Fragile X Syndrome: Lessons Learned and What New Treatment Avenues Are on the Horizon

2021 ◽  
Vol 62 (1) ◽  
Author(s):  
Randi J. Hagerman ◽  
Paul J. Hagerman
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Single Gene ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Lessons Learned ◽  
Annual Review ◽  
Publication Date ◽  
Cgg Repeat ◽  
New Treatment

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and the leading single-gene form of autism spectrum disorder, encompassing cognitive, behavioral, and physical forms of clinical involvement. FXS is caused by large expansions of a noncoding CGG repeat (>200 repeats) in the FMR1 gene, at which point the gene is generally silenced. Absence of FMR1 protein (FMRP), important for synaptic development and maintenance, gives rise to the neurodevelopmental disorder. There is, at present, no therapeutic approach that directly reverses the loss of FMRP; however, there is an increasing number of potential treatments that target the pathways dysregulated in FXS, including those that address the enhanced activity of the mGluR5 pathway and deficits in GABA pathways. Based on studies of targeted therapeutics to date, the prospects are good for one or more effective therapies for FXS in the near future. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Abnormal neurogensis in the hippocampus of a mouse model of fragile X syndromes

2007 ◽  
Vol 30 (4) ◽  
pp. 80
Author(s):  
B Eadie ◽  
B Christie
Keyword(s):  
Mouse Model ◽  
Learning And Memory ◽  
Fragile X Syndrome ◽  
Knockout Mice ◽  
Fragile X ◽  
Single Gene ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Fmr1 Gene ◽  
Learning Impairment

Fragile X syndrome is the most common inherited form of mental retardation. It is a neurodevelopmental disorder that is similar in clinical presentation to autism spectrum disorder. However, unlike autism, Fragile X syndrome is caused by the silencing of a single gene, and in recent years, a mouse model of Fragile X syndrome has been generated by deletion of the Fmr1 gene. Surprisingly, a clear neurobiological basis for the learning impairment observed in both these knockout mice and patients has been difficult to elucidate. We hypothesized that neurogenesis, a process that continues into adulthood in the hippocampus, may be abnormal in this syndrome. Support for such a hypothesis comes from the findings that these new neurons may disproportionately contribute to synaptic plasticity in networks engaged during learning and memory. We have shown that the survival of new cells in the hippocampus of young Fmr1 knockout mice is significantly decreased in the ventral hippocampus, a sub-region which may be more involved with emotional, rather than, spatial memory. Further experiments are being conducted to assess the differentiation of these new cells into neurons and glia. We are also characterizing the normal expression of the Fmr1 gene product, FMRP, across the phases of neurogenesis in control mice. In conclusion, we have discovered a clear impairment in a process that may be critical to emotionally-significant learning and memory in a mouse model of Fragile X syndrome.

scholarly journals Fragile X syndrome: Lessons learned from the most translated neurodevelopmental disorder in clinical trials

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Phan Q. Duy ◽  
Dejan B. Budimirovic
Keyword(s):  
Clinical Trials ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Full Range ◽  
Autism Spectrum ◽  
Lessons Learned ◽  
Success Story ◽  
Negative Results ◽  
Neural Signaling

AbstractFragile X syndrome (FXS) is the leading genetic cause of autism spectrum disorder (ASD) and inherited intellectual disability (ID) worldwide. Preclinical successes in understanding the biology of FXS have led to numerous translational attempts in human clinical trials of therapeutics that target the excitatory/inhibitory neural signaling imbalances thought to underlie FXS. Despite the preclinical success story, the negative results of the human clinical trials have been deemed to be at least in part disappointing by the field. In this commentary, we contend that such negative studies results in clinical trials may actually propel the FXS field forward by serving as important lessons for designing and implementing improved future clinical trials such that can objectively assess the full range of responses to new therapeutics.

scholarly journals Cascade Testing for Fragile X Syndrome in a Rural Setting in Cameroon (Sub-Saharan Africa)

Genes ◽  
2020 ◽  
Vol 11 (2) ◽  
pp. 136
Author(s):  
Karen Kengne Kamga ◽  
Séraphin Nguefack ◽  
Khuthala Minka ◽  
Edmond Wonkam Tingang ◽  
Alina Esterhuizen ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Autism Spectrum ◽  
Sub Saharan Africa ◽  
Rural Setting ◽  
Premature Menopause ◽  
Molecular Testing ◽  
Full Mutation ◽  
Cgg Repeat ◽  
Cgg Repeats

Fragile X Syndrome (FXS), an X-linked dominant monogenic condition, is the main genetic cause of intellectual disability (ID) and autism spectrum disorder (ASD). FXS is associated with an expansion of CGG repeat sequence in the Fragile X Mental Retardation gene 1 (FMR1) on chromosome X. Following a neuropediatric assessment of two male siblings who presented with signs of FXS that was confirmed with molecular testing, we provided cascade counselling and testing to the extended family. A total of 46 individuals were tested for FXS; among them, 58.70% (n = 27) were females. The mean age was 9.4 (±5) years for children and 45.9 (±15.9) years for adults. Pedigree analysis suggested that the founder of these families was likely a normal transmitting male. Four out of 19 males with clinical ID were confirmed to have a full mutation for FXS, while 14/27 females had a pathologic CGG expansion (>56 CGG repeats) on one of their X chromosomes. Two women with premature menopause were confirmed of being carriers of premutation (91 and 101 CGG repeats). We also identified maternal alleles (91 and 126 CGG repeats) which expanded to a full mutation in their offspring (>200 CGG repeats). This study is a rare report on FXS from Africa and illustrates the case scenario of implementing genetic medicine for a neurogenetic condition in a rural setting.

scholarly journals Screening for FMR1 CGG Repeat Expansion in Thai Patients with Autism Spectrum Disorder

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Areerat Hnoonual ◽  
Charunee Jankittunpaiboon ◽  
Pornprot Limprasert
Keyword(s):  
Autism Spectrum Disorder ◽  
Fragile X ◽  
Single Gene ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Fmr1 Gene ◽  
Normal Male ◽  
Cgg Repeat ◽  
Cgg Repeats ◽  
Normal Controls

Autism spectrum disorder (ASD) is a complex disorder with a heterogeneous etiology. Fragile X syndrome (FXS) is recognized as the most common single gene mutation associated with ASD. FXS patients show some autistic behaviors and may be difficult to distinguish at a young age from autistic children. However, there have been no published reports on the prevalence of FXS in ASD patients in Thailand. In this study, we present a pilot study to analyze the CGG repeat sizes of the FMR1 gene in Thai autistic patients. We screened 202 unrelated Thai patients (168 males and 34 females) with nonsyndromic ASD and 212 normal controls using standard FXS molecular diagnosis techniques. The distributions of FMR1 CGG repeat sizes in the ASD and normal control groups were similar, with the two most common alleles having 29 and 30 CGG repeats, followed by an allele with 36 CGG repeats. No FMR1 full mutations or premutations were found in either ASD individuals or the normal controls. Interestingly, three ASD male patients with high normal CGG and intermediate CGG repeats (44, 46, and 53 CGG repeats) were identified, indicating that the prevalence of FMR1 intermediate alleles in Thai ASD patients was approximately 1% while these alleles were absent in the normal male controls. Our study indicates that CGG repeat expansions of the FMR1 gene may not be a common genetic cause of nonsyndromic ASD in Thai patients. However, further studies for mutations other than the CGG expansion in the FMR1 gene are required to get a better information on FXS prevalence in Thai ASD patients.

scholarly journals Cerebral Expression of Metabotropic Glutamate Receptor Subtype 5 in Idiopathic Autism Spectrum Disorder and Fragile X Syndrome: A Pilot Study

2021 ◽  
Vol 22 (6) ◽  
pp. 2863
Author(s):  
James Robert Brašić ◽  
Ayon Nandi ◽  
David S. Russell ◽  
Danna Jennings ◽  
Olivier Barret ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Fragile X Syndrome ◽  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Fragile X ◽  
Single Gene ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Receptor Subtype ◽  
Metabotropic Glutamate

Multiple lines of evidence suggest that dysfunction of the metabotropic glutamate receptor subtype 5 (mGluR5) plays a role in the pathogenesis of autism spectrum disorder (ASD). Yet animal and human investigations of mGluR5 expression provide conflicting findings about the nature of dysregulation of cerebral mGluR5 pathways in subtypes of ASD. The demonstration of reduced mGluR5 expression throughout the living brains of men with fragile X syndrome (FXS), the most common known single-gene cause of ASD, provides a clue to examine mGluR5 expression in ASD. We aimed to (A) compare and contrast mGluR5 expression in idiopathic autism spectrum disorder (IASD), FXS, and typical development (TD) and (B) show the value of positron emission tomography (PET) for the application of precision medicine for the diagnosis and treatment of individuals with IASD, FXS, and related conditions. Two teams of investigators independently administered 3-[18F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([18F]FPEB), a novel, specific mGluR5 PET ligand to quantitatively measure the density and the distribution of mGluR5s in the brain regions, to participants of both sexes with IASD and TD and men with FXS. In contrast to participants with TD, mGluR5 expression was significantly increased in the cortical regions of participants with IASD and significantly reduced in all regions of men with FXS. These results suggest the feasibility of this protocol as a valuable tool to measure mGluR5 expression in clinical trials of individuals with IASD and FXS and related conditions.

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 Interneuron Dysfunction and Inhibitory Deficits in Autism and Fragile X Syndrome

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2610
Author(s):  
Toshihiro Nomura
Keyword(s):  
Fragile X Syndrome ◽  
Therapeutic Potential ◽  
Fragile X ◽  
Single Gene ◽  
Autism Spectrum ◽  
Gamma Aminobutyric Acid ◽  
Inhibitory Neurotransmitter ◽  
Inhibitory Circuits ◽  
Inhibitory Deficits ◽  
Inhibitory Circuit

The alteration of excitatory–inhibitory (E–I) balance has been implicated in various neurological and psychiatric diseases, including autism spectrum disorder (ASD). Fragile X syndrome (FXS) is a single-gene disorder that is the most common known cause of ASD. Understanding the molecular and physiological features of FXS is thought to enhance our knowledge of the pathophysiology of ASD. Accumulated evidence implicates deficits in the inhibitory circuits in FXS that tips E–I balance toward excitation. Deficits in interneurons, the main source of an inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), have been reported in FXS, including a reduced number of cells, reduction in intrinsic cellular excitability, or weaker synaptic connectivity. Manipulating the interneuron activity ameliorated the symptoms in the FXS mouse model, which makes it reasonable to conceptualize FXS as an interneuronopathy. While it is still poorly understood how the developmental profiles of the inhibitory circuit go awry in FXS, recent works have uncovered several developmental alterations in the functional properties of interneurons. Correcting disrupted E–I balance by potentiating the inhibitory circuit by targeting interneurons may have a therapeutic potential in FXS. I will review the recent evidence about the inhibitory alterations and interneuron dysfunction in ASD and FXS and will discuss the future directions of this field.

scholarly journals FMR1 and Autism, an Intriguing Connection Revisited

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1218
Author(s):  
William Fyke ◽  
Milen Velinov
Keyword(s):  
Fragile X ◽  
Major Gene ◽  
Single Gene ◽  
Autism Spectrum ◽  
Protein Product ◽  
Loss Of Function ◽  
Cgg Repeat ◽  
Statistical Manual ◽  
The Us ◽  
The Central Nervous System

Autism Spectrum Disorder (ASD) represents a distinct phenotype of behavioral dysfunction that includes deficiencies in communication and stereotypic behaviors. ASD affects about 2% of the US population. It is a highly heritable spectrum of conditions with substantial genetic heterogeneity. To date, mutations in over 100 genes have been reported in association with ASD phenotypes. Fragile X syndrome (FXS) is the most common single-gene disorder associated with ASD. The gene associated with FXS, FMR1 is located on chromosome X. Accordingly, the condition has more severe manifestations in males. FXS results from the loss of function of FMR1 due to the expansion of an unstable CGG repeat located in the 5′′ untranslated region of the gene. About 50% of the FXS males and 20% of the FXS females meet the Diagnostic Statistical Manual 5 (DSM-5) criteria for ASD. Among the individuals with ASD, about 3% test positive for FXS. FMRP, the protein product of FMR1, is a major gene regulator in the central nervous system. Multiple pathways regulated by FMRP are found to be dysfunctional in ASD patients who do not have FXS. Thus, FXS presents the opportunity to study cellular phenomena that may have wider applications in the management of ASD and to develop new strategies for ASD therapy.

scholarly journals Fragile X syndrome – a common disease rarely diagnosed

2017 ◽  
Vol 30 (1) ◽  
pp. 27-30
Author(s):  
Malgorzata Zofia Lisik
Keyword(s):  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Single Gene ◽  
Strong Association ◽  
Autism Spectrum ◽  
Common Disease ◽  
Medical Evaluation ◽  
The Family ◽  
Physical Features

Abstract Fragile X syndrome (FXS) is a single-gene disorder with a broad spectrum of involvement, including cognitive and behavioural impairments of varying degrees with specific physical features and with strong association with autism. The study was conducted on 23 males (10-32 years old) who had full mutation in the FMR1 gene. A complete medical evaluation, including medical history, family history, psychological testing and physical examination was conducted on each subject. Three of the FXS patients (13%) were isolated cases of mental retardation in the family. The remaining 20 FXS patients belonged to 15 families, where there were other mentally retarded family members present. The degree of mental retardation (MR) varied. Mild MR was diagnosed in 1/23 (4.35%), moderate MR in 12/23 (52.17%), severe MR in 10/23 (43.48 %). Moreover, autism spectrum disorder was diagnosed in 5/23 (21.74%) FXS patients. Analysis of the BMI showed that in FXS patients, 14 of 23 (60.68%) had too high body weight - 9/23 (39.13%) were overweight and 5/23 (21.74%) were obese. The diagnosis of FXS is difficult because of nonspecific symptoms, yet early diagnosis is crucial for early intervention and genetic counseling. The risk of recurrence is 50%.

scholarly journals How Knowledge Mapping Can Bridge the Communication Gap Between Caregivers and Health Professionals Supporting Individuals With Complex Medical Needs: A Study in Fragile X Syndrome

2021 ◽  
Vol 12 ◽  
Author(s):  
Karen Kelm ◽  
Francois V. Bolduc
Keyword(s):  
Fragile X Syndrome ◽  
Health Professionals ◽  
Concept Maps ◽  
Healthcare Professionals ◽  
Fragile X ◽  
Single Gene ◽  
Autism Spectrum ◽  
Knowledge Mapping ◽  
Medical Needs ◽  
Care Maps

The challenges of caring for children with complex health needs, such as intellectual disability (ID) and autism spectrum disorder (ASD), are multiple and experienced by both caregivers and health professionals. Fragile X syndrome (FXS) is the most common single gene cause of ID and ASD, and provides a pertinent model to understand these complexities of care, as well as the communication challenges experienced between caregivers and healthcare professionals. In recent years both caregivers and healthcare professionals have recognized the need for enhancing communication both in clinical and research settings. Knowledge mapping has emerged as a tool to support quality communication between team participants. Here we review how differences in mental models, as well as challenges related to health literacy and knowledge transfer can have an impact on communication. Next, we present different knowledge mapping approaches used in complex situations, with a focus on concept maps and care maps. Finally, we highlight the potential benefits and limitations of mapping to improve communication issues related to caring for individuals with FXS and potentially other neurodevelopmental disorders (NDDs).

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