BACKGROUND: Self-determination refers to setting goals and making decisions regarding one\'s own life with support from others as needed. Research on people with intellectual and developmental disabilities has established the importance of self-determination for quality of life outcomes, such as increased independence and life satisfaction. However, self-determination has not been characterised specifically in fragile X syndrome (FXS), the leading inherited cause of intellectual disability. Relative to youth with other forms of intellectual and developmental disabilities, youth with FXS may face exceptional barriers to the development of self-determined behaviour. In addition to intellectual disability, the FXS behavioural profile is characterised by high rates of autism and anxiety that may further limit opportunities for youth with FXS. The heritable nature of the condition can also yield a distinctive family environment, with siblings and parents also living with fragile X or its associated conditions. Considering these unique challenges, the present study examined self-determination in young adult males and females with FXS and explored whether factors such as language skills, adaptive behaviour and autism traits were associated with self-determination capacity and opportunities.
METHODS: The present study included 9 females and 36 males with FXS between the ages of 17 and 25 years. Caregivers (mothers or fathers) completed the American Institute for Research Self-Determination Assessment, which is a questionnaire that yields three scores: self-determination capacity, opportunities for self-determination at home and opportunities for self-determination at school.
RESULTS: Caregivers endorsed a wide range of self-determination capacity and opportunities, with ratings for opportunities at home and school exceeding ratings of capacity. Better adaptive behaviour skills were associated with more self-determination capacity, and the presence of more autism traits was associated with fewer opportunities at school.
CONCLUSIONS: Results from this study contribute to our understanding of avenues to best support young adults with FXS as they transition to adulthood. Our findings also have implications for practice, such that interventions targeting adaptive behaviours and self-determination may be an effective approach for promoting autonomy and independence for young adults with FXS. Additionally, caregivers and educators should continue to provide opportunities to practise self-determination, regardless of their perception of capacity.

In this study, the potential role and interaction of the APOε and KLOTHO genes on the penetrance of fragile X-associated tremor/ataxia syndrome (FXTAS) and on the IQ trajectory were investigated. FXTAS was diagnosed based on molecular, clinical and radiological criteria. Males with the premutation (PM) over 50 years, 165 with and 34 without an FXTAS diagnosis, were included in this study and were compared based on their APO (ε2-ε3-ε4) and KLOTHO variant (KL-VS) genotypes. The effect of APOε4 on FXTAS stage and on diagnosis did not differ significantly by KL-VS genotype with interaction effect p = 0.662 and p = 0.91, respectively. In the FXTAS individuals with an APOε2 allele, a marginal significance was observed towards a larger decline in verbal IQ (VIQ) in individuals with an APOε4 allele compared to those without an APOε4 allele (p = 0.071). In conclusion, our findings suggest that the APOε4 and KL-VS genotypes alone or through their interaction effect do not appear to predispose to either FXTAS diagnosis or stage in male carriers of the PM allele. A further study is needed to establish the trend of IQ decline in the FXTAS individuals who carry APOε4 with APOε2 compared to those without APOε4.

UNASSIGNED: The purpose of the present study was to assess the psychiatric manifestations of early to middle stages of fragile X-associated tremor-ataxia syndrome (FXTAS) and their relationship with executive function and FMR1 cytosine-guanine-guanine (CGG) repeat numbers across genders.
UNASSIGNED: Cross-sectional data from 100 participants (62 men, 38 women; mean±SD age=67.11±7.90 years) with FXTAS stage 1, 2, or 3 were analyzed, including demographic information, cognitive measures, psychiatric assessments (Symptom Checklist-90-Revised and Behavioral Dyscontrol Scale-II [BDS-II]), and CGG repeat number.
UNASSIGNED: Participants with FXTAS stage 3 exhibited significantly worse psychiatric outcomes compared with participants with either stage 1 or 2, with distinct gender-related differences. Men showed differences in anxiety and hostility between stage 3 and combined stages 1 and 2, whereas women exhibited differences in anxiety, depression, interpersonal sensitivity, obsessive-compulsive symptoms, and somatization, as well as in the Global Severity Index, the Positive Symptom Distress Index, and the Positive Symptom Total. Among male participants, negative correlations were observed between BDS-II total scores and obsessive-compulsive symptoms, as well as between anxiety and CGG repeat number.
UNASSIGNED: These findings suggest that even at early FXTAS stages, patients have significant cognitive and other psychiatric symptoms, with notable gender-specific differences. This study underscores the clinical and prognostic relevance of comorbid psychiatric conditions in FXTAS, highlighting the need for early intervention and targeted support for individuals with relatively mild motor deficits.

It is currently not known whether mRNAs fulfill structural roles in the cytoplasm. Here, we report the fragile X-related protein 1 (FXR1) network, an mRNA-protein (mRNP) network present throughout the cytoplasm, formed by FXR1-mediated packaging of exceptionally long mRNAs. These mRNAs serve as an underlying condensate scaffold and concentrate FXR1 molecules. The FXR1 network contains multiple protein binding sites and functions as a signaling scaffold for interacting proteins. We show that it is necessary for RhoA signaling-induced actomyosin reorganization to provide spatial proximity between kinases and their substrates. Point mutations in FXR1, found in its homolog FMR1, where they cause fragile X syndrome, disrupt the network. FXR1 network disruption prevents actomyosin remodeling-an essential and ubiquitous process for the regulation of cell shape, migration, and synaptic function. Our findings uncover a structural role for cytoplasmic mRNA and show how the FXR1 RNA-binding protein as part of the FXR1 network acts as an organizer of signaling reactions.

OBJECTIVE: Our purpose was to report on a novel method of identifying variables associated with challenging behaviors in natural interactions between mothers and their adolescents with Fragile X syndrome (FXS).
METHODS: Videotaped interactions of 47 dyads interacting with an iPad game, completing a puzzle, and making a snack and were coded for challenging behaviors by adolescents with FXS, and maternal behaviors that preceded these behaviors. We described the frequencies of adolescent challenging behaviors, then used sequential and survival analyses to identify maternal and adolescent behaviors that preceded self-injurious behavior (SIB) and aggression.
RESULTS: Across all the dyads, 109 instances of SIB and 79 instances of aggression were identified during the 30 min of recorded interaction. Most of these challenging behaviors occurred during the iPad activity. The sequential analysis indicated that maternal requests for behavioral compliance frequently preceded both SIB and aggression. Survival analyses revealed that the likelihood of SIB or aggression was increased if the mothers requested behavioral compliance after the child engaged in another challenging behavior.
CONCLUSIONS: Challenging behaviors including SIB and aggression were frequently observed in many participants. The sequential and survival analyses were useful for identifying precursors to these behaviors. Further research is needed to investigate preventative strategies based on the results of sequential and survival analyses.

Fragile X Syndrome (FXS), the most common inherited form of human intellectual disability, is a monogenic neurodevelopmental disorder caused by a loss-of-function mutation of the FMR1 gene. FMR1 is encoding the Fragile X Messenger Ribonucleo Protein (FMRP) an RNA-binding protein that regulates the translation of synaptic proteins. The absence of FMRP expression has many important consequences on synaptic plasticity and function, leading to the FXS clinical phenotype. Over the last decade, a visual neurosensorial phenotype had been described in the FXS patients as well as in the murine model (Fmr1-/ymice), characterized by retinal deficits associated to retinal perception alterations. However, although the transcriptomic profile in the absence of FMRP has been studied in the cerebral part of the central nervous system (CNS), there are no actual data for the retina which is an extension of the CNS. Herein, we investigate the transcriptomic profile of mRNA from whole retinas of Fmr1-/ymice. Interestingly, we found a specific signature of Fmrp absence on retinal mRNA expression with few common genes compared to other brain studies. Gene Ontology on these retinal specific genes demonstrated an enrichment in retinal development genes as well as in synaptic genes. These alterations could be linked to the reported retinal phenotype of the FXS condition. In conclusion, we describe for the first time, retinal-specific transcriptomic changes in the absence of FMRP.

Fragile X Syndrome (FXS) stands out as a prominent cause of inherited intellectual disability and a prevalent disorder closely linked to autism. FXS is characterized by substantial alterations in social behavior, encompassing social withdrawal, avoidance of eye contact, heightened social anxiety, increased arousal levels, language deficits, and challenges in regulating emotions. Conventional behavioral assessments primarily focus on short-term interactions within controlled settings. In this study, we conducted a comprehensive examination of the adaptive group behavior of Fmr1 KO male mice over a three-day period, without introducing experimental interventions or task-based evaluations. The data unveiled intricate behavioral anomalies, with the most significant changes manifesting during the initial adaptation to unfamiliar environments. Notably, certain behaviors exhibited a gradual return to typical patterns over time. This dynamic Fmr1 KO phenotype exhibited heightened activity, featuring increased exploration, amplified social interest, and an unconventional approach to social interactions characterized by a higher frequency of shorter engagements. These findings contribute to the growing understanding of social behavior in individuals with FXS and underscore the significance of comprehending their adaptive responses in various environmental contexts.

Fragile X syndrome (FXS) is caused by the full mutation in the FMR1 gene on the Xq27.3 chromosome region. It is the most common monogenic cause of autism spectrum disorder (ASD) and inherited intellectual disability (ID). Besides ASD and ID and other symptoms, individuals with FXS may exhibit sleep problems and impairment of circadian rhythm (CR). The Drosophila melanogaster models of FXS, such as dFMR1B55, represent excellent models for research in the FXS field. During this study, sleep patterns and CR in dFMR1B55 mutants were analyzed, using a new platform based on continuous high-resolution videography integrated with a highly-customized version of an open-source software. This methodology provides more sensitive results, which could be crucial for all further research in this model of fruit flies. The study revealed that dFMR1B55 male mutants sleep more and can be considered weak rhythmic flies rather than totally arrhythmic and present a good alternative animal model of genetic disorder, which includes impairment of CR and sleep behavior. The combination of affordable videography and software used in the current study is a significant improvement over previous methods and will enable broader adaptation of such high-resolution behavior monitoring methods.

Intellectual disability is defined as limitations in cognitive and adaptive behavior that often arise during development. Disordered sleep is common in intellectual disability and, given the importance of sleep for cognitive function, it may contribute to other behavioral phenotypes. Animal models of intellectual disability, in particular of monogenic intellectual disability syndromes (MIDS), recapitulate many disease phenotypes and have been invaluable for linking some of these phenotypes to specific molecular pathways. An emerging feature of MIDS, in both animal models and humans, is the prevalence of metabolic abnormalities, which could be relevant for behavior. Focusing on specific MIDS that have been molecularly characterized, we review sleep, circadian, and metabolic phenotypes in animal models and humans and propose that altered metabolic state contributes to the abnormal sleep/circadian phenotypes in MIDS.

Fragile X syndrome (FXS) is the most common genetic cause of autism spectrum disorder engendered by transcriptional silencing of the fragile X messenger ribonucleoprotein 1 (FMR1) gene. Given the early onset of behavioral and molecular changes, it is imperative to know the optimal timing for therapeutic intervention. Case reports documented benefits of metformin treatment in FXS children between 2 and 14 y old. In this study, we administered metformin from birth to Fmr1-/y mice which corrected up-regulated mitogen-2 activated protein kinase/extracellular signal-regulated kinase and mammalian/mechanistic target of rapamycin complex 1 signaling pathways and specific synaptic mRNA-binding targets of FMRP. Metformin rescued increased number of calls in ultrasonic vocalization and repetitive behavior in Fmr1-/y mice. Our findings demonstrate that in mice, early-in-life metformin intervention is effective in treating FXS pathophysiology.