Search

Abstract Background Fragile X syndrome (FXS) and autism spectrum disorder (ASD) are neurodevelopmental conditions that often have a substantial impact on daily functioning and quality of life. FXS is the most common cause of inherited intellectual disability (ID) and the most common monogenetic cause of ASD. Previous literature has shown that electrophysiological activity measured by electroencephalogram (EEG) during resting state is perturbated in FXS and ASD. However, whether electrophysiological profiles of participants with FXS and ASD are similar remains unclear. The aim of this study was to compare EEG alterations found in these two clinical populations presenting varying degrees of cognitive and behavioral impairments. Methods Resting state EEG signal complexity, alpha peak frequency (APF) and power spectral density (PSD) were compared between 47 participants with FXS (aged between 5–20), 49 participants with ASD (aged between 6–17), and 52 neurotypical (NT) controls with a similar age distribution using MANCOVAs with age as covariate when appropriate. MANCOVAs controlling for age, when appropriate, and nonverbal intelligence quotient (NVIQ) score were subsequently performed to determine the impact of cognitive functioning on EEG alterations. Results Our results showed that FXS participants manifested decreased signal complexity and APF compared to ASD participants and NT controls, as well as altered power in the theta, alpha and low gamma frequency bands. ASD participants showed exaggerated beta power compared to FXS participants and NT controls, as well as enhanced low and high gamma power compared to NT controls. However, ASD participants did not manifest altered signal complexity or APF. Furthermore, when controlling for NVIQ, results of decreased complexity in higher scales and lower APF in FXS participants compared to NT controls and ASD participants were not replicated. Conclusions These findings suggest that signal complexity and APF might reflect cognitive functioning, while altered power in the low gamma frequency band might be associated with neurodevelopmental conditions, particularly FXS and ASD.

This study explores sex-differences in (a) rates and profiles of autism symptoms as well as in (b) the contribution of intellectual quotient (IQ) to autism symptom presentation in Down syndrome (DS). Participants were 40 males and 38 females with DS, aged 6 to 23 years. Autism symptoms were rated through the Autism Diagnostic Observation Schedule-Second Edition (ADOS-2). Results show no sex differences in the ADOS-2 Calibrated Severity Scores (CSS). However, only females with DS who are classified as DS-Only have higher scores on verbal IQ than those classified as DS + autism. Furthermore, associations between IQ and all CSSs are found for females, but not for males. Findings suggest that verbal cognition may play differential roles for females and males with DS.

IntroductionMetformin has been used as a targeted treatment to potentially improve cognition and slow the typical IQ decline that occurs during development among individuals with fragile X syndrome (FXS). In this follow-up study, we are following the trajectory of IQ and adaptive behavior changes over 1 to 3 years in individuals with FXS who are clinically treated with metformin in an open label trial.MethodIndividuals with FXS ages 6 to 25 years (mean 13.15 ± 5.50) and nonverbal IQ mean 57.69 (±15.46) were treated for 1–3 years (1.88 ± 0.63). They all had a baseline IQ test using the Leiter-III non-verbal cognitive assessment and the Vineland-III adaptive behavior assessment before the start of metformin. Repeat Leiter-III and Vineland-III were completed after at least 1 year of metformin (500–1,000 mg/dose given twice a day).ResultThere were no significant changes in non-verbal IQ or in the adaptive behavior measurements at FDR

Down syndrome (DS) is the leading genetic cause of intellectual disability globally, affecting about 1 in every 800 births. Individuals with DS often face various neuropsychiatric conditions alongside intellectual disabilities due to altered brain development. Despite the diverse phenotypic expressions of DS, typical physical characteristics frequently influence language development and acquisition. EEG studies have identified abnormal oscillatory patterns in individuals with DS. Emerging interventions targeting the enhancement of gamma (40 Hz) neuronal oscillations show potential for improving brain electrical activity and cognitive functions in this population. However, effective cognitive interventions for DS remain scarce. Extensive research indicates that transcranial photobiomodulation (t-PBM) with near-infrared (NIR) light can penetrate deeply into the cerebral cortex, modulate cortical excitability, and enhance cerebral perfusion and oxygenation. Furthermore, t-PBM has been shown to improve cognitive functions such as language, attention, inhibition, learning, and memory, including working memory. This study presents the rationale and design of an ongoing randomized, sham-controlled clinical trial aimed at assessing the effectiveness of t-PBM using NIR light in enhancing the language abilities of individuals with DS.

Abstract The lack of psychometrically sound outcome measures has been a barrier to evaluating the efficacy of treatments proposed for core symptoms of intellectual disability (ID). Research on Expressive Language Sampling (ELS) procedures suggest it is a promising approach to measuring treatment efficacy. ELS entails collecting samples of a participant’s talk in interactions with an examiner that are naturalistic but sufficiently structured to ensure consistency and limit examiner effects on the language produced. In this study, we extended previous research on ELS by analyzing an existing dataset to determine whether psychometrically adequate composite scores reflecting multiple dimensions of language can be derived from ELS procedures administered to 6- to 23-year-olds with fragile X syndrome (n = 80) or Down syndrome (n = 78). Data came from ELS conversation and narration procedures administered twice in a 4-week test–retest interval. We found that several composites emerged from variables indexing syntax, vocabulary, planning processes, speech articulation, and talkativeness, although there were some differences in the composites for the two syndromes. Evidence of strong test–retest reliability and construct validity of two of three composites were obtained for each syndrome. Situations in which the composite scores would be useful in evaluating treatment efficacy are outlined.

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.

Abstract The primary goal of this study was to determine whether expressive language skills contribute to adaptive behavior (e.g., socialization and daily living skills) in children, adolescents, and young adults with Down syndrome (DS) whilst controlling for age and nonverbal cognitive ability. 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. Socialization and daily living skills of participants with DS were measured with the Vineland Adaptive Behavior Scales, 2nd edition (VABS-2) parent/caregiver rating form. Our results show that the three ELS measures were significantly correlated with multiple measures from the VABS-2 when controlling for age. Several correlations remained significant even when nonverbal cognitive ability was included as a control variable. Our results suggest that expressive language skills contribute to adaptive behavior in children, adolescents, and young adults with DS regardless of age and some of these associations are not explained solely by overall cognitive delays. Further studies including longitudinal data are needed to extend our results.

Abstract 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.

Abstract 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.

Abstract Background Social communication is a key area of difficulty in fragile X syndrome (FXS) and there are not yet adequate outcome measurement tools. Appropriate outcome measures for FXS have been identified as a key area of research interest in order to evaluate future therapeutic trials. The Brief Observation of Social Communication Change-Minimally Verbal (BOSCC-MV), an outcome measure with strong psychometrics developed for autism spectrum disorder, has promise as an outcome measure to assess social communication change with FXS participants. Methods We examined the BOSCC-MV via central coders in this multi-site-trial to assess its appropriateness for FXS. Eighteen minimally verbal males ages 3–12 years were enrolled and assessed on two consecutive days and 7 participants completed a third visit 6 months later. We examined test-retest reliability, inter-rater reliability, and both convergent and divergent validity with standard clinical measures including the Autism Diagnostic and Observation Schedule-2, Vineland 3, Social Responsiveness Scale, and the Aberrant Behavior Checklist. Results The BOSCC-MV in FXS demonstrated strong inter-rater and test-retest reliability, comparable to previous trials in idiopathic ASD. Strong convergent validity was found with Autism Diagnostic Observation Schedule-2 and Vineland-3. Divergent validity was demonstrated between BOSCC-MV and unrelated measures. Conclusions The BOSCC-MV shows promise as a FXS social communication outcome measure, warranting further large-scale evaluation.

Early development marks a period of rapid learning facilitated by children’s natural curiosity about the people around them. In children with typical development, these early social attentional preferences set the foundation for learning about and from the surrounding world of people. Much of this learning happens using joint attention, the ability to coordinate attention between people and objects of mutual interest. It is well documented that decreased gaze use is commonly observed in individuals with autism and individuals with fragile X syndrome (FXS). Despite the growing body of research comparing phenotypic similarities between individuals with autism and individuals with FXS, no studies have directly compared joint attention performance between these groups. In the present study, we considered the similarities and differences in joint attention between preschool-aged boys with autism or FXS, and the relation between joint attention, language, and other phenotypic characteristics known to differ between boys with autism and boys with FXS. Although joint attention appeared similar, between-group differences emerged when controlling for the influence of age, non-verbal IQ, and autism symptom severity. Differences were also observed when considering how joint attention performance related to other aspects of the phenotype. For example, strong positive associations were observed between joint attention and language performance in boys with autism but not boys with FXS, even after controlling for non-verbal IQ. In contrast, the negative association between joint attention and anxiety symptom severity was significant and stronger in boys with FXS than in autism. These data offer preliminary insights into the similarities and differences between the autism and FXS phenotypes.

This study contributes to a greater understanding of the utility of molecular biomarkers to identify clinical phenotypes of fragile X syndrome (FXS). Correlations of baseline clinical trial data (molecular measures—FMR1 mRNA, CYFIP1 mRNA, MMP9 and FMRP protein expression levels, nonverbal IQ, body mass index and weight, language level, NIH Toolbox, adaptive behavior rating, autism, and other mental health correlates) of 59 participants with FXS ages of 6–32 years are reported. FMR1 mRNA expression levels correlated positively with adaptive functioning levels, expressive language, and specific NIH Toolbox measures. The findings of a positive correlation of MMP-9 levels with obesity, CYFIP1 mRNA with mood and autistic symptoms, and FMR1 mRNA expression level with better cognitive, language, and adaptive functions indicate potential biomarkers for specific FXS phenotypes. These may be potential markers for future clinical trials for targeted treatments of FXS.

Abstract Background The 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. Method Participants 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. Results Low 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. Conclusion The 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.

Abstract Background It 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. Methods In 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. Results Changes 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. Conclusions Our 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.

Abstract 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.

Abstract Background The 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. Methods Participants were 106 individuals with FXS between ages 6 and 23 years who had IQs within the range of intellectual disability (IQ

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.

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.

Expressive language sampling (ELS) is a frequently used tool for language analysis, as it can be used across widely ranging cognitive and language abilities. ELS can also evaluate pragmatic language, including excessive self-repetition, which is challenging to assess with traditional standardized assessments. This study explored how a well-established ELS protocol can assess three types of linguistic self-repetition in three neurodevelopmental disabilities: fragile X syndrome (FXS), autism spectrum disorder (ASD), and Down syndrome (DS). We examined its ability to differentiate between these disorders, the relationships between repetitive language and other participant characteristics, and initial construct validity. We found that the groups with FXS and ASD differed significantly on each of the three repetitive language measure, and that the group with DS differed from either ASD or FXS on two. Cognitive ability was significantly related to phrase repetition in the group with ASD. When the groups were combined, there was evidence of convergent and divergent validity. This study extends previous research on ELS and supports its use as a means to characterize pragmatic language. It also provides information about the relationships between repetitive language and other phenotypic characteristics.

Abstract 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.

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.

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.

In the original publication of this article [1], the author name Leonard Abbeduto was misspelled as Leonardkk Abbeduto. The original article has been corrected.

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.

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.

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 nonsyndromic 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 nonsyndromic 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 nonsyndromic 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 nonsyndromic ASD. Together, these data suggest that there are clinically important differences between FXS and nonsyndromic 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.