Language use predicts symptoms of fragile X-associated tremor/ataxia syndrome in men and women with the FMR1 premutation.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an age-related neurodegenerative disorder caused by a premutation of the FMR1 gene on the X chromosome. Despite the pervasive physical and cognitive effects of FXTAS, no studies have examined language in symptomatic males and females, limiting utility as an outcome measure in clinical trials of FXTAS. The goal of this work is to determine (a) the extent to which male and female FMR1 premutation carriers with FXTAS symptoms differ in their language use and (b) whether language production predicts FXTAS symptoms. Thirty-one individuals with the FMR1 premutation (21M, 10F), ages 58-85 years with some symptoms of FXTAS, were recruited from a larger cross-sectional study. Participants completed a five-minute monologic language sample. Language transcripts were assessed for rate of dysfluencies, lexical-semantics, syntax, and speech rate. Multivariable linear and ordinal regressions were used to predict FXTAS-associated symptoms, cognitive functioning, and executive functioning. Males and females did not differ in their language use. Language production predicted FXTAS symptom severity, cognitive functioning, and executive functioning. Language production difficulties may co-occur with FXTAS-associated symptoms and may be a viable outcome measure in future clinical trials, with future research needed.

An Exploratory Study of Pragmatic Language Use Across Contexts With the Pragmatic Rating Scale-School Age Among Autistic Boys and Boys With Fragile X Syndrome Plus Autism.

PURPOSE: Autistic boys and boys with co-occurring fragile X syndrome and autism spectrum disorder (FXS + ASD) demonstrate similar pragmatic language difficulties. The Pragmatic Rating Scale-School Age (PRS-SA) captures ecologically valid metrics of pragmatic language impairments in these populations. It is traditionally scored based on the Autism Diagnostic Observation Schedule (ADOS), which may limit the use of the PRS-SA more broadly in research and clinical contexts. METHOD: This study evaluated the feasibility of the PRS-SA based on a shorter, semistructured conversational context compared to the ADOS in school-age autistic boys (n = 16) and boys with FXS + ASD (n = 16), matched on ASD traits. Differences across ADOS and conversational contexts and associations with ASD-related social difficulties were evaluated. RESULTS: Findings revealed differences in PRS-SA scores between ADOS and conversational contexts, but only for the FXS + ASD group. Limited associations were observed between PRS-SA scores and ASD traits. CONCLUSIONS: Results from this study indicate the feasibility of using the PRS-SA in a shorter conversational context than the ADOS to assess pragmatic language among autistic boys. For boys with FXS + ASD, contextual differences warrant careful consideration in future work.

A longitudinal investigation of pragmatic language across contexts in autism and related neurodevelopmental conditions.

Background: Pragmatic language, or the use of language in social contexts, is a critical skill in daily life, supporting social interactions and the development of meaningful social relationships. Pragmatic language is universally impacted in autism spectrum disorder (ASD) and pragmatic deficits are also common in other neurodevelopmental conditions, particularly those related to ASD, such as fragile X syndrome (FXS). This study used a multi-method, longitudinal approach to characterize potentially unique pragmatic profiles across different neurodevelopmental disabilities, and across contexts that varied in degree of social demand. The utility of computational linguistic analyses, as an efficient tool for capturing pragmatic abilities, was also explored. Methods: Pragmatic skills of boys with idiopathic ASD (ASD-O, n = 43), FXS with and without ASD (FXS-ASD, n = 57; FXS-O, n = 14), Down syndrome (DS, n = 22), and typical development (TD, n = 24) were compared using variables obtained from a standardized measure, narrative, and semi-naturalistic conversation at up to three time points. Results: Pragmatic language was most significantly impacted among males with ASD-O and FXS-ASD across all three contexts, with more difficulties in the least structured context (conversation), and also some differences based on FXS comorbidity. Patterns of group differences were more nuanced for boys with FXS-O and DS, with context having less of an impact. Clinical groups demonstrated minimal changes in pragmatic skills with age, with some exceptions. Computational language measurement tools showed some utility for measuring pragmatic skills, but were not as successful as traditional methods at capturing differences between clinical groups. Conclusion: Overlap and differences between ASD and other forms of neurodevelopmental disability in general, and between idiopathic and syndromic ASD in particular, have important implications for developing precisely tailored assessment and intervention approaches, consistent with a personalized medicine approach to clinical study and care in ASD.

Comparison of Linguistic Error Production in Conversational Language Among Boys With Fragile X Syndrome + Autism Spectrum Disorder and Autistic Boys.

PURPOSE: Expressive language impairments are common among school-age boys with fragile X syndrome (FXS) and autistic boys. Given the high co-occurrence of autism spectrum disorder (ASD) among individuals with FXS, cross-condition comparisons can elucidate the specificity of such impairments as they relate to ASD. Language samples can provide fruitful information regarding individuals' grammatical skills in less structured formats relative to standardized measures. This study examined grammatical errors produced during a conversational language sample among 20 boys with FXS and co-occurring ASD (FXS + ASD) and 19 autistic boys matched on ASD severity. METHOD: Language samples were coded for omissions and errors at the word and utterance levels. Participants' grammatical errors were also compared to separate mental age-matched and mean length of utterance-matched boys from a reference database. RESULTS: Boys with FXS + ASD and autistic boys produced similar rates of errors across all categories. Relative to their matched comparison groups, boys with FXS + ASD and autistic boys produced significantly more omissions during conversation. CONCLUSIONS: These findings suggest that omissions may be a unique grammatical marker associated with the ASD phenotype. Further examination of omissions across diagnostic groups would aid in clarifying the specificity of omissions in the language phenotype of ASD.

FMR1 CGG Repeats and Stress Influence Self-Reported Cognitive Functioning in Mothers.

Variation in the FMR1 gene may affect aspects of cognition, such as executive function and memory. Environmental factors, such as stress, may also negatively impact cognitive functioning. Participants included 1,053 mothers of children with and without developmental disabilities. Participants completed self-report measures of executive function, memory, and stress (i.e., life events, parenting status), and provided DNA to determine CGG repeat length (ranging from 7 to 192 CGGs). Stress exposure significantly predicted greater self-reported difficulties in executive function and the likelihood of memory problems. Cubic CGG effects independently predicted executive function and memory difficulties, suggesting effects of both genetic variation and environmental stress exposure on cognitive functioning.

Speech-language pathologists' practices in augmentative and alternative communication during early intervention.

This survey study examined augmentative and alternative communication (AAC) practices reported by early intervention speech-language pathologists (SLPs) across the United States (N = 376). The study examined (a) types of AAC that SLPs reported using (i.e., sign language, photographs, pictures, symbols, talking switches, and iPad apps or dedicated speech-generating devices); (b) SLPs' perspectives on the influence of child spoken language ability on AAC recommendations; (c) factors that influenced AAC decision-making within early intervention; and (d) perceived barriers associated with AAC implementation. SLPs reported that they were significantly more likely to introduce all types of AAC to children without spoken language abilities compared to children in later stages of language development. On average, they were most likely to report using or recommending sign language and photographs, and least likely to report using or recommending talking switches or speech-generating devices. Of the options provided, child expressive and receptive language abilities were rated as the most important factors to consider when determining AAC use, followed by cognitive ability, diagnosis, and chronological age. SLPs identified caregiver buy-in and carryover across providers as the most significant barriers to AAC implementation. Recommendations for future research and current AAC practices within early intervention are discussed.

Assessing the Quantity and Quality of Language Used by Mothers and Fathers of Children with Down Syndrome During Shared Book Reading.

Young children with Down syndrome (DS) have language delays beginning early in life. Book reading with parents provides a context for capitalizing on language learning opportunities. This study evaluated the quantity and quality of language input among mothers and fathers of young children with DS during book reading interactions and investigated associations with child language. Findings revealed that mothers were more talkative and used more descriptive language, whereas fathers spent more time reading the book text. Moreover, maternal and paternal input were correlated with different measures of child language, suggesting that mothers and fathers may use divergent approaches to support language development.

Verbal inhibition declines among older women with high FMR1 premutation expansions: A prospective study.

The FMR1 premutation has been associated with difficulties in executive functioning, including verbal inhibition. However, little is known about the longitudinal profiles of verbal inhibition among FMR1 premutation carriers, particularly in women, and how individual factors such as aging and CGG repeat length may contribute to changes in verbal inhibition over time. The present study examined verbal inhibition performance (i.e., inhibition errors) on the Hayling Sentence Completion Task in a cohort of 92 women with the FMR1 premutation across two timepoints approximately three years apart. We examined the effects of age, CGG repeat length, and their interactions on verbal inhibition over time. We also evaluated whether response latency affected verbal inhibition errors. We found no significant change in verbal inhibition in the full cohort during the three-year study period. However, a subset of FMR1 premutation carriers, namely older participants with higher CGG repeats, evidenced greater declines in verbal inhibition over time. Longer response latencies did not compensate for verbal inhibition errors. The findings suggest that a subset of women with the FMR1 premutation may be at earlier, increased risk for changes in executive functioning, which if confirmed, should be considered as part of the clinical profile associated with the premutation.

Brief Report: Linguistic Mazes and Perseverations in School-Age Boys with Fragile X Syndrome and Autism Spectrum Disorder and Relationships with Maternal Maze Use.

Autism spectrum disorder (ASD) and fragile X syndrome (FXS) are neurodevelopmental disorders with overlapping pragmatic language impairments. Prior work suggests pragmatic language differences may run in families. This study examined specific pragmatic difficulties (i.e., linguistic mazes and perseverations) in boys (9-18 years) with idiopathic ASD (n = 26) and FXS+ASD (n = 29), and relationships with maternal maze use. Language samples were obtained separately for boys and mothers. Nonparametric analyses suggested that boys largely did not differ in their rates of mazes, but that boys with FXS+ASD exhibited more perseverations. Mazes were correlated between fragile X dyads. Maternal mazes were correlated with child perseverations among idiopathic ASD dyads. These findings have implications for the etiological significance of ASD-related language phenotypes.

The Phenotypic Profile Associated With the FMR1 Premutation in Women: An Investigation of Clinical-Behavioral, Social-Cognitive, and Executive Abilities.

The FMR1 gene in its premutation (PM) state has been linked to a range of clinical and subclinical phenotypes among FMR1 PM carriers, including some subclinical traits associated with autism spectrum disorder (ASD). This study attempted to further characterize the phenotypic profile associated with the FMR1 PM by studying a battery of assessments examining clinical-behavioral traits, social-cognitive, and executive abilities in women carrying the FMR1 PM, and associations with FMR1-related variability. Participants included 152 female FMR1 PM carriers and 75 female controls who were similar in age and IQ, and screened for neuromotor impairments or signs of fragile X-associated tremor/ataxia syndrome. The phenotypic battery included assessments of ASD-related personality and language (i.e., pragmatic) traits, symptoms of anxiety and depression, four different social-cognitive tasks that tapped the ability to read internal states and emotions based on different cues (e.g., facial expressions, biological motion, and complex social scenes), and a measure of executive function. Results revealed a complex phenotypic profile among the PM carrier group, where subtle differences were observed in pragmatic language, executive function, and social-cognitive tasks that involved evaluating basic emotions and trustworthiness. The PM carrier group also showed elevated rates of ASD-related personality traits. In contrast, PM carriers performed similarly to controls on social-cognitive tasks that involved reliance on faces and biological motion. The PM group did not differ from controls on self-reported depression or anxiety symptoms. Using latent profile analysis, we observed three distinct subgroups of PM carriers who varied considerably in their performance across tasks. Among PM carriers, CGG repeat length was a significant predictor of pragmatic language violations. Results suggest a nuanced phenotypic profile characterized by subtle differences in select clinical-behavioral, social-cognitive, and executive abilities associated with the FMR1 PM in women.

Stress and genetics influence hair cortisol in FMR1 premutation carrier mothers of children with fragile X syndrome.

To investigate genetic and environmental influences on cortisol levels, mothers of children with fragile X syndrome (FXS) were studied four times over a 7.5-year period. All participants (n = 84) were carriers of the FMR1 "premutation", a genetic condition associated with impaired HPA axis functioning. Genetic variation was indicated by expansions in the number of CGG (cytosine-guanine-guanine) repeats in the FMR1 gene (67-138 repeats in the present sample). The environmental factor was cumulative exposure to adverse life events during the study period. Cortisol was measured at the beginning of the study via saliva samples and at the end of the study via hair samples; hormone values from these two specimen types were significantly correlated. The interactions between CGG repeat number and adverse life events significantly predicted hair cortisol concentration, including after accounting for the initial salivary cortisol level. For those with fewer CGG repeats, stress exposure was associated with elevated cortisol, the expected response to stress, although women with a higher number of CGGs had a reduced cortisol response to adverse events, which might be related to HPA dysfunction. These results indicate that both exogenous and endogenous factors affect HPA functioning in this population of women.

A Unique Visual Attention Profile Associated With the FMR1 Premutation.

Atypical visual attention patterns have been observed among carriers of the fragile X mental retardation gene (FMR1) premutation (PM), with some similarities to visual attention patterns observed in autism spectrum disorder (ASD) and among clinically unaffected relatives of individuals with ASD. Patterns of visual attention could constitute biomarkers that can help to inform the neurocognitive profile of the PM, and that potentially span diagnostic boundaries. This study examined patterns of eye movement across an array of fixation measurements from three distinct eye-tracking tasks in order to investigate potentially overlapping profiles of visual attention among PM carriers, ASD parents, and parent controls. Logistic regression analyses were conducted to examine whether variables constituting a PM-specific looking profile were able to effectively predict group membership. Participants included 65PM female carriers, 188 ASD parents, and 84 parent controls. Analyses of fixations across the eye-tracking tasks, and their corresponding areas of interest, revealed a distinct visual attention pattern in carriers of the FMR1 PM, characterized by increased fixations on the mouth when viewing faces, more intense focus on bodies in socially complex scenes, and decreased fixations on salient characters and faces while narrating a wordless picture book. This set of variables was able to successfully differentiate individuals with the PM from controls (Sensitivity = 0.76, Specificity = 0.85, Accuracy = 0.77) as well as from ASD parents (Sensitivity = 0.70, Specificity = 0.80, Accuracy = 0.72), but did not show a strong distinction between ASD parents and controls (Accuracy = 0.62), indicating that this set of variables comprises a profile that is unique to PM carriers. Regarding predictive power, fixations toward the mouth when viewing faces was able to differentiate PM carriers from both ASD parents and controls, whereas fixations toward other social stimuli did not differentiate PM carriers from ASD parents, highlighting some overlap in visual attention patterns that could point toward shared neurobiological mechanisms. Results demonstrate a profile of visual attention that appears strongly associated with the FMR1 PM in women, and may constitute a meaningful biomarker.

Brief Report: Socioeconomic Factors Associated with Minimally Verbal Status in Individuals with ASD.

About 30% of adults with autism are minimally verbal. Past research suggested that after age five, few gain verbal fluency, but studies have rarely investigated whether family environmental factors contribute to the acquisition of verbal fluency. The present study utilized data from the Autism Diagnostic Interview-Revised to compare changes in verbal fluency for 404 individuals with autism from childhood to adolescence and adulthood. Socioeconomic factors were examined across fluency groups (i.e., those who did/did not achieve verbal fluency). Findings indicated that fully 60% of those who were minimally verbal in early childhood acquired verbal fluency in adolescence and adulthood. Parent socioeconomic status differed across fluency groups, suggesting the importance of environmental factors for individual development.

Elevated Polygenic Burden for Autism Spectrum Disorder Is Associated With the Broad Autism Phenotype in Mothers of Individuals With Autism Spectrum Disorder.

BACKGROUND: Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental disorder that encompasses a complex and heterogeneous set of traits. Subclinical traits that mirror the core features of ASD, referred to as the broad autism phenotype (BAP), have been documented repeatedly in unaffected relatives and are believed to reflect underlying genetic liability to ASD. The BAP may help inform the etiology of ASD by allowing the stratification of families into more phenotypically and etiologically homogeneous subgroups. This study explores polygenic scores related to the BAP. METHODS: Phenotypic and genotypic information were obtained from 2614 trios from the Simons Simplex Collection. Polygenic scores of ASD (ASD-PGSs) were generated across the sample to determine the shared genetic overlap between the BAP and ASD. Maternal and paternal ASD-PGSs were explored in relation to BAP traits and their child's ASD symptomatology. RESULTS: Maternal pragmatic language was related to child's social communicative atypicalities. In fathers, rigid personality was related to increased repetitive behaviors in children. Maternal (but not paternal) ASD-PGSs were related to the pragmatic language and rigid BAP domains. CONCLUSIONS: Associations emerged between parent and child phenotypes, with more associations emerging in mothers than in fathers. ASD-PGS associations emerged with BAP in mothers only, highlighting the potential for a female protective factor, and implicating the polygenic etiology of ASD-related phenotypes in the BAP.

Understanding Social Communication Differences in Autism Spectrum Disorder and First-Degree Relatives: A Study of Looking and Speaking.

This study examined narrative ability in ASD and parents across two contexts differing in structure and emotional content, and explored gaze patterns that may underlie narrative differences by presenting narrative tasks on an eye tracker. Participants included 37 individuals with ASD and 38 controls, 151 parents of individuals with ASD and 63 parent controls. The ASD and ASD parent groups demonstrated lower narrative quality than controls in the less structured narrative task only. Subtler, context-dependent differences emerged in gaze and showed some associations with narrative quality. Results indicate a narrative ability profile that may reflect genetic liability to ASD, and subtle links between visual attention and complex language skills that may be influenced by ASD genetic risk.

A Multi-Method Investigation of Pragmatic Development in Individuals With Down Syndrome.

This longitudinal study examined pragmatic language in boys and girls with Down syndrome (DS) at up to three time points, using parent report, standardized and direct assessments. We also explored relationships among theory of mind, executive function, nonverbal mental age, receptive and expressive vocabulary, grammatical complexity, and pragmatic competence. Controlling for cognitive and language abilities, children with DS demonstrated greater difficulty than younger typically developing controls on parent report and standardized assessments, but only girls with DS differed on direct assessments. Further, pragmatic skills of individuals with DS developed at a delayed rate relative to controls. Some sex-specific patterns of pragmatic impairments emerged. Theory of mind and executive function both correlated with pragmatic competence. Clinical and theoretical implications are discussed.

The Influence of Maternal Pragmatics on the Language Skills of Children with Autism.

OBJECTIVE: This study examined the relationship between mothers' pragmatics and child language in autism spectrum disorder (ASD) and non-ASD language delay (LD) mother-child dyads. METHODS: Participants consisted of 20 dyads of mothers and their toddlers aged 24 to 48 months, with ASD (n = 10) or non-ASD LD (n = 10). Groups were matched on child chronological age, language, and cognition. Maternal pragmatic language was qualified based on the degree of pragmatic violations during a semistructured interview, and was examined in relation to both child language, as measured by the Preschool Language Scale-4 and maternal use of language facilitation strategies during play. RESULTS: Lower rates of maternal pragmatic violations were associated with higher expressive language scores in children with ASD, and with higher receptive language scores for children with non-ASD LD. Within ASD dyads, maternal pragmatic violations were negatively related to mothers' use of linguistic expansions. CONCLUSION: These findings indicate that parental pragmatics likely contribute to early language learning, and that the effects of maternal pragmatics on early language in ASD may be indirect (e.g., through parents' use of facilitative strategies). Parent-mediated language interventions for ASD should therefore consider parent pragmatics, especially given that pragmatic differences have been identified in unaffected family members of individuals with ASD.