Overlapping Molecular Pathways Leading to Autism Spectrum Disorders, Fragile X Syndrome, and Targeted Treatments.
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ABSTRACT:
SUBMITTER: Salcedo-Arellano MJ
PROVIDER: S-EPMC8116395 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Autism is a neurodevelopmental disorder consisting of a constellation of symptoms that sometimes occur as part of a complex disorder characterized by impairments in social interaction, communication and behavioral domains. It is a highly disabling disorder and there is a need for treatment targeting the core symptoms. Although autism is accepted as highly heritable, there is no genetic cure at this time. Autism is shown to be linked to several genes and is a feature of some complex genetic disorders, including fragile X syndrome (FXS), fragile X premutation involvement, tuberous sclerosis and Rett syndrome. The term autism spectrum disorders (ASDs) covers autism, Asperger syndrome and pervasive developmental disorders (PDD-NOS) and the etiologies are heterogeneous. In recent years, targeted treatments have been developed for several disorders that have a known specific genetic cause leading to autism. Since there are significant molecular and neurobiological overlaps among disorders, targeted treatments developed for a specific disorder may be helpful in ASD of unknown etiology. Examples of this are two drug classes developed to treat FXS, Arbaclofen, a GABA(B) agonist, and mGluR5 antagonists, and both may be helpful in autism without FXS. The mGluR5 antagonists are also likely to have a benefit in the aging problems of fragile X premutation carriers, the fragile X -associated tremor ataxia syndrome (FXTAS) and the Parkinsonism that can occur in aging patients with fragile X syndrome. Targeted treatments in FXS which has a well known genetic etiology may lead to new targeted treatments in autism.
| S-EPMC3498468 | biostudies-literature
Project description:Fragile X syndrome (FXS) is the most common form of monogenic hereditary cognitive impairment. FXS patient exhibit a high comorbidity rate with autism spectrum disorders (ASDs). This makes FXS a model disease for understanding how synaptic dysregulation alters neuronal excitability, learning and memory, social behavior, and more. Since 1991, with the discovery of fragile X mental retardation 1 (FMR1) as the sole gene that is mutated in FXS, thousands of studies into the function of the gene and its encoded protein FMR1 protein (FMRP), have been conducted, yielding important information regarding the pathophysiology of the disease, as well as insight into basic synaptic mechanisms that control neuronal networking and circuitry. Among the most important, are molecular mechanisms directly involved in plasticity, including glutamate and γ-aminobutyric acid (GABA) receptors, which can control synaptic transmission and signal transduction, including short- and long-term plasticity. More recently, several novel mechanisms involving growth factors, enzymatic cascades and transcription factors (TFs), have been proposed to have the potential of explaining some of the synaptic dysregulation in FXS. In this review article, I summarize the main mechanisms proposed to underlie synaptic disruption in FXS and ASDs. I focus on studies conducted on the Fmr1 knock-out (KO) mouse model and on FXS-human pluripotent stem cells (hPSCs), emphasizing the differences and even contradictions between mouse and human, whenever possible. As FXS and ASDs are both neurodevelopmental disorders that follow a specific time-course of disease progression, I highlight those studies focusing on the differential developmental regulation of synaptic abnormalities in these diseases.
| S-EPMC6417395 | biostudies-literature
Project description:Fragile X Syndrome (FXS) is the most common cause of inherited intellectual disability with prevalence rates estimated to be 1:5,000 in males and 1:8,000 in females. The increase of >200 Cytosine Guanine Guanine (CGG) repeats in the 5' untranslated region of the Fragile X Mental Retardation 1 (FMR1) gene results in transcriptional silencing on the FMR1 gene with a subsequent reduction or absence of fragile X mental retardation protein (FMRP), an RNA binding protein involved in the maturation and elimination of synapses. In addition to intellectual disability, common features of FXS are behavioral problems, autism, language deficits and atypical physical features. There are still no currently approved curative therapies for FXS, and clinical management continues to focus on symptomatic treatment of comorbid behaviors and psychiatric problems. Here we discuss several treatments that target the neurobiological pathway abnormal in FXS. These medications are clinically available at present and the data suggest that these medications can be helpful for those with FXS.
| S-EPMC6930353 | biostudies-literature
Project description:Autism spectrum disorder (ASD) and Fragile X syndrome (FXS) are relatively common childhood neurodevelopmental disorders with increasing incidence in recent years. They are currently accepted as disorders of the synapse with alterations in different forms of synaptic communication and neuronal network connectivity. The major excitatory neurotransmitter system in brain, the glutamatergic system, is implicated in learning and memory, synaptic plasticity, neuronal development. While much attention is attributed to the role of metabotropic glutamate receptors in ASD and FXS, studies indicate that the ionotropic glutamate receptors (iGluRs) and their regulatory proteins are also altered in several brain regions. Role of iGluRs in the neurobiology of ASD and FXS is supported by a weight of evidence that ranges from human genetics to in vitro cultured neurons. In this review we will discuss clinical, molecular, cellular and functional changes in NMDA, AMPA and kainate receptors and the synaptic proteins that regulate them in the context of ASD and FXS. We will also discuss the significance for the development of translational biomarkers and treatments for the core symptoms of ASD and FXS.
| S-EPMC3915351 | biostudies-literature
Project description:Fragile X syndrome (FXS) is the most common inherited form of intellectual disability, and is the leading single-gene cause of autism spectrum disorders. It is due to a loss of the fragile X mental retardation protein, which leads to molecular, behavioral, and cognitive deficits in these patients. Improvements in our understanding of its pathophysiology have led to the development of numerous targeted treatments in FXS as highlighted by metabotropic glutamate receptor antagonists and gamma-Aminobutyric acid receptor modulators. This review will summarize relevant pre-clinical data and results from clinical trials in human subjects with FXS. It will also highlight upcoming studies and future directions for clinical trials as well.
| S-EPMC4995416 | biostudies-literature
Project description:Fragile X spectrum disorder (FXSD) includes: fragile X syndrome (FXS), fragile X-associated tremor ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI), as well as other medical, psychiatric and neurobehavioral problems associated with the premutation and gray zone alleles. FXS is the most common monogenetic cause of autism (ASD) and intellectual disability (ID). The understanding of the neurobiology of FXS has led to many targeted treatment trials in FXS. The first wave of phase II clinical trials in FXS were designed to target the mGluR5 pathway; however the results did not show significant efficacy and the trials were terminated. The advances in the understanding of the GABA system in FXS have shifted the focus of treatment trials to GABA agonists, and a new wave of promising clinical trials is under way. Ganaxolone and allopregnanolone (GABA agonists) have been studied in individuals with FXSD and are currently in phase II trials. Both allopregnanolone and ganaxolone may be efficacious in treatment of FXS and FXTAS, respectively. Allopregnanolone, ganaxolone, riluzole, gaboxadol, tiagabine, and vigabatrin are potential GABAergic treatments. The lessons learned from the initial trials have not only shifted the targeted system, but also have refined the design of clinical trials. The results of these new trials will likely impact further clinical trials for FXS and other genetic disorders associated with ASD.
| S-EPMC4830341 | biostudies-literature
Project description:BACKGROUND: Autism is a behavioral disorder with impaired social interaction, communication, and repetitive and stereotypic behaviors. About 5-10 % of individuals with autism have 'secondary' autism in which an environmental agent, chromosome abnormality, or single gene disorder can be identified. Ninety percent have idiopathic autism and a major gene has not yet been identified. We have assessed the incidence of chromosome abnormalities and Fragile X syndrome in a population of autistic patients referred to our laboratory. METHODS: Data was analyzed from 433 patients with autistic traits tested using chromosome analysis and/or fluorescence in situ hybridization (FISH) and/or molecular testing for fragile X syndrome by Southern and PCR methods. RESULTS: The median age was 4 years. Sex ratio was 4.5 males to 1 female [354:79]. A chromosome (cs) abnormality was found in 14/421 [3.33 %] cases. The aberrations were: 4/14 [28%] supernumerary markers; 4/14 [28%] deletions; 1/14 [7%] duplication; 3/14 [21%] inversions; 2/14 [14%] translocations. FISH was performed on 23 cases for reasons other than to characterize a previously identified cytogenetic abnormality. All 23 cases were negative. Fragile-X testing by Southern blots and PCR analysis found 7/316 [2.2 %] with an abnormal result. The mutations detected were: a full mutation (fM) and abnormal methylation in 3 [43 %], mosaic mutations with partial methylation of variable clinical significance in 3 [43%] and a permutation carrier [14%]. The frequency of chromosome and fragile-X abnormalities appears to be within the range in reported surveys (cs 4.8-1.7%, FRAX 2-4%). Limitations of our retrospective study include paucity of behavioral diagnostic information, and a specific clinical criterion for testing. CONCLUSIONS: Twenty-eight percent of chromosome abnormalities detected in our study were subtle; therefore a high resolution cytogenetic study with a scrutiny of 15q11.2q13, 2q37 and Xp23.3 region should be standard practice when the indication is autism. The higher incidence of mosaic fragile-X mutations with partial methylation compared to FRAXA positive population [50% vs 15-40%] suggests that faint bands and variations in the Southern band pattern may occur in autistic patients.
| S-EPMC548305 | biostudies-literature
Project description: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.
| S-EPMC6315847 | biostudies-literature
Project description:Current therapeutics in autism spectrum disorders (ASD) only treat the associated symptoms, without addressing core social dysfunctions. A paradigm shift in research of the pathogenesis of ASD, its synaptic abnormalities and altered signaling in multiple dynamic systems, have led to new experimental treatments for treating the core social abnormalities of ASD. NMDA antagonists, especially memantine, have been introduced in clinical trials addressing glutamatergic transmission in children and adolescents with ASD. GABAergic signaling has been targeted in trials using the GABAB receptor agonist arbaclofen for ASD patients with promising results. Oxytocin has been recognized as implicated in social development and affiliative behaviors. Preliminary findings from clinical trials using oxytocin in children with ASD show encouraging improvements in social cognition, but larger studies are needed. In two of the single gene disorders associated with ASD, Insulin Growth Factor (IGF-1) is a new treatment that has been tested in Rett syndrome and Phelan-McDermid syndrome (Chromosome 22 deletion syndrome). IGF-1 has been demonstrated to reverse the reduction in the number of excitatory synapses and the density of neurons that characterize these conditions in animal studies and it is being introduced as an experimental treatment. As a novel approach to verify treatment efficacy, neural processing modifications were recently evaluated by fMRI after a pivotal response training intervention. Another study of neural changes in response to treatment examined variations in EEG signaling in patients after an Early Start Denver Model (ESDM) intervention.
| S-EPMC4064155 | biostudies-literature
Project description:Autism spectrum disorder (ASD) is a highly prevalent and complex genetic disorder. The complex genetic make-up of ASD has been extensively studied and both common and rare genetic variants in up to 1000 genes have been linked to increased ASD risk. While these studies highlight the genetic complexity and begin to provide a window for delineating pathways at risk in ASD, the pathogenicity and specific contribution of many mutations to the disorder are poorly understood. Defining the convergent pathways disrupted by this large number of ASD-associated genetic variants will help to understand disease pathogenesis and direct future therapeutic efforts for the groups of patients with distinct etiologies. Here, we review some of the common regulatory pathways including chromatin remodeling, transcription, and alternative splicing that have emerged as common features from genetic and transcriptomic profiling of ASD. For each category, we focus on one gene (CHD8, FOXP1, and RBFOX1) that is significantly linked to ASD and functionally characterized in recent years. Finally, we discuss genetic and transcriptomic overlap between ASD and other neurodevelopmental disorders.
| S-EPMC6249101 | biostudies-literature