclude that measuring anxiety and autism traits in fragile X syndrome and autism spectrum disorder is complex with features that overlap and interact in a dynamic manner.

Adaptive behavior in infants and toddlers with Down syndrome and fragile X syndrome.

Individuals with Down syndrome (DS) experience deficits across all domains of adaptive functioning, however little is known about the emergence and age-related changes of these impairments compared to other neurogenetic disorders with similar intellectual disability impairments, such as fragile X syndrome (FXS). Adaptive behavior is key for optimal functioning in these populations. Participants aged 5-45 months comprised three age-matched groups, DS (n = 64), FXS (n = 69), and typically developing controls (TD; n = 69). Adaptive behavior was measured on the Vineland Adaptive Behavior Scales-II. Regressions were used to examine adaptive behavior in a cross-sectional design across age. DS infants and toddlers evidenced deficits across all areas of adaptive behaviors compared to the age-matched TD group, with clear impairments present in the first year of life. Motor skills were the area of greatest weakness in children with DS with significant impairment evident at 12 months of age that remained low through 3 years. Compared to age-matched children with FXS, children with DS showed initially lower standard scores at 12 months of age, but slower declines in standard scores across age, resulting in less impaired functioning at 36 months. This is the first study to compare adaptive behavior in infants and toddlers with DS to FXS, and demonstrate the phenotypic specificity of adaptive profiles in this diagnostic group. These findings provide evidence that adaptive behavior should be a major target of intervention in children with FXS and DS, and that these differences are potentially driven by unique etiologies attributable to each disorder.

HPA axis function predicts development of working memory in boys with FXS.

The present study examines verbal working memory over time in boys with fragile X syndrome (FXS) compared to nonverbal mental-age (NVMA) matched, typically developing (TD) boys. Concomitantly, the relationship between cortisol-a physiological marker for stress-and verbal working memory performance over time is examined to understand the role of physiological mechanisms in cognitive development in FXS. Participants were assessed between one and three times over a 2-year time frame using two verbal working memory tests that differ in complexity: memory for words and auditory working memory with salivary cortisol collected at the beginning and end of each assessment. Multilevel modeling results indicate specific deficits over time on the memory for words task in boys with FXS compared to TD controls that is exacerbated by elevated baseline cortisol. Similar increasing rates of growth over time were observed for boys with FXS and TD controls on the more complex auditory working memory task, but only boys with FXS displayed an association of increased baseline cortisol and lower performance. This study highlights the benefit of investigations of how dynamic biological and cognitive factors interact and influence cognitive development over time.

Phonological awareness and reading in boys with fragile X syndrome.

BACKGROUND: Reading delays are well documented in children with fragile X syndrome (FXS), but few studies have examined linguistic precursors of reading in this population. This study examined the longitudinal development of phonological awareness and its relationship with basic reading in boys with FXS. Individual differences in genetic, social-behavioral and environmental factors were also investigated as predictors of phonological awareness. METHODS: Participants included 54 boys with FXS and 53 typically developing (TD) mental age-matched peers who completed assessments of phonological awareness, nonverbal intelligence, and reading annually for up to 4 years. FMRP level and autism symptomatology were also measured within the FXS group. Hierarchical linear modeling was used to examine change in phonological awareness over time and its predictors. Linear regression was used to examine phonological awareness as a predictor of word reading. RESULTS: Boys with FXS exhibited slower growth than TD peers in phonological awareness only when nonverbal cognitive abilities were not controlled. The rate of change in phonological awareness decreased significantly after age 10 in boys with FXS. Phonological awareness accounted for 18% unique variance in basic reading ability after controlling for nonverbal cognition, with similar relationships across groups. CONCLUSION: Phonological awareness skills in the boys with FXS were commensurate with their nonverbal cognitive abilities, with similar relationships between phonological awareness and reading as observed in the TD mental age-matched peers. More research is needed to examine potential causal relationships between phonological awareness, other language skills, and reading abilities in individuals with FXS and other neurodevelopmental disorders.

Maternal predictors of anxiety risk in young males with fragile X.

Children with fragile X syndrome (FXS) demonstrate high rates of anxiety disorders, with 65-83% meeting diagnostic criteria. The severity of anxiety symptoms in FXS has been shown to be partially predicted by elevated negative affect across early childhood [Tonnsen et al. (2013a); J Abnorm Child Psychol 41:267-280]. This association suggests that biologically driven vulnerability emerges early in development, as is reported in non-clinical populations. However, anxiety emergence is likely moderated by multifaceted genetic, biological and environmental risk and protective factors. Mothers with the FMR1 premutation have been shown to exhibit elevated parenting stress and internalizing symptoms, which have each been associated with child behavior problems [Bailey et al. (2008a); Am J Med Genet Part A 146A:2060-2069 and Bailey et al. (2008b) Am J Med Genet Part A 146A:720-729]. Despite these findings, it is unclear whether maternal factors directly relate to anxiety vulnerability in high-risk children with FXS, a question essential to informing targeted, family-sensitive treatment. The present study examines how maternal protective and risk factors relate to child inhibition reflected in (1) child anxiety symptoms, (2) child trajectories of negative affect, and (3) the association between child anxiety and negative affect. Primary predictors include maternal parenting stress, indicators of mental health risk (anxiety and depressive symptoms), and maternal optimism. We also examine genetic correlates in mothers (CGG repeats, activation ratio, mRNA). Our findings suggest that behavioral inhibition in young children with FXS is associated with higher parenting stress and lower optimism, and higher parenting stress is associated with lower maternal X-activation ratio. These findings underscore the need for family-sensitive treatment strategies for anxiety disorders in children with FXS.

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.

Similar Gap-Overlap Profiles in Children with Fragile X Syndrome and IQ-Matched Autism.

PURPOSE: Fragile X syndrome (FXS) is a single-gene disorder characterized by moderate to severe cognitive impairment and a high association with autism spectrum disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD). Atypical visual attention is a feature of FXS, ASD, and ADHD. Thus, studying early attentional patterns in young children with FXS can offer insight into early emerging neurocognitive processes underlying challenges and contribute to our understanding of common and unique features of ASD and ADHD in FXS. METHODS: The present study examined visual attention indexed by the gap-overlap paradigm in children with FXS (n = 39) compared to children with ASD matched on intellectual ability and age (n = 40) and age-matched neurotypical controls (n = 34). The relationship between gap-overlap performance and intellectual ability, ASD, and ADHD across groups was characterized. Saccadic reaction times (RT) were collected across baseline, gap, and overlap conditions. RESULTS: Results indicate no group differences in RT for any conditions. However, RT of the ASD and NT groups became slower throughout the experiment whereas RT of the FXS group did not change, suggesting difficulties in habituation for the FXS group. There was no relationship between RT and intellectual ability, ADHD, or ASD symptoms in the FXS and ASD groups. In the NT group, slower RT was related to elevated ADHD symptoms only. CONCLUSION: Taken together, findings suggest that the social attention differences documented in FXS and ASD may be due to other cognitive factors, such as reward or motivation, rather than oculomotor control of visual attention.

Developmental associations between motor and communication outcomes in Fragile X syndrome: Variation in the context of co-occurring autism.

LAY ABSTRACT: Fragile X syndrome (FXS), the leading heritable cause of intellectual disability, has a co-occurrence rate of autism spectrum disorder (ASD) estimated at ~60%. Children with FXS experience delayed achievement and slower development of key motor abilities, which happens to an even greater extent for children with both FXS and ASD. A multitude of studies have demonstrated that motor abilities are foundational skills related to later communication outcomes in neurotypical development, as well as in the context of ASD. However, these associations remain unexamined in FXS, or FXS + ASD. In this study, we aimed to determine the associations between early motor skills and their rate of development on communication outcomes in FXS. Furthermore, we investigated whether these associations varied in the context of co-occurring FXS + ASD. Results revealed within-FXS variation in the context of co-occurring ASD between some aspects of motor development and communication outcomes, yet within-FXS consistency between others. Findings provide evidence for variability in developmental processes and outcomes in FXS in the context of co-occurring ASD and offer implications for intervention.

Social Communication Delay in an Unbiased Sample of Preschoolers With the FMR1 Premutation.

PURPOSE: The Fragile X Messenger Ribonucleoprotein-1 (FMR1) premutation (FXpm) is a genetic variant that is common in the general population and is associated with health symptoms and disease in adulthood. However, poor understanding of the clinical phenotype during childhood has hindered the development of clinical practice guidelines for screening and intervention. Given that social communication difficulties have been widely documented in adults with the FXpm and are linked with reduced psychosocial functioning, the present study aimed to characterize the communication profile of the FXpm during early childhood. METHOD: Eighteen children with the FXpm who were identified through cascade testing (89%) or screening at birth (11%) were compared to 21 matched typically developing children, aged 2-4 years. Participants completed standardized assessments of language (Mullen Scales of Early Learning) and adaptive communication (Vineland Adaptive Behavior Scales-II). Social communication was rated from seminaturalistic interaction samples using the Brief Observation of Social Communication Change. RESULTS: Children with the FXpm showed delayed social communication development, with the magnitude of group differences highlighting social communication as a feature that distinguishes children with the FXpm from their peers (p = .046, ηp2 = .12). The groups did not differ on the standardized language and adaptive communication measures (ps > .297, ηp2s < .03). CONCLUSIONS: Early screening and treatment of social communication delays may be key to optimizing outcomes for children with the FXpm. Further research is needed to replicate findings in a larger sample, delineate the trajectory and consequences of social communication difficulties across the life span in the FXpm, and determine the potential epidemiological significance of FMR1 as a mediator of developmental communication differences within the general population.

Cardiovascular and behavioral response to auditory stimuli in boys with fragile X syndrome.

OBJECTIVE: The aim of this study was to determine whether young boys with fragile X syndrome (FXS) exhibit abnormal physiological or behavioral responses to a moderately intense auditory stimulus, as heightened sensory reactivity is believed to contribute to problem behaviors in this population. METHODS: We examined the physiological basis, via heart activity, of auditory startle in young boys with FXS (n = 22) compared with typically developing controls (n = 27). Associations with mental age, behavioral reactivity, and chronological age were examined. RESULTS: Results suggest that older boys with FXS display increased cardiac reactivity to auditory input than younger boys with FXS that distinguishes them from typically developing controls. Higher mental age was associated with decreased latency to react. CONCLUSIONS: Results contribute to increased understanding of the pathology in sensory processing in boys with FXS, which can inform refinement of the phenotype in young children with FXS and aid in the development of efficacious psychopharmacological and/or behavioral interventions.

Negative affect and respiratory sinus arrhythmia are differentially related to social anxiety and autism features in autistic preschoolers contrasted to fragile X syndrome.

Introduction: Autism spectrum disorder (ASD) is a highly heterogeneous and complex disorder with co-occurring disorders commonplace. This presents tremendous diagnostic challenges given the phenotypic overlap between autism and other diagnoses, including social anxiety, as well as variance in specific genetic disorders like fragile X syndrome (FXS). Biobehavioral measurement approaches integrate behavioral and biological data, and by so doing have the potential to address diagnostic challenges and shed light on the mechanisms underlying social impairments. Methods: The present study utilized a biobehavioral approach to evaluate how biologically based indices of baseline respiratory sinus arrhythmia (RSA) and temperamental negative affect differ and predict autism and anxiety in a sample of 120 preschoolers with non-syndromic autism (nsASD) with co-occurring intellectual impairment, FXS, and neurotypical (NT) development. Results: Results indicated that children with nsASD display elevated negative affect compared to both FXS and NT controls which did not differ from each other and females exhibited more negative affect relative to males. Interestingly, elevated negative affect predicted social anxiety, but not ASD in FXS. Baseline RSA did not differ across the groups; however, reduced RSA predicted elevated autism severity for the nsASD group but not those with FXS or NT development. Discussion: Taken together, biobehavioral markers differentiated the groups in discrete ways that advance our understanding of autism and promote improved diagnostic clarity using objective measurement.

Distinct social attention profiles in preschoolers with autism contrasted to fragile X syndrome.

Social attention is a critical skill for learning and development. Social attention difficulties are present in both non-syndromic autism spectrum disorder (nsASD) and fragile X syndrome (FXS), and our understanding of these difficulties is complicated by heterogeneity in both disorders, including co-occurring diagnoses like intellectual disability and social anxiety. Existing research largely utilizes a single index of social attention and rarely includes children with intellectual impairment or uses a cross-syndrome approach. This study investigated whether multi-trait social attention profiles including naturalistic initial eye contact, facial attention, and social scene attention differ in preschool children with nsASD and FXS matched on developmental ability (DQ) and contrasted to neurotypical (NT) controls. The relationship between DQ, ASD severity, and social anxiety and social attention profiles was also examined. Initial eye contact related to social scene attention, implicating that naturalistic social attention is consistent with responses during experimental conditions. Reduced eye contact and lower social scene attention characterized nsASD and FXS. Children with nsASD displayed less facial attention than FXS and NT children, who did not differ. Lower DQ and elevated ASD severity associated with decreased eye contact in nsASD and FXS, and lower DQ was associated with lower social scene attention in FXS. Sex, social anxiety, and age were not associated with social attention. These findings suggest social attention profiles of children with nsASD are highly similar to, yet distinct from, children with FXS. Children with nsASD may present with a global social attention deficit whereas FXS profiles may reflect context-dependent social avoidance.

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.

Predictors, Parental Views, and Concordance Across Diagnostic Sources of Autism in Male Youth with Fragile X Syndrome: Clinical Best Estimate and Community Diagnoses.

Persons with fragile X syndrome (FXS) with cooccurring autism spectrum disorder (ASD) are at risk for poorer educational, medical, employment, and independent living outcomes. Thus, the identification of ASD in those with FXS is fundamental to ensuring access to appropriate supports to achieve good quality of life. Yet, optimal diagnostic methods and the exact rate of ASD comorbidity remains controversial, and description of ASD identification in the community in FXS has been limited. This study characterized ASD in a sample of 49 male youth with FXS across multiple diagnostic sources: parent-reported community diagnoses, classification derived from ADOS-2 and ADI-R thresholds, and clinical best-estimate classifications from an expert multidisciplinary team. High concordance was found between ADOS-2/ADI-R and clinical best estimate classifications, with both methods supporting ASD in ~ 75% of male youth with FXS. In contrast, 31% had a community diagnosis. Findings supported gross under-identification of ASD in male youth with FXS in community settings; 60% of those who met clinical best estimate criteria for ASD had not received a diagnosis in the community. Moreover, community diagnoses were poorly aligned with the presence of ASD symptoms as perceived by parents and professionals and, unlike clinical best estimate diagnoses, were not associated with cognitive, behavioral, or language features. Findings highlight under-identification of ASD in community settings as a significant barrier to service access for male youth with FXS. Clinical recommendations should emphasize the benefits of seeking a professional ASD evaluation for children with FXS who are noted to display key ASD symptoms.