The Relationship between Expressive Language Sampling and Clinical Measures in Fragile X Syndrome and Typical Development

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.

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Joint Engagement and Early Language in Young Children With Fragile X Syndrome

Journal of Speech Language and Hearing Research ◽

10.1044/2016_jslhr-l-15-0005 ◽

2016 ◽

Vol 59 (5) ◽

pp. 1087-1098 ◽

Cited By ~ 2

Author(s):

Laura J. Hahn ◽

Nancy C. Brady ◽

Kandace K. Fleming ◽

Steven F. Warren

Keyword(s):

Young Children ◽

Fragile X Syndrome ◽

Rating Scale ◽

Fragile X ◽

Language Skills ◽

Expressive Language ◽

Autism Spectrum ◽

Language Abilities ◽

Joint Engagement ◽

Autism Symptomatology

PurposeIn this study, we examine joint engagement (JE) in young children with fragile X syndrome (FXS) and its relationship to language abilities and autism spectrum disorder symptomatology at 24 to 36 months (toddler period) and 59 to 68 months (child period).MethodParticipants were 28 children with FXS (24 boys, four girls) and their mothers. Videotaped home observations were conducted during the toddler period and coded for JE. Language abilities were measured at both ages from a developmental assessment, a functional measure, and from a language sample. The Childhood Autism Rating Scale (Schopler, Reichler, & Renner, 1988) was completed at both ages.ResultsChildren with FXS spent more time in supported JE than in coordinated JE. Using a weighted JE variable, we found that children with FXS who had higher weighted JE scores also had more advanced expressive language skills at both the toddler and child periods. Weighted JE was negatively related to autism symptomatology in the toddler period.ConclusionThis study provides evidence that children with FXS who use more JE also have more advanced expressive language skills in early development. Therefore, existing early interventions that target JE behaviors may be effective for promoting language, social communication, and social interaction in this population.

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Perseveration in the Connected Speech of Boys with Fragile X Syndrome with and Without Autism Spectrum Disorder

American Journal on Intellectual and Developmental Disabilities ◽

10.1352/1944-7558-117.5.384 ◽

2012 ◽

Vol 117 (5) ◽

pp. 384-399 ◽

Cited By ~ 24

Author(s):

Gary E. Martin ◽

Joanne E. Roberts ◽

Nancy Helm-Estabrooks ◽

John Sideris ◽

Jacqueline Vanderbilt ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Social Interaction ◽

Fragile X Syndrome ◽

Fragile X ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Typically Developing ◽

Connected Speech ◽

Language Sampling ◽

Language Characteristic

Abstract Verbal perseveration is a frequently reported language characteristic of males with Fragile X syndrome and may be a defining feature or hallmark of the syndrome. We compared the verbal perseveration of boys with Fragile X syndrome with (n = 29) and without (n = 30) autism spectrum disorder, boys with Down syndrome (n = 27), and typically developing boys (n = 25) at similar nonverbal mental ages. During a social interaction, boys with both Fragile X syndrome and autism spectrum disorder produced significantly more topic perseveration than all other groups. In social interaction as compared to narration, boys with Fragile X syndrome (regardless of autism status) produced significantly more topic perseveration. These findings suggest that autism status, as well as language sampling context, affect perseveration in boys with Fragile X syndrome.

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Phenotypic Trade-Offs: Deciphering the Impact of Neurodiversity on Drug Development in Fragile X Syndrome

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.730987 ◽

2021 ◽

Vol 12 ◽

Author(s):

Truong An Bui ◽

Julie Shatto ◽

Tania Cuppens ◽

Arnaud Droit ◽

François V. Bolduc

Keyword(s):

Clinical Trials ◽

Fragile X Syndrome ◽

Fragile X ◽

Single Gene ◽

Specific Treatment ◽

Autism Spectrum ◽

New Paradigm ◽

Trade Offs ◽

Wide Range ◽

The Impact

Fragile X syndrome (FXS) is the most common single-gene cause of intellectual disability and autism spectrum disorder. Individuals with FXS present with a wide range of severity in multiple phenotypes including cognitive delay, behavioral challenges, sleep issues, epilepsy, and anxiety. These symptoms are also shared by many individuals with other neurodevelopmental disorders (NDDs). Since the discovery of the FXS gene, FMR1, FXS has been the focus of intense preclinical investigation and is placed at the forefront of clinical trials in the field of NDDs. So far, most studies have aimed to translate the rescue of specific phenotypes in animal models, for example, learning, or improving general cognitive or behavioral functioning in individuals with FXS. Trial design, selection of outcome measures, and interpretation of results of recent trials have shown limitations in this type of approach. We propose a new paradigm in which all phenotypes involved in individuals with FXS would be considered and, more importantly, the possible interactions between these phenotypes. This approach would be implemented both at the baseline, meaning when entering a trial or when studying a patient population, and also after the intervention when the study subjects have been exposed to the investigational product. This approach would allow us to further understand potential trade-offs underlying the varying effects of the treatment on different individuals in clinical trials, and to connect the results to individual genetic differences. To better understand the interplay between different phenotypes, we emphasize the need for preclinical studies to investigate various interrelated biological and behavioral outcomes when assessing a specific treatment. In this paper, we present how such a conceptual shift in preclinical design could shed new light on clinical trial results. Future clinical studies should take into account the rich neurodiversity of individuals with FXS specifically and NDDs in general, and incorporate the idea of trade-offs in their designs.

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The Use of Peptides in the Treatment of Fragile X Syndrome: Challenges and Opportunities

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.754485 ◽

2021 ◽

Vol 12 ◽

Author(s):

Alice Romagnoli ◽

Daniele Di Marino

Keyword(s):

Fragile X Syndrome ◽

Protein Interactions ◽

Rna Binding ◽

Fragile X ◽

Pharmaceutical Research ◽

Autism Spectrum ◽

New Drugs ◽

Protein Protein Interactions ◽

Wide Range ◽

Challenges And Opportunities

Fragile X Syndrome (FXS) is the most frequent cause of inherited intellectual disabilities and autism spectrum disorders, characterized by cognitive deficits and autistic behaviors. The silencing of the Fmr1 gene and consequent lack of FMRP protein, is the major contribution to FXS pathophysiology. FMRP is an RNA binding protein involved in the maturation and plasticity of synapses and its absence culminates in a range of morphological, synaptic and behavioral phenotypes. Currently, there are no approved medications for the treatment of FXS, with the approaches under study being fairly specific and unsatisfying in human trials. Here we propose peptides/peptidomimetics as candidates in the pharmacotherapy of FXS; in the last years this class of molecules has catalyzed the attention of pharmaceutical research, being highly selective and well-tolerated. Thanks to their ability to target protein-protein interactions (PPIs), they are already being tested for a wide range of diseases, including cancer, diabetes, inflammation, Alzheimer's disease, but this approach has never been applied to FXS. As FXS is at the forefront of efforts to develop new drugs and approaches, we discuss opportunities, challenges and potential issues of peptides/peptidomimetics in FXS drug design and development.

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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

Journal of Neurodevelopmental Disorders ◽

10.1186/s11689-020-09314-5 ◽

2020 ◽

Vol 12 (1) ◽

Cited By ~ 1

Author(s):

Leonard Abbeduto ◽

Elizabeth Berry-Kravis ◽

Audra Sterling ◽

Stephanie Sherman ◽

Jamie O. Edgin ◽

...

Keyword(s):

Construct Validity ◽

Fragile X Syndrome ◽

Outcome Measures ◽

Fragile X ◽

Expressive Language ◽

Practice Effects ◽

Original Publication ◽

Retest Reliability ◽

Language Sampling ◽

Test Retest Reliability

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

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A neurophysiological model of speech production deficits in fragile X syndrome

Brain Communications ◽

10.1093/braincomms/fcz042 ◽

2019 ◽

Vol 2 (1) ◽

Cited By ~ 1

Author(s):

Lauren M Schmitt ◽

Jun Wang ◽

Ernest V Pedapati ◽

Angela John Thurman ◽

Leonard Abbeduto ◽

...

Keyword(s):

Fragile X Syndrome ◽

Speech Production ◽

Fragile X ◽

Expressive Language ◽

Temporal Cortex ◽

Autism Spectrum ◽

Event Related Potential ◽

Speech Sounds ◽

Speech Activity ◽

Gamma Power

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

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Physiological Arousal in Autism and Fragile X Syndrome: Group Comparisons and Links With Pragmatic Language

American Journal on Intellectual and Developmental Disabilities ◽

10.1352/1944.7558-118.6.475 ◽

2013 ◽

Vol 118 (6) ◽

pp. 475-495 ◽

Cited By ~ 25

Author(s):

Jessica Klusek ◽

Gary E. Martin ◽

Molly Losh

Keyword(s):

Fragile X Syndrome ◽

Language Impairment ◽

Fragile X ◽

Cardiac Activity ◽

Vagal Tone ◽

Autism Spectrum ◽

Pragmatic Language ◽

Typical Development ◽

Expressive Vocabulary

Abstract This study tested the hypothesis that pragmatic (i.e., social) language impairment is linked to arousal dysregulation in autism spectrum disorder (ASD) and fragile X syndrome (FXS). Forty boys with ASD, 39 with FXS, and 27 with typical development (TD), aged 4–15 years, participated. Boys with FXS were hyperaroused compared to boys with TD but did not differ from boys with ASD. Dampened vagal tone predicted pragmatic impairment in ASD, and associations emerged between cardiac activity and receptive/expressive vocabulary across groups. Findings support autonomic dysfunction as a mechanism underlying pragmatic impairment in ASD and suggest that biophysiological profiles are shared in ASD and FXS, which has implications for understanding the role of fragile X mental retardation-1 (FMR1, the FXS gene) in the pathophysiology of ASD.

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Clinical Development of Targeted Fragile X Syndrome Treatments: An Industry Perspective

Brain Sciences ◽

10.3390/brainsci8120214 ◽

2018 ◽

Vol 8 (12) ◽

pp. 214 ◽

Cited By ~ 16

Author(s):

Anna Lee ◽

Pamela Ventola ◽

Dejan Budimirovic ◽

Elizabeth Berry-Kravis ◽

Jeannie Visootsak

Keyword(s):

Clinical Trials ◽

Mental Retardation ◽

Intellectual Disability ◽

Fragile X Syndrome ◽

Fragile X ◽

Basic Research ◽

Autism Spectrum ◽

Pharmacological Agents ◽

Fragile X Mental Retardation ◽

Wide Range

Fragile X syndrome (FXS) is the leading known cause of inherited intellectual disability and autism spectrum disorder. It is caused by a mutation of the fragile X mental retardation 1 (FMR1) gene, resulting in a deficit of fragile X mental retardation protein (FMRP). The clinical presentation of FXS is variable, and is typically associated with developmental delays, intellectual disability, a wide range of behavioral issues, and certain identifying physical features. Over the past 25 years, researchers have worked to understand the complex relationship between FMRP deficiency and the symptoms of FXS and, in the process, have identified several potential targeted therapeutics, some of which have been tested in clinical trials. Whereas most of the basic research to date has been led by experts at academic institutions, the pharmaceutical industry is becoming increasingly involved with not only the scientific community, but also with patient advocacy organizations, as more promising pharmacological agents are moving into the clinical stages of development. The objective of this review is to provide an industry perspective on the ongoing development of mechanism-based treatments for FXS, including identification of challenges and recommendations for future clinical trials.

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