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Purpose: Cluttering is a fluency disorder that has been noted clinically in individuals with fragile X syndrome (FXS). Yet, cluttering has not been systematically characterized in this population, hindering identification and intervention efforts. This study examined the rates of cluttering in male young adults with FXS using expert clinical opinion, the alignment between expert clinical opinion and objectively quantified features of cluttering from language transcripts, and the association between cluttering and aspects of the FXS phenotype. Method: Thirty-six men with FXS (aged 18–26 years; M = 22, SD = 2.35) contributed language samples and completed measures of nonverbal cognition, autism symptoms, anxiety, and symptoms of attention-deficit/hyperactivity disorder (ADHD). The presence of cluttering was determined by the consensus of two clinical experts in fluency disorders based on characteristics exhibited in the language sample. Cluttering features (speech rate, disfluencies, etc.) were also objectively quantified from the language transcripts. Results: Clinical experts determined that 50% of participants met the criteria for a cluttering diagnosis. Phrase repetitions were the most salient feature that distinguished individuals who cluttered. Although the presence of cluttering was not associated with autism symptoms or mean length of utterance, cluttering was more likely to occur when nonverbal cognitive ability was higher, ADHD symptoms were elevated, and anxiety symptoms were low. Conclusions: Half of the male young adults with FXS exhibited cluttering, which supports FXS as a genetic diagnosis that is highly enriched for risk of cluttering. Cluttering was associated with increased ADHD symptoms and cognitive ability and reduced anxiety symptoms. This study contributes a new description of the clinical presentation of cluttering in men with FXS and may lead to improved understanding of the potential underlying mechanisms of cluttering and eventual refinements to treatment and diagnosis.

By adulthood, most males with fragile X syndrome (FXS) require support to navigate day-to-day settings. The present study cross-sectionally: (1) characterized the profile of daily living skills in males with FXS and (2) examined associated participant characteristics (i.e., fragile X mental retardation protein [FMRP] expression, nonverbal cognition, language, autism symptomatology, and anxiety symptomatology) using the Waisman-Activities of Daily Living questionnaire. Males with FXS (n = 57, ages 15–23 years) needed more help/support in the areas of domestic and community daily livings skills, than in the area of personal daily living skills. Significant associations were observed between reduced daily living skills and lower nonverbal cognition, receptive language, expressive language, and increased autism symptomatology. Receptive language emerged as the strongest unique predictor of daily living skill performance.

Purpose: This study examined relationships among family characteristics, caregiver change in use of strategies, and child growth in spoken language over the course of a parent-implemented language intervention (PILI) that was developed to address some of the challenges associated with the fragile X syndrome (FXS) phenotype. Method: Participants were 43 parent–child dyads from two different PILI studies, both of which taught parents various language facilitation strategies to support child language. Before starting the intervention, parents reported on their mental health, parenting stress, and parenting competence. This study focused on potential barriers to treatment gains by examining correlations between the measures of parent well-being and (a) parent change in use of intervention strategies taught in the PILI and (b) changes in child language outcomes from pre- to post-intervention. Results: Parents in this study had elevated mental health symptoms across several domains and increased rates of parenting stress. Furthermore, although PILI resulted in treatment gains for both parents and children, a variety of parent mental health symptoms were found to be significantly and negatively associated with change in use of strategies and growth in child language over the course of the intervention. Some inconsistent findings also emerged regarding the relationships between parenting stress and competence and change in parent strategy use and growth in child language. Conclusions: This study provides preliminary evidence that parents who are experiencing significant mental health challenges may have a more difficult time participating fully in PILIs and that there may be subsequent effects on child outcomes. Future PILIs could benefit from addressing parent well-being as a substantial part of the intervention program.

Broader phenotypes associated with genetic liability, including mild difficulties with pragmatic language skills, have been documented in mothers of children with autism spectrum disorder (ASD) and mothers of children with fragile X syndrome (FXS). This study investigated the relationship between pragmatic difficulties and indicators of maternal well-being and family functioning. Pragmatic difficulty was associated with loneliness in mothers of children with ASD or FXS, and with depression, decreased life satisfaction, and poorer family relationship quality in mothers of children with FXS only. Results inform subtle maternal pragmatic language difficulties as a risk factor that that may contribute to reduced health and well-being, informing tailored support services to better meet the unique needs of families of children with ASD or FXS.

Background There is substantial variability in adaptive skills among individuals with Down syndrome. Few studies, however, have focused on the early developmental period or on the potential sources of variability in adaptive skills. This study characterizes adaptive skills in young children with Down syndrome and investigates child characteristics associated with adaptive skills. Methods Participants were 44 children with Down syndrome ranging in age from 2.50 to 7.99 years (M = 4.66 years, SD = 1.46). The Vineland Adaptive Behavior Scales-3 (VABS-3) Comprehensive Interview Form was used to assess adaptive behavior in the three core domains: socialization, daily living, and communication skills. Caregivers also reported on motor skills and autism spectrum disorder symptoms. Child cognitive abilities were assessed. Results Analyses comparing mean standard score performance across the three VABS-3 core domains demonstrated significant differences between all pairs of domains, resulting in a group-level pattern of socialization > daily living > communication skills. At the individual level, 10 different patterns of relative strength and weakness were identified, with only 18% of participants evidencing significant differences between adaptive skill domain standard scores corresponding to the group-level pattern of significant differences. Child characteristics (cognitive abilities, motor skills, and autism spectrum disorder symptoms) were significantly associated with VABS-3 adaptive domain standard scores. Conclusion These findings underscore the importance of individualizing intervention programs focused on improving the adaptive skills of young children with Down syndrome based on consideration of the child’s relative adaptive strengths and weaknesses.

There is a need for psychometrically sound outcome measures for treatment studies that have a low burden for families and that are available in multiple languages. We have developed a language assessment in English and Spanish that parents can administer to their children at home via telehealth-delivered procedures. The current case study presents descriptive data on a single family of two parent-child dyads. Both the mother and father from a single family were trained in their primary language (Spanish) on how to administer the Expressive Language Sampling - Narration (ELS-N) in their secondary language (English) to their two English-speaking monolingual sons with ASD through telehealth-delivered procedures. Both parents learned to administer the procedures to a predetermined level of fidelity. Extension to a larger sample of bilingual families is needed for this home-based, parent-administered test; however, the present results suggest feasibility even when the language of training and administration differ.

BackgroundIt is well known that individuals with Down syndrome (DS) or fragile X syndrome (FXS) demonstrate expressive language difficulties beginning early in childhood. It is less clear, however, whether expressive language skills change during the adolescent period in these individuals, and if any of these changes are syndrome specific. Studying this, as well as the role of maternal and family-related factors in expressive language development, may provide the foundation for efficacious interventions for adolescents with DS or FXS.MethodsIn this study, we examined expressive language trajectories, assessed through conversation and narration, in 57 adolescent males with intellectual disability (ID) (20 DS and 37 FXS) in relation to the diagnostic group (DS vs. FXS) and family-related factors (maternal IQ, maternal psychological distress, closeness in the mother–child relationship, family income, and maternal and paternal education) after adjusting for chronological age (CA) and nonverbal cognition.ResultsChanges over repeated annual assessments for males with DS or FXS were observed only during conversation, such as an increase in talkativeness, but a decrease in syntax complexity and lexical diversity. We found a diagnosis-related effect in the change over time in conversational talkativeness favoring those with FXS. Finally, a closer mother–child relationship predicted less decrease over time in lexical diversity during conversation, and participants of mothers who graduated college showed a greater increase in conversational talkativeness over time compared to those of mothers with a high school education.ConclusionsOur results suggest that, during the adolescent period for males with DS or FXS, there is an increase in the amount of talk produced in conversational contexts, but also a decrease in the quality of the language produced. In addition, our results indicate syndrome-specificity for aspects of expressive language development and reinforce the protective role of family-related factors.

Language impairments are frequent, severe, and of prognostic value in autism spectrum disorder (ASD). Unfortunately, the evaluation of the efficacy of treatments targeting the language skills of those with ASD continues to be hindered by a lack of psychometrically sound outcome measures. Expressive Language Sampling (ELS) procedures offer a promising alternative to norm-referenced standardized tests for assessing expressive language in treatment studies. Until now, however, research on the validity and utility of ELS as outcome measures has been limited to administrations by a trained professional in a clinic setting and to use with English-speaking families. These limitations are a barrier for many families accessing the benefits of participation in treatment studies. The current study examines the feasibility of teaching native English-speaking parents (NESP) and native Spanish-speaking parents (NSSP) how to administer the ELS narrative task (ELS-N) to their sons and daughters with ASD (between ages 6 and 21) at home through telehealth-delivered procedures. The parent training was provided in the primary language of the participating parent (i.e., 11 NSSP and 11 NESP) and administered by the parent to the youth in the language that the parent reported to use to communicate with the youth at home (i.e., 9 Spanish and 13 English). Families were able to choose between using their own technology or be provided with the technology needed for participation. Of the 19 parents who completed the training, 16 learned to administer the ELS-N procedures. In addition, strong test-retest reliability and no practice effects over the 4-week interval were observed for ELS-N derived youth outcome measures (i.e., talkativeness, vocabulary, syntax, dysfluency, and intelligibility) for both NSSP and NESP. Results from this pilot study suggest that the home-based parent-implemented ELS-N procedures can be learned and administered at acceptable levels of fidelity by parents, with good test-retest reliability and limited practice effects observed in terms of outcome measures for youth with ASD. Implications for treatment studies and future directions are discussed.

Introduction: Fragile X syndrome (FXS) is a genetic disorder caused by a mutation of the fragile X mental retardation 1 gene (FMR1). FXS is associated with neurophysiological abnormalities, including cortical hyperexcitability. Alterations in electroencephalogram (EEG) resting-state power spectral density (PSD) are well-defined in FXS and were found to be linked to neurodevelopmental delays. Whether non-linear dynamics of the brain signal are also altered remains to be studied.Methods: In this study, resting-state EEG power, including alpha peak frequency (APF) and theta/beta ratio (TBR), as well as signal complexity using multi-scale entropy (MSE) were compared between 26 FXS participants (ages 5–28 years), and 77 neurotypical (NT) controls with a similar age distribution. Subsequently a replication study was carried out, comparing our cohort to 19 FXS participants independently recorded at a different site.Results: PSD results confirmed the increased gamma, decreased alpha power and APF in FXS participants compared to NT controls. No alterations in TBR were found. Importantly, results revealed reduced signal complexity in FXS participants, specifically in higher scales, suggesting that altered signal complexity is sensitive to brain alterations in this population. The replication study mostly confirmed these results and suggested critical points of stagnation in the neurodevelopmental curve of FXS.Conclusion: Signal complexity is a powerful feature that can be added to the electrophysiological biomarkers of brain maturation in FXS.

Across all ages, individuals with Down syndrome (DS) experience high rates of sleep problems as well as cognitive impairments. This study sought to investigate whether circadian rhythm disruption was also experienced by people with DS and whether this kind of sleep disorder may be correlated with cognitive performance. A cross-sectional study of 101 participants (58 with DS, 43 with typical development) included individuals in middle childhood (6–10 years old), adolescence (11–18 years old), and young adulthood (19–26 years old). Sleep and markers of circadian timing and robustness were calculated using actigraphy. Cognitive and behavioral data were gathered via a novel touchscreen battery (A-MAPTM, Arizona Memory Assessment for Preschoolers and Special Populations) and parent questionnaire. Results indicated that children and adolescents with DS slept the same amount as peers with typical development, but significant group differences were seen in phase timing. The circadian robustness markers, interdaily stability and intradaily variability of sleep-wake rhythms, were healthiest for children regardless of diagnostic group and worst for adults with DS. Amplitude of the 24-h activity profile was elevated for all individuals with DS. In analyses of the correlations between sleep quality, rhythms, and cognition in people with DS, interdaily stability was positively correlated with reaction time and negatively correlated with verbal and scene recall, a finding that indicates increased stability may paradoxically correlate with poorer cognitive outcomes. Further, we found no relations with sleep efficiency previously found in preschool and adult samples. Therefore, the current findings suggest that a thorough examination of sleep disorders in DS must take into account age as well as circadian robustness to better understand sleep-cognitive correlations in this group.

Background. Few individuals with fragile X syndrome (FXS) successfully meet adult normative expectations in education, employment, peer relations, and habitation, although there is within-syndrome variability in this regard. The primary goal of this study was to determine whether expressive language skills contribute to the capacity for independent functioning in adulthood even after controlling for nonverbal cognitive ability. Methods. Participants were 18- to 23-year-olds with FXS. Expressive language was assessed using the psychometrically validated Expressive Language Sampling (ELS) conversation and narration procedures. The language produced was transcribed and analyzed to yield measures of expressive vocabulary, syntax, and intelligibility. Parents concurrently completed questionnaires on the independent functioning of the participants with FXS. Results. All three ELS measures were significantly corelated with multiple measures of independence. The magnitudes of the correlations were reduced when nonverbal IQ was controlled through partial correlation. Nonetheless, many of the partial correlations were medium to large and several were statistically significant. Conclusions. Expressive language skills appear to contribute uniquely to the capacity for independence, although longitudinal data are needed to evaluate the possibility of a bidirectional relationship between these domains. Thus, language intervention may be a prerequisite for preparing youth with FXS for an independent adult life.

Children with Down syndrome (DS) are at risk for challenges with aspects of executive function (EF). The current study explores whether heterogeneity in EF profiles can be detected within a sample of children with DS. Participants were 69 children with DS, ages 3–10 years (M = 6.23, SD = 1.91). T-scores from a caregiver-report measure of executive function were modeled using latent profile analysis, and auxiliary analyses examined the association between demographic and biomedical factors and probability of profile membership. The two-profile solution was the best fit for the sample, with a profile that involved elevated scores in working memory only (“Working Memory Only” profile; 43% of sample) and a “Multi-Domain” profile that involved elevated scores in planning, inhibition, and working memory (57%). The presence of congenital heart defects was associated with a higher probability of assignment to the Multi-Domain profile. Findings from this study contribute to the characterization of heterogeneous outcomes associated with DS.

Establishing expressive language benchmarks (ELBs) for children with Down syndrome (DS), as developed by Tager-Flusberg et al. for children with autism, is critically needed to inform the development of novel treatments, identify individualized treatment targets, and promote accurate monitoring of progress. In the present study, we assessed ELB assignments in three language domains (phonology, vocabulary, and grammar) for 53 young children with DS (CA range: 2.50–7.99 years) using standardized assessments. The participants were classified into one of four ELB levels (preverbal, first words, word combinations, and sentences) in each language domain. Associations with additional measures of language, chronological age, nonverbal cognition, and verbal short-term memory were considered. Analyses of individual ELB profiles indicated substantial variability across the three language domains, with six different patterns of variation across domains emerging. At the same time, the ELB categories were significantly associated with independent language measures and broader developmental domains. Moreover, ELB changes were observed in a small sample of children with DS reassessed 18–24 months after the initial visit. Results from the present study suggest the procedures outlined by Tager-Flusberg et al. for defining ELBs are a potentially useful tool for describing the language abilities of children with DS.

Background Women who carry a premutation allele of the FMR1 gene are at increased vulnerability to an array of age-related symptoms and disorders, including age-related decline in select cognitive skills. However, the risk factors for age-related decline are poorly understood, including the potential role of family history and genetic factors. In other forms of pathological aging, early decline in syntactic complexity is observed and predicts the later onset of neurodegenerative disease. To shed light on the earliest signs of degeneration, the present study characterized longitudinal changes in the syntactic complexity of women with the FMR1 premutation across midlife, and associations with family history of fragile X-associated tremor/ataxia syndrome (FXTAS) and CGG repeat length. Methods Forty-five women with the FMR1 premutation aged 35–64 years at study entry participated in 1–5 longitudinal assessments spaced approximately a year apart (130 observations total). All participants were mothers of children with confirmed fragile X syndrome. Language samples were analyzed for syntactic complexity and participants provided information on family history of FXTAS. CGG repeat length was determined via molecular genetic testing. Results Hierarchical linear models indicated that women who reported a family history of FXTAS exhibited faster age-related decline in syntactic complexity than those without a family history, with that difference emerging as the women reached their mid-50 s. CGG repeat length was not a significant predictor of age-related change. Conclusions Results suggest that women with the FMR1 premutation who have a family history of FXTAS may be at increased risk for neurodegenerative disease, as indicated by age-related loss of syntactic complexity. Thus, family history of FXTAS may represent a personalized risk factor for age-related disease. Follow-up study is needed to determine whether syntactic decline is an early indicator of FXTAS specifically, as opposed to being a more general age-related cognitive decline associated with the FMR1 premutation.

BackgroundThe purpose of this study was to evaluate expressive language sampling (ELS) as a procedure for generating spoken language outcome measures for treatment research in Down syndrome (DS). We addressed (a) feasibility, (b) practice effects across two short-term administrations, (c) test-retest reliability across two short-term administrations, (d) convergent and discriminant construct validity, and (e) considered comparisons across the conversation and narration contexts.MethodParticipants were 107 individuals with DS between 6 and 23 years of age who presented with intellectual disability (IQ < 70). The utility of ELS procedures designed to collect samples of spoken language in conversation and narration were evaluated separately. Variables of talkativeness, vocabulary, syntax, utterance planning, and articulation quality, derived from transcripts segmented into C-units (i.e., an independent clause and its modifiers), were considered. A 4-week interval was used to assess practice effects and test-retest reliability. Standardized direct assessments and informant report measures were collected to evaluate construct validity of the ELS variables.ResultsLow rates of noncompliance were observed; youth who were under 12 years of age, had phrase-level speech or less, and had a 4-year-old developmental level or less were at particular risk for experiencing difficulty completing the ELS procedures. Minimal practice effects and strong test-retest reliability across the 4-week test-retest interval was observed. The vocabulary, syntax, and speech intelligibility variables demonstrated strong convergent and discriminant validity. Although significant correlations were found between the variables derived from both the conversation and narration contexts, some differences were noted.ConclusionThe ELS procedures considered were feasible and yielded variables with adequate psychometric properties for most individuals with DS between 6 and 23 years old. That said, studies of outcome measures appropriate for individuals with DS with more limited spoken language skills are needed. Context differences were observed in ELS variables suggest that comprehensive evaluation of expressive language is likely best obtained when utilizing both contexts.

In the present study, language performance on standardized assessments (e.g., overall verbal performance, receptive and expressive vocabulary) and spontaneous language produced in play was compared between preschool-aged boys with autism spectrum disorder ((n)ASD, n = 25) and boys with fragile X syndrome (FXS, n = 16). At the group-level, we observed weaknesses in the language skills of boys with (n)ASD relative to those with FXS (e.g., when considering raw score performance, standard score performance relative to nonverbal cognitive skills, frequency of talk in play), after controlling for nonverbal IQ and ASD symptom severity. Moreover, although individually most children in both groups demonstrated language delays relative to CA-expectations, language delays relative to nonverbal level-expectations were more common in boys with (n)ASD.

Background The purpose of this study was to conduct a 20-week controlled trial of lovastatin (10 to 40 mg/day) in youth with fragile X syndrome (FXS) ages 10 to 17 years, combined with an open-label treatment of a parent-implemented language intervention (PILI), delivered via distance video teleconferencing to both treatment groups, lovastatin and placebo. Method A randomized, double-blind trial was conducted at one site in the Sacramento, California, metropolitan area. Fourteen participants were assigned to the lovastatin group; two participants terminated early from the study. Sixteen participants were assigned to the placebo group. Lovastatin or placebo was administered orally in a capsule form, starting at 10 mg and increasing weekly or as tolerated by 10 mg increments, up to a maximum dose of 40 mg daily. A PILI was delivered to both groups for 12 weeks, with 4 activities per week, through video teleconferencing by an American Speech-Language Association-certified Speech-Language Pathologist, in collaboration with a Board-Certified Behavior Analyst. Parents were taught to use a set of language facilitation strategies while interacting with their children during a shared storytelling activity. The main outcome measures included absolute change from baseline to final visit in the means for youth total number of story-related utterances, youth number of different word roots, and parent total number of story-related utterances. Results Significant increases in all primary outcome measures were observed in both treatment groups. Significant improvements were also observed in parent reports of the severity of spoken language and social impairments in both treatment groups. In all cases, the amount of change observed did not differ across the two treatment groups. Although gains in parental use of the PILI-targeted intervention strategies were observed in both treatment groups, parental use of the PILI strategies was correlated with youth gains in the placebo group and not in the lovastatin group. Conclusion Participants in both groups demonstrated significant changes in the primary outcome measures. The magnitude of change observed across the two groups was comparable, providing additional support for the efficacy of the use of PILI in youth with FXS. Trial registration US National Institutes of Health (ClinicalTrials.gov), NCT02642653. Registered 12/30/2015.

BackgroundThe evaluation of treatment efficacy for individuals with fragile X syndrome (FXS) or intellectual disability (ID) more generally has been hampered by the lack of adequate outcome measures. We evaluated expressive language sampling (ELS) as a procedure for generating outcome measures for treatment research in FXS. We addressed: (a) feasibility, (b) practice effects over two administrations, (c) test-retest reliability over the repeated administrations, and (d) construct validity. We addressed these issues for the full sample as well as for subgroups defined by age, IQ, and ASD status.MethodsParticipants were 106 individuals with FXS between ages 6 and 23 years who had IQs within the range of intellectual disability (IQ< 70). ELS procedures for collecting samples in conversation and narration were followed and analyzed separately. Five measures were derived from transcripts segmented into C-units (i.e., an independent clause and its modifiers): number of C-units per minute (talkativeness), number of different word roots (vocabulary), C-unit length in morphemes (syntax), percentage of C-units containing dysfluency (utterance planning), and percentage of C-units that were fully or partly unintelligible (articulatory quality). ELS procedures were administered twice at 4-week intervals for each participant. Standardized tests and informant reports were administered and provided measures for evaluating construct validity of ELS measures.ResultsWe found low rates of noncompliance, suggesting the task can be completed meaningfully by most individuals with FXS, although noncompliance was higher for younger, lower IQ, and more autistic participants. Minimal practice effects and strong test-retest reliability over the 4-week interval were observed for the full sample and across the range of ages, IQs, and autism symptom severity. Evidence of convergent construct validity was observed for the measures of vocabulary, syntax, and unintelligibility for the full sample and across the range of IQ and autism symptom severity, but not for participants under age 12. Conversation and narration yielded largely similar results in all analyses.ConclusionsThe findings suggest that the ELS procedures are feasible and yield measures with adequate psychometric properties for a majority of 6 to 23 years with FXS who have ID. The procedures work equally well regardless of level of ID or degree of ASD severity. The procedures, however, are more challenging and have somewhat less adequate psychometric properties for individuals with FXS under age 12.

Fragile X syndrome is the most common inherited intellectual disability and monogenic cause of autism spectrum disorder. Expressive language deficits, especially in speech production, are nearly ubiquitous among individuals with fragile X, but understanding of the neurological bases for these deficits remains limited. Speech production depends on feedforward control and the synchronization of neural oscillations between speech-related areas of frontal cortex and auditory areas of temporal cortex. Interaction in this circuitry allows the corollary discharge of intended speech generated from an efference copy of speech commands to be compared against actual speech sounds, which is critical for making adaptive adjustments to optimize future speech. We aimed to determine whether alterations in coherence between frontal and temporal cortices prior to speech production are present in individuals with fragile X and whether they relate to expressive language dysfunction. Twenty-one participants with full-mutation fragile X syndrome (aged 7–55 years, eight females) and 20 healthy controls (matched on age and sex) completed a talk/listen paradigm during high-density EEG recordings. During the talk task, participants repeated pronounced short vocalizations of ‘Ah’ every 1–2 s for a total of 180 s. During the listen task, participants passively listened to their recordings from the talk task. We compared pre-speech event-related potential activity, N1 suppression to speech sounds, single trial gamma power and fronto-temporal coherence between groups during these tasks and examined their relation to performance during a naturalistic language task. Prior to speech production, fragile X participants showed reduced pre-speech negativity, reduced fronto-temporal connectivity and greater frontal gamma power compared to controls. N1 suppression during self-generated speech did not differ between groups. Reduced pre-speech activity and increased frontal gamma power prior to speech production were related to less intelligible speech as well as broader social communication deficits in fragile X syndrome. Our findings indicate that coordinated pre-speech activity between frontal and temporal cortices is disrupted in individuals with fragile X in a clinically relevant way and represents a mechanism contributing to prominent speech production problems in the disorder., Using high-density EEG during speech production, we demonstrate reduced fronto-temporal connectivity and elevated frontal gamma power prior to speech onset in individuals with fragile X syndrome, alterations associated with less intelligible speech. Thus, disrupted pre-speech activity interferes with corollary discharge processes, ultimately contributing to speech production deficits in fragile X syndrome., Graphical Abstract Graphical Abstract

Many males with FXS meet criteria for ASD. This study was designed to (1) describe ASD symptoms in adolescent and young adult males with FXS (n = 44) and (2) evaluate the contributions to ASD severity of cognitive, language, and psychiatric factors, as well as FMRP (the protein deficient in FXS). A few ASD symptoms on the ADOS-2 were universal in the sample. There was less impairment in restricted and repetitive behaviors (RRB) than in the social affective (SA) domain. The best predictor of overall ASD severity and SA severity was expressive syntactic ability. RRB severity was best predicted by the psychiatric factors. Implications for clinical practice and for understanding the ASD comorbidity in FXS are discussed.

There is a growing body of evidence to suggest that individuals with Down syndrome (DS) are diagnosed with autism spectrum disorders (ASD) at a higher rate than individuals in the general population. Nonetheless, little is known regarding the unique presentation of ASD symptoms in DS. The current study aims to explore the prevalence and profiles of ASD symptoms in a sample of individuals with DS (n = 83), aged between 6 and 23 years. Analysis of this sample (MAge = 15.13) revealed that approximately 37% of the sample met the classification cut-off for ASD using the Autism Diagnostic Observation Schedule 2 (ADOS-2) Calibrated Severity Score (CSS), an indicator of the participants’ severity of ASD-related symptoms. Item-level analyses revealed that multiple items on Module 2 and Module 3 of the ADOS-2, mostly in the Social Affect (SA) subdomain, differentiated the children with DS who did not meet ASD classification (DS-only) from those who did (DS + ASD). Lastly, comparisons of individuals with DS-only and those with DS + ASD differed significantly on the syntactic complexity of their expressive language. These findings shed light on the unique presentation of ASD symptoms in a sample of individuals with DS and suggest that expressive language abilities may play a pivotal role in the presentation of ASD symptoms in DS.

Purpose This study used a prospective longitudinal design to evaluate the trajectory and predictors of noncomprehension signaling in male and female youth with fragile X syndrome (FXS). Method A direction-following task in which some of the directions were inadequate was administered. Participants were 52 youth (36 boys, 16 girls) with FXS. Upon study entry, participants ranged from 10 to 16 years. The average number of annual assessments per participant was 3.65 (range = 1–4), providing 198 data points for analysis. Results Participants with FXS were less likely to signal noncomprehension than younger, typically developing, cognitively matched children. The average rate of change in noncomprehension signaling was not significantly different from 0 for either boys or girls, suggesting a plateau. Both FMRP and nonverbal IQ were significant independent predictors of noncomprehension signaling for boys. Variability in noncomprehension signaling among girls was not explained by any of the predictors, but trends similar to those observed for boys were observed. Conclusions Noncomprehension signaling appears to be an area of weakness for individuals with FXS. Because the failure to signal noncomprehension can have negative, cumulative effects on comprehension, the results suggest a need for interventions targeting the requisite cognitive skills.

Despite the similarities observed between the fragile X syndrome (FXS) and autism spectrum disorder (ASD) phenotypes, few studies have compared their behavioral profiles outside of ASD symptomatology. In the present study, we sought to compare lexical and grammatical abilities in these two conditions. Comparisons of language abilities in both of these conditions are particularly interesting because both conditions are characterized by difficulties navigating social interactions. Results suggest that although both FXS and ASD are associated with language difficulties, there are important differences between the two conditions in terms of the language profiles observed and the factors influencing language when considering children of similar developmental levels. Theoretical implications are discussed.

Language impairment is a core difficulty in fragile X syndrome (FXS), and yet standardized measures lack the sensitivity to assess developmental changes in the nature of these impairments. Expressive Language Sampling Narrative (ELS-N) has emerged as a promising new measure with research demonstrating its usefulness in a wide range of ages in developmental disabilities and typical development. We examined ELS-N results in FXS and age-matched typically developing (TD) controls along with cognitive, adaptive, and clinical measures. We found the groups differed significantly on all ELS-N variables. Cognitive abilities were related to lexical diversity, syntactic complexity, and unintelligibility for the FXS group, but only verbal abilities were related to syntactic complexity in TD. Autism spectrum disorder (ASD) symptomatology was related to less intelligibility in speech. Measures of hyperactivity were related to increased talkativeness and unintelligibility. In addition, FXS males in comparison to FXS females were more impaired in cognitive ability, ASD symptoms, hyperactivity, and anxiety. This study extends the previous ELS research, supporting its use in FXS research as a measure to characterize language abilities. It also demonstrates the relationships between ELS-N variables and measures of cognitive, adaptive, ASD symptoms, and clinical symptoms.

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.

Background Fragile X syndrome (FXS) is caused by a mutation in the FMR1 gene on the X chromosome, leading to decreased levels of FMR1 protein (FMRP), which causes the array of neuropsychological impairments that define FXS. Because FXS is an X-linked condition, fewer females display FXS and females with FXS are more mildly affected than males, on average. However, there is a considerable variability in terms of severity of affectedness among females with FXS. The current study was designed to investigate potential genetic (FMRP level and ratio of affected to total chromosomes) and environmental factors (maternal psychological distress and closeness in the mother–child relationship) influencing the cognitive (fluid and crystallized intelligence) and behavioral (anxiety and withdrawal) phenotype of females with FXS. Methods We conducted a prospective 3-year longitudinal study of 16 females with FXS (with up to four assessments, each separated by a year) using an accelerated longitudinal design so that we had coverage of the age range of 10–15 years at study start and 13–18 at study end. We focused on both the level of functioning related to chronological age expectations (standard scores) and absolute change in skill (raw scores) over the 3-year period. Results At a cross-sectional level, fluid intelligence and crystallized intelligence were both predicted by a closer mother–child relationship and lower maternal psychological distress. However, only fluid intelligence was predicted by a lower ratio of affected to total chromosomes. Anxiety and withdrawal were predicted by a higher ratio of affected to total chromosomes. Withdrawal was also predicted by lower closeness in the mother–child relationship and higher maternal distress. In terms of longitudinal change, gains were observed in fluid and crystallized intelligence, whereas anxious and withdrawn behaviors remained stable over visits. Gains in fluid intelligence were solely predicted by FXS biomarkers (higher FMRP level and lower ratio of affected to total chromosomes), while gains in crystallized intelligence were not predicted by any of the biological and environmental variables. Conclusions Our results show that FXS biomarkers and maternal variables contribute differentially to the cognitive and behavioral features of the adolescent female with FXS. These findings can help in the design of treatment studies aimed at enhancing cognitive and behavioral abilities in the FXS population.

Despite the shared presence of an intellectual disability (ID), there is a growing literature documenting important phenotypic differences between Down syndrome (DS) and fragile X syndrome (FXS). These conclusions, however, are based on a synthesis across studies, each of which typically includes only measures of a limited number of constructs, and with differing participant characteristics. Firmer conclusions regarding specific phenotypes require a single comprehensive multi-domain assessment of participants with the syndrome groups being well matched on chronological age (CA) and cognitive functioning. The current study was designed to fill this gap by assessing several important cognitive and behavioral domains relevant to communication, such as: structural language skills, false belief understanding, as well as pragmatics and behavioral difficulties, in 30 adolescents of both sexes with DS and 39 males with FXS, matched on CA and nonverbal (NV) cognition. After statistically controlling for NV cognition, we did not find significant syndrome differences in expressive and receptive structural language or false belief understanding. In contrast, participants with DS displayed less stereotyped language and fewer behavioral difficulties compared to males with FXS. Within-syndrome associations among the targeted domains are described. Finally, females with DS were less impaired than males with DS in almost all structural language domains, whereas no significant sex-related differences were observed in NV cognition, false belief understanding, pragmatics, or behavior. Clinical and methodological implications of the findings are discussed.

This study examined the impact of a distance-delivered parent-implemented narrative language intervention on the use of inferential language during shared storytelling by school-aged boys with fragile X syndrome, an inherited neurodevelopmental disorder. Nineteen school-aged boys with FXS and their biological mothers participated. Dyads were randomly assigned to an intervention or a treatment-as-usual comparison group. Transcripts from all pre- and post-intervention sessions were coded for child use of prompted and spontaneous inferential language coded into various categories. Children in the intervention group used more utterances that contained inferential language than the comparison group at post-intervention. Furthermore, children in the intervention group used more prompted inferential language than the comparison group at post-intervention, but there were no differences between the groups in their spontaneous use of inferential language. Additionally, children in the intervention group demonstrated increases from pre- to post-intervention in their use of most categories of inferential language. This study provides initial support for the utility of a parent-implemented language intervention for increasing the use of inferential language by school aged boys with FXS, but also suggests the need for additional treatment to encourage spontaneous use.

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.

In the present study, we examined the profile of psychiatric symptoms in boys with fragile X syndrome (FXS) using a parent report instrument. In addition, by comparing boys with FXS to boys with nonsyndromic autism spectrum disorder (ASD) utilizing multiple matching strategies, we examined between-group differences in the types of psychiatric symptoms observed and in the strength of their concurrent associations. Across all matching strategies, symptoms of manic/hyperactive behaviors and general anxiety were more frequently reported for boys with FXS than for boys with nonsyndromic ASD. Results also indicated a positive association between social avoidance and general anxiety in FXS that was stronger than that observed in nonsyndromic ASD across all matching strategies. Theoretical and treatment implications are discussed.

Symptoms of autism are frequent in males with fragile X syndrome (FXS), but it is not clear whether symptom profiles differ from those of nonsyndromic ASD. Using individual item scores from the Autism Diagnostic Inventory-Revised (ADI-R), we examined which current symptoms of autism differed in boys with FXS relative to same-aged boys diagnosed with nonsyndromic ASD. In addition, different subsamples of participants were matched on autism diagnostic status and severity of autism symptoms. Between-group comparisons revealed that boys with FXS showed significantly less impairment in Social Smiling than did age-, diagnostic, and severity-matched boys with nonsyndromic ASD. Severity-matched boys with FXS showed more impairment in Complex Mannerisms than did boys with nonsyndromic ASD. Behavioral differences between FXS and nonsyndromic ASD may be of theoretical importance in understanding the causes and correlates of ASD in FXS and in developing and implementing appropriate treatments.

The present study evaluated the ability of males with fragile X syndrome (FXS), nonsyndromic autism spectrum disorder (ASD), or typical development to learn new words by using as a cue to the intended referent an emotional reaction indicating a successful (excitement) or unsuccessful (disappointment) search for a novel object. Performance for all groups exceeded chance-levels in both search conditions. In the Successful Search condition, participants with nonsyndromic ASD performed similarly to participants with FXS after controlling for severity of ASD. In the Unsuccessful Search condition, participants with FXS performed significantly worse than participants with nonsyndromic ASD, after controlling for severity of ASD. Predictors of performance in both search conditions differed between the three groups. Theoretical and clinical implications are discussed.

Purpose This study examined use of a speaker's direction of gaze during word learning by boys with fragile X syndrome (FXS), boys with nonsyndromic autism spectrum disorder (ASD), and typically developing (TD) boys. Method A fast-mapping task with follow-in and discrepant labeling conditions was administered. We expected that the use of speaker gaze would lead to participants selecting as the referent of the novel label the object to which they attended in follow-in trials and the object to which the examiner attended in the discrepant labeling trials. Participants were school-aged boys with FXS ( n = 18) or ASD ( n = 18) matched on age, intelligence quotient, and nonverbal cognition and younger TD boys ( n = 18) matched on nonverbal cognition. Results All groups performed above chance in both conditions, although the TD boys performed closest to the expected pattern. Boys with FXS performed better during follow-in than in discrepant label trials, whereas TD boys and boys with ASD did equally well in both trial types. The type of trial administered first influenced subsequent responding. Error patterns also distinguished the groups. Conclusion The ability to utilize a speaker's gaze during word learning is not as well developed in boys with FXS or nonsyndromic ASD as in TD boys of the same developmental level.

This study was designed to examine longitudinal change in nonverbal cognitive abilities across adolescence for 20 males with Down syndrome (DS). We used hierarchical linear modeling to examine the rate of change in performance on the subtests of the Leiter-R Brief IQ across four annual time points and to determine the relation between maternal IQ and level and rate of change in performance. Results indicated no significant change in IQ (standard scores) with age in the sample, suggesting IQ stability during adolescence for individuals with DS, although several participants performed at floor level on the standard scores for the Leiter-R, limiting interpretation. Growth scores, however, provide a metric of absolute ability level, allow for the examination of change in Leiter-R performance in all participants, and minimize floor effects. Results from the analysis of growth scores indicated significant gain in absolute nonverbal cognitive ability levels (growth score values) over time for the adolescents with DS, although the growth varied by subdomain. Maternal IQ did not explain variability in cognitive performance or change in that performance over time in our sample of adolescents with DS.

Autism spectrum disorder (ASD) is a common comorbid condition in people with fragile X syndrome (FXS). It has been assumed that ASD symptoms reflect the same underlying psychological and neurobiological impairments in both FXS and non-syndromic ASD, which has led to the claim that targeted pharmaceutical treatments that are efficacious for core symptoms of FXS are likely to be beneficial for non-syndromic ASD as well. In contrast, we present evidence from a variety of sources suggesting that there are important differences in ASD symptoms, behavioral and psychiatric correlates, and developmental trajectories between individuals with comorbid FXS and ASD and those with non-syndromic ASD. We also present evidence suggesting that social impairments may not distinguish individuals with FXS with and without ASD. Finally, we present data that demonstrate that the neurobiological substrates of the behavioral impairments, including those reflecting core ASD symptoms, are different in FXS and non-syndromic ASD. Together, these data suggest that there are clinically important differences between FXS and non-syndromic ASD that are masked by reliance on the categorical diagnosis of ASD. We argue for use of a symptom-based approach in future research, including studies designed to evaluate treatment efficacy.