Fragile X Syndrome and FMR1 premutation: results from a survey on associated conditions and treatment priorities in Italy.

BACKGROUND AND OBJECTIVES: Fragile X Syndrome (FXS) is the most common cause of inherited intellectual disability, caused by CGG-repeat expansions (> 200) in the FMR1 gene leading to lack of expression. Espansion between 55 and 200 triplets fall within the premutation range (PM) and can lead to different clinical conditions, including fragile X- primary ovarian insufficiency (FXPOI), fragile X-associated neuropsychiatric disorders (FXAND) and fragile X-associated tremor/ataxia syndrome (FXTAS). Although there is not a current cure for FXS and for the Fragile X-PM associated conditions (FXPAC), timely diagnosis as well as the implementation of treatment strategies, psychoeducation and behavioral intervention may improve the quality of life (QoL) of people with FXS or FXPAC. With the aim to investigate the main areas of concerns and the priorities of treatment in these populations, the Italian National Fragile X Association in collaboration with Bambino Gesù Children's Hospital, conducted a survey among Italian participants. METHOD: Here, we present a survey based on the previous study that Weber and colleagues conducted in 2019 and that aimed to investigate the main symptoms and challenges in American individuals with FXS. The survey has been translated into Italian language to explore FXS needs of treatment also among Italian individuals affected by FXS, family members, caretakers, and professionals. Furthermore, we added a section designated only to people with PM, to investigate the main symptoms, daily living challenges and treatment priorities. RESULTS: Anxiety, challenging behaviors, language difficulties and learning disabilities were considered the major areas of concern in FXS, while PM was reported as strongly associated to cognitive problems, social anxiety, and overthinking. Anxiety was reported as a treatment priority in both FXS and PM. CONCLUSION: FXS and PM can be associated with a range of cognitive, affective, and physical health complications. Taking a patient-first perspective may help clinicians to better characterize the cognitive-behavioral phenotype associated to these conditions, and eventually to implement tailored therapeutic approaches.

Fragile X-associated tremor/ataxia syndrome treated with multitarget deep brain stimulation.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive hereditary neurodegenerative disorder which causes intention tremor and cerebellar ataxia. It typically affects the ageing population. Deep brain stimulation (DBS) is widely accepted in the treatment of common movement disorders and has been trialled in treating rare and complex neurodegenerative disorders. We report a case of a man in his 40s with a long history of tremor affecting his hands. MRI brain revealed high T2 signal in the middle cerebellar peduncles. Genetic testing revealed FMR1 premutation confirming the diagnosis of FXTAS. Subsequently, he was treated with multitarget DBS of the ventralis intermediate nucleus and ventralis oralis posterior nuclei bilaterally, with excellent neurological function at 9 years follow-up. This case suggests multitarget DBS for FXTAS with neurophysiology-guided DBS programming can provide excellent long-term tremor suppression in selected patients.

Proteomics insights into fragile X syndrome: Unraveling molecular mechanisms and therapeutic avenues.

Fragile X Syndrome (FXS) is a neurodevelopment disorder characterized by cognitive impairment, behavioral challenges, and synaptic abnormalities, with a genetic basis linked to a mutation in the FMR1 (Fragile X Messenger Ribonucleoprotein 1) gene that results in a deficiency or absence of its protein product, Fragile X Messenger Ribonucleoprotein (FMRP). In recent years, mass spectrometry (MS) - based proteomics has emerged as a powerful tool to uncover the complex molecular landscape underlying FXS. This review provides a comprehensive overview of the proteomics studies focused on FXS, summarizing key findings with an emphasis on dysregulated proteins associated with FXS. These proteins span a wide range of cellular functions including, but not limited to, synaptic plasticity, RNA translation, and mitochondrial function. The work conducted in these proteomic studies provides a more holistic understanding to the molecular pathways involved in FXS and considerably enhances our knowledge into the synaptic dysfunction seen in FXS.

State-of-the-art therapies for fragile X syndrome.

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by a full mutation (> 200 CGG repeats) in the FMR1 gene. FXS is the leading cause of inherited intellectual disabilities and the most commonly known genetic cause of autism spectrum disorder. Children with FXS experience behavioral and sleep problems, anxiety, inattention, learning difficulties, and speech and language delays. There are no approved medications for FXS; however, there are several interventions and treatments aimed at managing the symptoms and improving the quality of life of individuals with FXS. A combination of non-pharmacological therapies and pharmacotherapy is currently the most effective treatment for FXS. Currently, several targeted treatments, such as metformin, sertraline, and cannabidiol, can be used by clinicians to treat FXS. Gene therapy is rapidly developing and holds potential as a prospective treatment option. Soon its efficacy and safety in patients with FXS will be demonstrated. WHAT THIS PAPER ADDS: Targeted treatment of fragile X syndrome (FXS) is the best current therapeutic approach. Gene therapy holds potential as a prospective treatment for FXS in the future.

A holistic approach to fragile X syndrome integrated guidance for person-centred care.

BACKGROUND: The Fragile X community has expressed a desire for centralised, national guidelines in the form of integrated guidance for Fragile X Syndrome (FXS). METHODS: This article draws on existing literature reviews, primary research and clinical trials on FXS, a Fragile X Society conference workshop and first-hand experience of clinicians who have worked with those living with FXS over many years. RESULTS: The article scopes proposed integrated guidance over the life course, including appendices of symptoms, comorbidities and referral options for FXS and Fragile X Premutation Associated Conditions. CONCLUSION: Integrated guidance would provide an authoritative source for doctors, health professionals, therapists, care workers, social workers, educators, employers, families and those living with FXS, so that a holistic, person-centred approach can be taken across the United Kingdom to garner the best outcomes for those with FXS.

Insight and Recommendations for Fragile X-Premutation-Associated Conditions from the Fifth International Conference on FMR1 Premutation.

The premutation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene is characterized by an expansion of the CGG trinucleotide repeats (55 to 200 CGGs) in the 5' untranslated region and increased levels of FMR1 mRNA. Molecular mechanisms leading to fragile X-premutation-associated conditions (FXPAC) include cotranscriptional R-loop formations, FMR1 mRNA toxicity through both RNA gelation into nuclear foci and sequestration of various CGG-repeat-binding proteins, and the repeat-associated non-AUG (RAN)-initiated translation of potentially toxic proteins. Such molecular mechanisms contribute to subsequent consequences, including mitochondrial dysfunction and neuronal death. Clinically, premutation carriers may exhibit a wide range of symptoms and phenotypes. Any of the problems associated with the premutation can appropriately be called FXPAC. Fragile X-associated tremor/ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI), and fragile X-associated neuropsychiatric disorders (FXAND) can fall under FXPAC. Understanding the molecular and clinical aspects of the premutation of the FMR1 gene is crucial for the accurate diagnosis, genetic counseling, and appropriate management of affected individuals and families. This paper summarizes all the known problems associated with the premutation and documents the presentations and discussions that occurred at the International Premutation Conference, which took place in New Zealand in 2023.

Exploring the feasibility of collecting multimodal multiperson assessment data via distance in families affected by fragile X syndrome.

INTRODUCTION: Telehealth is an important tool in helping to provide services for hard-to-reach populations. One population that might benefit from telehealth are individuals with fragile X syndrome (FXS). Although FXS is the leading inherited cause of intellectual disability, it is nonetheless a low incidence disorder. Individuals with FXS and their families are involved in research studies, clinical trials and receive interventions - many of which are only offered in a few locations in the United States and thus, not easily accessible to many families. The current project explored the feasibility of using telehealth procedures to collect multimodal behavioural and psychological assessment data from these families. METHODS: Participation in the current study involved online surveys, measures of physiological indices of stress, live interviews and observations of mother-child interactions conducted via distance videoconferencing using the family's own technology when possible. Across all modes of data collection, we obtained information regarding the feasibility of participating entirely via distance by documenting missing data as well as each mother's overall impression of participating via distance. RESULTS: Our telehealth procedures were successfully implemented across a wide range of technology platforms with limited difficulty, and we documented little missing data due to technology-related challenges. Perhaps most importantly, however, our sample of mothers reported high satisfaction with participating via distance. DISCUSSION: These findings suggest that a wide range of services and types of assessments may be amenable to telehealth procedures. Further, the findings have immediate applications as the field shifts towards telehealth due to the coronavirus disease 2019 (COVID-19) pandemic.

Research Gaps in Fragile X Syndrome: An Updated Literature Review to Inform Clinical and Public Health Practice.

OBJECTIVE: The phenotypic impact of fragile X syndrome (FXS) has been well-documented since the discovery of the fragile X messenger ribonucleoprotein 1 gene 30 years ago. However, gaps remain in clinical and public health research. The purpose of this literature review was to determine the extent to which these gaps have been addressed and identify targeted areas of future research. METHODS: We conducted an electronic search of several scientific databases using a variety of key words. The search focused on 5 areas identified as research gaps by an earlier review: (1) diagnosis, (2) phenotypic presentation, (3) familial impact, (4) interventions and treatments, and (5) life span perspectives. Inclusion criteria included publication between 2014 and 2020, focus on human subjects, and publication in English. A total of 480 articles were identified, 365 were reviewed, and 112 are summarized in this review. RESULTS: Results are organized into the following categories: (1) FXS phenotype and subtypes (FXS subtypes, medical profile, cognitive/developmental profile, social and behavioral profile); (2) needs of adults; (3) public health needs (clinical diagnosis and newborn screening, health care needs, and access); (4) treatment (treatment priorities, pharmacological treatments, and behavioral and educational interventions); and (5) families (economic burden and mother-child relationship). CONCLUSION: Despite the progress in many areas of FXS research, work remains to address gaps in clinical and public health knowledge. We pose 3 main areas of focused research, including early detection and diagnosis, determinants of health, and development and implementation of targeted interventions.

[Clinical practice guidelines for Fragile X syndrome].

Fragile X syndrome (FXS) is the most common monogenic form of inherited intellectual disability and autism spectrum disorder (ASD). More than 99% of individuals with FXS are caused by the unstable expansion of CGG repeats located within the 5'-untranslated region of the FMR1 gene. The clinical features of FXS include various degrees of cognitive deficit, physical, behavioral and psychiatric problems. Early treatment and prevention from having further affected children can be guided by molecular genetic testing of the FMR1 gene. The following guideline has combined the relevant research, guidelines and consensus worldwide, and summarized the genetic knowledge and clinical treatment for FXS in order to achieve a standardized diagnosis, treatment and prevention for patients and families affected by this disease.

Long-term follow-up of telehealth-enabled behavioral treatment for challenging behaviors in boys with fragile X syndrome.

BACKGROUND: A significant proportion of boys with fragile X syndrome (FXS), the most common known genetic cause of intellectual disability, exhibit challenging behaviors such as aggression and self-injury that can cause significant distress to families. Recent evidence suggests that coaching caregivers to implement functional communication training (FCT) with their child via telehealth can help to ameliorate these behaviors in FXS. In the present study, we followed families who had participated in our previous randomized controlled trial of FCT to evaluate the longer-term effects of FCT on challenging behaviors in this population. METHODS: In study 1, follow-up emails, phone calls, text messages, and letters were sent to caregivers of 48 boys with FXS who had completed our previous study conducted between 2016 and 2019. The main outcome measures administered at follow-up were the Aberrant Behavior Checklist-Community (ABC-C) and the Parenting Stress Index, 4th Edition (PSI-4). In study 2, families who had received FCT treatment but whose child exhibited challenging behaviors daily at follow-up received a 1-h parent training booster session to determine whether the intervention effect could be recovered. RESULTS: Sixteen (66.7%) of 24 families who had received FCT treatment and 18 (75.0%) of 24 families who had received treatment as usual were traced and consented between March and August 2021. The mean follow-up time was 3.1 years (range, 1.4 to 4.2 years). Longitudinal mixed effects analyses indicated that boys who had received FCT were more likely to show improvements on the irritability and lethargy/social withdrawal subscales of the ABC-C over the follow-up interval compared to boys who had continued with treatment as usual. Four of the six boys who had received the booster parent training session via telehealth were reported to exhibit fewer forms of challenging behavior at a 4-week follow-up. CONCLUSIONS: Empowering parents to implement behavior analytic treatments with their child in their own home can have durable effects on maintaining low levels of challenging behaviors in boys with FXS. These data further support the need to implement parent-mediated interventions for challenging behaviors in this population at an early age. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03510156 . Registered 27 April 2018.

Disease-Targeted Treatment Translation in Fragile X Syndrome as a Model for Neurodevelopmental Disorders.

Fragile X syndrome (FXS), the most common monogenic cause of intellectual disability and autism spectrum disorder, has been one of the first neurodevelopmental disorders in which molecular and neuronal mechanisms of disease were identified, leading to the concept of targeting the underlying disease to reverse symptoms. Translating findings in basic science and animal models to humans with FXS has proven difficult. These challenges have prompted the FXS field to organize to build interlocking projects and initiatives to improve consistency of supportive care, make clinical research accessible to families, generate collaborative research on natural history, outcome measures and biomarkers, and create clinical trial consortia and novel trial designs. This work has resulted in improved success in recent clinical trials, providing key steps toward regulatory approval of disease-targeted treatments for FXS. Progress in the FXS field has informed translation of transformative new disease-targeted therapies for other monogenic neurodevelopmental disorders.

AAV-delivered diacylglycerol kinase DGKk achieves long-term rescue of fragile X syndrome mouse model.

Fragile X syndrome (FXS) is the most frequent form of familial intellectual disability. FXS results from the lack of the RNA-binding protein FMRP and is associated with the deregulation of signaling pathways downstream of mGluRI receptors and upstream of mRNA translation. We previously found that diacylglycerol kinase kappa (DGKk), a main mRNA target of FMRP in cortical neurons and a master regulator of lipid signaling, is downregulated in the absence of FMRP in the brain of Fmr1-KO mouse model. Here we show that adeno-associated viral vector delivery of a modified and FMRP-independent form of DGKk corrects abnormal cerebral diacylglycerol/phosphatidic acid homeostasis and FXS-relevant behavioral phenotypes in the Fmr1-KO mouse. Our data suggest that DGKk is an important factor in FXS pathogenesis and provide preclinical proof of concept that its replacement could be a viable therapeutic strategy in FXS.

Fragile X Syndrome: Supportive Treatment, Unmet Needs, and Paths to Novel Interventions and Disease-Targeted Therapies.

Fragile X syndrome (FXS), as a monogenic cause of intellectual disability and autism spectrum disorder, has been one of the first neurodevelopmental disorders in which molecular and neuronal mechanisms of disease have been identified, leading to the concept of targeting the underlying disease to reverse symptoms. Translating findings in basic science and animal models to humans with FXS has proven difficult. These challenges have prompted the FXS field to organize to build interlocking projects to support initiatives to improve supportive care, make clinical research accessible to families, generate collaborative research on natural history and outcome measures, and create clinical trial consortia and novel trial designs.

Family as a Context for Child Development: Mothers with the FMR1 Premutation and Their Children with Fragile X Syndrome.

Fragile X syndrome (FXS) is a genetic disorder caused by changes of the FMR1 gene that is passed along among families. A range of developmental processes may be impacted with wide variation in abilities across individuals with FXS. Mothers of children with FXS are often carriers of a "premutation" expansion on the FMR1 gene, which is associated with its own clinical phenotype. These maternal features may increase individual and family vulnerabilities, including increased risk for depression and anxiety disorders and difficulties in social and cognitive ability. These characteristics may worsen with age, and potentially interact with a child's challenging behaviors and with family dynamics. Thus, families of children with FXS may experience unique challenges related to genetic risk, manifested across both children and parents, that should be considered in therapeutic planning to optimize outcomes for children and their families. In this article, we review core features of the FMR1 premutation as expressed in mothers and aspects of the family environment that interface with developmental outcomes of children with FXS. Recommendations for family-centered support services are discussed.

Responsive Parenting as a Target for Telehealth Language Interventions in Fragile X Syndrome: Implications for Scalability and Best Practices.

This review highlights the ways in which telehealth procedures can be implemented to help bridge the research-to-practice gap in supporting developmental outcomes for youth with fragile X syndrome (FXS). We review how the literature to date has informed potential treatment targets in the areas of speech and language development with a focus on understanding and supporting the dyadic relationship between the child and their biological mother, who is also impacted biologically. Notably, parental responsivity is an area that is strongly related to child language outcomes, both early and into adolescence, and thus, it is an important treatment target for subsequent interventions. To date, several parent-implemented interventions have been done in FXS across a broad age range (2-17-year-olds) all showing support not only that parents are successful in learning responsive strategies but also that there are subsequent impacts to child language development. Moreover, these interventions were successfully implemented at a distance through telehealth procedures including video teleconferencing and shared recordings of parent-child interactions. This review also addresses potential moderators of treatment gains. Implications for scaling such interventions in the future as well as best practices for incorporating telehealth procedures into future research and intervention programs are also discussed.

Genetic removal of p70 S6K1 corrects coding sequence length-dependent alterations in mRNA translation in fragile X syndrome mice.

Loss of the fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS). FMRP is widely thought to repress protein synthesis, but its translational targets and modes of control remain in dispute. We previously showed that genetic removal of p70 S6 kinase 1 (S6K1) corrects altered protein synthesis as well as synaptic and behavioral phenotypes in FXS mice. In this study, we examined the gene specificity of altered messenger RNA (mRNA) translation in FXS and the mechanism of rescue with genetic reduction of S6K1 by carrying out ribosome profiling and RNA sequencing on cortical lysates from wild-type, FXS, S6K1 knockout, and double knockout mice. We observed reduced ribosome footprint (RF) abundance in the majority of differentially translated genes in the cortices of FXS mice. We used molecular assays to discover evidence that the reduction in RF abundance reflects an increased rate of ribosome translocation, which is captured as a decrease in the number of translating ribosomes at steady state and is normalized by inhibition of S6K1. We also found that genetic removal of S6K1 prevented a positive-to-negative gradation of alterations in translation efficiencies (RF/mRNA) with coding sequence length across mRNAs in FXS mouse cortices. Our findings reveal the identities of dysregulated mRNAs and a molecular mechanism by which reduction of S6K1 prevents altered translation in FXS.

Fragile X syndrome.

Paul Hagerman and Randi Hagerman introduce the X-linked neurodevelopmental disorder Fragile X syndrome (FXS) and discuss what causes this disorder and how it can be treated.

DNA Methylation, Mechanisms of FMR1 Inactivation and Therapeutic Perspectives for Fragile X Syndrome.

Among the inherited causes of intellectual disability and autism, Fragile X syndrome (FXS) is the most frequent form, for which there is currently no cure. In most FXS patients, the FMR1 gene is epigenetically inactivated following the expansion over 200 triplets of a CGG repeat (FM: full mutation). FMR1 encodes the Fragile X Mental Retardation Protein (FMRP), which binds several mRNAs, mainly in the brain. When the FM becomes methylated at 10-12 weeks of gestation, the FMR1 gene is transcriptionally silent. The molecular mechanisms involved in the epigenetic silencing are not fully elucidated. Among FXS families, there is a rare occurrence of males carrying a FM, which remains active because it is not methylated, thus ensuring enough FMRPs to allow for an intellectual development within normal range. Which mechanisms are responsible for sparing these individuals from being affected by FXS? In order to answer this critical question, which may have possible implications for FXS therapy, several potential epigenetic mechanisms have been described. Here, we focus on current knowledge about the role of DNA methylation and other epigenetic modifications in FMR1 gene silencing.