Update on the Treatment of Fragile X Syndrome

A special issue of Brain Sciences (ISSN 2076-3425).

Deadline for manuscript submissions: closed (15 June 2020) | Viewed by 36927

Special Issue Editors

1. Department of Psychiatry, Fragile X Clinic, Kennedy Krieger Institute, Baltimore, MD 21205, USA
2. Department of Psychiatry & Behavioral Sciences-Child Psychiatry, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
Interests: fragile X syndrome; clinical trials; targeted treatments; autism; autism spectrum disorder; fragile X premutation; fragile X-associated disorders
1. Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA;
2. MIND Institute, Department of Neurology, School of Medicine, University of California, Davis, CA 95817, USA
Interests: genetic intellectual disability and autism spectrum disorder; outcome measures; biomarkers; animal models of neurodevelopmental disorders
1. Division of Child & Adolescent Psychiatry, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA;
2. Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA
Interests: translational medicine; neurodevelopmental disorders; fragile X syndrome; autism spectrum disorder; Angelman Syndrome; clinical trials

Special Issue Information

Dear Colleagues,

Fragile X syndrome (FXS) is a well-defined genetic cause of inherited intellectual disability (ID). It is also the best-understood single-gene factor associated with autism spectrum disorder (ASD), which is purely behaviorally defined. Approximately 1%–3% of the general population is affected by IDs that are often comorbid with idiopathic ASD. Deficits in the fragile X gene’s key protein seem to be the critical unifying factor linked, at a synaptic level, to dysfunction in brain pathways and to at least some aspects of behavioral symptoms in idiopathic ASD. Indeed, FXS and idiopathic ASD may present with substantial overlap in molecular pathology and clinical and behavioral features, including ID, social interaction anxiety, and inattention. Thus, further advances in the understanding of FXS may help to inform studies on ID and other ASD in highly heterogenous idiopathic ASD. Currently, there is no FDA-approved treatment for FXS. Pharmacological interventions use a symptom-based approach to manage associated (as opposed to the core) symptoms in both FXS and ASD. However, in last decade, major progress in elucidating the underlying causes of FXS has generated new targeted approaches to manage them. Indeed, among all neurodevelopmental disabilities, FXS has been at the forefront of efforts to test preclinical evidence for these interventions in clinical studies. Yet, translating these findings into clinical trials with humans with FXS has proven to be a major challenge due to a lack of objective and/or directly observable quantitative measures of brain function. Other challenges include heterogeneity in the clinical presentation of FXS and environmental factors (placebo effect). In an ongoing effort to tackle the challenges, our group recently detailed best practices in FXS treatment development. Among them was a compelling need to include the use of extensive objective and/or directly observable quantitative measures of brain function, communication, and behavior in order to determine clinically-relevant sensitive changes with treatment. Additionally, a process of de-risking large-scale multi-site projects in FXS should be carried out, for example, utilizing well-conceived proof of concept early human studies of drugs for which there is improvement of a directly translatable animal marker (e.g., event-related potential (ERP) abnormality).

In this issue, we focus on the objective and/or directly observable quantitative measures of FXS pathophysiology of meaningful relevance not only to the treatment challenges but also to understanding the developmental trajectory in FXS, including novel topics with implications on ASD and ID. Examples of the aforementioned measures include language sampling, EEG/ERP, eye tracking, Transcranial magnetic stimulation (TMS), and blood assays. Examples of topics beyond placebo effects in FXS clincial trials to include are adaptive designs and cognitive endpoints (NIH Toolbox updates). In addition, possibilities of applying remote clinical trials using web tools and statistical analyses including selection of key secondary endpoints for pivotal trials are presented.

Dr. Dejan B. Budimirovic
Dr. Walter E. Kaufmann
Dr. Craig A. Erickson
Guest Editors

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Keywords

  • fragile X syndrome
  • intellectual diability
  • autism spectrum disorder
  • clinical trials
  • placebo effect
  • quantitative measures

Published Papers (10 papers)

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Editorial

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5 pages, 198 KiB  
Editorial
Fragile X Syndrome: Recent Research Updates toward Capturing Treatments’ Improvement in Clinical Trials
by Dejan B. Budimirovic and Dragana D. Protic
Brain Sci. 2022, 12(10), 1276; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci12101276 - 22 Sep 2022
Cited by 1 | Viewed by 1227
Abstract
This Brain Sciences 2020 Special Issue of nine manuscripts contribute novel data on treatment updates in fragile X syndrome (FXS) [...] Full article
(This article belongs to the Special Issue Update on the Treatment of Fragile X Syndrome)

Research

Jump to: Editorial

25 pages, 3104 KiB  
Article
A Genotype-Phenotype Study of High-Resolution FMR1 Nucleic Acid and Protein Analyses in Fragile X Patients with Neurobehavioral Assessments
by Dejan B. Budimirovic, Annette Schlageter, Stela Filipovic-Sadic, Dragana D. Protic, Eran Bram, E. Mark Mahone, Kimberly Nicholson, Kristen Culp, Kamyab Javanmardi, Jon Kemppainen, Andrew Hadd, Kevin Sharp, Tatyana Adayev, Giuseppe LaFauci, Carl Dobkin, Lili Zhou, William Ted Brown, Elizabeth Berry-Kravis, Walter E. Kaufmann and Gary J. Latham
Brain Sci. 2020, 10(10), 694; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci10100694 - 30 Sep 2020
Cited by 51 | Viewed by 4250
Abstract
Fragile X syndrome (FXS) is caused by silencing of the FMR1 gene, which encodes a protein with a critical role in synaptic plasticity. The molecular abnormality underlying FMR1 silencing, CGG repeat expansion, is well characterized; however, delineation of the pathway from DNA to [...] Read more.
Fragile X syndrome (FXS) is caused by silencing of the FMR1 gene, which encodes a protein with a critical role in synaptic plasticity. The molecular abnormality underlying FMR1 silencing, CGG repeat expansion, is well characterized; however, delineation of the pathway from DNA to RNA to protein using biosamples from well characterized patients with FXS is limited. Since FXS is a common and prototypical genetic disorder associated with intellectual disability (ID) and autism spectrum disorder (ASD), a comprehensive assessment of the FMR1 DNA-RNA-protein pathway and its correlations with the neurobehavioral phenotype is a priority. We applied nine sensitive and quantitative assays evaluating FMR1 DNA, RNA, and FMRP parameters to a reference set of cell lines representing the range of FMR1 expansions. We then used the most informative of these assays on blood and buccal specimens from cohorts of patients with different FMR1 expansions, with emphasis on those with FXS (N = 42 total, N = 31 with FMRP measurements). The group with FMRP data was also evaluated comprehensively in terms of its neurobehavioral profile, which allowed molecular–neurobehavioral correlations. FMR1 CGG repeat expansions, methylation levels, and FMRP levels, in both cell lines and blood samples, were consistent with findings of previous FMR1 genomic and protein studies. They also demonstrated a high level of agreement between blood and buccal specimens. These assays further corroborated previous reports of the relatively high prevalence of methylation mosaicism (slightly over 50% of the samples). Molecular-neurobehavioral correlations confirmed the inverse relationship between overall severity of the FXS phenotype and decrease in FMRP levels (N = 26 males, mean 4.2 ± 3.3 pg FMRP/ng genomic DNA). Other intriguing findings included a significant relationship between the diagnosis of FXS with ASD and two-fold lower levels of FMRP (mean 2.8 ± 1.3 pg FMRP/ng genomic DNA, p = 0.04), in particular observed in younger age- and IQ-adjusted males (mean age 6.9 ± 0.9 years with mean 3.2 ± 1.2 pg FMRP/ng genomic DNA, 57% with severe ASD), compared to FXS without ASD. Those with severe ID had even lower FMRP levels independent of ASD status in the male-only subset. The results underscore the link between FMR1 expansion, gene methylation, and FMRP deficit. The association between FMRP deficiency and overall severity of the neurobehavioral phenotype invites follow up studies in larger patient cohorts. They would be valuable to confirm and potentially extend our initial findings of the relationship between ASD and other neurobehavioral features and the magnitude of FMRP deficit. Molecular profiling of individuals with FXS may have important implications in research and clinical practice. Full article
(This article belongs to the Special Issue Update on the Treatment of Fragile X Syndrome)
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14 pages, 1098 KiB  
Article
Cognitive Training Deep Dive: The Impact of Child, Training Behavior and Environmental Factors within a Controlled Trial of Cogmed for Fragile X Syndrome
by Haleigh Scott, Danielle J. Harvey, Yueju Li, Yingratana A. McLennan, Cindy K. Johnston, Ryan Shickman, Joseph Piven, Julie B. Schweitzer and David Hessl
Brain Sci. 2020, 10(10), 671; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci10100671 - 25 Sep 2020
Cited by 7 | Viewed by 2475
Abstract
Children with fragile X syndrome (FXS) exhibit deficits in a variety of cognitive processes within the executive function domain. As working memory (WM) is known to support a wide range of cognitive, learning and adaptive functions, WM computer-based training programs have the potential [...] Read more.
Children with fragile X syndrome (FXS) exhibit deficits in a variety of cognitive processes within the executive function domain. As working memory (WM) is known to support a wide range of cognitive, learning and adaptive functions, WM computer-based training programs have the potential to benefit people with FXS and other forms of intellectual and developmental disability (IDD). However, research on the effectiveness of WM training has been mixed. The current study is a follow-up “deep dive” into the data collected during a randomized controlled trial of Cogmed (Stockholm, Sweden) WM training in children with FXS. Analyses characterized the training data, identified training quality metrics, and identified subgroups of participants with similar training patterns. Child, parent, home environment and training quality metrics were explored in relation to the clinical outcomes during the WM training intervention. Baseline cognitive level and training behavior metrics were linked to gains in WM performance-based assessments and also to reductions in inattention and other behaviors related to executive functioning during the intervention. The results also support a recommendation that future cognitive intervention trials with individuals with IDD such as FXS include additional screening of participants to determine not only baseline feasibility, but also capacity for training progress over a short period prior to inclusion and randomization. This practice may also better identify individuals with IDD who are more likely to benefit from cognitive training in clinical and educational settings. Full article
(This article belongs to the Special Issue Update on the Treatment of Fragile X Syndrome)
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17 pages, 301 KiB  
Article
Response to Placebo in Fragile X Syndrome Clinical Trials: An Initial Analysis
by Skylar Luu, Haley Province, Elizabeth Berry-Kravis, Randi Hagerman, David Hessl, Dhananjay Vaidya, Reymundo Lozano, Hilary Rosselot, Craig Erickson, Walter E. Kaufmann and Dejan B. Budimirovic
Brain Sci. 2020, 10(9), 629; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci10090629 - 11 Sep 2020
Cited by 20 | Viewed by 3101
Abstract
Fragile X syndrome (FXS) is the leading cause of inherited intellectual disability and autism spectrum disorder. Individuals with FXS often present with a wide range of cognitive deficits and problem behaviors. Educational, behavioral and pharmacological interventions are used to manage these and other [...] Read more.
Fragile X syndrome (FXS) is the leading cause of inherited intellectual disability and autism spectrum disorder. Individuals with FXS often present with a wide range of cognitive deficits and problem behaviors. Educational, behavioral and pharmacological interventions are used to manage these and other complex issues affecting individuals with FXS. Despite the success of preclinical models and early-phase drug clinical studies in FXS, large-scale randomized-controlled trials have failed to meet primary endpoints. Currently, no targeted or disease-modifying treatments for FXS have received regulatory approval. Here, we examined the placebo response in FXS clinical trials conducted between 2006 and 2018. Specifically, we performed a meta-analysis of placebo-treated groups in eight double-blind, randomized controlled trials. Placebo groups demonstrated significant improvements on caregiver-rated efficacy endpoints, which were greater in adolescents and adults than in children. Among the latter measures, the Visual Analog Scale scores displayed the greatest improvements, whereas the positive effects on the Vineland-II Adaptive Behavior Composite and the Aberrant Behavior Checklist-Community/fragile X version were statistically significant in both children and adolescents/adults. Although the Clinical Global Impression scale Improvement appears to have exhibited a substantial placebo effect in multiple clinical trials in FXS, limited data availability for meta-analysis, prevented us from drawing conclusions. No placebo-related improvements were observed in performance-rated measures. These findings raise substantial concerns about placebo effects in outcome measures commonly used in the randomized-controlled trials in FXS and suggest several potential improvements in the study design and implementation of such trials. Considering the small number of trials available for this study, larger and more detailed follow up meta-analyses are needed. Meanwhile, efforts to improve the measurement properties of endpoints and rater training in drug trials in FXS should be prioritized. Full article
(This article belongs to the Special Issue Update on the Treatment of Fragile X Syndrome)
19 pages, 269 KiB  
Article
Adaptive Skills in FXS: A Review of the Literature and Evaluation of the PEDI-Computer Adaptive Test (PEDI-CAT) to Measure Adaptive Skills
by Lisa Cordeiro, Adrienne Villagomez, Deanna Swain, Sophia Deklotz and Nicole Tartaglia
Brain Sci. 2020, 10(6), 351; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci10060351 - 06 Jun 2020
Cited by 8 | Viewed by 3315
Abstract
As adaptive skills (AS) are dynamic and may indicate the success of an intervention, they are a common domain measured in clinical trials. Typical interview tools for measuring AS are time-consuming, and questionnaire measures often lead to inconsistent information. The present study was [...] Read more.
As adaptive skills (AS) are dynamic and may indicate the success of an intervention, they are a common domain measured in clinical trials. Typical interview tools for measuring AS are time-consuming, and questionnaire measures often lead to inconsistent information. The present study was designed to evaluate the feasibility, validity and test-retest performance of the Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT) in Fragile X syndrome (FXS). The PEDI-CAT is administered via tablet and uses the item response theory to efficiently determine the items administered. The PEDI-CAT was administered to 42 individuals with FXS (27 males; 15 females) aged 1.6–50.9 years (M = 14.9; SD = 11.2), followed by the Vineland-3 (VABS-3) interview for comparison. Administration was efficient (M = 21.7 min; SD = 9.5; range 8–45 min; mode = 19). Males and females did not significantly differ on the PEDI-CAT domains, except for daily activities (t(40) = −2.22, p = 0.037). Floor effects were significant for both measures, although the PEDI-CAT showed more floor effects in the mobility (35.7%) and social-cognitive (50%) domains. PEDI-CAT daily activities, mobility, social-cognitive and responsibility domains were all significantly correlated with most of the VABS-3 domains (all rho > 0.5; p < 0.01). Test-rest of the PEDI-CAT was comparable to the VABS-3. Results suggest that the PEDI-CAT is efficient, and minimal training is needed to administer it; however, it lacks specificity and shares a high rate of floor effects with the VABS-3. Full article
(This article belongs to the Special Issue Update on the Treatment of Fragile X Syndrome)
22 pages, 1444 KiB  
Article
Evaluating Social Interactions Using the Autism Screening Instrument for Education Planning-3rd Edition (ASIEP-3): Interaction Assessment in Children and Adults with Fragile X Syndrome
by Lisa Cordeiro, Marcia Braden, Elizabeth Coan, Nanastasia Welnick, Tanea Tanda and Nicole Tartaglia
Brain Sci. 2020, 10(4), 248; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci10040248 - 22 Apr 2020
Cited by 6 | Viewed by 5112
Abstract
An efficient and direct measure of social interactions and autism symptoms is needed for fragile X syndrome (FXS) research and clinical care. The Autism Screening Instrument for Educational Planning-Third Edition (ASIEP-3) Interaction assessment is a brief standardized measure that quantifies social responses under [...] Read more.
An efficient and direct measure of social interactions and autism symptoms is needed for fragile X syndrome (FXS) research and clinical care. The Autism Screening Instrument for Educational Planning-Third Edition (ASIEP-3) Interaction assessment is a brief standardized measure that quantifies social responses under different conditions. The feasibility and validity of the ASIEP-3 was evaluated in 26 males and 13 females with FXS, along with cognitive testing and behavior questionnaires. The videos were scored at 10-second intervals, and the observed behaviors were scored as an interaction, independent play, no response, or aggression. In total, 39/41 participants successfully completed the ASIEP-3 (age M = 14.4 ± 10.2), with a range of cognitive abilities (abbreviated IQ (ABIQ) M = 58.9 ± 17.3, median = 50), behaviors (Aberrant Behavior Checklist (ABC) Total M = 37.00 ± 27.3), and autism diagnoses (N = 22/39). Reliable administration was demonstrated by all team members. The mean coded behaviors included interaction (40.6%), independent play (36.8%), no response (21.1%), and aggressive behavior (<10%). The interaction score was negatively correlated with the Social Communication Questionnaire (SCQ) score (p = 0.037), and the profiles differed by autism spectrum disorder (ASD) diagnosis. The intraclass correlation coefficients (ICCs) ranged from 0.79 to 0.93 for master’s level and above. Administration of the ASIEP-3 was feasible for FXS across sex, age, ability, and behavior ratings by a trained research team. Reliable scoring required advanced training in the assessment of social development and FXS experience. The scores correlated to ratings and diagnoses of ASD. The ASIEP-3 shows promise to reliably index social interactions in FXS. Full article
(This article belongs to the Special Issue Update on the Treatment of Fragile X Syndrome)
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21 pages, 766 KiB  
Article
Delineating Repetitive Behavior Profiles across the Lifespan in Fragile X Syndrome
by Debra L. Reisinger, Rebecca C. Shaffer, Nicole Tartaglia, Elizabeth Berry-Kravis and Craig A. Erickson
Brain Sci. 2020, 10(4), 239; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci10040239 - 17 Apr 2020
Cited by 15 | Viewed by 4913
Abstract
Restricted repetitive behaviors (RRBs) are a core area of impairment in autism spectrum disorder (ASD), but also affect several other neurodevelopmental disorders including fragile X syndrome (FXS). Current literature has begun to describe the RRB profile in FXS up through adolescence; however, little [...] Read more.
Restricted repetitive behaviors (RRBs) are a core area of impairment in autism spectrum disorder (ASD), but also affect several other neurodevelopmental disorders including fragile X syndrome (FXS). Current literature has begun to describe the RRB profile in FXS up through adolescence; however, little is known about the subtypes of RRBs in adolescents and adults. Further, literature on the RRB profile of females with FXS is limited. The present study examines the RRB profile across subtypes and specific items in both males and females with FXS while assessing for differences based on age, ASD diagnosis and the impact of IQ. Participants included 154 individuals with FXS (ages 2 to 50 years old). Results revealed a peak in RRB severity in FXS between 7–12 years for the majority of RRB subscales with the exception of Sensory-Motor behaviors peaking between 2 and 12 years before declining. Distinct RRB profiles in males and females with FXS emerged in addition to significant overlap among the item and subscale levels of RRBs across gender. Further, an added diagnosis of ASD significantly increased rates of RRBs across all subscale levels, but not necessarily across all items. Lastly, IQ did not solely account for the presence of RRBs in FXS, with Sensory-Motor behaviors being driven by comorbid ASD in males with FXS, and Restricted Interest behaviors being driven by comorbid ASD regardless of gender. These findings build on the current understanding of RRBs in FXS based on gender and comorbid ASD and lay important groundwork for the development of targeted behavioral and pharmacological treatments. Full article
(This article belongs to the Special Issue Update on the Treatment of Fragile X Syndrome)
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9 pages, 206 KiB  
Article
Examination of Correlates to Health-Related Quality of Life in Individuals with Fragile X Syndrome
by Marika C. Coffman, Rebecca C. Shaffer, Lauren M. Schmitt, Kelli C. Dominick, Ernest Pedapati, Angel Wang, Elizabeth Berry-Kravis, Nicole Tartaglia and Craig A. Erickson
Brain Sci. 2020, 10(4), 213; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci10040213 - 04 Apr 2020
Cited by 6 | Viewed by 3133
Abstract
Health-related quality of life (HRQoL) is a multidimensional concept involving physical, psychological, social, and cognitive aspects of life. Individuals with Fragile X syndrome (FXS) experience a life-long disorder that impacts the HRQoL of the affected individual and their family. Thus, HRQoL may be [...] Read more.
Health-related quality of life (HRQoL) is a multidimensional concept involving physical, psychological, social, and cognitive aspects of life. Individuals with Fragile X syndrome (FXS) experience a life-long disorder that impacts the HRQoL of the affected individual and their family. Thus, HRQoL may be an important outcome measure following intervention. However, it is yet not known whether HRQoL concerns relate to observed impairments in FXS. In the present study, we examined the nature and degree of association between HRQoL and established measures of functioning in FXS using the Parent Report for Children version of the PedsQL 4.0 Generic Core Scales and Cognitive Functioning Scale. We observed significant relationships between HRQoL a nd measures of adaptive behavior, maladaptive behaviors, and social functioning. The present study has implications for treatment outcomes for clinical trials in FXS. Full article
(This article belongs to the Special Issue Update on the Treatment of Fragile X Syndrome)
12 pages, 843 KiB  
Article
Language across the Lifespan in Fragile X Syndrome: Characteristics and Considerations for Assessment
by Anne Hoffmann, Angel Wang, Natalie Berger, Lisa Cordeiro, Rebecca Shaffer, Nicole Tartaglia, Craig Erickson and Elizabeth Berry-Kravis
Brain Sci. 2020, 10(4), 212; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci10040212 - 04 Apr 2020
Cited by 6 | Viewed by 3647
Abstract
While it is widely acknowledged that language development is delayed for the majority of individuals with fragile X syndrome (FXS), there has been limited research into how best to assess this area. This study aimed to deepen the understanding of standardized language assessment [...] Read more.
While it is widely acknowledged that language development is delayed for the majority of individuals with fragile X syndrome (FXS), there has been limited research into how best to assess this area. This study aimed to deepen the understanding of standardized language assessment in FXS by addressing the three following objectives: (1) Examine the feasibility and validity of widely-used, standardized assessments in participants with FXS; (2) describe linguistic and cognitive profiles for a large sample of individuals with FXS; and (3) Compare results obtained from objective testing in clinic to those obtained using caregiver report. Results indicate that previous results indicating strong correlations between cognition and language results hold true across a wide range of ages as well as across multiple assessments, with an exception in very young children. Caregiver report tended to give lower estimates of language ability than what was found using an objectively administered assessment. Appropriate assessments remain difficult to find as a significant percentage of individuals scored at floor when scaled scores were calculated. Further, a sub-group of participants were coded for behavioral response to testing demands, the majority being able to complete a standardized assessment. These results speak to the need for assessments that provide a wider range of items so individuals can both achieve a valid score and demonstrate progress in their attainment of language skills. Full article
(This article belongs to the Special Issue Update on the Treatment of Fragile X Syndrome)
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11 pages, 857 KiB  
Article
The Relationship between Expressive Language Sampling and Clinical Measures in Fragile X Syndrome and Typical Development
by Rebecca C. Shaffer, Lauren Schmitt, Angela John Thurman, Leonard Abbeduto, Michael Hong, Ernest Pedapati, Kelli Dominick, John Sweeney and Craig Erickson
Brain Sci. 2020, 10(2), 66; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci10020066 - 26 Jan 2020
Cited by 22 | Viewed by 4811
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Update on the Treatment of Fragile X Syndrome)
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