Acoustic properties of early vocalizations in infants with fragile X syndrome.

Fragile X syndrome (FXS) is a neurogenetic syndrome characterized by cognitive impairments and high rates of autism spectrum disorder (ASD). FXS is often highlighted as a model for exploring pathways of symptom expression in ASD due to the high prevalence of ASD symptoms in this population and the known single-gene cause of FXS. Early vocalization features-including volubility, complexity, duration, and pitch-have shown promise in detecting ASD in idiopathic ASD populations but have yet to be extensively studied in a population with a known genetic cause for ASD such as FXS. Investigating early trajectories of these features in FXS may inform our limited knowledge of potential mechanisms that predict later social communication outcomes. The present study addresses this need by presenting preliminary findings which (a) characterize early vocalization features in FXS relative to low-risk controls (LRC) and (b) test the specificity of associations between these features and language and ASD outcomes. We coded vocalization features during a standardized child-examiner interaction for 39 nine-month-olds (22 FXS, 17 LRC) whose clinical outcomes were assessed at 24 months. Our results provide preliminary evidence that within FXS, associations between vocalization features and 24-month language outcomes may diverge from those observed in LRC, and that vocalization features may be associated with later ASD symptoms. These findings provide a starting point for more research exploring these features as potential early markers of ASD in FXS, which in turn may lead to improved early identification methods, treatment approaches, and overall well-being of individuals with ASD. Autism Res2019. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Although vocal features of 9-month-olds with FXS did not differ from those of low-risk controls, several features were associated with later language and ASD outcomes at 24 months in FXS. These preliminary results suggest acoustic data may be related to clinical outcomes in FXS and potentially other high-risk populations. Further characterizing these associations may facilitate understanding of biological mechanisms and risk factors associated with social communication development and ASD.

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.

Validating and Applying the CSBS-ITC in Neurogenetic Syndromes.

Although social communication skills are commonly delayed in children with neurogenetic syndromes (NGS), skill profiles in very young children are largely under characterized, in part due to the lack of validated assessment measures appropriate for these populations. We addressed this gap by validating and applying a popular early social communication screening measure, the Communication and Symbolic Behavior Scales Developmental Profile - Infant-Toddler Checklist (CSBS-ITC) in three previously understudied neurogenetic groups: Angelman, Prader-Willi, and Williams syndromes. Our results suggest that when used within the appropriate scope of screening and surveillance, the CSBS-ITC detects meaningful variability in skills across ages in young children with NGS and may provide useful information about both individual- and population-level social communication profiles in these populations.

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.

Brief Report: Challenging Behaviors in Toddlers and Preschoolers with Angelman, Prader-Willi, and Williams Syndromes.

Children with neurogenetic syndromes (NGS) experience comorbid challenging behaviors and psychopathology. We examined challenging behaviors in 86 toddlers and preschoolers across three NGS [Angelman syndrome (AS), Prader-Willi syndrome (PWS), and Williams syndrome (WS)] and 43 low-risk controls (LRC), using the Child Behavior Checklist for Ages 1½-5. Challenging behavior profiles differed across NGS, with generally elevated behaviors in AS and WS, but not PWS, relative to LRC. Withdrawn and autism spectrum symptoms were particularly elevated in AS. Although several profiles were similar to those previously reported in older children and adults, we also observed inconsistencies that suggest non-linear developmental patterns of challenging behaviors. These findings underscore the importance of characterizing early challenging behaviors to inform atypical phenotypic development and targeted intervention.

Curvilinear Association Between Language Disfluency and FMR1 CGG Repeat Size Across the Normal, Intermediate, and Premutation Range.

Historically, investigations of FMR1 have focused almost exclusively on the clinical effects of CGG expansion within the categories of the premutation (55-200 CGG repeats) and fragile X syndrome (>200 CGG repeats). However, emerging evidence suggests that CGG-dependent phenotypes may occur across allele sizes traditionally considered within the "normal" range. This study adopted an individual-differences approach to determine the association between language production ability and CGG repeat length across the full range of normal, intermediate, and premutation alleles. Participants included 61 adult women with CGG repeats within the premutation (n = 37), intermediate (i.e., 41-54 repeats; n = 2), or normal (i.e., 6-40 repeats; n = 22) ranges. All participants were the biological mothers of a child with a developmental disorder, to control for the potential effects of parenting stress. Language samples were collected and the frequency of language disfluencies (i.e., interruptions in the flow of speech) served as an index of language production skills. Verbal inhibition skills, measured with the Hayling Sentence Completion Test, were also measured and examined as a correlate of language disfluency, consistent with theoretical work linking language disfluency with inhibitory deficits (i.e., the Inhibition Deficit Hypothesis). Blood samples were collected to determine FMR1 CGG repeat size. A general linear model tested CGG repeat size of the larger allele (allele-2) as the primary predictor of language disfluency, covarying for education level, IQ, age, and CGG repeats on the other allele. A robust curvilinear association between CGG length and language disfluency was detected, where low-normal (∼ <25 repeats) and mid-premutation alleles (∼90-110 repeats) were linked with higher rates of disfluency. Disfluency was not associated with inhibition deficits, which challenges prior theoretical work and suggests that a primary language deficit could account for elevated language disfluency in FMR1-associated conditions. Findings suggest CGG-dependent variation in language production ability, which was evident across individuals with and without CGG expansions on FMR1.

Heart rate-defined sustained attention in infants at risk for autism.

BACKGROUND: Although aberrant visual attention has been identified in infants at high familial risk for autism, the developmental emergence of atypical attention remains unclear. Integrating biological measures of attention into prospective high-risk infant studies may inform more nuanced developmental trajectories, clarifying the onset and course of atypical attention and potentially advancing early screening or treatment protocols. Heart rate-defined sustained attention (HRDSA) is a well-validated biological measure of attentional engagement that, in non-clinical infant populations, provides incremental information about attentional engagement beyond looking behaviors alone. The present study aimed to examine the characteristics and clinical correlates of HRDSA in high-risk infants, informing whether HRDSA may operate as a promising biological measure of attention and clinical symptoms in this population. METHODS: We examined age-related patterns of HRDSA during a passive looking task in 5- to 14-month-old high-risk infant siblings of children with autism (n = 21) compared to low-risk controls (n = 21), with most participants contributing multiple assessments. Emergent autism features were measured using the Autism Diagnostic Observation Schedule at 24 months. Primary dependent variables included the proportion of time in behavioral attention, proportion of time in HRDSA, and average heart rate deceleration during HRDSA. For each variable, we used nested multilevel models to examine whether attention differed by group, as well as whether attention predicted emergent autism features among high-risk infant siblings. RESULTS: As expected, HRDSA served as a global biological measure of attention in high-risk infants, predicting greater variability in group risk status than behavioral looking alone. Among high-risk infants, more severe ASD features were also associated with increasingly shallow heart rate deceleration during HRDSA across development, suggesting abnormal qualities of HRDSA may inform individual differences within this population. CONCLUSIONS: These preliminary findings provide initial evidence that HRDSA may offer a sensitive, affordable, and portable biological measure of attention that may enhance understanding of atypical attention in high-risk infants. Using this method, we also provide initial evidence that atypical patterns of heart activity previously reported in children and adults with autism may emerge in the first year of life, warranting further study of how HRDSA may specifically inform attention profiles in ASD.

Neural correlates of face processing in etiologically-distinct 12-month-old infants at high-risk of autism spectrum disorder.

Neural correlates of face processing were examined in 12-month-olds at high-risk for autism spectrum disorder (ASD), including 21 siblings of children with ASD (ASIBs) and 15 infants with fragile X syndrome (FXS), as well as 21 low-risk (LR) controls. Event-related potentials were recorded to familiar and novel face and toy stimuli. All infants demonstrated greater N290 amplitude to faces than toys. At the Nc component, LR infants showed greater amplitude to novel stimuli than to their mother's face and own toy, whereas infants with FXS showed the opposite pattern of responses and ASIBs did not differentiate based on familiarity. These results reflect developing face specialization across high- and low-risk infants and reveal neural patterns that distinguish between groups at high-risk for ASD.

Sleep phenotypes in infants and toddlers with neurogenetic syndromes.

BACKGROUND: Although sleep problems are well characterized in preschool- and school-age children with neurogenetic syndromes, little is known regarding the early emergence of these problems in infancy and toddlerhood. To inform syndrome-specific profiles and targets for intervention, we compared parent-reported sleep problems in infants and toddlers with Angelman syndrome (AS), Williams syndrome (WS), and Prader-Willi syndrome (PWS) with patterns observed among same-aged typically developing (TD) controls. METHODS: Mothers of 80 children (18 AS, 19 WS, 19 PWS, and 24 TD) completed the Brief Infant Sleep Questionnaire. Primary dependent variables included (1) sleep onset latency, (2) total sleep duration, (3) daytime and nighttime sleep duration, and (4) sleep problem severity, as measured by both maternal impression and National Sleep Foundation guidelines. RESULTS: Sleep problems are relatively common in children with neurogenetic syndromes, with 41% of mothers reporting problematic sleep and 29% of children exhibiting abnormal sleep durations as per national guidelines. Across genetic subgroups, problems are most severe in children with AS and WS, particularly in relation to nighttime sleep duration. Although atypical sleep is characteristically reported in each syndrome later in development, infants and toddlers with PWS exhibited largely typical patterns, potentially indicating delayed onset of sleep problems in concordance with other medical features of PWS. CONCLUSIONS: Our findings suggest that sleep problems in neurogenetic syndromes emerge as early as infancy and toddlerhood, with variable profiles across genetic subgroups. This work underscores the importance of early sleep screenings as part of routine medical care of neurosyndromic populations and the need for targeted, syndrome-sensitive treatment.

Prevalence of Autism Spectrum Disorders Among Children With Intellectual Disability.

Autism spectrum disorders (ASD) often co-occur with intellectual disability (ID) and are associated with poorer psychosocial and family-related outcomes than ID alone. The present study examined the prevalence, stability, and characteristics of ASD estimates in 2,208 children with ASD and ID identified through the South Carolina Autism and Developmental Disabilities Network. The prevalence of ASD in ID was 18.04%, relative to ASD rates of 0.60%-1.11% reported in the general South Carolina population. Compared to children with ASD alone, those with comorbid ID exhibited increased symptom severity and distinct DSM-IV-TR profiles. Further work is needed to determine whether current screening, diagnostic, and treatment practices adequately address the unique needs of children and families affected by comorbid ASD and ID diagnoses.

Brief Report: Autism Symptoms in Infants with Fragile X Syndrome.

Fragile X syndrome (FXS) is the most common known genetic cause of autism spectrum disorder (ASD). Although 50-75 % of children with FXS meet ASD criteria, no studies have compared ASD symptoms in infants with FXS versus other high risk groups, such as siblings of children with ASD (ASIBs). Using the Autism Observation Scale for Infants, our findings indicate that 53 % of 12-month infants with FXS fall in the "at risk" category compared to 17 and 6 % for age-matched ASIBs and controls, respectively. Elevated atypical motor behaviors were associated with elevated risk for FXS. Cross-syndrome comparisons are essential to understanding the heterogeneity of ASD and identifying candidate markers that will facilitate differential diagnosis of ASD in genetic disorders such as FXS.

Trajectory and Predictors of Depression and Anxiety Disorders in Mothers With the FMR1 Premutation.

BACKGROUND: Although the FMR1 premutation is associated with elevated prevalence of psychiatric disorders, the longitudinal course of symptoms has not been established. The present study followed a sample of women with the FMR1 premutation to characterize the incidence, stability, and predictors of mood and anxiety disorders across a 3-year period. METHODS: Participants included 83 women with the FMR1 premutation (mean age = 38.35) who completed the Structured Clinical Interview for DSM-IV Axis I Disorders at two time points, 3 years apart. Additional information was obtained regarding demographic, child, and biomedical (e.g., medication, menopause, CGG repeats) factors. RESULTS: We found increased prevalence of major depressive disorder (MDD) and anxiety disorders over time, with adverse outcomes predicted by complex interactions among biological, behavioral, and environmental risk factors. Lifetime MDD increased from 46% to 54% and lifetime anxiety disorders increased from 28% to 35%. Midrange CGG repeats, elevated child problem behaviors, and divorced marital status conveyed elevated risk for psychiatric diagnoses. Primary ovarian insufficiency was highly prevalent (41%) but did not account for elevated rates of psychiatric diagnoses. Medication use was highly reported (41%), particularly in women with MDD or anxiety, with selective serotonin reuptake inhibitors reported as the most commonly used medication across diagnostic groups. CONCLUSIONS: The elevated prevalence of depression and anxiety in women with the FMR1 premutation is a clear and pressing concern given the frequent occurrence of the FMR1 premutation in the general community and the adverse outcomes-at both individual and systems levels-associated with psychiatric disorders in this population.

Developmental trajectories of attentional control in preschool males with fragile X syndrome.

Attention problems are among the most impairing features associated with fragile X syndrome (FXS). However, few studies have examined behavioral development of inhibitory control in very young children with FXS. We examined attentional control in 3-6 year boys with FXS using both an experimental inhibitory control paradigm and parent-report of attention problems. Study 1 examined attentional control in FXS compared to comparison groups matched on chronological and mental age. To determine the stability of impairments over time in FXS, Study 2 examined patterns of developmental change in an expanded longitudinal sample. Across studies, males with FXS demonstrated persistent impairments in inhibitory control and parent-reported attention problems. Inhibitory control was related to, but not solely driven by, lower mental age. Although parent-rated attention problems remained stable across ages, inhibitory control improved with time. Children with more severe attention problems often displayed initially poorer inhibitory control. However, these trajectories also improved more rapidly with age. Our findings indicate that despite persistent deficits in attentional control in young children with FXS, multi-method assessment can be used to capture developmental growth that should be further supported through early, targeted intervention.

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.

Temperament factor structure in fragile X syndrome: the children's behavior questionnaire.

Early patterns of temperament lay the foundation for a variety of developmental constructs such as self-regulation, psychopathology, and resilience. Children with fragile X syndrome (FXS) display unique patterns of temperament compared to age-matched clinical and non-clinical samples, and early patterns of temperament have been associated with later anxiety in this population. Despite these unique patterns in FXS and recent reports of atypical factor structure of temperament questionnaires in Williams Syndrome (Leyfer, John, Woodruff-Borden, & Mervis, 2012), no studies have examined the latent factor structure of temperament scales in FXS to ensure measurement validity in this sample. The present study used confirmatory factor analysis to examine the factor structure of a well-validated parent-reported temperament questionnaire, the Children's Behavior Questionnaire (Rothbart, Ahadi, Hershey, & Fisher, 2001), in a sample of 90 males with FXS ages 3-9 years. Our data produced a similar, but not identical, three-factor model that retained the original CBQ factors of negative affectivity, effortful control, and extraversion/surgency. In particular, our FXS sample demonstrated stronger factor loadings for fear and shyness than previously reported loadings in non-clinical samples, consistent with reports of poor social approach and elevated anxiety in this population. Although the original factor structure of the Children's Behavior Questionnaire is largely retained in children with FXS, differences in factor loading magnitudes may reflect phenotypic characteristics of the syndrome. These findings may inform future developmental and translational research efforts.

Biobehavioral indicators of social fear in young children with fragile X syndrome.

Anxiety is among the most impairing conditions associated with Fragile X syndrome (FXS) and is putatively linked to atypical physiological arousal. However, few studies have examined this association in young children with FXS. The authors examined whether patterns of arousal and behavior during an experimental stranger approach paradigm differ between a cross-sectional sample of 21 young children with FXS and 19 controls (12-58 months old). Groups did not differ in mean levels of behavioral fear. Unlike the control group, however, the FXS group demonstrated increased facial fear at older ages, as well as age-dependent changes in associations between heart activity and distress vocalizations. These findings may inform theoretical models of anxiety etiology in FXS and early detection efforts.

Early negative affect predicts anxiety, not autism, in preschool boys with fragile X syndrome.

Children with fragile X syndrome (FXS) face high risk for anxiety disorders, yet no studies have explored FXS as a high-risk sample for investigating early manifestations of anxiety outcomes. Negative affect is one of the most salient predictors of problem behaviors and has been associated with both anxiety and autistic outcomes in clinical and non-clinical pediatric samples. In light of the high comorbidity between autism and anxiety within FXS, the present study investigates the relationship between longitudinal trajectories of negative affect (between 8 and 71 months) and severity of anxiety and autistic outcomes in young males with FXS (n = 25). Multilevel models indicated associations between elevated anxiety and higher fear and sadness, lower soothability, and steeper longitudinal increases in approach. Autistic outcomes were unrelated to negative affect. These findings suggest early negative affect differentially predicts anxiety, not autistic symptoms, within FXS. Future research is warranted to determine the specificity of the relationship between negative affect and anxiety, as well as to explore potential moderators. Characterizing the relationship between early negative affect and anxiety within FXS may inform etiology and treatment considerations specific to children with FXS, as well as lend insight into precursors of anxiety disorders in other clinical groups and community samples.

Treatment effects of stimulant medication in young boys with fragile X syndrome.

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and is caused by a CGG repeat expansion at Xq27.3 on the FMR1 gene. The majority of young boys with FXS display poor attention and hyperactivity that is disproportionate to their cognitive disability, and approximately 70% meet diagnostic criteria for attention-deficit/hyperactivity disorder. Psychopharmacology is employed with 82% of young males 5-17 years of age, with stimulant medication as the most common medication prescribed. This study evaluated the effects of stimulant medication on the academic performance, attention, motor activity, and psychophysiological arousal of boys with FXS, as well as the concordance of effects within individuals. Participants in this study included 12 boys with FXS who were treated with stimulants. Participants completed videotaped academic testing on two consecutive days and were randomly assigned to be off stimulants for 1 day and on stimulants the other day. On each day, multiple measures including academic performance, behavior regulation, and psychophysiological arousal were collected. Approximately 75% of participants performed better on attention and academic measures, and 70% showed improved physiological regulation while on stimulant medication. A high degree of concordance among measures was found. Lower intelligence quotient (IQ), but not age, correlated with greater improvements in in-seat behavior. IQ and age did not relate to on-task behaviors. The frequency and magnitude of response to stimulant medication in boys with FXS is higher than those reported for most children with non-specific intellectual disabilities and autism spectrum disorder.