scholarly journals Delineating Repetitive Behavior Profiles across the Lifespan in Fragile X Syndrome

2020 ◽  
Vol 10 (4) ◽  
pp. 239
Author(s):  
Debra L. Reisinger ◽  
Rebecca C. Shaffer ◽  
Nicole Tartaglia ◽  
Elizabeth Berry-Kravis ◽  
Craig A. Erickson
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Repetitive Behavior ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Motor Behaviors ◽  
Sensory Motor ◽  
Adolescents And Adults ◽  
Males And Females ◽  
The Impact

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.

Altered Behaviour Associated With Autism in a Mouse Model of Fragile X Syndrome Treated With Bacteroides Fragilis BF839

2020 ◽  
Author(s):  
Chu-Hui Lin ◽  
Ting Zeng ◽  
Jian-Hong Lin ◽  
Feng Xiao ◽  
Bing-Mei Li ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Escape Latency ◽  
Fragile X ◽  
Bacteroides Fragilis ◽  
Autism Spectrum ◽  
Cognitive Capacity ◽  
Surrounding Environment ◽  
Maze Test ◽  
Plus Maze ◽  
The Impact

Abstract Background: Fragile X syndrome (FXS), tightly related to the morbidity of Autism spectrum disorder (ASD), is a common hereditary syndrome often associated with retardation of intelligence. Some key symptoms of ASD such as anxiety, cognitive impairment and social anxiety disorder are also the predominant features in FXS. Children with ASD are often performed with gastrointestinal symptoms. According to the existing research, with the treatment with Bacteroides Fragilis BF839, mice with ASD will have better performance in communication and social behaviours with less anxiety and perceptual disorder. In this article, we have observed the impact of Bacteroides Fragilis BF839, a well-established Chinese bacteria strain with the human intestine origin, on mice with FXS and their behavioural disorders accordingly. Result: Based on the Open Field test, compared to the Fmr1KO group, mice treated with BF839 showed prolonged staying time in the center of the container. This finding suggests that BF839 can improve Fmr1KO mice's self-exploration behaviour and dented their anxiety. The Elevated Plus Maze test indicated BF839 treated mice presented more activities in entering open arms, prolonged time of staying and significantly less distance travelled at the plus-maze, along with less entering behaviours in the closed arms with less time of staying and more distance travelled. This result proved that with the treatment of BF839, Fmr1KO mice have improved ability in recognizing the surrounding environment and greater senses at detecting danger. Three-box Social Interaction test confirmed that BF839 strengthens the social novelty preference of the Fmr1KO mice, proven by their increasing duration and frequency in social interacting with the stranger mouse. The final experiment named the Pool Maze test presented the result that on the fourth day, BF839 treated mice have shown significantly shortened escape latency. Meanwhile, on Day 5, BF839 treated group performed increasing frequency in passing through the platform, which, along with the shortened escape latency, demonstrated BF839 has the function of improving Fmr1KO mice's cognitive capacity and their ability to extract information from the surrounding environment.Conclusion: Based on the outcome of each test performed, Bacteroides Fragilis BF839 can successfully improve Autism related abnormal behaviours in mice with FXS. Bacteroides Fragilis BF839 can be a potential intervention strategy in treating FXS and ASD safely and effectively.

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

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.

scholarly journals Autism in Fragile X Syndrome; A Functional MRI Study of Facial Emotion-Processing

Genes ◽  
2019 ◽  
Vol 10 (12) ◽  
pp. 1052
Author(s):  
Andrew G. McKechanie ◽  
Sonya Campbell ◽  
Sarah E. A. Eley ◽  
Andrew C. Stanfield
Keyword(s):  
Autism Spectrum Disorder ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Emotion Processing ◽  
Autistic Traits ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Facial Emotion ◽  
Facial Emotion Processing ◽  
The Impact

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism spectrum disorder, and among those with fragile X syndrome, approximately 1/3rd meet a threshold for an autism spectrum disorder (ASD) diagnosis. Previous functional imaging studies of fragile X syndrome have typically focused on those with fragile X syndrome compared to either neurotypical or autism spectrum disorder control groups. Further, the majority of previous studies have tended to focus on those who are more intellectually able than is typical for fragile X syndrome. In this study, we examine the impact of autistic traits in individuals with fragile X syndrome on a paradigm looking at facial emotion processing. The study included 17 individuals with fragile X syndrome, of whom 10 met criteria for autism as measured by the Autism Diagnostic Observation Schedule (ADOS). Prior to the scan, participants rehearsed on a mock scanner to help acclimatize to the scanner environment and thus allow more severely affected individuals to participate. The task examined the blood-oxygen-level-dependent (BOLD) response to fearful and neutral faces taken from the Ekman faces series. Individuals in the autism group had a region of significantly reduced activity centered on the left superior temporal gyrus, compared to those with FXS alone, in response to the fearful faces. We suggest that autism in individuals with fragile X syndrome is associated with similar changes in the neurobiology of facial emotion processing as seen in idiopathic autism.

scholarly journals Early negative affect in males and females with fragile X syndrome: implications for anxiety and autism

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Carla A. Wall ◽  
Abigail L. Hogan ◽  
Elizabeth A. Will ◽  
Samuel McQuillin ◽  
Bridgette L. Kelleher ◽  
...  
Keyword(s):  
Young Children ◽  
Negative Affect ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Autism Spectrum ◽  
Prospective Longitudinal Study ◽  
Sex Effects ◽  
Increased Risk ◽  
Males And Females ◽  
Prospective Longitudinal

Abstract Background Fragile X syndrome (FXS) is a genetic disorder that is highly comorbid with anxiety and autism spectrum disorder (ASD). Elevated negative affect in young children has been associated with increased risk for both anxiety and ASD; however, these relations remain poorly understood in FXS. Methods The present prospective longitudinal study examined the trajectory of negative affect from infancy through preschool in males and females with FXS and typical development and its relation to anxiety and ASD. Results Results indicate a complex association reflecting group, developmental, and sex effects. Specifically, the group with FXS displayed a trajectory of increasing negative affect across age that was distinct from the typical controls. This atypical trajectory of negative affect in FXS was driven by sex effects in that males showed lower negative affect during infancy followed by steep increases across the toddler and preschool years whereas the females displayed a flatter trajectory. Finally, elevated negative affect predicted anxiety symptoms in males, but not females, with no relationship to ASD in males or females with FXS. Conclusions The current work addresses the importance of studying the development of psychopathology in a specific neurogenetic population. Temperamental negative affect was shown to be an important early marker for anxiety in young children with FXS, with subtle differences observed between males and females.

scholarly journals Neural Correlates of Auditory Hypersensitivity in Fragile X Syndrome

2021 ◽  
Vol 12 ◽  
Author(s):  
Khaleel A. Razak ◽  
Devin K. Binder ◽  
Iryna M. Ethell
Keyword(s):  
Fragile X Syndrome ◽  
Sensory Processing ◽  
Fragile X ◽  
Neural Correlates ◽  
Autism Spectrum ◽  
Gamma Band ◽  
Repetitive Behaviors ◽  
Neural Responses ◽  
Eeg Abnormalities ◽  
Eeg Recordings

The mechanisms underlying the common association between autism spectrum disorders (ASD) and sensory processing disorders (SPD) are unclear, and treatment options to reduce atypical sensory processing are limited. Fragile X Syndrome (FXS) is a leading genetic cause of intellectual disability and ASD behaviors. As in most children with ASD, atypical sensory processing is a common symptom in FXS, frequently manifesting as sensory hypersensitivity. Auditory hypersensitivity is a highly debilitating condition in FXS that may lead to language delays, social anxiety and ritualized repetitive behaviors. Animal models of FXS, including Fmr1 knock out (KO) mouse, also show auditory hypersensitivity, providing a translation relevant platform to study underlying pathophysiological mechanisms. The focus of this review is to summarize recent studies in the Fmr1 KO mouse that identified neural correlates of auditory hypersensitivity. We review results of electroencephalography (EEG) recordings in the Fmr1 KO mice and highlight EEG phenotypes that are remarkably similar to EEG findings in humans with FXS. The EEG phenotypes associated with the loss of FMRP include enhanced resting EEG gamma band power, reduced cross frequency coupling, reduced sound-evoked synchrony of neural responses at gamma band frequencies, increased event-related potential amplitudes, reduced habituation of neural responses and increased non-phase locked power. In addition, we highlight the postnatal period when the EEG phenotypes develop and show a strong association of the phenotypes with enhanced matrix-metalloproteinase-9 (MMP-9) activity, abnormal development of parvalbumin (PV)-expressing inhibitory interneurons and reduced formation of specialized extracellular matrix structures called perineuronal nets (PNNs). Finally, we discuss how dysfunctions of inhibitory PV interneurons may contribute to cortical hyperexcitability and EEG abnormalities observed in FXS. Taken together, the studies reviewed here indicate that EEG recordings can be utilized in both pre-clinical studies and clinical trials, while at the same time, used to identify cellular and circuit mechanisms of dysfunction in FXS. New therapeutic approaches that reduce MMP-9 activity and restore functions of PV interneurons may succeed in reducing FXS sensory symptoms. Future studies should examine long-lasting benefits of developmental vs. adult interventions on sensory phenotypes.

scholarly journals Melatonin as an Interventional Novel Candidate for the Individual with Autistic Fragile X Syndrome in Human

2017 ◽  
Author(s):  
Jinyoung Won ◽  
Yunho Jin ◽  
Tae Ho Lee ◽  
Sang-Rae Lee ◽  
Kyu-Tae Chang ◽  
...  
Keyword(s):  
Circadian Rhythm ◽  
Fragile X Syndrome ◽  
Molecular Mechanisms ◽  
Fragile X ◽  
Neuroprotective Effect ◽  
Circadian Variation ◽  
Autism Spectrum ◽  
Behavioral Abnormalities ◽  
Metabolic Systems ◽  
The Impact

Fragile X syndrome (FXS) is the most frequent monogenic form of autism spectrum disorder (ASD). Autistic FXS is caused by loss of the fmr1 gene product, the fragile X mental retardation protein (FMRP), triggering physiological and behavioral abnormalities. It is correlated with clock components for behavioral circadian rhythm. Mutation of this gene causes the disturbances in sleep patterns and circadian behavior commonly observed in patients with autistic FXS, accompanied by frequent dysregulation of melatonin synthesis and melatonin-dependent signaling. These changes impair vigilance, learning and memory, and are also linked to autistic behavior including the abnormal anxiety response. However, although several possible causes, symptoms, and clinical features of ASD have been investigated, the correlation between an altered circadian rhythm and autistic FXS has not been extensively studied. Recent works have highlighted the impact of melatonin on the nervous, immune, and metabolic systems. Even though utilization of melatonin for sleep disorder in ASD has been considered in clinical research, further studies should be aimed at its neuroprotective role in ASD during developmental period. In this review, we focus on the regulatory circuits involved in melatonin dysregulation and circadian system disruption in those with autistic FXS. Additionally, we discuss the neuroprotective effect of melatonin intervention. This may improve neuroplasticity and physical capability. We also review the underlying molecular mechanisms, and suggest that melatonin may be a useful novel treatment for autistic FXS, countering the adverse effects of circadian variation.

scholarly journals The Impact of COVID-19 on the Adaptive Functioning, Behavioral Problems, and Repetitive Behaviors of Italian Children with Autism Spectrum Disorder: An Observational Study

Children ◽  
2021 ◽  
Vol 8 (2) ◽  
pp. 96
Author(s):  
Martina Siracusano ◽  
Eugenia Segatori ◽  
Assia Riccioni ◽  
Leonardo Emberti Gialloreti ◽  
Paolo Curatolo ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Behavioral Problems ◽  
Adaptive Functioning ◽  
Children With Autism ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Assessment System ◽  
Spectrum Disorder ◽  
Adaptive Skills ◽  
The Impact

Children with autism spectrum disorder (ASD) and their families have represented a fragile population on which the extreme circumstances of the COVID-19 outbreak may have doubly impaired. Interruption of therapeutical interventions delivered in-person and routine disruption constituted some of the main challenges they had to face. This study investigated the impact of the COVID-19 lockdown on adaptive functioning, behavioral problems, and repetitive behaviors of children with ASD. In a sample of 85 Italian ASD children (mean age 7 years old; 68 males, 17 females), through a comparison with a baseline evaluation performed during the months preceding COVID-19, we evaluated whether after the compulsory home confinement any improvement or worsening was reported by parents of ASD individuals using standardized instruments (Adaptive Behavior Assessment System (Second Edition), Achenbach Child Behavior Checklist, Repetitive Behavior Scale-Revised). No significant worsening in the adaptive functioning, problematic, and repetitive behaviors emerged after the compulsory home confinement. Within the schooler children, clinical stability was found in reference to both adaptive skills and behavioral aspects, whereas within preschoolers, a significant improvement in adaptive skills emerged and was related to the subsistence of web-delivered intervention, parental work continuance, and online support during the lockdown.

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