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

BACKGROUND: Fragile X syndrome (FXS) and non-syndromic autism spectrum disorder (ASD) are distinct disorders with overlapping behavioral features. Both disorders are also highly associated with anxiety with abnormal physiological regulation implied mechanistically. Some reports suggest atypical hypothalamus-pituitary-adrenal (HPA) axis function, indexed via aberrant cortisol reactivity, in both FXS and non-syndromic ASD. However, no study has compared cortisol reactivity across these two disorders, or its relationship to ASD symptom severity. METHODS: Cortisol reactivity (prior to and following a day of assessments) was measured in 54 adolescent/young adult males with FXS contrasted to 15 males with non-syndromic ASD who had low cognitive abilities. RESULTS: Greater ASD symptom severity was related to increased cortisol reactivity and higher levels at the end of the day, but only in the non-syndromic ASD group. Elevated anxiety was associated with increased HPA activation in the group with FXS alone. CONCLUSIONS: Taken together, findings suggest a unique neuroendocrine profile that distinguishes adolescent/young adult males with FXS from those with non-syndromic ASD. Severity of ASD symptoms appears to be related to cortisol reactivity in the non-syndromic ASD sample, but not in FXS; while anxiety symptoms are associated with HPA activation in the FXS sample, but not in ASD despite a high prevalence of ASD, anxiety and physiological dysregulation characteristic in both populations.

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

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

Effects of AFQ056 on language learning in fragile X syndrome.

BACKGROUNDFXLEARN, the first-ever large multisite trial of effects of disease-targeted pharmacotherapy on learning, was designed to explore a paradigm for measuring effects of mechanism-targeted treatment in fragile X syndrome (FXS). In FXLEARN, the effects of metabotropic glutamate receptor type 5 (mGluR5) negative allosteric modulator (NAM) AFQ056 on language learning were evaluated in 3- to 6-year-old children with FXS, expected to have more learning plasticity than adults, for whom prior trials of mGluR5 NAMs have failed.METHODSAfter a 4-month single-blind placebo lead-in, participants were randomized 1:1 to AFQ056 or placebo, with 2 months of dose optimization to the maximum tolerated dose, then 6 months of treatment during which a language-learning intervention was implemented for both groups. The primary outcome was a centrally scored videotaped communication measure, the Weighted Communication Scale (WCS). Secondary outcomes were objective performance-based and parent-reported cognitive and language measures.RESULTSFXLEARN enrolled 110 participants, randomized 99, and had 91 who completed the placebo-controlled period. Although both groups made language progress and there were no safety issues, the change in WCS score during the placebo-controlled period was not significantly different between the AFQ056 and placebo-treated groups, nor were there any significant between-group differences in change in any secondary measures.CONCLUSIONDespite the large body of evidence supporting use of mGluR5 NAMs in animal models of FXS, this study suggests that this mechanism of action does not translate into benefit for the human FXS population and that better strategies are needed to determine which mechanisms will translate from preclinical models to humans in genetic neurodevelopmental disorders.TRIAL REGISTRATIONClincalTrials.gov NCT02920892.FUNDING SOURCESNeuroNEXT network NIH grants U01NS096767, U24NS107200, U24NS107209, U01NS077323, U24NS107183, U24NS107168, U24NS107128, U24NS107199, U24NS107198, U24NS107166, U10NS077368, U01NS077366, U24NS107205, U01NS077179, and U01NS077352; NIH grant P50HD103526; and Novartis IIT grant AFQ056X2201T for provision of AFQ056.

Family and Caregiver Characteristics Contribute to Caregiver Change in Use of Strategies and Growth in Child Spoken Language in a Parent-Implemented Language Intervention in Fragile X Syndrome.

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 preto 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.

Spoken language outcome measures for treatment studies in Down syndrome: feasibility, practice effects, test-retest reliability, and construct validity of variables generated from expressive language sampling.

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.

Controlled trial of lovastatin combined with an open-label treatment of a parent-implemented language intervention in youth with fragile X syndrome.

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.

Correction to: Expressive language sampling as a source of outcome measures for treatment studies in fragile X syndrome: feasibility, practice effects, test-retest reliability, and construct validity.

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

Expressive language sampling as a source of outcome measures for treatment studies in fragile X syndrome: feasibility, practice effects, test-retest reliability, and construct validity.

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 < 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. RESULTS: We 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. CONCLUSIONS: The 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.

ASD Comorbidity in Fragile X Syndrome: Symptom Profile and Predictors of Symptom Severity in Adolescent and Young Adult Males.

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.

A comparison of contexts for assessing joint attention in toddlers on the autism spectrum.

Children on the autism spectrum often demonstrate atypical joint attention, leading some researchers to consider joint attention deficits a core feature of the autism spectrum. Structured measures, such as the Early Social Communication Scales (ESCS), are commonly used to provide a metric of joint attention. To explore the assessment of joint attention in multiple contexts, we implemented an alternative system for coding joint attention behaviors. We compared initiation of joint attention (IJA) and response to joint attention (RJA) behaviors coded from naturalistic examiner-child play samples with similar IJA and RJA behaviors elicited within the structured ESCS protocol. Participants were 20 toddlers on the autism spectrum. Levels of IJA and RJA within the two assessment contexts were significantly and positively correlated, providing support for the use of naturalistic sampling of joint attention skills as a viable alternative, or supplement, to structured measures.

Distance delivery of a spoken language intervention for school-aged and adolescent boys with fragile X syndrome.

A small randomized group design (N = 20) was used to examine a parent-implemented intervention designed to improve the spoken language skills of school-aged and adolescent boys with FXS, the leading cause of inherited intellectual disability. The intervention was implemented by speech-language pathologists who used distance video-teleconferencing to deliver the intervention. The intervention taught mothers to use a set of language facilitation strategies while interacting with their children in the context of shared story-telling. Treatment group mothers significantly improved their use of the targeted intervention strategies. Children in the treatment group increased the duration of engagement in the shared story-telling activity as well as use of utterances that maintained the topic of the story. Children also showed increases in lexical diversity, but not in grammatical complexity.

Inferential language use by school-aged boys with fragile X syndrome: Effects of a parent-implemented spoken language intervention.

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.

Developmental correlates of different types of motor imitation in young children with autism spectrum disorders.

This study used a concurrent correlational design to examine associations between three types of motor imitation with objects and three proposed correlates in 32 two- and three-year-old children diagnosed with ASD. Attention-following and fine motor ability were significant, unique correlates of imitation in an observational learning context. Attention-following was a significant correlate of imitation in a direct elicitation context. Social reciprocity was a significant correlate of imitation in an interactive play context. These associations were observed after controlling for general developmental level. Results support previous findings that motor imitation may not reflect a unitary construct for children with ASD and that different skills may underlie the performance of different types of motor imitation. Implications for interventions targeting motor imitation are discussed.

Use of speaker intent and grammatical cues in fast-mapping by adolescents with Down syndrome.

PURPOSE: The authors asked whether adolescents with Down syndrome (DS) could fast-map novel nouns and verbs when word learning depended on using the speaker's pragmatic or syntactic cues. Compared with typically developing (TD) comparison children, the authors predicted that syntactic cues would prove harder for the group with DS to use and that action verbs would be harder to fast-map than nouns. METHOD: Twenty participants with DS, aged 12-18 years, and 19 TD participants, aged 3-6 years, were matched on syntax comprehension and engaged in 4 fast-mapping tasks. Both comprehension and production of novel words were assessed for each task. Through use of hierarchical regression models, hearing, cognition, and working memory were considered as predictors of total comprehension and production performance for each group. RESULTS: Both groups used speaker intent in fast-mapping labels to object referents but performed more poorly on fast-mapping verbs. Neither group appeared to use grammatical cues to disambiguate the intended referent. Syntax comprehension was replicated as a predictor of fast-mapping comprehension for the DS group. Syntax comprehension and chronological age were replicated as predictors of TD fast-mapping. CONCLUSION: Participants with DS had better recall for the object or action seen most recently during speaker intent tasks. They had better recall for the object presented first and the action presented last during grammatical cue tasks. Response patterns may have depended on the structure of specific task paradigms. Verb acquisition may be facilitated when either the action or label is familiar.

Distance delivery of a parent-implemented language intervention for young boys with fragile X syndrome.

BACKGROUND: In addition to significant cognitive delays, boys with fragile X syndrome display phenotypic characteristics that include delays in language, inattention, social anxiety, and escape-maintained challenging behaviors. Despite these challenges, families affected by fragile X syndrome often have limited access to center-based intervention programs. METHODS: The present study utilized a multiple baseline design across participants to examine the preliminary effectiveness of a 12-week, parent-implemented spoken language intervention for three 5- to 7-year-old boys with fragile X syndrome. The goal of the intervention was to teach the biological mothers of each boy to use a set of verbally responsive language support strategies while participating in shared book reading activities with her child. All aspects of the intervention, including pre- and post-treatment measures, were delivered into the family's home via distance video teleconferencing. RESULTS: Results from this study provide preliminary support for the efficacy of this parent-implemented language intervention approach by demonstrating generalized improvements in both targeted maternal strategy use and measures of child spoken language. CONCLUSIONS: The present study expands upon prior language intervention research utilizing distance delivery of services for families affected by fragile X syndrome. Additionally, the study provides early support for the feasibility of collecting pre- and post-treatment assessments at a distance.

Language Skills of Males with Fragile X Syndrome or Nonsyndromic Autism Spectrum Disorder.

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.

Labels increase attention to novel objects in children with autism and comprehension-matched children with typical development.

This study used an intact group comparison to examine attention following in 34 children aged 2 years diagnosed with autism spectrum disorder (ASD) matched pairwise for vocabulary comprehension with a group of typically developing toddlers. For both groups of children, the presence of verbal labels during a referential task increased attention to a novel object over and above the attention-facilitating effect of child-directed talking without labeling. The typically developing children displayed more attention following than comprehension matched children with ASD across experimental conditions and there was no significant difference between the groups in the facilitative effect of hearing verbal labels. Implications for word-learning theory, intervention strategies and future research are considered.

A Spoken-Language Intervention for School-Aged Boys With Fragile X Syndrome.

Using a single case design, a parent-mediated spoken-language intervention was delivered to three mothers and their school-aged sons with fragile X syndrome, the leading inherited cause of intellectual disability. The intervention was embedded in the context of shared storytelling using wordless picture books and targeted three empirically derived language-support strategies. All sessions were implemented through distance videoteleconferencing. Parent education sessions were followed by 12 weekly clinician coaching and feedback sessions. Data were collected weekly during independent homework and clinician observation sessions. Relative to baseline, mothers increased their use of targeted strategies, and dyads increased the frequency and duration of story-related talking. Generalized effects of the intervention on lexical diversity and grammatical complexity were observed. Implications for practice are discussed.

Early Language Intervention Using Distance Video-Teleconferencing: A Pilot Study of Young Boys With Fragile X Syndrome and Their Mothers.

PURPOSE: This study examined the effects of a naturalistic parent-implemented language intervention on the use of verbally responsive language by mothers of 6 young boys with fragile X syndrome. The intervention included parent education sessions and clinician coaching delivered onsite and by distance video-teleconferencing. METHOD: A single-case multiple baseline across participants was used to examine intervention effects on maternal use of language support strategies. A nonparametric analysis was used to evaluate the relative effectiveness of onsite compared with distance coaching sessions. RESULTS: Mothers increased their use of utterances that followed into their child's focus of attention and prompted child communication acts. Intervention effects were not observed for maternal contingent responses to child communication, possibly due to the limited number of spontaneous communication acts children produced. Children showed moderate increases in the use of prompted communication acts, whereas intervention effects on spontaneous communication acts were more modest and variable. Comparable increases in maternal strategy use were observed during onsite and distance sessions. CONCLUSIONS: No previous study has examined a distance-delivered parent-implemented language intervention for young boys with fragile X syndrome. Mothers were able to increase their use of verbally responsive language. Intervention efficacy might be enhanced by incorporating an augmentative and alternative communication device for some children and a more concerted focus on increasing the frequency of child communication acts. Findings provide preliminary support for the efficacy of the distance delivery format.

Prelinguistic predictors of vocabulary in young children with autism spectrum disorders.

PURPOSE: The goal of the current study was to identify a predictive model of vocabulary comprehension and production in a group of young children with autism spectrum disorders. Four prelinguistic behaviors were selected for consideration as predictors based on theoretical and empirical support for the relationship of these behaviors to language development. METHOD: The study used a longitudinal correlational design. Participants were twenty-nine 2- and 3-year-olds diagnosed with autism spectrum disorders. The prelinguistic behaviors-attention-following, motor imitation, commenting, and requesting-were measured at the initial visit. Vocabulary comprehension and production were measured 6 months later. RESULTS: Commenting was the only unique predictor of comprehension after the degree of cognitive delay was controlled. Both commenting and motor imitation of actions without objects were unique predictors of production over and above the other skills and when the degree of cognitive delay was controlled. CONCLUSIONS: The finding that both commenting and motor imitation simultaneously accounted for unique variance in vocabulary production is new to the literature and requires replication. However, results suggest that increasing behaviors that allow children with autism to make their current focus of attention obvious to social partners may be an effective approach for supporting word learning in young children with autism.